ENTITYA TYPEA IDA DATABASEA ENTITYB TYPEB IDB DATABASEB EFFECT MECHANISM RESIDUE SEQUENCE TAX_ID CELL_DATA TISSUE_DATA MODULATOR_COMPLEX TARGET_COMPLEX MODIFICATIONA MODASEQ MODIFICATIONB MODBSEQ PMID DIRECT NOTES ANNOTATOR SENTENCE SIGNOR_ID PML-RARalpha "fusion protein" SIGNOR-FP2 SIGNOR CCNA1 protein P78396 UNIPROT "up-regulates activity" 9606 11090075 t apalma "We show that the ectopic expression of PML-RARα is sufficient to elevate levels of cyclin A1 in U937 myeloid leukemia cells and cyclin A1 is negatively regulated by the RARα pathway." SIGNOR-256373 AKT1 protein P31749 UNIPROT HNRNPA1 protein P09651 UNIPROT down-regulates phosphorylation Ser199 SQRGRSGsGNFGGGR 9606 18562319 t gcesareni "Our data also suggest that akt negatively regulates hnrnp a1-mediated ires activity via phosphorylation at ser199." SIGNOR-252519 MC3R protein P41968 UNIPROT GNAL protein P38405 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-256748 CTNND2 protein Q9UQB3 UNIPROT CDH2 protein P19022 UNIPROT "up-regulates quantity by stabilization" binding 9606 BTO:0001109 14610055 t miannu "To clarify the role of p120 in mammalian cells, we have knocked down p120 with siRNA in cells expressing epithelial (E-), placental (P-), neuronal (N-), and vascular endothelial (VE-) cadherins. We report that each of these cadherins, as well as α- and β-catenins, were rapidly degraded in the absence of p120, resulting in loss of cell–cell adhesion. The effect was clearly dose dependent, indicating that p120 expression levels may directly determine cadherin levels. Degradation of p120-uncoupled cadherin occurred after its arrival at the surface, indicating that p120 regulates cadherin turnover at the level of internalization or recycling. p120 homologues ARVCF and δ-catenin could substitute for p120, so at least one family member is likely required to maintain adhesion. Thus, cadherin complexes are rapidly turned over and degraded in mammalian cells in the absence of direct interaction with p120 or a p120 family member." SIGNOR-252131 PLK1 protein P53350 UNIPROT CENPQ protein Q7L2Z9 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser253 HNSSQMKsMSTFIEE 9606 BTO:0000567 25670858 t lperfetto "Notably, although Plk1 did not alter the level of PBIP1 and CENP-Q ubiquitination, Plk1-dependent phosphorylation and delocalization of these proteins from kinetochores appeared to indirectly lead to their degradation in the cytosol. From these analyses, we identified nine CENP-Q residues (Thr-123, Thr-135, Ser-138, Ser-139, Ser-248, Ser-249, Ser-253, Ser-255, and Thr-256) that were phosphorylated in both in vitro and in vivo samples (Fig. 4B), suggesting that Plk1 phosphorylates these sites." SIGNOR-265232 CDK1 protein P06493 UNIPROT MYOD1 protein P15172 UNIPROT down-regulates phosphorylation Ser200 YSGDSDAsSPRSNCS 9606 SIGNOR-C17 21902831 t gcesareni "Phosphorylation of myod at s200 is common to other cdks, such as the mitotic cyclin b/cdk1, which may prevent inappropriate myod accumulation during mitosis." SIGNOR-176505 Tubulin proteinfamily SIGNOR-PF46 SIGNOR Microtubule_polimerization phenotype SIGNOR-PH106 SIGNOR up-regulates 9606 28347630 f miannu "Microtubules are essential for the generation, migration and differentiation of neurons. Within dendrites microtubules have also been implicated in the formation and plasticity of spines. For instance, the treatment of hippocampal neurons with low doses of the microtubule destabilizing drug Nocodazole impairs BDNF induced dendritic spine formation" SIGNOR-266827 MAPK3 protein P27361 UNIPROT STAT3 protein P40763 UNIPROT up-regulates phosphorylation Ser727 NTIDLPMsPRTLDSL 9606 BTO:0001271 BTO:0000671 14551213 t gcesareni "The activation of stat-3 is regulated by phosphorylation of tyrosine 705 by receptor and nonreceptor protein tyrosine kinases these include epidermal growth factor receptor (egfr) kinase,92 src,5 janus-activated kinases (jak), and extracellular signal-regulated kinase (erk)a constitutively active galpha16 mutant, galpha16ql, stimulated stat3-dependent luciferase activity as well as the phosphorylation of stat3 at both tyr705 and ser727. Galpha16ql-induced stat3 activation was enhanced by overexpression of extracellular signal-regulated kinase 1 (erk1" SIGNOR-118596 GDNF protein P39905 UNIPROT NRN1 protein Q9NPD7 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10116 BTO:0002881 15212950 f miannu "We characterize the network of 43 genes induced by GDNF overproduction of neuronal progenitor cells (ST14A), which mainly regulate migration and differentiation of neuronal progenitor cells.Laminin, Mpl3, Alcam, Bin1, Id1, Id2, Id3, neuregulin1, the ephrinB2-receptor, neuritin, focal adhesion kinase (FAK), Tc10, Pdpk1, clusterin, GTP-cyclooxygenase1, and follistatin are genes up-regulated by GDNF overexpression." SIGNOR-252183 MAPK1 protein P28482 UNIPROT SMAD3 protein P84022 UNIPROT "down-regulates activity" phosphorylation Thr179 PQSNIPEtPPPGYLS 9606 10197981 t llicata "Oncogenically activated ras inhibits the tgfbeta-induced nuclear accumulation of smad2 and smad3 and smad-dependent transcription. Ras acting via erk map kinases causes phosphorylation of smad2 and smad3 at specific sites in the region linking the dna-binding domain and the transcriptional activation domain." SIGNOR-66746 SOCS1 protein O15524 UNIPROT IFNGR1 protein P15260 UNIPROT down-regulates binding 9606 18708154 t gcesareni "Suppressor of cytokine signaling (socs)-1, the key negative regulator of interferon (ifn)-gamma-dependent signaling, is induced in response to ifngamma. Socs-1 binds to and inhibits the ifngamma receptor-associated kinase janus-activated kinase (jak) 2 and inhibits its function in vitrothe binding of socs-1 to tyr441 also blocks the access of stat1 to tyr419 and that this effect may be the principal mechanism of inhibition of downstream signaling" SIGNOR-180140 PCDHA2 protein Q9Y5H9 UNIPROT PCDHGC5 protein Q9Y5F6 UNIPROT "up-regulates activity" binding 9606 BTO:0000227 16697637 t miannu "The clustered protocadherins comprise the largest subfamily of the cadherin superfamily and are predominantly expressed in the nervous system. Pcdh-alpha proteins interact with beta1-integrin to promote cell adhesion. They also form oligomers with Pcdh-gamma proteins at the same membrane sites." SIGNOR-265683 RPL26L1 protein Q9UNX3 UNIPROT "60S cytosolic large ribosomal subunit" complex SIGNOR-C287 SIGNOR "form complex" binding -1 25901680 t lperfetto "Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins." SIGNOR-262496 KDM2B protein Q8NHM5 UNIPROT PPARG protein P37231 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 10090 BTO:0000011 25533466 f miannu "We concluded that FBXL10 recruits the noncanonical PRC1 complex to directly repress Cdk1, Uhrf1, and Pparg that may account for the FBXL10-mediated inhibition of adipogenesis." SIGNOR-252246 "GABA-A (a2-b1-g2) receptor" complex SIGNOR-C331 SIGNOR CRHR2 protein Q13324 UNIPROT down-regulates 9606 BTO:0000614 33536967 f lperfetto "OT inhibits corticotropin-releasing factor (CRF) mRNA expression at the hypothalamus, resulting in antistress and anti-anxiety effects| It has been demonstrated that the inhibitory effect of OT on CRF mRNA expression is not a direct one on CRF neurons. GABAergic neurons are present in the surroundings of the PVN (peri-PVN). These GABA-projecting neurons into the PVN inhibits CRF expression via GABAA receptors" SIGNOR-268590 SYN3 protein O14994 UNIPROT ACTB protein P60709 UNIPROT "up-regulates activity" binding 9606 BTO:0000938 15265865 t miannu "Synapsins, a family of neuron-specific phosphoproteins, have been demonstrated to regulate the availability of synaptic vesicles for exocytosis by binding to both synaptic vesicles and the actin cytoskeleton in a phosphorylation-dependent manner." SIGNOR-269183 MAPK8 protein P45983 UNIPROT MAPK8IP1 protein Q9UQF2 UNIPROT unknown phosphorylation Ser197 DRVSRSSsPLKTGEQ 9534 BTO:0000298 12756254 t miannu "After mapping JNK-dependent JIP1 phosphorylation sites and testing their functional significance, it was observed that phosphorylation by JNK of JIP1 on Thr-103 and not other phosphorylated JIP1 residues is necessary for the regulation of DLK association with JIP1, DLK activation, and subsequent module activation. The data presented corroborates our previous observations using endogenous proteins, demonstrates that JNK binding to JIP1 is necessary for module activation, and shows that activation of JIP1-JNK module dynamics requires phosphorylation of JIP1 on Thr-103 by JNK. and Thr-205 are phosphorylated directly by JNK after JNK binds to JIP1." SIGNOR-250124 BRCA1 protein P38398 UNIPROT Cell_cycle_block phenotype SIGNOR-PH10 SIGNOR up-regulates 15549093 f lperfetto "The BRCA1 protein also contributes to cell-cycle arrest and DNA repair by homologous recombination" SIGNOR-251499 PRKCB protein P05771 UNIPROT TOP2A protein P11388 UNIPROT "up-regulates activity" phosphorylation Ser29 EDAKKRLsVERIYQK 9606 BTO:0000567 12569090 t lperfetto "Here, we have shown that the enzymatic activity of topoisomerase II alpha protein purified from HeLa cell nuclei was strongly enhanced following phosphorylation by protein kinase C. | Site-directed mutagenesis studies indicated that phosphorylation of serine 29 generated both of these phosphopeptides." SIGNOR-249195 DVL1 protein O14640 UNIPROT GSK3B/Axin/APC complex SIGNOR-C110 SIGNOR "down-regulates activity" binding 9606 20837657 t lperfetto "In canonical wnt signaling, dsh phosphorylation inhibits the apcaxingsk3 complex, leading to beta-catenin stabilization." SIGNOR-227914 CDKN1A protein P38936 UNIPROT CyclinB/CDK1 complex SIGNOR-C17 SIGNOR "down-regulates activity" binding 10913154 t lperfetto "P21 Inhibits Thr161 Phosphorylation of Cdc2 to Enforce the G2 DNA Damage Checkpoint|The cyclin-dependent kinase inhibitor p21 is required for a sustained G2 arrest after activation of the DNA damage checkpoint. Here we have addressed the mechanism by which p21 can contribute to this arrest in G2. We show that p21 blocks the activating phosphorylation of Cdc2 on Thr161" SIGNOR-251498 PLK1 protein P53350 UNIPROT FOXM1 protein Q08050 UNIPROT up-regulates phosphorylation Ser739 SKILLDIsFPGLDED 9606 19737929 t lperfetto "It has been reported that plk1 could directly phosphorylate foxm1 at ser-715 and ser-724 for full activation and proper mitotic progression" SIGNOR-187892 STIL protein Q15468 UNIPROT PIN1 protein Q13526 UNIPROT up-regulates binding 9606 BTO:0001271 16024801 t miannu "Cell cycle-dependent phosphorylation of sil is required for its interaction with pin1, a regulator of mitosis. Point mutation of the seven (s/t)p sites between amino acids 567 and 760 reduces mitotic phosphorylation of sil, pin1 binding, and spindle checkpoint duration." SIGNOR-138677 MAPK1 protein P28482 UNIPROT RPS6KA3 protein P51812 UNIPROT up-regulates phosphorylation 9606 19282669 t gcesareni "Erk-activates the rsk family of serine/threonine kinases,rsk1, rsk2, and rsk3." SIGNOR-161518 GSK3B protein P49841 UNIPROT RELA protein Q04206 UNIPROT up-regulates phosphorylation Ser468 AVFTDLAsVDNSEFQ 9606 SIGNOR-C13 17183360 t gcesareni "Rela is phosphorylated at: ser276 by the catalytic subunit of protein kinase a (pkac), msk1 and msk2; at ser311 by the atypical pkczeta; at ser468 by ikkbeta, ikkepsilon and glycogen-synthase kinase-3beta (gsk3beta); at ser529 by ck2; and at ser536 by ikkbeta, ikkalfa, ikkepsilon, nf-kb activating kinase (nak, also known as tank-binding kinase-1 tbk1)) and rsk1 (also known as p90 ribosomal protein s6 kinase (p90s6k) ." SIGNOR-151422 AKT1 protein P31749 UNIPROT CCDC88A protein Q3V6T2 UNIPROT unknown phosphorylation Ser1417 INRERQKsLTLTPTR 9606 16139227 t llicata "Akt phosphorylates serine at position 1416 in girdin, and phosphorylated girdin accumulates at the leading edge of migrating cells." SIGNOR-252482 "all-trans-retinoic acid" smallmolecule CHEBI:15367 ChEBI RARB protein P10826 UNIPROT "up-regulates activity" "chemical activation" 9606 17132853 t miannu "The physiological effects of retinoic acids (RAs) are mediated by members of two families of nuclear receptors, the retinoic acid receptors (RARs) and the retinoid X receptors (RXRs), which are encoded by three distinct human genes, RXRalpha, RXRbeta, and RXRgamma." SIGNOR-256195 ITGB1BP1 protein O14713 UNIPROT ITGB8 protein P26012 UNIPROT "down-regulates activity" binding 9606 19118207 t miannu "Integrins also bind to many PTBdomain-containing proteins (Calderwood et al., 2003) – including Dok1 and integrincytoplasmic-domain-associated protein 1 (ICAP1) – and these can compete with talin for binding to integrin and so can impair activation" SIGNOR-257667 ARHGAP21 protein Q5T5U3 UNIPROT RHOA protein P61586 UNIPROT "down-regulates activity" "gtpase-activating protein" 9606 BTO:0000007 32203420 t Luana "We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2)." SIGNOR-260475 "ibritumomab tiuxetan" antibody DB00078 DRUGBANK MS4A1 protein P11836 UNIPROT "down-regulates activity" binding 9606 27497027 t miannu "Zevalin® (ibritumomab tiuxetan) is a radioactive drug product, which is the combination of a β-emitting isotope, 90Y, linked to the anti-CD20 monoclonal antibody (mAb), rituximab. It has demonstrated therapeutic efficacy with durable responses and allows delivery of ionizing radiation directly to the tumor site, while minimizing toxicity to normal tissue. Ibritumomab tiuxetan is indicated for treatment of patients with relapsed or refractory low-grade, follicular NHL" SIGNOR-259893 SF3B5 protein Q9BWJ5 UNIPROT SF3b complex SIGNOR-C442 SIGNOR "form complex" binding 9606 32140746 t lperfetto "Characterization of the purified SF3b complex indicated that it consists of seven proteins with a molecular size ranging from 10 to 155 kDa [10–12] (Fig. 1a). Due to methodological differences in identifying SF3b components in human and yeast, a number of names have been designated for these proteins across different species. In this review, I will use SF3b1-7 for consistency and clarity (Fig. 1a)." SIGNOR-268407 FEZF2 protein Q8TBJ5 UNIPROT MDM2 protein Q00987 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 23677067 f lperfetto "FEZF2, a novel 3p14 tumor suppressor gene, represses oncogene EZH2 and MDM2 expression and is frequently methylated in nasopharyngeal carcinoma." SIGNOR-268974 SLC27A3 protein Q5K4L6 UNIPROT "Fatty acid" stimulus SIGNOR-ST19 SIGNOR "up-regulates quantity" relocalization 9606 28457600 t miannu "Astrocytes and endothelial cells, two major components of the blood brain barrier, are the major contributors to the transportation of PUFAs from the circulation to brain. There are four classes of lipid transportation proteins involved in lipid synthesis and transportation in adult brain, including fatty acid translocase (FAT/CD36), caveolin-1, fatty acid binding proteins (FABPs) long chain acyl-coA synthase (ACS) and fatty acid transportation proteins (FATPs)." SIGNOR-264464 TRIM21 protein P19474 UNIPROT GMPS protein P49915 UNIPROT down-regulates ubiquitination 9606 24462112 t miannu "Cytoplasmic sequestration of gmps requires ubiquitylation by trim21, a ubiquitin ligase associated with autoimmune disease." SIGNOR-204478 KPNA2 protein P52292 UNIPROT IRF3 protein Q14653 UNIPROT "up-regulates activity" relocalization 9606 32979938 t miannu "The results from Figure 1C suggest that ORF6 inhibits IFN-β production through IRF3 or a component downstream of IRF3. Thus, we examined the effect of ORF6 on IRF3 nuclear translocation. Upon poly(I:C) treatment, IRF3 translocated to the cell nucleus in the absence of ORF6, whereas the expression of ORF6 blocked its nuclear translocation (Figure 2D). Karyopherin α 1–6 (KPNA1–6) are importing factors for nuclear translocation of cargos, including IRF3, IRF7, and STAT1 (Chook and Blobel, 2001). Co-immunoprecipitation showed that ORF6 selectively interacted with KPNA2, but not the other KPNAs (Figure 2E), suggesting that ORF6 inhibits IFN-β production by binding to KPNA2 to block IRF3 nuclear translocation (Figure 2F)." SIGNOR-262514 PRKCA protein P17252 UNIPROT SNAP23 protein O00161 UNIPROT unknown phosphorylation Ser161 ENLTQVGsILGNLKD 9606 12930825 t lperfetto "Ion trap mass spectrometry revealed that platelet SNAP-23 was phosphorylated at Ser23/Thr24 and Ser161, after cell activation by thrombin; these sites were also identified in PKC-phosphorylated r-SNAP-23. SNAP-23 mutants that mimic phosphorylation at Ser23/Thr24 inhibited syntaxin 4 interactions, whereas a phosphorylation mutant of Ser161 had only minor effects. | Because mutants that mimic SNAP-23 phosphorylation affect syntaxin 4 interactions, we hypothesize that SNAP-23 phosphorylation may be important for modulating SNARE-complex interactions during membrane trafficking and fusion." SIGNOR-249227 MAPK3 protein P27361 UNIPROT SMAD2 protein Q15796 UNIPROT "up-regulates activity" phosphorylation 9606 BTO:0000763;BTO:0000149 10197981 t lperfetto "These results suggest that oncogenic ras, acting through mek1 and erk kinases, induces the phosphorylation of smad2 and smad3 .we show that phosphorylation of smad2, a mediator of the activin/transforming growth factor-beta signal, by activated extracellular signal-regulated kinase 1 (erk1) increases the amount of smad2 protein and leads to enhanced transcriptional activity" SIGNOR-236067 SLBP protein Q14493 UNIPROT H2BC17 protein P23527 UNIPROT "up-regulates quantity by expression" "translation regulation" 9606 BTO:0001938 19155325 t lperfetto "Synthesis of mature histone mRNA requires only a single processing reaction: an endonucleolytic cleavage between a conserved stem-loop and a purine-rich downstream element to form the 3' end. The stem-loop binding protein (SLBP) is required for processing, and following processing, histone mRNA is transported to the cytoplasm, where SLBP participates in translation of the histone mRNA|We used radiolabeled probes generated by PCR targeting the open reading frame (ORF) to detect histones H2A, H2B, H3, H4, and H1 and used 7SK snRNA as a loading control (Fig. 2A). The abundance of histone H2A, H2B, H3, and H4 mRNAs is reduced to 37% to 70% of control levels in the SLBP knockdown cells when compared to the C2 control." SIGNOR-265379 PTPRK protein Q15262 UNIPROT ZNRF3 protein Q9ULT6 UNIPROT "up-regulates activity" dephosphorylation 9606 BTO:0003009 31934854 t "We show that PTPRK acts via the transmembrane E3 ubiquitin ligase ZNRF3, a negative regulator of Wnt signaling promoting Wnt receptor degradation, which is also expressed in the organizer." SIGNOR-260110 CDK6 protein Q00534 UNIPROT CyclinD1/CDK6 complex SIGNOR-C143 SIGNOR "form complex" binding 9606 8114739 t lperfetto "Here, we show that the human PLSTIRE gene product is a novel cyclin-dependent kinase, cdk6. The cdk6 kinase is associated with cyclins D1, D2, and D3 in lysates of human cells and is activated by coexpression with D-type cyclins in Sf9 insect cells." SIGNOR-250681 XIAP protein P98170 UNIPROT CASP7 protein P55210 UNIPROT "down-regulates quantity by destabilization" binding -1 11257231 t lperfetto "Our crystal structure of the complex between xiap (linker-bir2) and caspase-7 surprisingly revealed that the linker is the major determinant of binding and inhibition for the caspase." SIGNOR-105732 Ub:E2 complex SIGNOR-C497 SIGNOR SIAH2 protein O43255 UNIPROT "up-regulates activity" ubiquitination 9606 34199813 t miannu "The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t" SIGNOR-271121 RET protein P07949 UNIPROT RET protein P07949 UNIPROT up-regulates phosphorylation Tyr981 DNCSEEMyRLMLQCW 9606 14711813 t lperfetto "Mass spectrometric analysis revealed that ret tyr806, tyr809, tyr900, tyr905, tyr981, tyr1062, tyr1090, and tyr1096 were autophosphorylation sitesthe results suggest that phosphorylation of tyr981 is not obligatorily required for the catalytic activity but plays a supplementary role in initiating autophosphorylation of tyr905, which brings about the overall kinase activity." SIGNOR-121169 glucocorticoid smallmolecule CHEBI:24261 ChEBI NR3C1 protein P04150 UNIPROT "up-regulates activity" binding 9606 18049904 t miannu "Glucocorticoid action in cells is mediated by a specific receptor protein, the glucocorticoid receptor (GR). GR is a member of a superfamily of ligand-inducible transcription factors that control a variety of physiological functions; such as, metabolism, development, and reproduction." SIGNOR-268048 IGF1R protein P08069 UNIPROT CSK protein P41240 UNIPROT up-regulates 9606 10026153 f lperfetto "The results suggest that c-src and csk are involved in igf-ir and ir signaling and that the interaction of csk with the igf-ir may play a role in the decrease in c-src activity following igf-i stimulation" SIGNOR-64676 ECM stimulus SIGNOR-ST20 SIGNOR "A6/b4 integrin" complex SIGNOR-C174 SIGNOR up-regulates 9606 30889378 t miannu "Upon binding to the extracellular matrix (ECM), the integrins organize the cytoskeleton and activate intracellular signaling, regulating complex cellular behaviors, including survival, proliferation, migration, and various cell fate transitions" SIGNOR-259034 "D-ribofuranose 5-phosphate(2-)" smallmolecule CHEBI:78346 ChEBI "5-phospho-α-D-ribose 1-diphosphate" smallmolecule CHEBI:58017 ChEBI "up-regulates quantity" "precursor of" 9606 16939420 t miannu "PRPP (phosphoribosylpyrophosphate) is an important metabolite essential for nucleotide synthesis and PRS (PRPP synthetase) catalyses synthesis of PRPP from R5P (ribose 5-phosphate) and ATP." SIGNOR-267080 NFKB1 protein P19838 UNIPROT KLK3 protein P07288 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0001321 11909978 t "NF-kappa B activates prostate-specific antigen expression and is upregulated in androgen-independent prostate cancer." SIGNOR-253668 CSNK2A1 protein P68400 UNIPROT PDCL protein Q13371 UNIPROT up-regulates phosphorylation Ser18 EKLQYYYsSSEDEDS 9606 16717095 t lperfetto "Phosducin-like protein (phlp) is a widely expressed binding partner of the g protein betagamma subunit complex (gbetagamma) that has been recently shown to catalyze the formation of the gbetagamma dimer from its nascent polypeptides. Phosphorylation of phlp at one or more of three consecutive serines (ser-18, ser-19, and ser-20) is necessary for gbetagamma dimer formation and is believed to be mediated by the protein kinase ck2." SIGNOR-146825 LPAR4 protein Q99677 UNIPROT GNA14 protein O95837 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257432 CYCS protein P99999 UNIPROT CASP9 protein P55211 UNIPROT "up-regulates activity" binding 9606 BTO:0000567 9390557 t lperfetto "Caspase-9 and apaf-1 bind to each other via their respective nh2-terminal ced-3 homologous domains in the presence of cytochrome c and datp, an event that leads to caspase-9 activation." SIGNOR-53585 GSK3B protein P49841 UNIPROT JUN protein P05412 UNIPROT "down-regulates activity" phosphorylation Ser243 PGETPPLsPIDMESQ 9606 BTO:0000007 16023596 t lperfetto "The c-jun and c-myc oncogenic transcription factors are highly unstable proteins due to polyubiquitination. Similar to c-myc, we report here that phosphorylation of c-jun by gsk3 creates a high-affinity binding site for the e3 ligase fbw7, which targets c-jun for polyubiquitination and proteasomal degradation similar to c-myc, we report here that phosphorylation of c-jun by gsk3 creates a high-affinity binding site for the e3 ligase fbw7, which targets c-jun for polyubiquitination and proteasomal degradation.Phosphorylation of Thr-239 and Ser-243 is required for Fbw7-mediated c-Jun disappearance" SIGNOR-235892 RPS6K proteinfamily SIGNOR-PF26 SIGNOR RPS6 protein P62753 UNIPROT up-regulates phosphorylation Ser244 LRASTSKsESSQK 9606 21233202 t lperfetto "In response to mitogenic stimuli, rps6 undergoes ordered c-terminal phosphorylation by p70 s6 kinases and p90 ribosomal s6 kinases on four conserved ser residues (ser-235, ser-236, ser-240, and ser-244) whose modification potentiates rps6 cap binding activity" SIGNOR-252764 PRKCA protein P17252 UNIPROT FERMT3 protein Q86UX7 UNIPROT "up-regulates activity" phosphorylation Ser484 LSLQRTGsGGPGNHP 9606 BTO:0000565 25609252 t miannu " PKC-induced phosphorylation events, as we have shown kindlin-3 to be a PKC phosphorylation target (Fig. 6C), are often followed by rapid activation of phosphatases (38). " SIGNOR-266415 DCC protein P43146 UNIPROT PTK2 protein Q05397 UNIPROT "up-regulates activity" binding 9606 15494734 t miannu "Here we show that different regions of the intracellular domain of DCC directly interacted with the tyrosine kinases Src and focal adhesion kinase (FAK). Netrin activated both FAK and Src and stimulated tyrosine phosphorylation of DCC. Inhibition of Src family kinases reduced DCC tyrosine phosphorylation and blocked both axon attraction and outgrowth of neurons in response to netrin. Mutation of the tyrosine phosphorylation residue in DCC abolished its function of mediating netrin-induced axon attraction. On the basis of our observations, we suggest a model in which DCC functions as a kinase-coupled receptor, and FAK and Src act immediately downstream of DCC in netrin signaling." SIGNOR-268371 GEMIN6 protein Q8WXD5 UNIPROT "SMN complex" complex SIGNOR-C158 SIGNOR "form complex" binding 12065586 t lperfetto "SMN is part of a large macromolecular complex that also contains Gemin2, Gemin3, Gemin4, Gemin5, and Gemin6. The SMN complex functions in the assembly of spliceosomal small nuclear ribonucleoproteins and probably other ribonucleoprotein particles. We have identified a novel protein component of the SMN complex termed Gemin7 using native purified SMN complexes and peptide sequencing by mass spectrometry." SIGNOR-253120 MAPK14 protein Q16539 UNIPROT ATF2 protein P15336 UNIPROT up-regulates phosphorylation Thr69 SVIVADQtPTPTRFL 9606 10085140 t gcesareni "On the other hand, sapks such as jnks and p38 phosphorylate atf-2 at thr-69, thr-71, and ser-90 which lie close to the n-terminal transcriptional activation domain and stimulate itstrans-activating capacity our results indicate that atf-2 not only directly binds to smad3/4 hetero-oligomers but also that atf-2 is phosphorylated by tgf- signaling via tak1 and p38." SIGNOR-65597 SMO protein Q99835 UNIPROT MBP protein P02686 UNIPROT "up-regulates quantity" "transcriptional regulation" 10090 35082605 f "Non-canonical pathway (Gli1-indipendent): SMO/AMPK" SimoneGraziosi "We show that GSA-10 promotes Gli2 upregulation, MBP and MAL/OPALIN expression via Smo/AMPactivated Protein Kinase (AMPK) signaling, and efficiently increases the number of axonal contact/ensheathment for each oligodendroglial cell." SIGNOR-269226 DEAF1 protein O75398 UNIPROT RAC3 protein P60763 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0001939 18826651 t Gianni "Affymetrix gene profiling studies revealed Rac3 as a potential target gene and quantitative RT-PCR analysis confirmed that Rac3 was upregulated by Deaf-1 in immortalized mouse mammary epithelial cells." SIGNOR-269059 CFI protein P05156 UNIPROT C3 protein P01024 UNIPROT "down-regulates activity" cleavage 9606 BTO:0000089 26806831 t lperfetto "FH also serves as cofactor for the serine protease factor I (FI) that cleaves C3b into iC3b, unable to form C3 convertase (Fig 1B)." SIGNOR-263489 RPL3 protein P39023 UNIPROT "60S cytosolic large ribosomal subunit" complex SIGNOR-C287 SIGNOR "form complex" binding -1 25901680 t lperfetto "Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins." SIGNOR-262495 DDX3X protein O00571 UNIPROT EIF4E protein P06730 UNIPROT "down-regulates activity" binding 9606 BTO:0001950 17667941 t miannu "DDX3 is a human RNA helicase with plethoric functions. we identified translation initiation factor eukaryotic initiation factor 4E (eIF4E) as a DDX3-binding partner. Interestingly, DDX3 utilizes a consensus eIF4E-binding sequence YIPPHLR to interact with the functionally important dorsal surface of eIF4E in a similar manner to other eIF4E-binding proteins. Furthermore, cap affinity chromatography analysis suggests that DDX3 traps eIF4E in a translationally inactive complex by blocking interaction with eIF4G." SIGNOR-269200 PPP3CC protein P48454 UNIPROT NFATC2 protein Q13469 UNIPROT "up-regulates activity" dephosphorylation Ser326 PPKMWKTsPDPSPVS 9606 BTO:0000567 11030334 t "NFAT1 is phosphorylated on fourteen conserved phosphoserine residues in its regulatory domain, thirteen of which are dephosphorylated upon stimulation. Dephosphorylation of all thirteen residues is required to mask a nuclear export signal (NES), cause full exposure of a nuclear localization signal (NLS), and promote transcriptional activity" SIGNOR-248523 RXRB protein P28702 UNIPROT RARB protein P10826 UNIPROT up-regulates binding 9606 1310351 t gcesareni "Here we report that the transcriptional activity of rar and rxr can be reciprocally modulated by direct interactions between the two proteins." SIGNOR-16677 LPAR5 protein Q9H1C0 UNIPROT GNAI1 protein P63096 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-256718 AIMP1 protein Q12904 UNIPROT "Multiaminoacyl-tRNA synthetase" complex SIGNOR-C472 SIGNOR "form complex" binding 9606 32644155 t miannu "In mammalian cells, eight cytoplasmic aminoacyl-tRNA synthetases (AARS), and three non-synthetase proteins, reside in a large multi-tRNA synthetase complex (MSC). the MSC is suggested to be a super-complex of two identical, symmetrically arranged sub-units, each containing a single copy of the constituents, with the exception of LysRS which is present as a dimer in each sub-unit (Figure ​1B, adapted from (27,28)). The sub-units are proposed to be joined by dimers of AspRS and the ProRS domain of GluProRS, and possibly by LysRS tetramers (20). Four AARSs containing GST-like domains important in protein-protein interactions form a MetRS-AIMP3–GluProRS–AIMP2 core of the complex (27,29). These proteins, together with AspRS, and possibly LeuRS and IleRS (30), form a distinct sub-complex denoted as sub-complex I (27). Sub-complex II consists of AIMP1, GlnRS, ArgRS, a dimer of LysRS, and AIMP2 (which is shared by both sub-complexes)." SIGNOR-270359 PRKCZ protein Q05513 UNIPROT PRKCZ protein Q05513 UNIPROT up-regulates phosphorylation Thr560 TSEPVQLtPDDEDAI 9606 11141077 t gcesareni "Our findings suggest that insulin, via pip(3), provokes increases in pkc-zeta enzyme activity through (a) pdk-1-dependent t410 loop phosphorylation, (b) t560 autophosphorylation" SIGNOR-85505 CAMK2G protein Q13555 UNIPROT SPR protein P35270 UNIPROT unknown phosphorylation Ser213 QQLARETsVDPDMRK 11825621 t llicata "Phosphorylation sites of rat sepiapterin reductase (rSPR) by Ca2+/calmodulin-dependent protein kinase II were determined in the present study. Using specific monoclonal anti-phospho-Ser and -Thr antibodies, we found that only Ser residues of rSPR were phosphorylated. We constructed several point mutants of SPR by systematically replacing the three Ser residues by Ala ones. These mutants showed that all three Ser residues, i.e. S46, S196, and S214, of rSPR were phosphorylated. We also recognized that only Ser-213 of human SPR was phosphorylated. " SIGNOR-250705 CLTC protein Q00610 UNIPROT "AP-1/clathrin vescicle" complex SIGNOR-C251 SIGNOR "form complex" binding 9606 23103167 t lperfetto "Clathrin-coated pits and vesicles are diffraction-limited objects with typical diameters ranging between 75 and 130 nm. The smaller ∼75 nm coats contain at least 36 copies of clathrin, a heterohexameric protein of three heavy chains and three light chains, and about half that number of copies of the heterotetrameric AP adaptor complex | Intracellular clathrin-coated vesicles contain AP1 or AP3 adaptors" SIGNOR-260676 WWTR1 protein Q9GZV5 UNIPROT PAX8 protein Q06710 UNIPROT up-regulates binding 9606 BTO:0000763 19010321 t miannu "Taz is a coactivator for pax8 and ttf-1, two transcription factors involved in thyroid differentiation. / we show that this interaction leads to a significant enhancement of the transcriptional activity of pax8 and ttf-1 on the thyroglobulin promoter thus suggesting a role of taz in the control of genes involved in thyroid development and differentiation." SIGNOR-182253 CTCF protein P49711 UNIPROT APP protein P05067 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 11706010 f miannu "Depleting HeLa cell nuclear extract of endogenous CTCF specifically reduced transcriptional activity from the APP promoter. CTCF activates transcription from the APP promoter and that the activation domain is located on the N-terminal side of the zinc finger domain." SIGNOR-253823 KLF1 protein Q13351 UNIPROT KLF8 protein O95600 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 BTO:0000759 18687676 t Luana "Here we report that Klf8 is repressed by Klf3 in vivo and is up-regulated by Klf1. Transcript analysis indicates that Klf8 has two promoters, both containing multiple CACCC elements. Transactivation assays and chromatin immunoprecipitation experiments indicate that Klf3 represses Klf8 directly and that Klf1 activates Klf8 directly. " SIGNOR-266050 MAPK9 protein P45984 UNIPROT TOB1 protein P50616 UNIPROT down-regulates phosphorylation Ser154 SSVSSSPsPPFGHSA 9606 12050114 t gcesareni "Biochemical analyses have then shown that erk mapk (erk2) and jnk/sapk (jnk2) bind to and phosphorylate tob in vitro." SIGNOR-88744 EDNRB protein P24530 UNIPROT GNA14 protein O95837 UNIPROT "up-regulates activity" binding 9606 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257428 FFAR1 protein O14842 UNIPROT GNAI1 protein P63096 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257071 PRKDC protein P78527 UNIPROT POU2F1 protein P14859 UNIPROT down-regulates phosphorylation Thr226 LQAQNLLtQLPQQSQ 9606 9368058 t lperfetto "Through a similar strategy, t226 and s232 were characterized as the dna-pk phosphorylation sites" SIGNOR-53262 POGLUT1 protein Q8NBL1 UNIPROT NOTCH proteinfamily SIGNOR-PF30 SIGNOR up-regulates glycosylation 9606 22872643 t O-glycosilation gcesareni "O-glucosylation of epidermal growth factor-like (egf) repeats in the extracellular domain of notch is essential for notch function. A udp-glucose:protein o-glucosyltransferase (poglut/rumi) transfers o-glucose to serine within the o-glucose consensus." SIGNOR-254319 MAPK3 protein P27361 UNIPROT RAF1 protein P04049 UNIPROT down-regulates phosphorylation 9606 15664191 t gcesareni "Mapkerk1/2 is also able to phopshorylate the egf receptor, the ras exchange factor sos, mkkkraf1, and mkkmek1. The phosphorylation of each of these proteins by mapkerk1/2 is believed to reduce their catalytic activity. previous studies have shown that phosphorylation is required for raf-1 activation, and here, we identify six phosphorylation sites that contribute to the downregulation of raf-1 after mitogen stimulation. Five of the identified sites are proline-directed targets of activated erk" SIGNOR-133345 MAPK1 protein P28482 UNIPROT GIGYF2 protein Q6Y7W6 UNIPROT unknown phosphorylation Ser30 SITSPPLsPALPKYK 10090 22028470 t miannu "We have optimized a chemical genetic system using analog-sensitive ERK2, a form of ERK2 engineered to use an analog of adenosine 5'-triphosphate (ATP), to tag and isolate ERK2 substrates in vitro. This approach identified 80 proteins phosphorylated by ERK2, 13 of which are known ERK2 substrates. With this improved methodology, we detected 98 sites directly phosphorylated by ERK2 on 80 proteins from NIH 3T3-L1 fibroblasts. Thirteen of these proteins are known substrates and the rest represent previously unknown kinase/substrate interactions. (table1)" SIGNOR-262775 ELAVL3 protein Q14576 UNIPROT ADAM10 protein O14672 UNIPROT "up-regulates quantity" "post transcriptional regulation" 9606 19221430 t miannu "Neuronal ELAV (nELAV) proteins are RNA-binding proteins which play a physiological role in controlling gene expression in memory formation, and their alteration may contribute to cognitive impairment associated with neurodegenerative pathologies such as Alzheimer's disease (AD). The experiments show for the first time that ADAM10mRNA represents a nELAV target and that these RNA-binding proteins can play a role in the post-transcriptional regulation of ADAM10 expression. nELAV proteins specifically bind the ADAM10 mRNA and this binding is disrupted following Aβ exposure" SIGNOR-266864 ESCRT-III complex SIGNOR-C379 SIGNOR Cytoskeleton_organization phenotype SIGNOR-PH89 SIGNOR up-regulates 9606 26775243 f miannu "The ESCRT machinery drives a diverse collection of membrane remodeling events, including multivesicular body biogenesis, release of enveloped retroviruses and both reformation of the nuclear envelope and cytokinetic abscission during mitotic exit." SIGNOR-265535 DDX5 protein P17844 UNIPROT AR protein P10275 UNIPROT up-regulates binding 9606 18829551 t miannu "P68 is a nuclear protein and interacts with ar / p68 co-occupies the active psa promoter at are regions and enhances ar transcriptional activity" SIGNOR-181456 INSR protein P06213 UNIPROT IRS1 protein P35568 UNIPROT "up-regulates activity" phosphorylation Tyr612 TLHTDDGyMPMSPGV 10029 BTO:0000246 7651388 t lperfetto "Therefore, during insulin stimulation irs-1 undergoes tyrosine phosphorylation, and a portion of tyrosine phosphorylated irs-1 associated with the insulin receptor. The insulin receptor substrate-1 (irs-1) is rapidly phosphorylated on several tyrosine residues by the activated insulin receptor. Insulin signals are mediated through tyrosine phosphorylation of specific proteins such as insulin receptor substrate 1 (irs-1) and shc by the activated insulin receptor (ir)." SIGNOR-236756 NR1H4 protein Q96RI1 UNIPROT ABCB4 protein P21439 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000575 14527955 f miannu "Here we show that the MDR3 gene is trans-activated by the farnesoid X receptor (FXR) via a direct binding of FXR/retinoid X receptor alpha heterodimers to a highly conserved inverted repeat element (a FXR response element) at the distal promoter (-1970 to -1958)." SIGNOR-254833 MAPK14 protein Q16539 UNIPROT MAP3K11 protein Q16584 UNIPROT down-regulates phosphorylation 9606 20626350 t gcesareni "Jnk and p38 mapk activation have antagonistic effects in many cases. From a mechanicistic point of view, the p38 mapk pathway can negatively regulate jnk activity at the level of map3ks, either by phosphorylating mlk3 or the tak1 regulatory subunit tab2" SIGNOR-166605 TGFBI protein Q15582 UNIPROT "A1/b1 integrin" complex SIGNOR-C159 SIGNOR "up-regulates activity" binding 26387839 t lperfetto "BIGH3 binds molecules of the ECM, including fibronectin, laminin and different collagens ( Hashimoto et al., 1997 ; Hanssen et al., 2003) and serves as a ligand for several integrins|BIGH3 has been shown to interact with α3β1, αvβ3, αvβ5, α1β1, α6β4 and α7β1 integrin heterodimers" SIGNOR-253269 CSNK2A1 protein P68400 UNIPROT DDHD1 protein Q8NEL9 UNIPROT "down-regulates activity" phosphorylation Ser711 NPAKEPTsVSENEGI -1 11328814 t miannu "Here we incubated a recombinant preparation of the phospholipase in vitro with several enzymes including protein kinase CK2 (CK2), extracellular signal-regulated kinase 2 (ERK2), and protein phosphatase 2A (PP2A) to identify effects that might be of regulatory importance in vivo.Major findings were that 1) CK2 phosphorylated the phospholipase on serines 93, 105, and 716; 2) ERK2 phosphorylated the enzyme on serine 730; 3) there was cross-antagonism between the reactions that phosphorylated serines 716 and 730; 4) PP2A selectively hydrolyzed phosphate groups that were esterified to serines 716 and 730. The results of two independent experiments with each type of assay indicated that the incubation caused a 50% loss of phospholipase activity (TableV). These results differed from those of corresponding incubation experiments with PA-PLA1α plus ERK2 and MgATP (see “Experimental Procedures”), which provided no evidence for complex formation or phosphorylation-dependent loss of phospholipase activity" SIGNOR-262977 PRKACB protein P22694 UNIPROT BAD protein Q92934 UNIPROT down-regulates phosphorylation Ser118 GRELRRMsDEFVDSF 9606 10949026 t gcesareni "Ser-155 is the major phosphoacceptor site for pka on bad, but that pka also phosphorylates ser-112 and ser-136." SIGNOR-81141 CDX2/PAX6/P300 complex SIGNOR-C33 SIGNOR GCG protein P01275 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 10506141 f miannu "Pax-6 and cdx-2 also directly interacted with one another at the protein level. pax-6, bound to its dna recognition site in the glucagon g1 promoter element, tethered cdx-2 to the molecular complex of pax-6 and p300. Further, we found that the presence of cdx-2 enhanced the interaction of pax-6 with p300, thus establishing a molecular complex of transcription factors implicated in tissue-specific glucagon gene expression with the basal transcriptional machinery." SIGNOR-70957 ATM protein Q13315 UNIPROT BRCA1 protein P38398 UNIPROT up-regulates phosphorylation Ser1466 KSSEYPIsQNPEGLS 9606 BTO:0000150 10550055 t lperfetto "The brca1 (breast cancer gene 1) tumor suppressor protein is phosphorylated in response to dna damage. phosphorylation of brca1 by the checkpoint kinase atm may be critical for proper responses to dna double-strand breaks" SIGNOR-72060 COL12A1 protein Q99715 UNIPROT ECM_synthesis phenotype SIGNOR-PH8 SIGNOR up-regulates 9606 21949456 t "Types XII and XIV collagen are fibril-associated collagens with interrupted triple helices (FACITs) localized primarily to perimysium.23 While they appear to link fibrillar collagen to other ECM components, their precise function is not known" SIGNOR-254671 TFIIH complex SIGNOR-C457 SIGNOR POLR2A protein P24928 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser1738 SPSYSPTsPSYSPTS 9606 14662762 t lperfetto "Although there is some inconsistency in the literature, it is generally thought that cdk7, a component of the transcription factor (tf) iih, is a major ser-5 kinase, whereas cdk9, a component of positive transcription elongation factor (p-tef) b, is a major ser-2 kinase within cells. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination." SIGNOR-269340 PRKACA protein P17612 UNIPROT KCNQ5 protein Q9NR82 UNIPROT "up-regulates activity" phosphorylation Ser88 GKQGARMsLLGKPLS 9606 BTO:0001660 30061510 t miannu "We conclude that phosphorylation of S53 on the amino terminus of Kv7.5 is essential for PKA-dependent enhancement of channel activity in response to βAR activation in vascular and airway smooth muscle cells." SIGNOR-265980 CSNK2A1 protein P68400 UNIPROT SLC18A2 protein Q05940 UNIPROT unknown phosphorylation Ser511 PIGEDEEsESD -1 9045708 t llicata "Purified CKI and CKII phosphorylate the wild-type carboxyl terminus of VMAT2, but not a double mutant with both serines 512 and 514 replaced by alanine. The protein kinase inhibitor CKI-7 and unlabeled GTP both block in vitro phosphorylation by cell homogenates, indicating a role for CKII and possibly CKI in vivo. Both kinases phosphorylate the VMAT2 fusion protein to a much greater extent than a similar fusion protein containing the carboxyl terminus of VMAT1, consistent with differential phosphorylation of the two transporters observed in intact cells. " SIGNOR-250953 ABL1 protein P00519 UNIPROT CASP9 protein P55211 UNIPROT "up-regulates activity" phosphorylation Tyr153 LAYILSMePCGHCLI 9606 15657060 t Manara "We show that ABL1 phosphorylates caspase-9 on Tyr-153 in vitro and in cells treated with DNA damaging agents. ! Moreover, inhibition of ABL1 with STI571 blocked DNA damage-induced autoprocessing of caspase-9 to the p35 subunit and activation of caspase-3." SIGNOR-260792 PRMT1 protein Q99873 UNIPROT CNBP protein P62633 UNIPROT down-regulates methylation Arg25 ECPTGGGrGRGMRSR 9606 24726729 t miannu "Cnbp interacts with protein arginine methyltransferase prmt1 / r25 or r27 appear to be the major methylation sites in cnbp /arginine methylation of cnbp impedes rna binding" SIGNOR-204958 Ub:E2 complex SIGNOR-C497 SIGNOR RNF43 protein Q68DV7 UNIPROT "up-regulates activity" ubiquitination 9606 34199813 t miannu "The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t" SIGNOR-271009 DGC complex SIGNOR-C217 SIGNOR "GABA-A (a6-b1-g2) receptor" complex SIGNOR-C334 SIGNOR "up-regulates quantity" binding 9606 BTO:0000938;BTO:0002606 22626542 t miannu " In brain, the DGC is involved in the organisation of GABA(A) receptors (GABA(A)Rs) and aquaporin-4 (AQP4)-containing protein complexes in neurons and glia, respectively. DGC-like complexes function in the postsynaptic clustering and stabilisation of GABAARs in a subset of inhibitory GABAergic synapses." SIGNOR-265439 MAML1 protein Q92585 UNIPROT NOTCH1 protein P46531 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 12370315 f gcesareni "It has been shown that maml1 binds directly to the ankyrin repeat region of notch1 and forms a dna-binding complex with icn and csl" SIGNOR-94029 PLXNB3 protein Q9ULL4 UNIPROT FSCN1 protein Q16658 UNIPROT "up-regulates activity" 10090 BTO:0000526 21706053 f miannu "Sema5A regulates the phosphorylation states of fascin-1 through plexin-B3." SIGNOR-268374 GDNF protein P39905 UNIPROT RET protein P07949 UNIPROT up-regulates binding 9606 BTO:0000938 BTO:0000142 9182803 t gcesareni "A receptor complex comprised of trnr1 (gdnfr alpha) and ret was recently identified and found to be capable of mediating both gdnf and ntn signaling" SIGNOR-49094 AKT2 protein P31751 UNIPROT FOXO3 protein O43524 UNIPROT "down-regulates quantity by destabilization" phosphorylation Thr32 QSRPRSCtWPLQRPE 19951971 t lperfetto "AKT phosphorylates FOXO3a at three conserved sites (Thr32, Ser253 and Ser315), therefore creating binding sites for the 14-3-3 chaperone proteins and leading to the active export of FOXO3a to the cytoplasm where it is targeted for proteasomal degradation." SIGNOR-249639 MAPK1 protein P28482 UNIPROT PITPNM1 protein O00562 UNIPROT up-regulates phosphorylation Thr794 LEMLVPStPTSTSGA 9606 15125835 t lperfetto "Both cdk1 and erk2 induced phosphorylation of the wild-type nir2. Substitution of t794 by alanine reduced the phosphorylation by erk2, whereas the double mutations t794/1223a completely abolished it. The requirement of multiple nir2 phosphorylation sites for plk1 binding may provide a mechanism that sets a threshold for the nir2-plk1 interaction during mitosis." SIGNOR-124650 AKT3 protein Q9Y243 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR "down-regulates quantity by destabilization" phosphorylation Ser315 DFRSRTNsNASTVSG 19951971 t lperfetto "AKT phosphorylates FOXO3a at three conserved sites (Thr32, Ser253 and Ser315), therefore creating binding sites for the 14-3-3 chaperone proteins and leading to the active export of FOXO3a to the cytoplasm where it is targeted for proteasomal degradation." SIGNOR-252875 SLBP protein Q14493 UNIPROT H2BW2 protein P0C1H6 UNIPROT "up-regulates quantity by expression" "translation regulation" 9606 BTO:0001938 19155325 t lperfetto "Synthesis of mature histone mRNA requires only a single processing reaction: an endonucleolytic cleavage between a conserved stem-loop and a purine-rich downstream element to form the 3' end. The stem-loop binding protein (SLBP) is required for processing, and following processing, histone mRNA is transported to the cytoplasm, where SLBP participates in translation of the histone mRNA|We used radiolabeled probes generated by PCR targeting the open reading frame (ORF) to detect histones H2A, H2B, H3, H4, and H1 and used 7SK snRNA as a loading control (Fig. 2A). The abundance of histone H2A, H2B, H3, and H4 mRNAs is reduced to 37% to 70% of control levels in the SLBP knockdown cells when compared to the C2 control." SIGNOR-265395 AKT1 protein P31749 UNIPROT FOXO6 protein A8MYZ6 UNIPROT down-regulates phosphorylation 9606 21798082 t gcesareni "Akt inactivates protein degradation by phosphorylating and thus repressing the transcription factors of the foxo family, and stimulates protein synthesis via the mammalian target of rapamycin (mtor) and glycogen synthase kinase 3b (gsk3b)." SIGNOR-175294 Ub:E2 complex SIGNOR-C497 SIGNOR NHLRC1 protein Q6VVB1 UNIPROT "up-regulates activity" ubiquitination 9606 34199813 t miannu "The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t" SIGNOR-271135 PLCD4 protein Q9BRC7 UNIPROT "1D-myo-inositol 1,4,5-trisphosphate" smallmolecule CHEBI:16595 ChEBI up-regulates "chemical modification" 9606 8395015 t gcesareni "Hydrolysis of phosphatidylinositol 4,5-bisphosphate (pip2) by phosphatidylinositol-specific phospholipase c (pi-plc) generates two second messengers, inositol 1,4,5-trisphosphate and 1,2-diacylglycerol." SIGNOR-39041 DLL4 protein Q9NR61 UNIPROT PP2B proteinfamily SIGNOR-PF18 SIGNOR "up-regulates activity" binding 9606 BTO:0000776 16140393 t lperfetto "Notch signaling is a highly conserved pathway involved in cell fate choice during development with Delta and Jagged constituting the two evolutionary conserved families of Notch ligands. These ligands are transmembrane proteins with conserved biochemical structure that share their receptors and signal through a common mechanism. Upon ligand binding Notch receptors are proteoliticaly cleaved, the intracellular domain of Notch (NICD) is released and translocated to the nucleus, where it activates target genes. In mammals, four receptors and five ligands have been described. Delta-1, Delta-3 and Delta-4 are homologues to Drosophila Delta and Jagged-1 and Jagged-2 to Drosophila Serrate." SIGNOR-209744 NFE2L1 protein Q14494 UNIPROT NQO1 protein P15559 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 8962164 f irozzo "These results indicated that hARE-mediated expression of the NQO1 gene and its induction by xenobiotics and antioxidants are mediated by Nrf1 and Nrf2." SIGNOR-256280 Ub:E2 complex SIGNOR-C497 SIGNOR CCNB1IP1 protein Q9NPC3 UNIPROT "up-regulates activity" ubiquitination 9606 34199813 t miannu "The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t" SIGNOR-271052 SREBF2 protein Q12772 UNIPROT SND1 protein Q7KZF4 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 29296233 t irozzo "These findings reveal that SREBP-2 and SREBP-1 bind to specific sites in SND1 promoter and regulate SND1 transcription in opposite ways; it is induced by SREBP-2 activating conditions and repressed by SREBP-1 overexpression." SIGNOR-259136 PI4KA protein P42356 UNIPROT ATP(4-) smallmolecule CHEBI:30616 ChEBI "down-regulates quantity" "chemical modification" 9606 10101268 t miannu "The enzymes PtdIns 4-kinase (PI4K, for nomenclature see [3]) and PtdIns(4)P 5-kinase (PI4P5K) catalyse the phosphorylation of PtdIns at the D4 and consecutively at the D5 position." SIGNOR-269096 NPC complex SIGNOR-C263 SIGNOR XPOT protein O43592 UNIPROT "up-regulates quantity" relocalization 9606 9660920 t miannu "Exportin-t Is Predominantly Nuclear, Binds NPCs, and Shuttles Rapidly between Nucleus and Cytoplasm. RanGTP appears to have at least two functions in this complex. First, it stabilizes the tRNA/exportin-t interaction (see Figure 4B). Second, exportin-t apparently has to bind RanGTP for rapid exit from the nucleus . RanGTP causing a conformational change in exportin-t, which increases the affinity for export sites at the NPC. Exportin-t probably makes a direct contact to the NPC and accounts for the interactions that drive translocation of the tRNA/exportin-t/RanGTP complex out of the nucleus." SIGNOR-261394 FGFR1 protein P11362 UNIPROT PDK1 protein Q15118 UNIPROT up-regulates phosphorylation Tyr243 ARRLCDLyYINSPEL 9606 22195962 t llicata "Mitochondrial pdhk1 is tyrosine phosphorylated and activated by fgfr1 in cancer cells further mass spectrometric analysis identified three tyrosine residues of pdhk1, including y136, y243 and y244, that are phosphorylated by fgfr1" SIGNOR-191723 NRG4 protein Q8WWG1 UNIPROT ERBB4 protein Q15303 UNIPROT up-regulates binding 9606 BTO:0000887 7477375 t "Does not bind to the ERBB1, ERBB2 and ERBB3 receptors" gcesareni "The neuregulins (also called heregulins and neu differentiation factors) nrg-1 and nrg-2 bind erbb-3 and erbb-4;and nrg-3 and nrg-4 bind erbb-4." SIGNOR-26280 PRKCA protein P17252 UNIPROT TRPC3 protein Q13507 UNIPROT down-regulates phosphorylation Ser703 SLVPSPKsFVYFIMR 9606 BTO:0000671 15533987 t gcesareni "There are two known phosphorylation-mediated inactivation mechanisms for trpc3 channels. Protein kinase g (pkg) inactivates trpc3 by direct phosphorylation on thr-11 and ser-263 of the trpc3 proteins, and protein kinase c (pkc) inactivates trpc3 by phosphorylation on ser-712." SIGNOR-130269 MRGPRD protein Q8TDS7 UNIPROT Fibrosis phenotype SIGNOR-PH90 SIGNOR down-regulates 10116 23446738 f Luana "Alamandine produces several physiological actions that resemble those produced by angiotensin-(1-7), including vasodilation, antifibrosis, antihypertensive, and central effects. Interestingly, our data reveal that its actions are independent of the known vasodilator receptors of the RAS, Mas, and angiotensin II type 2 receptor. Rather, we demonstrate that alamandine acts through the Mas-related G-protein-coupled receptor, member D." SIGNOR-262309 PPP2CA protein P67775 UNIPROT PAK1 protein Q13153 UNIPROT "down-regulates activity" dephosphorylation Ser57 KKDRFYRsILPGDKT 10116 18586681 t "Both sites were dephosphorylated with the same kinetics; the anti-Ser(P)198 antibody was subsequently used as it exhibited lower background staining. Direct comparison of PP2Cα with purified PP1 and PP2A lead us to conclude that at the same molar ratio PP2Cα was the most efficient in dephosphorylating PAK1 (Fig. 1D). In this case we monitored two autophosphorylation sites in the Pak1 N-terminal regulatory region (Ser57 and Ser198/203) using phosphospecific antibodies: both sites showed the same kinetics of inactivation." SIGNOR-248641 STAT3 protein P40763 UNIPROT HAMP protein P81172 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0001950 18671304 f miannu "HCV-induced ROS stabilized the expression of two negative hepcidin regulators, HIF1alpha and HIF2alpha, and its expression was decreased by a HDAC inhibitor or an anti-oxidant. HCV-induced ROS also caused hypoacetylation of histones and inhibited binding of two positive regulators, C/EBPalpha and STAT3, to the hepcidin promoter, whereas anti-oxidant treatment of cells recovered C/EBPalpha and STAT3 binding to the hepcidin promoter." SIGNOR-255239 Ub:E2 complex SIGNOR-C497 SIGNOR RNF182 protein Q8N6D2 UNIPROT "up-regulates activity" ubiquitination 9606 34199813 t miannu "The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t" SIGNOR-271072 RPL32 protein P62910 UNIPROT "60S cytosolic large ribosomal subunit" complex SIGNOR-C287 SIGNOR "form complex" binding -1 25901680 t lperfetto "Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins." SIGNOR-262468 TGFB1 protein P01137 UNIPROT TGFBR1 protein P36897 UNIPROT up-regulates binding 9606 26194464 t "MARCO ROSINA" "TGF-b ligands bind to TGF-b type II receptor (TbRII), which transphosphorylates and activates TGF-b type I receptor (TbRI)." SIGNOR-255031 HAP1 protein P54257 UNIPROT AHI1 protein Q8N157 UNIPROT "up-regulates activity" binding 9606 BTO:0000452 23532844 t miannu "Huntingtin-associated protein-1 (Hap1) is a regulatory protein that binds Ahi1, and Hap1 knock-out mice have been reported to have JBTS-like phenotypes, suggesting a role for Hap1 in ciliogenesis." SIGNOR-269081 CSNK2A1 protein P68400 UNIPROT HMGA1 protein P17096 UNIPROT unknown phosphorylation Ser99 KEEEEGIsQESSEEE -1 2806554 t llicata "Sequence analysis of the native peptide (90-107) after treatment, which specifically converts phosphoserine residues to S-ethylcysteine, revealed that 70-80% of serine residues 102 and 103 were phosphorylated in vivo. Both residues were fully phosphorylated in vitro by incubation with casein kinase II. These results suggest that casein kinase II is involved in the regulation of HMG-I function in the cells. | After an 80 min incubation with CK-II, both serines were fully phosphorylated to 1 mol/mol and serine-99 to 0.3 mol/mol." SIGNOR-250894 RAI1 protein Q7Z5J4 UNIPROT ARNTL protein O00327 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 22578325 f miannu "Data further show that haploinsufficiency of RAI1 and Rai1 in SMS fibroblasts and the mouse hypothalamus, respectively, results in the transcriptional dysregulation of the circadian clock and causes altered expression and regulation of multiple circadian genes, including PER2, PER3, CRY1, BMAL1, and others." SIGNOR-266843 "26S Proteasome" complex SIGNOR-C307 SIGNOR Protein_degradation phenotype SIGNOR-PH96 SIGNOR up-regulates 9606 29636472 f lperfetto "The proteasome is a sophisticated ATP-dependent molecular machine responsible for protein degradation in all known eukaryotic cells. " SIGNOR-263375 KMT2C protein Q8NEZ4 UNIPROT "MLL3 complex" complex SIGNOR-C446 SIGNOR "form complex" binding 9606 34156443 t miannu "MLL3/KMT2C and MLL4/KMT2D are two paralogous histone modifiers that belong to the SET1/MLL (also named COMPASS) family of lysine methyltransferases and play critical roles in enhancer-regulated gene activation. MLL3 and MLL4 form identical multi-protein complexes for modifying mono-methylation of histone H3 lysine 4 (H3K4) at enhancers, which together with the p300/CBP-mediated H3K27 acetylation can generate an active enhancer landscape for long-range target gene activation." SIGNOR-268809 SGCA protein Q16586 UNIPROT DGC complex SIGNOR-C217 SIGNOR "form complex" binding 9606 15117830 t apalma "The DGC is composed of dystrophin (blue), an elongated cytoskeletal protein that links to cytoplasmic γ-actin and the transmembrane components of the DGC. Dystrophin binds to the tail of β-dystroglycan (orange). Dystroglycan is composed of 2 subunits, α and β, each produced from the same gene. Dystroglycan binds to the extracellular matrix protein laminin-α2. The sarcoglycan complex (blue-green) is composed of multiple subunits. Mutations in the genes encoding α-, β-, γ-, and δ-sarcoglycan lead to a similar phenotype as dystrophin mutations and include cardiomyopathy and muscular dystrophy in humans and mice. Additional subcomplexes in the DGC in skeletal muscle include α and β dystrobrevin, the syntrophins, nNOS, and caveolin 3 (pink)." SIGNOR-255985 TLN1 protein Q9Y490 UNIPROT "A8/b1 integrin" complex SIGNOR-C165 SIGNOR "up-regulates activity" binding 10090 BTO:0000132 19118207 t miannu "Over the past 10 years, the binding of talin to the cytoplasmic tail of integrin-β subunits has been established to have a key role in integrin activation. Binding of the phosphotyrosinebinding (PTB)-domain-like subdomain of the protein 4.1, ezrin, radixin, moesin (FERM) domain of talin to the conserved WxxxNP(I/L)Y motif of the β-integrin tail permits additional weaker interactions between talin and the membrane-proximal region of the tail that trigger integrin activation, probably through the disruption of inhibitory interactions between α- and β-subunit cytoplasmic tails." SIGNOR-257614 HECTD3 protein Q5T447 UNIPROT STX8 protein Q9UNK0 UNIPROT "down-regulates quantity by destabilization" polyubiquitination 9606 BTO:0000007 18821010 t miannu "Our co-immunoprecipitation experiments show that Syntaxin 8 directly interacts with HECTd3 and that the overexpression of HECTd3 promotes the ubiquitination of Syntaxin 8.  Immunoprecipitates probed with the anti-ubiquitin (Santa Cruz) antibody could be recognized by the anti-ubiquin antibody (Fig. 3a), indicating that the shift of the His-syntaxin 8 protein bands were caused by polyubiquitin conjugations. Our data suggest that HECTd3 may function as an E3 ubiquitin-protein ligase to promote the ubiquitination and degradation of Syntaxin 8 through the proteasome pathway." SIGNOR-271772 COL4A4 protein P53420 UNIPROT ECM_synthesis phenotype SIGNOR-PH8 SIGNOR up-regulates 9606 12778132 t "Type IV collagen is the most abundant Type IV collagen is the most abundant constituent of the BM…All of the type IV collagen in mammals is derived from six genetically distinct alpha-chain polypeptides (alpha1-alpha6)" SIGNOR-254668 "NLRC4 inflammasome" complex SIGNOR-C223 SIGNOR Pyroptosis phenotype SIGNOR-PH105 SIGNOR up-regulates 9606 30166988 f miannu "Once activated by a ligand, inflammasomes lead to the activation of a caspase. Activated caspases allow the release of mature forms of interleukin-1β and interleukin-18 and trigger a specific pro-inflammatory cell death termed pyroptosis. Accumulating data suggest that inflammasomes, mainly NLRP3, NLRP1, and AIM2, are involved in the generation of tissue damage and immune dysfunction after trauma." SIGNOR-263122 FOXO3 protein O43524 UNIPROT FOXO3 protein O43524 UNIPROT "up-regulates quantity" "transcriptional regulation" 22848740 t "We show that FOXO3 binds and activates its own promoter via a positive autoregulatory feedback loop" SIGNOR-255757 GSK3B protein P49841 UNIPROT CTNNB1 protein P35222 UNIPROT "down-regulates activity" phosphorylation Ser33 QQQSYLDsGIHSGAT 9606 BTO:0000586 SIGNOR-C110 16293724 t gcesareni "This leads to the inactivation and release of glycogen synthase kinase 3beta from its complex with axin, thereby relieving the inhibitory phosphorylation of beta-catenin and activating its signaling pathway." SIGNOR-141799 ADRA2B protein P18089 UNIPROT GNAZ protein P19086 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257109 LRP1B protein Q9NZR2 UNIPROT DVL2 protein O14641 UNIPROT "down-regulates activity" binding 9606 28408316 t irozzo "In this study, we have shown that LRP1B inhibited the activity of beta-catenin/TCF signaling possibly by interacting with DVL2. The molecular mechanism study revealed that LRP1B interacted with DVL2, inhibited the interaction between DVL2 and Axin, and negatively regulated beta-catenin/TCF signaling." SIGNOR-259090 FLT3 protein P36888 UNIPROT BCL2L11 protein O43521 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 10090 14981546 f "FLT3-ITD signaling contributes to transcriptional inhibition of p27Kip1 and Bim gene expression" SIGNOR-261525 MC5R protein P33032 UNIPROT GNAI3 protein P08754 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257183 SRC protein P12931 UNIPROT SRC protein P12931 UNIPROT "down-regulates activity" phosphorylation Tyr530 FTSTEPQyQPGENL 9606 8755732 t lperfetto "Rapid digestion of pp60c-src tyrosine kinase (src TK) in combination with electrospray ionization mass spectrometry enabled the determination of the time course for autophosphorylation of three tyrosine sites (Y338, Y419, and Y530) and a correlation with src TK activity. Here, conditions were identified which promoted essentially complete autophosphorylation of y530. Phosphorylation of y530 was directly correlated to a decrease in tyrosine kinase activity" SIGNOR-43315 PRKCG protein P05129 UNIPROT EIF4E protein P06730 UNIPROT unknown phosphorylation Ser209 DTATKSGsTTKNRFV 10090 8662663 t lperfetto "Phosphorylation of eIF-4E on serine 209 by protein kinase C is inhibited by the translational repressors, 4E-binding proteins." SIGNOR-248947 "sorafenib tosylate" chemical CHEBI:50928 ChEBI PDGFRB protein P09619 UNIPROT "down-regulates activity" "chemical inhibition" -1 16757355 t miannu "Further characterization of sorafenib revealed that this molecule was a multikinase inhibitor that targeted the vascular endothelial growth factor receptor family (VEGFR-2 and VEGFR-3) and platelet-derived growth factor receptor family (PDGFR-beta and Kit), which play key roles in tumor progression and angiogenesis. The in vitro and cellular profile of sorafenib is summarized in Table I." SIGNOR-259227 PRKACA protein P17612 UNIPROT NOLC1 protein Q14978 UNIPROT "up-regulates activity" phosphorylation Ser622 KKGEKRAsSPFRRVR -1 12167624 t miannu "PKA-dependent Nopp140 phosphorylation is important for its role in agp gene activation. both Ser627 and Ser628 are phosphorylated by PKA." SIGNOR-250019 4-fluoro-N-{2-[4-(7-methoxynaphthalen-1-yl)piperazin-1-yl]ethyl}benzamide chemical CHEBI:64101 ChEBI HTR1A protein P08908 UNIPROT "up-regulates activity" "chemical activation" 10029 BTO:0000246 9760039 t miannu "A range of serotonergic agonists and partial agonists were tested for their capacity to stimulate 5-HT1A receptor mediated GTPg binding in CHO-h5-HT1A membranes. The methoxynaphtylpiperazine ligand, S 14671,was the most potent agonist tested, with virtually full agonist activity, relative to 5-HT Table 1; Fig. 2C consistent with its exceptionally potent and efficacious actions in in vivo functional paradigms. Its analogue, S 14506 was also a highly potent and efficacious ligand (Emax90%) in agreement with previous in vivo studies ( Schreiber et al., 1994 ). (+)UH 301 exhibited partial agonist activity at 5-HT1A receptors" SIGNOR-258858 PTPN11 protein Q06124 UNIPROT GAB1 protein Q13480 UNIPROT "down-regulates activity" dephosphorylation Tyr627 KGDKQVEyLDLDLDS 9606 11323411 t "These results suggest that Tyr(P)-627 and Tyr(P)-659 of Gab1 constitute a bisphosphoryl tyrosine-based activation motif (BTAM) that binds and activates SHP2.|Thus, physical association of activated SHP2 with Gab1 is necessary and sufficient to mediate the ERK mitogen-activated protein kinase activation. Phosphopeptides derived from Gab1 were dephosphorylated by active SHP2 in vitro." SIGNOR-248674 ARHGAP31 protein Q2M1Z3 UNIPROT RAC1 protein P63000 UNIPROT "down-regulates activity" "gtpase-activating protein" 9606 BTO:0000007 32203420 t Luana "We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2)." SIGNOR-260489 SRC protein P12931 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR "up-regulates activity" phosphorylation Tyr315 TFCGTPEyLAPEVLE 9606 BTO:0000007 12600984 t lperfetto "We also showed that phosphorylation of Tyr-315 in Akt induced by Src or EGF is dependent on the integrity of this proline-rich motif. Furthermore, the Akt mutant lacking this proline motif fails to block the transcription activity of Forkhead in 293 cells and poorly stimulates the proliferation of Madin-Darby canine kidney cells. Taken together, our data suggest that the interaction between the SH3 domain of Src family kinases and the proline-rich motif in the C-terminal regulatory region of Akt is required for tyrosine phosphorylation of Akt and its subsequent activation." SIGNOR-246373 PRKAA1 protein Q13131 UNIPROT MLXIPL protein Q9NP71 UNIPROT down-regulates phosphorylation 9606 SIGNOR-C15 21892142 t gcesareni "Ampk has also been suggested to phosphorylate the glucose-sensitive transcription factor chrebpthe dna binding activity, as assayed in a gel-shift assay of the truncated chrebp, was gradually inactivated with time by treatment with ampk" SIGNOR-176494 CSNK2A1 protein P68400 UNIPROT HDAC1 protein Q13547 UNIPROT up-regulates phosphorylation Ser421 IACEEEFsDSEEEGE 9606 11602581 t gcesareni "Human hdac1 protein was analyzed by ion trap mass spectrometry, and two phosphorylated serine residues, ser(421) and ser(423), were unambiguously identified. Loss of phosphorylation at ser(421) and ser(423) due to mutation to alanine or disruption of the casein kinase 2 consensus sequence directing phosphorylation reduced the enzymatic activity and complex formation of hdac1." SIGNOR-111011 F2 protein P00734 UNIPROT F2R protein P25116 UNIPROT "up-regulates activity" cleavage Arg41 TNATLDPrSFLLRNP -1 10978167 t lperfetto "Thrombin cleaved PAR1E at the Arg41-Ser42 activation site at concentrations known to induce cellular activation, supporting a native conformation of the recombinant polypeptide." SIGNOR-263569 MAPKAPK2 protein P49137 UNIPROT LSP1 protein P33241 UNIPROT unknown phosphorylation Ser252 PKLARQAsIELPSMA -1 8995217 t miannu "LSP1 is the major substrate for mitogen-activated protein kinase-activated protein kinase 2 in human neutrophils. . Inspection of the human LSP1 protein sequence (22) identifies two serine residues at positions 204 and 252 as potential phosphorylation sites. The results show that LSP1 is a substrate for MAPKAP kinase 2 in vitro and that the phosphorylation site(s) are located in the C-terminal 152 amino acid residues, as predicted from the sequence." SIGNOR-250148 PRKCD protein Q05655 UNIPROT HABP4 protein Q5JVS0 UNIPROT "down-regulates activity" phosphorylation Thr354 RKPANDItSQLEINF 9606 BTO:0004974 14699138 t lperfetto "We found a strong phosphorylation of Ki-1/57 by PKCalphabeta, PKCdelta, PKClambda/zeta, and especially by PKCsigma, however not by PKCmi. These data show that Ki-1/57 can serve in principal as a substrate for a wide variety of different PKC isoforms but also that its phosphorylation is strongest with PKCsigma. | This suggests that the two threonine residues present in this fragment (Thr354 and Thr375) might be the main target residues for phosphorylation by PKC in vitro. | Ki-1/57 Exits the Nucleus upon PMA Activation" SIGNOR-249248 RPS6KA1 protein Q15418 UNIPROT RPTOR protein Q8N122 UNIPROT up-regulates phosphorylation Ser719 PCTPRLRsVSSYGNI 9606 SIGNOR-C3 18722121 t llicata "Ser719, ser721, and ser722 are the predominant rsk-dependent phosphorylation sites in raptor raptor phosphorylation regulates mtorc1 activity" SIGNOR-180458 panobinostat chemical CHEBI:85990 ChEBI HDAC1 protein Q13547 UNIPROT "down-regulates activity" "chemical inhibition" -1 17868033 t Luana "Our findings suggest that hydroxamic acid-derived compounds such as TSA, NVP-LAQ824, panobinostat, ITF2357, vorinostat and belinostat act as potent pan-HDAC isoform inhibitors. A notable observation was the similarity between belinostat and vorinostat in the biochemical isoform assays; both compounds exhibit similar EC50 values in all but the HDAC8 assay." SIGNOR-257754 HBB protein P68871 UNIPROT TNF protein P01375 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000876 11901318 f "Regulation of expression" miannu "Free hemoglobin enhances tumor necrosis factor-alpha production in isolated human monocytes." SIGNOR-251752 PAX3 protein P23760 UNIPROT LEF1 protein Q9UJU2 UNIPROT "up-regulates activity" binding 9606 20006729 t gcesareni "Pax3 binds to lef1 pax3 activity may directly effect the expression of factors regulated by signal transduction pathways dependent on lef1." SIGNOR-162100 ZRANB1 protein Q9UGI0 UNIPROT TWIST1 protein Q15672 UNIPROT "down-regulates activity" deubiquitination 9606 BTO:0000007 29748601 t miannu "Trabid inhibits Twist1 activity by cleaving RNF8-mediated Twist1 K63-linked ubiquitination" SIGNOR-273502 paliperidone chemical CHEBI:82978 ChEBI HTR2A protein P28223 UNIPROT "down-regulates activity" "chemical inhibition" 10090 BTO:0000331 8935801 t miannu "Risperidone and its active metabolite 9-OH-risperidone were compared to reference antipsychotic drugs (haloperidol, pipamperone, fluspirilene, clozapine, zotepine) and compounds under development (olanzapine, seroquel, sertindole, ORG-5222, ziprasidone) for in vitro binding to neurotransmitter receptors in brain tissue and on membranes of recombinant cells expressing cloned human receptors and for in vivo occupancy of neurotransmitter receptors in rat and guinea-pig brain following acute treatment (2 h., s.c.). The binding affinities of the compounds for various neurotransmitter receptors were measured using membrane preparations of animal brain regions and of recombinant cells expressing cloned, mostly human receptors. Receptors, tissues and cells are indicated in Table I; results are shown in Table 4A-B." SIGNOR-258564 TARS1 protein P26639 UNIPROT AMP smallmolecule CHEBI:456215 ChEBI "up-regulates quantity" "chemical modification" 9606 25824639 t miannu "Here we show, using X-ray crystal structures and functional analyses, that a single molecule of borrelidin simultaneously occupies four distinct subsites within the catalytic domain of bacterial and human ThrRSs. These include the three substrate-binding sites for amino acid, ATP and tRNA associated with aminoacylation, and a fourth 'orthogonal' subsite created as a consequence of binding." SIGNOR-270505 SRC protein P12931 UNIPROT ABL1 protein P00519 UNIPROT "up-regulates activity" phosphorylation Tyr393 RLMTGDTyTAHAGAK 9606 11847100 t lperfetto "c-Src-induced c-Abl activation involves phosphorylation of Y245 and Y412, two residues required for c-Abl mitogenic function." SIGNOR-246311 ATG4B protein Q9Y4P1 UNIPROT MAP1LC3C protein Q9BXW4 UNIPROT "up-regulates activity" cleavage 9606 BTO:0000007;BTO:0000567 15187094 t lperfetto "Human atg4 homologues cleave the carboxyl termini of the three human atg8 homologues, microtubule-associated protein light chain 3 (lc3), gabarap, and gate-16." SIGNOR-125489 CTNNB1 protein P35222 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 18697834 f "Simone Vumbaca" "we showed that β-catenin, a key component of the canonical Wnt-signalling cascade, is present in quiescent satellite cells in the inactive form, but subsequently becomes activated following satellite-cell activation. This observation suggests that the proliferation initiated by the Wnt-signalling cascade does not have to rely on transcription of β-catenin, but rather on activation of this protein, which is already present within the quiescent satellite cells." SIGNOR-255654 UHMK1 protein Q8TAS1 UNIPROT MBP protein P02686 UNIPROT down-regulates phosphorylation Ser299 GRDSRSGsPMARR 9606 10880969 t lperfetto "Phosphorylation decreased the ability of mbp to polymerize actin and to bundle actin filaments but had no effect on the dissociation constant of the mbp-actin complex or on the ability of ca2+-calmodulin to dissociate the complex. The most significant effect of phosphorylation on the mbp-actin complex was a dramatic reduction in its ability to bind to negatively charged lipid bilayers. Mass spectrometry and peptide sequencing allowed us to identify serine 164 of mbp as the unique site phosphorylated by kis. Phosphorylation of synthetic peptides indicated the importance of the proline residue at position +1." SIGNOR-78895 MITF protein O75030 UNIPROT BEST1 protein O76090 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0004595 14982938 f miannu "These studies define the VMD2 promoter region sufficient to drive RPE-specific expression in the eye, identify positive regulatory regions in vitro, and suggest that MITF as well as other E-box binding factors may act as positive regulators of VMD2 expression." SIGNOR-254586 BRCA1 protein P38398 UNIPROT CDKN1B protein P46527 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000150 16331276 f miannu "We identified a foxa1 binding site within the brca1-responsive element of the p27(kip1) promoter and showed that foxa1 activated the promoter alone and in conjunction with brca1." SIGNOR-142888 phosphonatoenolpyruvate smallmolecule CHEBI:58702 ChEBI pyruvate smallmolecule CHEBI:15361 ChEBI "up-regulates quantity" "precursor of" 9606 15996096 t miannu "Pyruvate kinase (PK)1 is an important regulatory enzyme that is able to generate ATP under hypoxic conditions as well as regulate glucose consumption. Pyruvate kinase catalyzes the last step in glycolysis converting the substrate phosphoenolpyruvate (PEP) into pyruvate, while producing one molecule of ATP per reaction per cycle (Figure 1A)." SIGNOR-266532 MAPK1 protein P28482 UNIPROT ELK1 protein P19419 UNIPROT "up-regulates activity" phosphorylation Ser383 IHFWSTLsPIAPRSP 10090 BTO:0000944 7889942 t lperfetto "We demonstrate that elk-1, a protein closely related to p62tcf in function, is a nuclear target of two members of the map kinase family, erk1 and erk2, erk1 phosphorylates five c-terminal sites in elk-1 (s324,t336, s383, s389 and s422) with varying degrees of efficiency." SIGNOR-235455 RABGGTA protein Q92696 UNIPROT RAB5A protein P20339 UNIPROT "up-regulates activity" lipidation 9606 BTO:0000007 18532927 t miannu "Prenylation (or geranylgeranylation) of Rab GTPases is catalysed by RGGT (Rab geranylgeranyl transferase) and requires REP (Rab escort protein). In the classical pathway, REP associates first with unprenylated Rab, which is then prenylated by RGGT. In the alternative pathway, REP associates first with RGGT; this complex then binds and prenylates Rab proteins. Rab GTPases need to be geranylgeranylated on either one or two cysteine residues in their Ctermini in order to localize to the correct intracellular membrane and be functional" SIGNOR-265572 "KMN network" complex SIGNOR-C366 SIGNOR Chromosome_segregation phenotype SIGNOR-PH44 SIGNOR up-regulates 9606 BTO:0000567 18007590 f lperfetto "Based on our results, we propose that the cooperative action of CENP-A NAC/CAD subunits and the KMN network drives efficient chromosome segregation and bipolar spindle assembly during mitosis." SIGNOR-265220 CDK7 protein P50613 UNIPROT POLR2A protein P24928 UNIPROT down-regulates phosphorylation Ser1913 SPKYSPTsPTYSPTS 9606 14662762 t lperfetto "Although there is some inconsistency in the literature, it is generally thought that cdk7, a component of the transcription factor (tf) iih, is a major ser-5 kinase, whereas cdk9, a component of positive transcription elongation factor (p-tef) b, is a major ser-2 kinase within cells. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination." SIGNOR-120060 SUN1 protein O94901 UNIPROT TERB1 protein Q8NA31 UNIPROT "up-regulates activity" binding 9606 BTO:0000007 SIGNOR-C303 SIGNOR-C305 33015044 t lperfetto "In this study, we found that SUN1 not only interacted with TERB1 but also interacted with MAJIN, and the interaction of SUN1 with MAJIN is stronger than TERB1. We also found that SUN1 interacted with SPDYA, an activator of CDK2. | It will be of great interest to test this hypothesis to fully understand the mechanisms of stable telomere–NE connection and telomere movement along the NE driven by the LINC complex." SIGNOR-263299 MAPK1 protein P28482 UNIPROT POLR2A protein P24928 UNIPROT down-regulates phosphorylation Ser1871 SPKYSPTsPKYSPTS 9606 14662762 t lperfetto "Erk1/2 are major ser-5 kinases after h2o2 treatment. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination." SIGNOR-120132 CDK7 protein P50613 UNIPROT POLR2A protein P24928 UNIPROT down-regulates phosphorylation Ser1675 SPSYSPTsPSYSPTS 9606 14662762 t lperfetto "Although there is some inconsistency in the literature, it is generally thought that cdk7, a component of the transcription factor (tf) iih, is a major ser-5 kinase, whereas cdk9, a component of positive transcription elongation factor (p-tef) b, is a major ser-2 kinase within cells. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination." SIGNOR-120012 ATP5F1A protein P25705 UNIPROT "ATP synthase" complex SIGNOR-C264 SIGNOR "form complex" binding 9606 21874297 t miannu "Human mitochondrial ATP synthase, or complex V, consists of two functional domains, F1 and Fo. F1 comprises 5 different subunits (three α, three β, and one γ, δ and ε) and is situated in the mitochondrial matrix. Fo contains subunits c, a, b, d, F6, OSCP and the accessory subunits e, f, g and A6L." SIGNOR-261396 RAR proteinfamily SIGNOR-PF45 SIGNOR RXR proteinfamily SIGNOR-PF44 SIGNOR "up-regulates activity" binding 9606 1310351 t miannu "Cellular responsiveness to retinoic acid and its metabolites is conferred through two structurally and pharmacologically distinct families of receptors: the retinoic acid receptors (RAR) and the retinoid X receptors (RXR). Here we report that the transcriptional activity of RAR and RXR can be reciprocally modulated by direct interactions between the two proteins." SIGNOR-256198 FZR1 protein Q9UM11 UNIPROT ANLN protein Q9NQW6 UNIPROT "down-regulates quantity by destabilization" binding 9606 BTO:0000567 16040610 t miannu " Ubiquitination of anillin required a destruction-box and was mediated by Cdh1, an activator of APC/C. Overexpression of Cdh1 reduced the levels of anillin, whereas inactivation of APC/C(Cdh1) increased the half-life of anillin." SIGNOR-272654 JARID2 protein Q92833 UNIPROT NPPA protein P01160 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 10116 BTO:0003324 15542826 f miannu "JMJ physically associates with Nkx2.5 and GATA4 in vitro and in vivo as determined by glutathione S-transferase pull-down and immunoprecipitation assays. we show that JMJ represses ANF gene expression by inhibiting transcriptional activities of Nkx2.5 and GATA4." SIGNOR-224790 PRKCD protein Q05655 UNIPROT NCF1 protein P14598 UNIPROT up-regulates phosphorylation Ser320 QRSRKRLsQDAYRRN 9606 BTO:0000130 12056906 t esanto "Pkc alpha, beta ii, delta, and zeta expressed in human neutrophils can individually phosphorylate p47(phox) and induce both its translocation and nadph oxidase activation. The use of p47phox mutants identified serines 303, 304, 315, 320, 328, 359, 370, and 379 as targets of pkc?, ???, And ?." SIGNOR-89229 CNKSR1 protein Q969H4 UNIPROT RASSF1 protein Q9NS23 UNIPROT up-regulates binding 9606 22830020 t gcesareni "Cnk1 binds to rassf1a and promotes apoptosis through a pathway that requires rassf1a and mst kinases." SIGNOR-198432 NMBR protein P28336 UNIPROT GNAI1 protein P63096 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257047 CSF2RA protein P15509 UNIPROT CSF2RA/CSF2RB complex SIGNOR-C212 SIGNOR "form complex" binding 9606 9680354 t apalma "The high-affinity GMR is known to be composed of a specific ligand-binding alpha subunit (GMRα) and a common beta subunit (βc), which is also a component of the interleukins-3 (IL-3) and -5 (IL-5) receptors." SIGNOR-255582 PAK2 protein Q13177 UNIPROT PAK2 protein Q13177 UNIPROT "up-regulates activity" phosphorylation Ser55 KPRHKIIsIFSGTEK -1 10075701 t miannu "Eight autophosphorylation sites were identified in Cdc42-activated gamma-PAK, six of which are in common with those previously reported in alpha-PAK, while Ser-19 and Ser-165 appear to be uniquely phosphorylated in the gamma-form. Further, the phosphorylation of Ser-141, Ser-165, and Thr-402 was found to correlate with gamma-PAK activation. Autophosphorylation of γ-PAK with MgATP alone takes place at Ser-19, Ser-20, Ser-55, Ser-192, and Ser-197." SIGNOR-250229 DGC complex SIGNOR-C217 SIGNOR "GABA-A (a3-b1-g2) receptor" complex SIGNOR-C332 SIGNOR "up-regulates quantity" binding 9606 BTO:0000938;BTO:0002606 22626542 t miannu " In brain, the DGC is involved in the organisation of GABA(A) receptors (GABA(A)Rs) and aquaporin-4 (AQP4)-containing protein complexes in neurons and glia, respectively. DGC-like complexes function in the postsynaptic clustering and stabilisation of GABAARs in a subset of inhibitory GABAergic synapses." SIGNOR-265434 ACVR1 protein Q04771 UNIPROT SMAD1 protein Q15797 UNIPROT up-regulates phosphorylation 9606 9748228 t fspada "Bmp7 stimulated phosphorylation of endogenous smad1 and 5, formation of complexes with smad4 and induced the promoter for the homeobox gene, tlx2" SIGNOR-60174 PP1 proteinfamily SIGNOR-PF54 SIGNOR AKT proteinfamily SIGNOR-PF24 SIGNOR "down-regulates activity" dephosphorylation 9606 14633703 t lperfetto "Here, we identify PP1 as a serine/threonine phosphatase that associates with and dephosphorylates AKT in breast cancer cells|The heat shock protein 90 inhibitor geldanamycin and the ErbB inhibitor ZD1839 promote rapid PP1 phosphatase-dependent inactivation of AKT in ErbB2 overexpressing breast cancer cells" SIGNOR-264659 CREB1 protein P16220 UNIPROT NR2F6 protein P10588 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 15955695 f miannu "In cancer tissue, the expression levels of EAR-2, COUP-TF1, EARgamma, Snail, and Slug decrease, and aromatase expression is then up-regulated through the binding of ERRalpha to S1 and the binding of CREB1 or related factors to CREaro." SIGNOR-253793 SLBP protein Q14493 UNIPROT H2BC5 protein P58876 UNIPROT "up-regulates quantity by expression" "translation regulation" 9606 BTO:0001938 19155325 t lperfetto "Synthesis of mature histone mRNA requires only a single processing reaction: an endonucleolytic cleavage between a conserved stem-loop and a purine-rich downstream element to form the 3' end. The stem-loop binding protein (SLBP) is required for processing, and following processing, histone mRNA is transported to the cytoplasm, where SLBP participates in translation of the histone mRNA|We used radiolabeled probes generated by PCR targeting the open reading frame (ORF) to detect histones H2A, H2B, H3, H4, and H1 and used 7SK snRNA as a loading control (Fig. 2A). The abundance of histone H2A, H2B, H3, and H4 mRNAs is reduced to 37% to 70% of control levels in the SLBP knockdown cells when compared to the C2 control." SIGNOR-265378 PTPRJ protein Q12913 UNIPROT MET protein P08581 UNIPROT "down-regulates activity" dephosphorylation Tyr1365 NVKCVAPyPSLLSSE 9606 BTO:0000007 12475979 t "When co-expressed in 293 cells, the full-length substrate-trapping mutant form of DEP-1 formed a stable complex with the chimeric receptor colony stimulating factor 1 (CSF)-Met and wild type DEP-1 dephosphorylated CSF-Met. Furthermore, we observed that DEP-1 preferentially dephosphorylated a Gab1 binding site (Tyr(1349)) and a COOH-terminal tyrosine implicated in morphogenesis (Tyr(1365))," SIGNOR-248703 "Cullin 1-RBX1-Skp1" complex SIGNOR-C529 SIGNOR SMURF1 protein Q9HCE7 UNIPROT "down-regulates quantity by destabilization" polyubiquitination 9606 BTO:0000007 25721664 t miannu "F-box protein Fbxo3 targets Smurf1 ubiquitin ligase for ubiquitination and degradation. Here we show that another F-box protein Fbxo3, belonging to the FBXO type protein family, also interacts with and targets Smurf1 for poly-ubiquitination and proteasomal degradation. The SCF complex is composed of F-box protein, Skp1, Cullin1 (Cul1) and ROC1. Fbxo3, whose substrates are few, forms SCF Fbxo3 ubiquitin ligase and regulates the degradations of Fbxl2, p62, HIPK2 and p300 through the ubiquitin-proteasome pathway." SIGNOR-272443 IL15RA protein Q13261 UNIPROT PPARG protein P37231 UNIPROT "down-regulates activity" 9606 30029643 f areggio "In addition, level of mRNAs encoding C/EBPa, PPARg and FABP4, the classic adipogenic markers, was significantly lower in samples administrated with IL-15" SIGNOR-256228 CSNK1E protein P49674 UNIPROT YAP1 protein P46937 UNIPROT down-regulates phosphorylation Ser400 SRDESTDsGLSMSSY 9606 phosphorylation:Ser127 PQHVRAHsSPASLQL 24715453 t milica "LATS1/2-mediated phosphorylation of a conserved serine in this region (Ser311 in human TAZ; Ser397 in human YAP) primes for further phosphorylation by CK1_/_ kinases (Ser314 on human TAZ; Ser400/403 in human YAP)" SIGNOR-230728 DVL1 protein O14640 UNIPROT RAC1 protein P63000 UNIPROT "up-regulates activity" binding 9606 19365405 t gcesareni "B-catenin-independent wnt signaling can activate rho family gtpases through at least two mechanisms: (1) direct activation of rac1 by dvl;and (2) activation of rhoa via dvl-associated activator of morphogenesis-1 (daam1), possibly through the weak-similarity guaninenucleotide exchange factor (wgef)1." SIGNOR-185274 Ub:E2 complex SIGNOR-C497 SIGNOR RNF20 protein Q5VTR2 UNIPROT "up-regulates activity" ubiquitination 9606 34199813 t miannu "The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t" SIGNOR-271111 PRKCD protein Q05655 UNIPROT PRKD1 protein Q15139 UNIPROT up-regulates phosphorylation Ser742 GEKSFRRsVVGTPAY 9606 15024053 t llicata "Here we show that activation of pkd in response to oxidative stress requires two sequential signaling events, i.e., phosphorylation of tyr463 by abl, which in turn promotes a second step, phosphorylation of the pkd activation loop (ser738/ser742). We show that this is mediated by pkcdelta (protein kinase cdelta)" SIGNOR-123453 RBM10 protein P98175 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR up-regulates 9606 BTO:0001938 30403180 f irozzo "Cell apoptosis is an important event in cancer progression. Overexpression of RBM10 dramatically induced U2OS cell apoptosis compared with negative control cells." SIGNOR-259150 KLHL25 protein Q9H0H3 UNIPROT "Cullin 3-RBX1-Skp1" complex SIGNOR-C526 SIGNOR "up-regulates activity" binding 9606 BTO:0002552 27664236 t miannu "Here, we found that CUL3 interacts with ACLY through its adaptor protein, KLHL25 (Kelch-like family member 25), to ubiquitinate and degrade ACLY in cells. " SIGNOR-272334 DEF6 protein Q9H4E7 UNIPROT RAP1B protein P61224 UNIPROT "up-regulates activity" binding 9606 BTO:0000782 26483383 t lperfetto "Mechanistic studies revealed that SLAT interacts, through its PH domain, with a key component of inside-out signaling, namely the active form of the small GTPase Rap1 (which has two isoforms, Rap1A and Rap1B). This interaction has been further shown to facilitate the interdependent recruitment of Rap1 and SLAT to the T cell immunological synapse upon TCR engagement. Furthermore, a SLAT mutant lacking its PH domain drastically inhibited LFA-1 activation and CD4(+) T cell adhesion." SIGNOR-253366 RPS6K proteinfamily SIGNOR-PF26 SIGNOR ETV1 protein P50549 UNIPROT "up-regulates activity" phosphorylation Ser216 PMYQRQMsEPNIPFP 9606 12213813 t lperfetto "Here we describe that the 90-kDa ribosomal S6 kinase 1 (RSK1), a protein kinase downstream of the extracellular signal-regulated kinase (ERK) subclass of MAPKs, binds to ER81, phosphorylates it, and enhances ER81-dependent transcription. Two in vivo RSK1 phosphorylation sites within ER81, Ser(191) and Ser(216), were identified, whose mutation to alanine reduces ER81 activity upon ERK-MAPK stimulation." SIGNOR-252769 Ub:E2 complex SIGNOR-C497 SIGNOR TRIM3 protein O75382 UNIPROT "up-regulates activity" ubiquitination 9606 34199813 t miannu "The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t" SIGNOR-271146 NUMA1 protein Q14980 UNIPROT TUBB4A protein P04350 UNIPROT up-regulates binding 9606 11956313 t miannu "Direct binding of numa to tubulin is mediated by a novel sequence motif in the tail domain that bundles and stabilizes microtubules." SIGNOR-117025 PPP2CA protein P67775 UNIPROT Gbeta proteinfamily SIGNOR-PF4 SIGNOR down-regulates dephosphorylation 9606 12840032 t "inferred from 70% of family members" gcesareni "P-erk1/2 proteins were efficiently dephosphorylated in vitro by protein phosphatases 1 and 2a (pp1/2a) and mapk phosphatase 3 (mkp3)." SIGNOR-269896 BACH1 protein O14867 UNIPROT HK2 protein P52789 UNIPROT "up-regulates quantity" "transcriptional regulation" 9606 31257027 t "BACH1 activates transcription of Hexokinase 2 and Gapdh and increases glucose uptake, glycolysis rates, and lactate secretion, thereby stimulating glycolysis-dependent metastasis of mouse and human lung cancer cells." SIGNOR-259338 CDX2 protein Q99626 UNIPROT TFF3 protein Q07654 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9534 BTO:0004055 17182120 t "The transcription of human TFF3 reporter genes was significantly up-regulated by the transient overexpression of CDX2 in COS-7 cells and AGS gastric cells." SIGNOR-253967 PPP1R9B protein Q96SB3 UNIPROT F-actin_assembly phenotype SIGNOR-PH18 SIGNOR up-regulates 10090 BTO:0001976 15996550 f miannu "Neurabin and spinophilin are preferentially expressed in neurons, where they are highly localized to dendritic spines via an interaction with F-actin. The results obtained in the present study suggest a mechanism by which neurabin or spinophilin contributes to the organization of the F-actin cytoskeleton in dendritic spines, and in turn to the regulation of spine morphology, via the activity-dependent recruitment of the Rho-specific GEF Lfc" SIGNOR-269179 LYST protein Q99698 UNIPROT RAB5A protein P20339 UNIPROT "down-regulates activity" binding 7227 33725482 t lperfetto "Mauve interacts with Rab5, Msps, and gamma-tubulin|Mauve/LYST opposes Rab5, which promotes vesicle fusion affecting PCM recruitment" SIGNOR-266001 PRKACA protein P17612 UNIPROT KCNK3 protein O14649 UNIPROT "up-regulates activity" phosphorylation Ser393 GLMKRRSsV 9606 21357689 t lperfetto "Mutation of the ser393 to alanine, which can neither be phosphorylated nor mimic a phosphorylated residue, resulted in the channel failing to pass current all of our findings support the conclusion that camp-dependent protein kinase is responsible for the phosphorylation of the terminal serine in both k2p3.1 and k2p9.1." SIGNOR-172430 PPP2CA protein P67775 UNIPROT TNNI3 protein P19429 UNIPROT down-regulates dephosphorylation Ser24 APIRRRSsNYRAYAT 9606 BTO:0000887 15769444 t lperfetto "The major phosphatase thought to dephosphorylate ctni and phospholamban is type 2a protein phosphatase (pp2a) [61]. Activation of pp2a and ensuing dephosphorylation of regulatory proteins is involved in the anti-adrenergic effects of adenosine and muscarinic receptor activation see also fig2." SIGNOR-134601 HTR1D protein P28221 UNIPROT GNA14 protein O95837 UNIPROT "up-regulates activity" binding 9606 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257208 PP1 proteinfamily SIGNOR-PF54 SIGNOR AURKA protein O14965 UNIPROT down-regulates dephosphorylation 9606 11551964 t lperfetto "Pp1 is shown to dephosphorylate active stk15 and abolish its activity in vitro." SIGNOR-264651 TNF protein P01375 UNIPROT SCN4A protein P35499 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 BTO:0004102 26112872 f miannu "TNF-α increases Na(+) currents by accelerating the channel activation as well as increasing the expression of VGSCs in a mechanism dependent upon NF-κB and p38 MAPK signal pathways in CNS neurons. TNF-α increased Na(+) currents by accelerating the activation of VGSCs. VGSCs were up-regulated at both the mRNA and protein levels." SIGNOR-253481 "Ub:E1 (UBA6 substrate)" complex SIGNOR-C496 SIGNOR UBE2E1 protein P51965 UNIPROT "up-regulates activity" ubiquitination 9606 34199813 t miannu "The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t" SIGNOR-271359 PTPRR protein Q15256 UNIPROT MAPK1 protein P28482 UNIPROT "down-regulates activity" dephosphorylation Tyr187 HTGFLTEyVATRWYR 9534 BTO:0004055 11493009 t "Specifically, the complex formation between PTP-SL and ERK2 involves an unusual interaction leading to the phosphorylation of PTP-SL by ERK2 at Thr253 and the inactivating dephosphorylation of ERK2 by PTP-SL.|PTP-SL dephosphorylates the regulatory phosphotyrosine on the active loop of ERK1/2. Tyrosine dephosphorylation of ERK1/2 causes the inactivation of ERK1/2 and its retention in the cytoplasm" SIGNOR-248840 SESN1 protein Q9Y6P5 UNIPROT GATOR2 complex SIGNOR-C193 SIGNOR "down-regulates activity" binding 10090 BTO:0002572 25457612 t "We describe AMPK-independent mechanism of mTORC1 regulation by the Sestrins, in which the Sestrins inhibit mTORC1 localization to the lysosomes in a Rag-dependent manner through an interaction with GATOR2" SIGNOR-253559 MYF6 protein P23409 UNIPROT DES protein P17661 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 8382796 t lperfetto "Desmin, the muscle specific intermediate filament (IF) protein, is expressed at low levels in myoblasts and at the onset of differentiation its expression increases several fold. In an effort to explore the mechanism involved in the tissue-specific and developmentally regulated expression of desmin, we have isolated the mouse desmin gene.Co-transfection of myoD, myogenin, MRF4 and Myf5, with the desmin-CAT construct into 10T-1/2 cells demonstrated that all these factors could transactivate desmin gene expression" SIGNOR-241497 FOXO proteinfamily SIGNOR-PF27 SIGNOR G6PC1 protein P35575 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 18805788 f gcesareni "In the gk gene regulation, foxo1 represses hnf-4-potentiated transcription of the gene, whereas it synergizes with hnf-4 in activating the g6pase gene transcription." SIGNOR-252922 Jervine chemical CHEBI:6088 ChEBI SMO protein Q99835 UNIPROT down-regulates "chemical inhibition" 9606 BTO:0000150 BTO:0000149 16112412 t gcesareni "Here, we demonstrate that cyclopamine and jervine, two structurally related inhibitors of smo, force ciliary translocation of smo." SIGNOR-139865 CTSD protein P07339 UNIPROT APP protein P05067 UNIPROT "up-regulates activity" cleavage Phe709 ENPTYKFfEQMQN -1 10605825 t lperfetto "In this work, we used a sensitive in vitro method of detection to investigate the role of cathepasin D in the proteolytic processing of a 100-amino acid C-terminal fragment (C100) inclusive of βA4 and cytoplasmic domain of APP. Digestion of C100 with cathepsin D resulted in cleavage at the amyloidogenic γ-cleavage sites. This occurred preferentially at Thr43–Val44 and at Ala42–Thr43, generating full length βA4 43 and βA4 42 amyloid peptides, respectively. Cathepsin D was also found to cleave the substrate at the following nonamyloidogenic sites; Leu34–Met35, Thr48–Leu49 and Leu49–Val50. A high concentration of cathepsin D resulted in cleavage also occurring at Phe19–Phe20, Phe20–Ala21 and Phe93–Phe94 of the C100, suggesting that these sites are somewhat less sensitive to the action of cathepsin D." SIGNOR-261778 USP7 protein Q93009 UNIPROT CHFR protein Q96EP1 UNIPROT "up-regulates quantity by stabilization" deubiquitination 9606 BTO:0000007 17442268 t miannu "In this study, we identified USP7 (also known as HAUSP), which is a member of a family of proteins that cleave polyubiquitin chains and/or ubiquitin precursors, as an interacting protein with Chfr by immunoaffinity purification and mass spectrometry, and their interaction greatly increases the stability of Chfr. In fact, USP7 can remove ubiquitin moiety from the autoubiquitinated Chfr both in vivo and in vitro, which results in the accumulation of Chfr in the cell.  USP7 mediates deubiquitination of Chfr." SIGNOR-271462 NFYA protein P23511 UNIPROT OGG1 protein O15527 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 14688259 f miannu "these results demonstrate that MMS can up-regulate hOGG1 expression through the induction of the transcription factor, NF-YA, and increased transcription level of the hOGG1 gene correlates with an increase in enzyme activity providing functional protection from MMS." SIGNOR-254817 CDH16 protein O75309 UNIPROT CTNNB1 protein P35222 UNIPROT "up-regulates activity" binding 9606 21255999 t miannu "At its C-terminus, cadherin interacts with β-catenin, which dynamically associates with α-catenin, a direct binding partner of filamentous actin" SIGNOR-265855 MMP14 protein P50281 UNIPROT ECM_disassembly phenotype SIGNOR-PH80 SIGNOR up-regulates 17318226 f lperfetto "Historically, MMPs were thought to function mainly as enzymes that degrade structural components of the ECM." SIGNOR-272359 CBL protein P22681 UNIPROT LRIG1 protein Q96JA1 UNIPROT down-regulates ubiquitination 9606 BTO:0001253 15282549 t gcesareni "We report upregulation of lrig1 transcript and protein upon egf stimulation, and physical association of the encoded protein with the four egfr orthologs of mammals. Upregulation of lrig1 is followed by enhanced ubiquitylation and degradation of egfr. The underlying mechanism involves recruitment of c-cbl, an e3 ubiquitin ligase that simultaneously ubiquitylates egfr and lrig1 and sorts them for degradation." SIGNOR-127289 MAPK1 protein P28482 UNIPROT EIF2AK2 protein P19525 UNIPROT up-regulates phosphorylation Thr451 KRTRSKGtLRYMSPE 9606 9528799 t gcesareni "Our results provide strong evidence that dsrna binding is required for dimerization of full-length pkr molecules in vivo, leading to autophosphorylation in the activation loop and stimulation of the eif2alpha kinase function of pkr." SIGNOR-56337 CDK12 protein Q9NYV4 UNIPROT POLR2A protein P24928 UNIPROT up-regulates phosphorylation Ser1868 SPTSPKYsPTSPKYS 9606 22012619 t miannu "Cyck/cdk12 can activate transcription and phosphorylate ser2 in the ctd of rnapii / phosphorylation of serine at position 2 (ser2) is thought to be responsible for productive transcriptional elongation and synthesis of full-length mature mrna" SIGNOR-176797 EPGN protein Q6UW88 UNIPROT ERBB4 protein Q15303 UNIPROT up-regulates binding 9606 BTO:0001801 16469638 t gcesareni "They both bind to betacellulin and the heparin-binding ligand, hb-egf, as well as to two low-affinity ligands, epiregulin and epigen." SIGNOR-144399 CIT protein O14578 UNIPROT MYL9 protein P24844 UNIPROT "up-regulates activity" phosphorylation Thr19 KKRPQRAtSNVFAMF -1 21457715 t Giulio "Activation of the catalytic ATPase domain residing in the N‐terminus of the heavy chain relies on the reversible phosphorylation of the associated MLC on Ser19 (monophosphorylation), or in some cases on both Thr18 and Ser19 (diphosphorylation)|We detected Ser19 of MLC as the common phosphorylation site for the catalytic domains of MRCK_/_, ROK_, MLCK and PAK_, but only ROK_ and CRIK are able to phosphorylate both Thr18 and Ser19 residues causing diphosphorylation." SIGNOR-260306 ZAP70 protein P43403 UNIPROT ZAP70 protein P43403 UNIPROT "up-regulates activity" phosphorylation Tyr292 DTLNSDGyTPEPARI 9606 BTO:0000782;BTO:0000776 8756661 t lperfetto "The data further support a model in which ZAP-70 is first phosphorylated by Lck at Tyr-493 to upregulate the catalytic activity of ZAP-70. This in turn per- mits additional phosphorylation of ZAP-70 mediated, in part, by autophosphorylation at sites including Tyr-292 and -492" SIGNOR-43324 4-methyl-3-[[1-methyl-6-(3-pyridinyl)-4-pyrazolo[3,4-d]pyrimidinyl]amino]-N-[3-(trifluoromethyl)phenyl]benzamide chemical CHEBI:91447 ChEBI EPHB4 protein P54760 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-194916 ROCK1 protein Q13464 UNIPROT GFAP protein P14136 UNIPROT "down-regulates activity" phosphorylation Thr7 tSAARRSY -1 12686604 t lperfetto "We report here that aurora-b phosphorylates gfap and desmin in vitro, and this phosphorylation leads to a reduction in filament forming ability. The sites phosphorylated by aurora-b;thr-7/ser-13/ser-38 of gfap, and thr-16 of desmin are common with those related to rho-associated kinase (rho-kinase), which has been reported to phosphorylate gfap and desmin at cleavage furrow during cytokinesis. We identified ser-59 of desmin to be a specific site phosphorylated by aurora-b in vitro." SIGNOR-100192 MAS1 protein P04201 UNIPROT Inflammation phenotype SIGNOR-PH12 SIGNOR down-regulates 9606 23488800 f miannu "The discovery that Ang-(1-7) offsets the major biological effects of Ang II has contributed to the realization that the RAS is composed of two opposing axes. The first axis is constituted by the enzyme ACE, with Ang II as the end product, and the AT1 receptor as the main effector mediating the biological actions of Ang II. The second axis results from ACE2-mediated hydrolysis of Ang II, leading to production of Ang-(1-7), with Mas receptor as the main effector conveying the vasodilator, antiproliferative, anti-inflammatory and anti-fibrotic effects of Ang-(1-7). Activation of the ACE2/Ang-(1-7)/Mas axis decreases inflammatory cell function and fibrogenesis in diverse models of human diseases." SIGNOR-260228 RIMS2 protein Q9UQ26 UNIPROT CACNA1D protein Q01668 UNIPROT "up-regulates activity" binding 9606 BTO:0005822 28642685 t miannu "Here, we report an interaction of the C2B domain of RIM2α and RIM3γ with the C-terminus of the pore-forming α-subunit of CaV1.3 channels (CaV1.3α1), which mediate stimulus-secretion coupling at the ribbon synapses of cochlear inner hair cells (IHCs). In conclusion, we propose that RIM2α and RIM3γ directly interact with the C-terminus of the pore-forming subunit of CaV1.3 Ca2+ channels and positively regulate their plasma membrane expression in HEK293 cells." SIGNOR-264356 MAPK3 protein P27361 UNIPROT SMAD2 protein Q15796 UNIPROT up-regulates phosphorylation Ser245 NQSMDTGsPAELSPT 9606 19115199 t gcesareni "These results suggest that oncogenic ras, acting through mek1 and erk kinases, induces the phosphorylation of smad2 and smad3 .we show that phosphorylation of smad2, a mediator of the activin/transforming growth factor-beta signal, by activated extracellular signal-regulated kinase 1 (erk1) increases the amount of smad2 protein and leads to enhanced transcriptional activity" SIGNOR-182988 PRKD1 protein Q15139 UNIPROT HDAC7 protein Q8WUI4 UNIPROT unknown phosphorylation Ser486 RPLSRAQsSPAAPAS -1 15738054 t lperfetto "We demonstrate that protein kinase D (PKD; also known as PKCmi), which is activated upon engagement of the TCR, stimulates HDAC7 nuclear export by direct phosphorylation on four serine residues. Conversely, selective PKD inhibition blocks TCR-induced HDAC7 nuclear export and Nur77 expression. In addition, an HDAC7 mutant specifically deficient in phosphorylation by PKD blocks TCR-mediated apoptosis. | PKD1 phosphorylates S155, S181, S321, and S449 of HDAC7 in vitro." SIGNOR-249276 TACR1 protein P25103 UNIPROT GNAL protein P38405 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-256919 KIF11 protein P52732 UNIPROT "Plus-end directed sliding movement" phenotype SIGNOR-PH216 SIGNOR up-regulates 9606 19773780 f "In general, N-kinesins and C-kinesins drive microtubule plus end- and minus end-directed motilities, respectively, and M-kinesins depolymerize microtubules1,9 (Box 1).|Forty-five genes that encode kinesin superfamily proteins (also known as KIFs) have been discovered in the mouse and human genomes.|KIFs are molecular motors that directionally transport various cargos, including membranous organelles, protein complexes and mRNAs, along the microtubule system." SIGNOR-272521 KIF1A protein Q12756 UNIPROT "Plus-end directed sliding movement" phenotype SIGNOR-PH216 SIGNOR up-regulates 9606 19773780 f "In general, N-kinesins and C-kinesins drive microtubule plus end- and minus end-directed motilities, respectively, and M-kinesins depolymerize microtubules1,9 (Box 1).|Forty-five genes that encode kinesin superfamily proteins (also known as KIFs) have been discovered in the mouse and human genomes.|KIFs are molecular motors that directionally transport various cargos, including membranous organelles, protein complexes and mRNAs, along the microtubule system." SIGNOR-272522 NR3C1 protein P04150 UNIPROT PPARG protein P37231 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 BTO:0000011 11279134 f lperfetto "The differentiation of 3T3-L1 preadipocytes is regulated in part by a cascade of transcriptional events involving activation of the CCAAT/enhancer-binding proteins (C/EBPs) and peroxisome proliferator-activated receptor gamma (PPARgamma) by dexamethasone (DEX), 3-isobutyl-1-methylxanthine (MIX), and insulin" SIGNOR-250561 MAPK1 protein P28482 UNIPROT RPS6KB1 protein P23443 UNIPROT up-regulates phosphorylation Ser447 GSPRTPVsPVKFSPG 9606 7545671 t gcesareni "Erk phosphorylates multiple cytoplasmatic and cytoskeletal proteins, including mapk-activated protein kinases and the ribosomal p70-s6 kinase" SIGNOR-28800 STAT5A protein P42229 UNIPROT CDKN1A protein P38936 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 15003515 f "Flt3 Mutation Activates p21WAF1/CIP1 Gene Expression Through the Action of STAT5. Co-transfection of p21 promoter-luciferase constructs with Flt3-ITD plasmid into K562 and BaF3 cells results in the induction of p21 promoter activity and a -692/-684 STAT site is important for the induction. STAT5a binds specifically to this element and Flt3-ITD enhances the protein binding to this site." SIGNOR-261518 KIF21B protein O75037 UNIPROT "Plus-end directed sliding movement" phenotype SIGNOR-PH216 SIGNOR up-regulates 9606 28290984 f "In this study, we showed that KIF21B is a highly processive MT plus-end directed motor, which can potently induce pausing of MT plus ends. This activity depends on several regions of this large motor protein." SIGNOR-272515 SP1 protein P08047 UNIPROT FMR1 protein Q06787 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 15479157 f miannu "we show that Sp1 (specificity protein 1) and Sp3 are also strong positive regulators of FMR1 promoter activity." SIGNOR-255204 MAPK1 protein P28482 UNIPROT ELK1 protein P19419 UNIPROT "up-regulates activity" phosphorylation Ser324 RDLELPLsPSLLGGP 10090 BTO:0000944 7889942 t lperfetto "We demonstrate that elk-1, a protein closely related to p62tcf in function, is a nuclear target of two members of the map kinase family, erk1 and erk2, erk1 phosphorylates five c-terminal sites in elk-1 (s324,t336, s383, s389 and s422) with varying degrees of efficiency." SIGNOR-235459 PRKACA protein P17612 UNIPROT ADD1 protein P35611 UNIPROT "down-regulates activity" phosphorylation Ser408 REKSKKYsDVEVPAS -1 8810272 t miannu "Protein kinase A phosphorylates -adducin at three sites in the neck domain (Ser-408, ’436, and ’481) in addition to the MARCKS-related domain of both subunits. Phosphorylation by PKA, in contrast to PKC, reduced affinity of erythrocyte adducin for spectrin-F-actin complexes as well as activity of adducin in promoting binding of spectrin to F-actin." SIGNOR-250329 PP1 proteinfamily SIGNOR-PF54 SIGNOR AKT1 protein P31749 UNIPROT "down-regulates activity" dephosphorylation Ser473 RPHFPQFsYSASGTA 9606 BTO:0002419 14633703 t lperfetto "Here, we identify PP1 as a serine/threonine phosphatase that associates with and dephosphorylates AKT in breast cancer cells|The heat shock protein 90 inhibitor geldanamycin and the ErbB inhibitor ZD1839 promote rapid PP1 phosphatase-dependent inactivation of AKT in ErbB2 overexpressing breast cancer cells" SIGNOR-264658 AVPR1B protein P47901 UNIPROT GNAQ protein P50148 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257264 PIAS1 protein O75925 UNIPROT SMAD4 protein Q13485 UNIPROT up-regulates sumoylation 9606 15028714 t lperfetto "These data demonstrate that pias1 protein positively modulates tgf-beta responses as a sumo e3 ligase for smad4" SIGNOR-123462 CDK1 protein P06493 UNIPROT NEDD1 protein Q8NHV4 UNIPROT "up-regulates activity" phosphorylation Thr550 PPINGSStPNPKIAS 9606 BTO:0000567 19509060 t lperfetto "Here we report that the function of Nedd1 is regulated by Cdk1 and Plk1. During mitosis, Nedd1 is firstly phosphorylated at T550 by Cdk1, which creates a binding site for the polo-box domain of Plk1. Then, Nedd1 is further phosphorylated by Plk1 at four sites: T382, S397, S637 and S426. The sequential phosphorylation of Nedd1 by Cdk1 and Plk1 promotes its interaction with gamma-tubulin for targeting the gammaTuRC to the centrosome and is important for spindle formation." SIGNOR-272973 EPHB2 protein P29323 UNIPROT NRCAM protein Q92823 UNIPROT "up-regulates activity" phosphorylation Tyr1276 DGSFIGQySGKKEKE 9606 BTO:0000007 24023801 t miannu "EphB receptors were found to induce phosphorylation of NrCAM on the tyrosine residue within the FIGQY ankyrin binding motif, inhibiting ankyrin recruitment. Furthermore, NrCAM phospho-FIGQY levels in the SC were decreased in EphB1/3 and EphB1/2/3 null mice and increased in mutant mice overexpressing constitutively active EphB2 kinase. " SIGNOR-262863 dexmedetomidine chemical CHEBI:4466 ChEBI ADRA2A protein P08913 UNIPROT "up-regulates activity" "chemical activation" 9606 BTO:0000007 9605427 t miannu "AR agonists stimulated binding of [35S]GTPgS to HEK 293 cell membranes containing the human a2a, a2b, or a2c ARs (Fig. 6). EPI and NE were full agonists; clonidine and oxymetazoline were partial agonists, while antagonists (e.g. rauwolscine, 5 mM) did not stimulate [35S]GTPgS incorporation (Table 3). Although a few agonists showed a great deal of selectivity for a single receptor subtype, the rank order of agonist potency for selected compounds at the human receptors (Table 3) was: a2a: Dexmedetomidine . guanabenz . UK-14304 .clonidine . ST-91 . NE a2b: Dexmedetomidine . clonidine . guanabenz . NE .ST-91 . UK-14304 a2c: Dexmedetomidine . NE . UK-14304 . ST-91 $ clonidine .. guanabenz" SIGNOR-258906 AKT proteinfamily SIGNOR-PF24 SIGNOR FOXO3 protein O43524 UNIPROT "down-regulates activity" phosphorylation 10090 14981546 t miannu "Phosphorylation of Foxo proteins through FLT3-ITD signaling promotes their translocation from the nucleus into the cytoplasm, which requires the presence of conserved Akt phosphorylation sites in Forkhead transcription factors and PI3K activity." SIGNOR-261526 SELE protein P16581 UNIPROT ITGAL protein P20701 UNIPROT up-regulates 9606 BTO:0000130 23994464 f apalma "This deceleration is due to the expression of E-selectins on the inflamed endothelium which provides increased number of binding sites for PSGL-1 and also triggers an intermediate-affinity conformational state of the beta2-integrin LFA-1 on neutrophils." SIGNOR-255968 GOT2 protein P00505 UNIPROT 2-oxoglutarate(2-) smallmolecule CHEBI:16810 ChEBI "up-regulates quantity" "chemical modification" 9606 31422819 t miannu "This is a pyridoxal 5‚Ä≤-phosphate (PLP)-dependent enzyme that exists as cytosolic (GOT1) and intramitochondrial (GOT2) isoforms. Both isoforms catalyze the reversible interconversion of oxaloacetate and glutamate into aspartate and Œ±-ketoglutarate. These enzymes are part of the malate-aspartate shuttle (MAS), a key player in intracellular NAD(H) redox homeostasis (Figure 1)." SIGNOR-267513 WNT1 protein P04628 UNIPROT FZD3 protein Q9NPG1 UNIPROT "up-regulates activity" binding 9606 15578921 t gcesareni "Wnt proteins bind to the frizzled receptors and lrp5/6 co-receptors, and through stabilizing the critical mediator betBeta-catenin, initiate a complex signaling cascade that plays an important role in regulating cell proliferation and differentiation." SIGNOR-131571 TNF protein P01375 UNIPROT Adipogenesis phenotype SIGNOR-PH26 SIGNOR down-regulates 9606 21514273 f "via a ?-catenin-dependent pathway" fspada "Tumor necrosis factor-? (TNF-alpha) Is known to suppress adipocyte differentiation via a Beta-catenin-dependent pathway." SIGNOR-173421 MRPL27 protein Q9P0M9 UNIPROT "39S mitochondrial large ribosomal subunit" complex SIGNOR-C285 SIGNOR "form complex" binding -1 25838379 t lperfetto "We have determined the structure of the intact mitoribosome to 3.5 angstrom resolution by single-particle electron cryo-microscopy. It reveals 80 extensively interconnected proteins, 36 of which are specific to mitochondria, and three rRNA molecules" SIGNOR-262368 FIG4 protein Q92562 UNIPROT 1,2-dioctanoyl-sn-glycero-3-phospho-(1D-myo-inositol-3,5-bisphosphate)(5-) smallmolecule CHEBI:85342 ChEBI "down-regulates quantity" "chemical modification" -1 23165282 t miannu "Fig4/Sac3 can decrease PI(3,5)P2 levels via its phosphatase function and also promote PI3,5P2 synthesis by acting as a secondary scaffold for the Fab1/Vac14 interaction. However, the later function appears dominant." SIGNOR-253535 MST1 protein P26927 UNIPROT H2BC3 protein P33778 UNIPROT unknown phosphorylation Ser15 APAPKKGsKKAITKA 9606 21212262 t lperfetto "The mst1 is a serine/threonine kinase that is activated upon apoptotic stimulation, which in turn activates its downstream targets, jnk/p38, histone h2b and foxo. Mst1 induces apoptosis by phosphorylating histone h2b on a relatively conserved site, ser-14 in mammalian cells" SIGNOR-171005 GART protein P22102 UNIPROT (6S)-5,6,7,8-tetrahydrofolate(2-) smallmolecule CHEBI:57453 ChEBI "up-regulates quantity" "chemical modification" 9606 11381136 t miannu "The third step is catalyzed by the enzyme glycinamide ribonucleotide transformylase (GAR Tfase). The two folate-requiring reactions, glycinamide ribonucleotide transformylase (GAR Tfase) and aminoimidazole ribonucleotide transformylase (AICAR Tfase), have attracted particular attention because some of the most successful anticancer drugs to date have been folate antimetabolites such as methotrexate (3). These two enzymes carry out similar chemistry in catalyzing the transfer of a formyl group from 10-formyltetrahydrofolate to the amino group of the substrates GAR and AICAR to form fGAR and fAICAR." SIGNOR-267304 SMARCE1 protein Q969G3 UNIPROT "SWI/SNF ACTL6B varian" complex SIGNOR-C476 SIGNOR "form complex" binding 9606 30397315 t miannu "Mammalian SWI/SNF (mSWI/SNF) complexes are ATP-dependent chromatin remodelers that modulate genomic architecture and DNA accessibility, enabling timely and appropriate control of gene expression. They are combinatorially assembled from the products of 29 total genes into three final-form complexes: canonical BAF, PBAF (polybromo-associated BAF complexes), and a newly-defined non-canonical BAF (ncBAF), with specific subunits specifying distinct complexes, such as PBRM1, ARID2, and BRD7 in PBAF complexes, ARID1A/ARID1B and DPF2 in canonical BAF (cBAF) complexes, and GLTSCR1/GLTSCR1L and BRD9 in ncBAF complexes" SIGNOR-270602 GAS2L3 protein Q86XJ1 UNIPROT F-actin_assembly phenotype SIGNOR-PH18 SIGNOR up-regulates 9606 24706950 f miannu "Previous work has shown that members of the growth-arrest-specific 2 (GAS2) family mediate the crosstalk between filamentous actin (F-actin) and MTs, but the molecular basis of this process remained unclear. By using fluorescence microscopy, we demonstrate that three members of this family, GAS2-like 1, GAS2-like 2 and GAS2-like 3 (G2L1, G2L2 and G2L3, also known as GAS2L1, GAS2L2 and GAS2L3, respectively) are differentially involved in mediating the crosstalk between F-actin and MTs. " SIGNOR-273702 CSNK1D protein P48730 UNIPROT CDH1 protein P12830 UNIPROT "down-regulates activity" phosphorylation Ser844 GSGSEAAsLSSLNSS 17353278 t lperfetto "Casein kinase 1 is a novel negative regulator of E-cadherin-based cell-cell contacts|CK1 colocalizes with E-cadherin and phosphorylates the cytoplasmic domain of E-cadherin in vitro and in a cell culture system. We show that the major CK1 phosphorylation site of E-cadherin is serine 846" SIGNOR-274046 PAK2 protein Q13177 UNIPROT SORT1 protein Q99523 UNIPROT "down-regulates activity" phosphorylation Ser793 RFLVHRYsVLQQHAE 9606 BTO:0000007 31767632 t miannu "PAKs specifically phosphorylate Ser15 of the sortilin-cd and alter its trafficking. It can be concluded that PAK1-3 may indeed instigate the phosphorylation of sortilin and that they target a single serine residue (Ser15) located in the kinase domain-binding site of the sortilin-cd. Full-length sortilins with the serine at position 793 (residue 15 in the cytoplasmic domain) (for the sequence, see Fig. 2). Phosphorylation (Ser15) downregulates the sortilin–AP-1 interaction." SIGNOR-273717 VAMP8 protein Q9BV40 UNIPROT "STX17-VAMP8 SNARE complex" complex SIGNOR-C551 SIGNOR "form complex" binding 9606 BTO:0000007 23217709 t miannu "Here, we identify syntaxin 17 (Stx17) as the autophagosomal SNARE required for fusion with the endosome/lysosome. Stx17 localizes to the outer membrane of completed autophagosomes but not to the isolation membrane (unclosed intermediate structures); for this reason, the lysosome does not fuse with the isolation membrane. Stx17 interacts with SNAP-29 and the endosomal/lysosomal SNARE VAMP8." SIGNOR-273711 "STX17-VAMP8 SNARE complex" complex SIGNOR-C551 SIGNOR Membrane_fusion phenotype SIGNOR-PH122 SIGNOR "up-regulates activity" 9606 BTO:0000007 23217709 f miannu "Here, we identify syntaxin 17 (Stx17) as the autophagosomal SNARE required for fusion with the endosome/lysosome. Stx17 localizes to the outer membrane of completed autophagosomes but not to the isolation membrane (unclosed intermediate structures); for this reason, the lysosome does not fuse with the isolation membrane. Stx17 interacts with SNAP-29 and the endosomal/lysosomal SNARE VAMP8." SIGNOR-273712 PINK1 protein Q9BXM7 UNIPROT ZNF746 protein Q6NUN9 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser613 APPDPFKsPASKGPL 9606 BTO:0000793 28122242 t miannu "PINK1 is required for Parkin ubiquitination and degradation of PARIS. PINK1 interacts with and phosphorylates serines 322 and 613 of PARIS to control its ubiquitination and clearance by parkin." SIGNOR-273725 PLK1 protein P53350 UNIPROT PARP10 protein Q53GL7 UNIPROT "up-regulates activity" phosphorylation Thr601 EVRELLAtLEGLDLD 10090 BTO:0000578 32060423 t miannu "PLK1, an important regulator for cell mitosis, directly interacts with and phosphorylates PARP10 at T601. PARP10 phosphorylation at T601 significantly decreases its binding to NEMO and disrupts its inhibition to NEMO ubiquitination, thereby enhancing the transcription activity of NF-κB toward multiple target genes and promoting HCC development. " SIGNOR-273728 SCF-betaTRCP complex SIGNOR-C5 SIGNOR CDH1 protein P12830 UNIPROT "down-regulates quantity by destabilization" ubiquitination phosphorylation:Ser146 LLTFPNSsPGLRRQK 23972993 t "For phosphorylated residues see Figure 7" lperfetto "Priming phosphorylation of Cdh1 by the Cdk2/cyclin A kinase complex allows Plk1 to bind to Cdh1 and phosphorylate Cdh1 at Ser138 and Ser146. Phosphorylation of Cdh1 at Ser138 and Ser146 then triggers its interaction with, and subsequent ubiquitination by, SCFbeta-TRCP" SIGNOR-274055 NAT10 protein Q9H0A0 UNIPROT PARP1 protein P09874 UNIPROT "up-regulates quantity by stabilization" acetylation Lys949 PKGKHSVkGLGKTTP 9606 BTO:0000007 31616951 t done miannu "MORC2 directly interacts with PARP1. MORC2 mediates the interaction between PARP1 and NAT10 and thereby promotes NAT10-mediated PARP1 acetylation at K949, which blocks CHFR-mediated ubiquitination and degradation of PARP1." SIGNOR-273715 KMT2A protein Q03164 UNIPROT SPI1 protein P17947 UNIPROT "up-regulates quantity by expression" methylation 10090 BTO:0002884 22012064 t irozzo "Furthermore, we show that both MLL and AML1/CBFβ are required for maintaining the H3K4-me3 mark at the PU.1 upstream regulatory element (URE) and promoter region, and for full PU.1 gene expression." SIGNOR-255874 BTC protein P35070 UNIPROT ERBB4 protein Q15303 UNIPROT up-regulates binding 9606 BTO:0000142 22232668 t gcesareni "For example, betacellulin binds to and activates both erbb1 and erbb4, whereas epiregulin binds to erbb1, erbb3 and erbb4" SIGNOR-195347 FAM83G protein A6ND36 UNIPROT CSNK1A1L protein Q8N752 UNIPROT "up-regulates quantity" binding 9606 BTO:0000007 29789297 t miannu "We identified members of the FAM83 family of proteins as partners of CK1 in cells. All eight members of the FAM83 family (FAM83A–H) interacted with the α and α-like isoforms of CK1; FAM83A, -B, -E, and -H also interacted with the δ and ε isoforms of CK1. The intrinsic catalytic activity of CK1 is not affected by or required for the association of CK1 with FAM83 proteins. Our findings imply that the DUF1669 domains of FAM83 proteins anchor CK1 α, α-like, δ, and ε isoforms in specific subcellular compartments and potentially mediate their association with substrates." SIGNOR-273753 FAM83B protein Q5T0W9 UNIPROT CSNK1D protein P48730 UNIPROT "up-regulates quantity" binding 9606 BTO:0000007 29789297 t miannu "We identified members of the FAM83 family of proteins as partners of CK1 in cells. All eight members of the FAM83 family (FAM83A–H) interacted with the α and α-like isoforms of CK1; FAM83A, -B, -E, and -H also interacted with the δ and ε isoforms of CK1. The intrinsic catalytic activity of CK1 is not affected by or required for the association of CK1 with FAM83 proteins. Our findings imply that the DUF1669 domains of FAM83 proteins anchor CK1 α, α-like, δ, and ε isoforms in specific subcellular compartments and potentially mediate their association with substrates." SIGNOR-273766 MAPK12 protein P53778 UNIPROT MAPK12/CARM1 complex SIGNOR-C218 SIGNOR "form complex" binding 29681515 t apalma "Basal localization of the p38γ/p-Carm1 complex in muscle stem cells occurs via binding to the dystrophin-glycoprotein complex (DGC) through β1-syntrophin. In dystrophin-deficient muscle stem cells undergoing asymmetric division, p38γ/β1-syntrophin interactions are abrogated" SIGNOR-255981 CTNNB1 protein P35222 UNIPROT LEF1 protein Q9UJU2 UNIPROT "up-regulates activity" binding 9606 23151663 t gcesareni "Upon wnt activation, cytoplasmic beta-catenin is stabilized and enters the nucleus, where it associates with transcription factors, notably tcf (t cell factor) and lef (lymphoid enhancer-binding factor), to regulate the transcription of target genes. Thus beta-catenin regulates gene expression by direct interaction with transcription factors such as lef-1, providing a molecular mechanism for the transmission of signals, from cell-adhesion components or wnt protein to the nucleus." SIGNOR-199378 CSRP3 protein P50461 UNIPROT MYF6 protein P23409 UNIPROT "up-regulates activity" binding 10090 BTO:0004058 9234731 t 2 miannu "we found that nuclear MLP functions through a physical interaction with the muscle basic helix-loop-helix (bHLH) transcription factors MyoD, MRF4, and myogenin. we propose that it serves as a cofactor for the myogenic bHLH proteins by increasing their interaction with specific DNA regulatory elements." SIGNOR-241096 TGFBR1 protein P36897 UNIPROT SMAD2 protein Q15796 UNIPROT "up-regulates activity" phosphorylation 9606 BTO:0000801 10973958 t lperfetto "The pathway restricted (r)Smads (e.g. Smad1, 2, 3, and 5) are serine/threonine kinase activated proteins that interact in an unphosphorylated state with a TGF-b superfamily receptor. Upon ligand binding they are phosphorylated by the receptor and released." SIGNOR-249549 SRC protein P12931 UNIPROT AFAP1 protein Q8N556 UNIPROT unknown phosphorylation Tyr94 SSLPEGYyEEAVPLS 9534 9655255 t lperfetto "In this report, site-directed mutagenesis and a transient expression system that permits co-expression of activated pp60c-src (Src527F) and AFAP-110 in Cos-1 cells were used to identify the SH2-binding motif in AFAP-110. Four tyrosine residues, two in the amino terminus (Y93 and Y94) and two in the carboxy terminus (Y451 and Y453), were mutated to phenylalanine, significantly reducing overall steady-state levels of tyrosine phosphorylation and preventing Src527F from forming a stable complex with AFAP-110." SIGNOR-246363 PRKG1 protein Q13976 UNIPROT RGS18 protein Q9NS28 UNIPROT "up-regulates activity" phosphorylation Ser216 PTNLRRRsRSFTCNE 9606 BTO:0000132 24244663 t done miannu "Cyclic AMP- and cyclic GMP-dependent kinases (PKA, PKG) inhibit the interaction of RGS18 and 14-3-3 by phosphorylating S216. S216 phosphorylation might activate PP1 leading to dephosphorylation of both 14-3-3 binding sites, S49 and S218, and detachment of 14-3-3. Removal of 14-3-3 activates RGS18 to turn off Gq signaling thus contributing to platelet inhibition." SIGNOR-273785 PTPN1 protein P18031 UNIPROT MET protein P08581 UNIPROT down-regulates dephosphorylation Tyr1234 RDMYDKEyYSVHNKT 9606 16537444 t gcesareni "Using substrate trapping mutants of ptp1b or tcptp, we have demonstrated that both phosphatases interact with met and that these interactions require phosphorylation of twin tyrosines (tyr-1234/1235) in the activation loop of the met kinase domain. We demonstrate that phosphorylation of tyr-1234/1235 in the activation loop of the met receptor is elevated in the absence of either ptp1b or tcptp and further elevated upon loss of both phosphatases. This enhanced phosphorylation of met corresponds to enhanced biological activity and cellular invasion." SIGNOR-145141 STARD8 protein Q92502 UNIPROT CDC42 protein P60953 UNIPROT "down-regulates activity" "gtpase-activating protein" 9606 BTO:0000007 32203420 t Luana "We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2)." SIGNOR-260520 FES protein P07332 UNIPROT BCR protein P11274 UNIPROT down-regulates phosphorylation Tyr283 YQPYQSIyVGGMMEG 9606 BTO:0000007 8955135 t lperfetto "In the present study, we demonstrate that bcr tyr-246 and at least one of the closely spaced tyrosine residues, tyr-279, tyr-283, and tyr- 289 (3y cluster), are phosphorylated by fes both in vitro and in 32p(i)- labeled cells. tyrosine phosphorylation of bcr by fes suppressed bcr serine/threonine kinase activity toward the 14-3-3 protein and bcr substrate, bap-1." SIGNOR-45343 CSNK1D protein P48730 UNIPROT MAPT protein P10636 UNIPROT down-regulates phosphorylation Ser519 SGYSSPGsPGTPGSR 9606 BTO:0000007 14761950 t "The effect has been demonstrated using P10636-8" lperfetto "Casein kinase 1 delta phosphorylates tau and disrupts its binding to microtubules.Here we characterized the contribution of one ck1 isoform, ckidelta, to the phosphorylation of tau at residues ser202/thr205 and ser396/ser404 in human embryonic kidney 293 cells." SIGNOR-121705 IFNLR1 protein Q8IU57 UNIPROT TYK2 protein P29597 UNIPROT up-regulates binding 9606 15120645 t gcesareni "Despite signaling through distinct receptor complexes, type i ifns and ifn-_s activate similar signaling events and biological activities, consistent with their common ability to mediate an antiviral state in cells (fig. 6). In both cases, receptor engagement leads via the activation of the jak kinases jak1 and tyk2" SIGNOR-124483 AKT proteinfamily SIGNOR-PF24 SIGNOR KLHL3 protein Q9UH77 UNIPROT "up-regulates activity" phosphorylation Ser433 PMNTRRSsVGVGVVE -1 26435498 t done miannu "Consistent with the fact that S433 is a component of Akt and PKA phosphorylation motifs, in vitro kinase assay demonstrated that Akt and PKA can phosphorylate KLHL3 at S433, that was previously reported to be phosphorylated by PKC. " SIGNOR-273825 APH1A protein Q96BI3 UNIPROT PSEN2 protein P49810 UNIPROT up-regulates binding 9606 BTO:0000142 12297508 t gcesareni "Gamma secretase subunit. Leads to ps1/ps2 eterodimer complex stabilisation. By using co-immunoprecipitation and nickel affinity pull-down approaches, we now show that mammalian aph-1 (maph-1), a conserved multipass membrane protein, physically associates with nicastrin and the heterodimers of the presenilin amino- and carboxyl-terminal fragments in human cell lines and in rat brain." SIGNOR-93265 C5AR1 protein P21730 UNIPROT SELL protein P14151 UNIPROT "down-regulates quantity by repression" 1847994 f lperfetto "The C5a receptor mediates the pro-inflammatory and chemotactic actions of the complement anaphylatoxin C5a. In addition to stimulating chemotaxis, granule enzyme release and superoxide anion production, this receptor stimulates upregulation of expression and activity of the adhesion molecule MAC-1, and of CR1, and a decrease in cell-surface glycoprotein 100MEL-14 on neutrophils." SIGNOR-263468 CDKL1 protein Q00532 UNIPROT CDKN2B protein P42772 UNIPROT "up-regulates activity" phosphorylation 9606 BTO:0001616 28352193 t miannu "We demonstrated that depletion of CDKL1 notably upregulated the protein expression of P15. P15 is shown to be a target of CDKL1 in CRC, either direct or indirect." SIGNOR-273862 SMAD5 protein Q99717 UNIPROT GATA3 protein P23771 UNIPROT "up-regulates quantity" "transcriptional regulation" 10090 22219353 t Gianni "Chromatin immunoprecipitation (ChIP) revealed a subset of the BIG (BMP4 induced genes) signature, including Satb2, Smad6, Hand1, Gadd45γ and Gata3, that was bound by Smad1/5 in the developing mandible, revealing direct Smad-mediated regulation" SIGNOR-268943 "PAN2-PAN3 deadenylation complex" complex SIGNOR-C553 SIGNOR "messenger RNA" smallmolecule CHEBI:33699 ChEBI "down-regulates quantity by destabilization" "chemical modification" 9606 34280615 t miannu "There are two major deadenylase complexes, Ccr4-Not and Pan2-Pan3, which shorten the 3′ poly(A) tail of mRNA and are conserved from yeast to human.The Ccr4-Not complex has two catalytic subunits including the Ccr4 (Carbon catabolite repressor 4) and Pop2 (PGK promoter directed overproduction). The Pan2-Pan3 complex comprises the catalytic subunit Pan2, a member of the RNase D family, and the regulatory subunit Pan3. Degradation of mRNA begins with either shortening of the poly(A) tail by deadenylases or removal of 5′ cap structure by the decapping enzyme Dcp1-Dcp2." SIGNOR-273872 DOK7 protein Q18PE1 UNIPROT CRK protein P46108 UNIPROT "up-regulates activity" binding 10090 BTO:0000165 20603078 t miannu "Here, we identify two tyrosine residues in Dok-7 that are phosphorylated by Agrin stimulation, and show that two proteins, Crk and Crk-L, are recruited to these phosphorylation sites in Dok-7." SIGNOR-273847 MUSK protein O15146 UNIPROT DOK7 protein Q18PE1 UNIPROT "up-regulates activity" phosphorylation Tyr395 CLPGTVEyQVPTSLR 10090 BTO:0000165 20603078 t miannu "Here, we demonstrate that Dok-7 also functions downstream from MuSK, and we identify the proteins that are recruited to the C-terminal domain of Dok-7. We show that Agrin stimulates phosphorylation of two tyrosine residues in the C-terminal domain of Dok-7, which leads to recruitment of two adapter proteins: Crk and Crk-L. Y396 and Y406 are the major tyrosine phosphorylation sites in Dok-7 expressed in C2 myotubes." SIGNOR-273845  EPHB6 protein O15197 UNIPROT CBLC protein Q9ULV8 UNIPROT "up-regulates activity" binding 9606 34360976 t miannu "We suggest that although mammalian EphB6 is kinase-negative, it has retained the allosteric regulatory mechanisms involving the juxtamembrane and the SAM domain linker that are used to regulate the kinase activity of kinase-active Eph receptors. he inability to recruit c-Cbl by EphB6 meant that heightened levels of EphA2 remained active in the cell because they had evaded c-Cbl-mediated degradation. The authors suggest that mutation of residues 901–926 within EphB6 reduces the flexibility of the SAM domain such that c-Cbl cannot be recruited." SIGNOR-273852 LRRK2 protein Q5S007 UNIPROT SH3GL2 protein Q99962 UNIPROT down-regulates phosphorylation 9606 22998870 t miannu "We show that lrrk2 affects synaptic endocytosis by phosphorylating endoa at s75, a residue in the bar domain / our work uncovers a regulatory mechanism that indicates that reduced lrrk2 kinase activity facilitates endoa membrane association, while increased kinase activity inhibits membrane association." SIGNOR-192075 GRK2 protein P25098 UNIPROT BDKRB2 protein P30411 UNIPROT "down-regulates activity" phosphorylation Ser366 EPIQMENsMGTLRTS 9606 BTO:0000007 11517230 t "Ligand-induced phosphorylation is found at Ser339 and Ser346/Ser348 that could be executed by several G protein-coupled receptor kinases. 32P labeling of peptide 3 containing pS346/pS348 was enhanced 1.5–3-fold as compared with mock-transfected cells in the order GRK6 < GRK5 < GRK2 < GRK4α < GRK3. several endogenous GRKs may phosphorylate the B2R and that the various GRKs, even without apparent effect on total GPCR phosphorylation levels, may induce distinct phosphorylation patterns with possible functional consequences for receptor desensitization and sequestration." SIGNOR-251444 CEP135 protein Q66GS9 UNIPROT SASS6 protein Q6UVJ0 UNIPROT "up-regulates activity" binding 9606 23511974 t miannu "In this study, we demonstrate that the human microcephaly protein, CEP135, directly interacts with hSAS-6 via its carboxyl-terminus and with MTs via its amino-terminus. Unexpectedly, CEP135 also interacts with another microcephaly protein CPAP via its amino terminal domain. Depletion of CEP135 not only perturbed the centriolar localization of CPAP, but also blocked CPAP-induced centriole elongation. We propose that CEP135 may serve as a linker protein that directly connects the central hub protein, hSAS-6, to the outer MTs, and suggest that this interaction stabilizes the proper cartwheel structure for further CPAP-mediated centriole elongation." SIGNOR-269676 AMPK complex SIGNOR-C15 SIGNOR MAPT protein P10636 UNIPROT "down-regulates activity" phosphorylation Ser420 KHPTPGSsDPLIQPS -1 21204788 t miannu "AMPK phosphorylation inhibits tau binding of microtubules. In order to study further the phosphorylation of tau by AMPK, we compared phosphorylation of tau by MARK4 or AMPK using a panel of phospho-tau antibodies (Figure 2A). Five phosphorylation sites common to both kinases were identified (Thr231, Ser262, Ser356, Ser396 and Ser422). In addition, AMPK, but not MARK4, was capable of phosphorylating Ser214 (Figure 2A)." SIGNOR-273931 SRC protein P12931 UNIPROT EZR protein P15311 UNIPROT up-regulates phosphorylation Tyr478 PPPPPPVyEPVSYHV 9606 15623525 t lperfetto "Src phosphorylates ezrin at tyrosine 477 and induces a phosphospecific association between ezrin and a kelch-repeat protein family member" SIGNOR-132907 MAPK1 protein P28482 UNIPROT NDE1 protein Q9NXR1 UNIPROT "up-regulates activity" phosphorylation -1 12556484 t done miannu "We found that Nudel and NudE were also phosphorylated in M phase (Fig. ​(Fig.22 and ​and3).3). First, Nudel and NudE were specifically phosphorylated in M phase. Moreover, both proteins were phosphorylated by Cdc2 and Erk2 in vitro.Due to conservation of the S/TP motifs, NudE may also be phosphorylated at similar sites by these kinases, though it contains an additional potential Cdk site at S282 (SPNR)." SIGNOR-274078 MAP2K7 protein O14733 UNIPROT MAPK13 protein O15264 UNIPROT "up-regulates activity" phosphorylation Thr180 RHADAEMtGYVVTRW 9606 BTO:0000007 10066767 t done miannu "p38-δ is activated by environmental stress, extracellular stimulants, and MAPK kinase-3, -4, -6, and -7. we investigated whether this Thr180-Gly-Tyr182 motif was essential for p38-δ activation. Taken together, these results suggest that the dual phosphorylation TGY motif is required for p38-δ activation." SIGNOR-273954 AKT1 protein P31749 UNIPROT CDKN1B protein P46527 UNIPROT down-regulates phosphorylation 9606 14967450 t gcesareni "Furthermore, akt promotes cell cycle progression through downregulation of the cyclin dependent kinase inhibitor p27kip1." SIGNOR-121944 CDC7 protein O00311 UNIPROT DTD1 protein Q8TEA8 UNIPROT "up-regulates activity" phosphorylation Ser196 RKEDRSAsSGAEGDV -1 25258324 t done miannu " Here we show that DUE-B is de-phosphorylated in M phase and phosphorylated in G1/S phase. Phosphorylated DUE-B forms homodimers, whereas de-phosphorylated DUE-B interacts with the Mcm2–7 complex and aminoacyl-tRNA synthetases. We find that CKII can prime DUE-B for Cdc7 phosphorylation. Confirming the importance of DUE-B phosphorylation in replication initiation, a C-terminal Ser/Thr to Ala mutant blocks Cdc45 and RPA loading on sperm chromatin and inhibits DNA replication. DUE-B C-terminal phosphorylation sites (serine 179, 181, 182, 194, 196, 197, 204, 205, and threonine 187) were mutated to unphosphorylatable alanine (DUE-B(S/T)-A) or phosphomimic aspartic acid (DUE-B(S/T)-D)." SIGNOR-273962 PDPK1 protein O15530 UNIPROT AKT1 protein P31749 UNIPROT "up-regulates activity" phosphorylation Thr308 KDGATMKtFCGTPEY 19951971 t lperfetto "PIP3 recruits PDK1 and AKT to the plasma membrane, where PDK1 phosphorylates AKT on Thr308 in the activation loop of the kinase domain." SIGNOR-249629 CDC7 protein O00311 UNIPROT DTD1 protein Q8TEA8 UNIPROT "up-regulates activity" phosphorylation Ser205 GAEGDVSsEREP -1 25258324 t done miannu " Here we show that DUE-B is de-phosphorylated in M phase and phosphorylated in G1/S phase. Phosphorylated DUE-B forms homodimers, whereas de-phosphorylated DUE-B interacts with the Mcm2–7 complex and aminoacyl-tRNA synthetases. We find that CKII can prime DUE-B for Cdc7 phosphorylation. Confirming the importance of DUE-B phosphorylation in replication initiation, a C-terminal Ser/Thr to Ala mutant blocks Cdc45 and RPA loading on sperm chromatin and inhibits DNA replication. DUE-B C-terminal phosphorylation sites (serine 179, 181, 182, 194, 196, 197, 204, 205, and threonine 187) were mutated to unphosphorylatable alanine (DUE-B(S/T)-A) or phosphomimic aspartic acid (DUE-B(S/T)-D)." SIGNOR-273969 CSNK2A1 protein P68400 UNIPROT CERS5 protein Q8N5B7 UNIPROT "up-regulates activity" phosphorylation Ser356 RSDVESSsEEEDVTT 9606 BTO:0000007 26887952 t miannu "Most of the phosphorylated residues conformed to a consensus motif for phosphorylation by casein kinase 2 (CK2), and treatment of cells with the CK2-specific inhibitor CX-4945 lowered the phosphorylation levels of CERS2, -4, -5, and -6. Phosphorylation of CERS2 was especially important for its catalytic activity, acting mainly by increasing itsVmaxvalue. " SIGNOR-273986 CSNK2A1 protein P68400 UNIPROT CERS6 protein Q6ZMG9 UNIPROT "up-regulates activity" phosphorylation Ser341 KVSKDDRsDIESSSD 9606 BTO:0000007 26887952 t miannu "Most of the phosphorylated residues conformed to a consensus motif for phosphorylation by casein kinase 2 (CK2), and treatment of cells with the CK2-specific inhibitor CX-4945 lowered the phosphorylation levels of CERS2, -4, -5, and -6. Phosphorylation of CERS2 was especially important for its catalytic activity, acting mainly by increasing itsVmaxvalue. " SIGNOR-273990 JNK proteinfamily SIGNOR-PF15 SIGNOR BCL2L1 protein Q07817 UNIPROT down-regulates phosphorylation Thr115 LTSQLHItPGTAYQS 9606 10617621 t lperfetto "Sapk phosphorylates bcl-x(l) on threonine 47 (thr-47) and threonine 115 (thr-115) in vitro and in vivo. In contrast to wild-type bcl-x(l), a mutant bcl-x(l) with the two threonines substituted by alanines (ala-47, ala-115) is a more potent inhibitor of ionizing radiation-induced apoptosis" SIGNOR-73638 RET protein P07949 UNIPROT RET protein P07949 UNIPROT unknown phosphorylation Tyr687 AQAFPVSySSSGARR 9534 BTO:0004055 8621380 t lperfetto "Based on the phosphopeptide maps, we can identify six tyrosine phosphorylation sites in RET: Tyr-687, Tyr-826, Tyr-1062, Tyr-1096, Tyr-1015, and Tyr-1029. By comparing the peptide map of each mutant to the wild-type receptor, we can tentatively assign each tryptic peptide containing phosphorylation sites to individual P-labeled spots on the two-dimensional map " SIGNOR-248941 PTK2 protein Q05397 UNIPROT PIK3R1 protein P27986 UNIPROT up-regulates binding 9606 9416004 t gcesareni "Pi3-kinase has also been shown to bind fak in a cell cell adhesion-dipendent manner at the major autophosphorylation site y397. This association could live to activation of pi3-kinase and its downstream effectors." SIGNOR-53979 TERF1 protein P54274 UNIPROT "Shelterin complex" complex SIGNOR-C306 SIGNOR "form complex" binding 9606 15383534 t lperfetto "Telosome, a mammalian telomere-associated complex formed by multiple telomeric proteins|Gel filtration reveals a complex consisting of POT1 , RAP1, TRF1, ACD, TERF2 and TINF2 proteins." SIGNOR-263316 SRC protein P12931 UNIPROT FCRL3 protein Q96P31 UNIPROT "up-regulates activity" phosphorylation Tyr722 EEDDEENyENVPRVL -1 12051764 t miannu "Tyrosine phosphorylation of SPAP2a by c-Src and in vitro. Tyrosine-phosphorylated SPAP2 is specifically associated with SH2 domain-containing tyrosine kinases Syk and Zap70 and SH2 domain-containing tyrosine phosphatases SHP-1 and SHP-2. Site-specific mutagenesis studies revealed that tyrosyl residues 650 and 662 embedded in the ITIMs are responsible for the binding of Syk and Zap70 while tyrosyl residues 692 and 722 embedded in the ITIMs are involved in interactions with SHP-1 and SHP-2." SIGNOR-274009 FCRL3 protein Q96P31 UNIPROT SYK protein P43405 UNIPROT "up-regulates activity" binding -1 12051764 t miannu "Tyrosine phosphorylation of SPAP2a by c-Src and in vitro. Tyrosine-phosphorylated SPAP2 is specifically associated with SH2 domain-containing tyrosine kinases Syk and Zap70 and SH2 domain-containing tyrosine phosphatases SHP-1 and SHP-2. Site-specific mutagenesis studies revealed that tyrosyl residues 650 and 662 embedded in the ITIMs are responsible for the binding of Syk and Zap70 while tyrosyl residues 692 and 722 embedded in the ITIMs are involved in interactions with SHP-1 and SHP-2." SIGNOR-274011 regorafenib chemical CHEBI:68647 ChEBI FLT3 protein P36888 UNIPROT "down-regulates activity" "chemical inhibition" 9606 24756792 t miannu "In biochemical in vitro or cell-based assays, Regorafenib or its major human active metabolites M-2 and M-5 inhibited the activity of RET,VEGFR 1-3, KIT, PDGFR-alpha, PDGFR-beta, FGFR1, FGFR2, TIE2, DDR2, TrkA, Eph2A, RAF-1, BRAF, BRAFV600E, SAPK2, PTK5, and Abl at concentrations that can be achieved clinically." SIGNOR-259214 PRKDC protein P78527 UNIPROT XRCC6 protein P12956 UNIPROT "up-regulates activity" phosphorylation Ser27 QEENLEAsGDYKYSG 9606 BTO:0001546 26337656 t done miannu "Ku70 phosphorylation occurs within minutes of genotoxic stress and involves DNA-PKcs and/or ATM kinase activities.By using specific vectors enabling the simultaneous shRNA-mediated inhibition of endogenous Ku70 and the expression of exogenous Ku70 resistant to shRNA (i.e. S27-S33-Ku70 and A27-A33-Ku70 expressing cells), we showed that phospho-Ku70 contributes to faster but error-prone DNA repair resulting in higher levels of chromosomal breaks." SIGNOR-274022 GGCX protein P38435 UNIPROT RUNX2 protein Q13950 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10116 31539109 f miannu "GGCX can regulate osteoporosis via promoting the TGFβ/smad signaling pathway, facilitating BMSCs osteogenic differentiation, and inhibiting BMSCs adipogenic differentiation. The transfection of pcDNA-GGCX plasmid significantly promoted BMSC cell proliferation, increased calcified nodule formation, inhibited adipogenic differentiation, enhanced ALP activity, elevated RUNX2, and OPN mRNA expressions, and upregulated TGFβ1, Smad2, and Smad7 expressions (p < 0.05)." SIGNOR-261230 ULK1 protein O75385 UNIPROT PFKM protein P08237 UNIPROT "down-regulates activity" phosphorylation Ser74 EATWESVsMMLQLGG 9606 BTO:0000007 27153534 t done miannu "Here, we demonstrate that, during deprivation of amino acid and growth factors, ULK1/2 directly phosphorylate key glycolytic enzymes including hexokinase (HK), phosphofructokinase 1 (PFK1), enolase 1 (ENO1), and the gluconeogenic enzyme fructose-1,6-bisphosphatase (FBP1).Phosphorylation of these enzymes leads to enhanced HK activity to sustain glucose uptake but reduced activity of FBP1 to block the gluconeogenic route and reduced activity of PFK1 and ENO1 to moderate drop of glucose-6-phosphate and to repartition more carbon flux to pentose phosphate pathway (PPP), maintaining cellular energy and redox homeostasis at cellular and organismal levels.Similar results were also obtained using ULK2 as the kinase (data not shown)." SIGNOR-274035 ULK1 protein O75385 UNIPROT PFKM protein P08237 UNIPROT "down-regulates activity" phosphorylation Ser762 YEIDLDTsDHAHLEH 9606 BTO:0000007 27153534 t done miannu "Here, we demonstrate that, during deprivation of amino acid and growth factors, ULK1/2 directly phosphorylate key glycolytic enzymes including hexokinase (HK), phosphofructokinase 1 (PFK1), enolase 1 (ENO1), and the gluconeogenic enzyme fructose-1,6-bisphosphatase (FBP1).Phosphorylation of these enzymes leads to enhanced HK activity to sustain glucose uptake but reduced activity of FBP1 to block the gluconeogenic route and reduced activity of PFK1 and ENO1 to moderate drop of glucose-6-phosphate and to repartition more carbon flux to pentose phosphate pathway (PPP), maintaining cellular energy and redox homeostasis at cellular and organismal levels.Similar results were also obtained using ULK2 as the kinase (data not shown)." SIGNOR-274036 Amyloid_fibril_formation phenotype SIGNOR-PH59 SIGNOR PI3K complex SIGNOR-C156 SIGNOR down-regulates 26721223 f "Excessive accumulation of Aβ protein in the AD brain may lead to a decrease in the levels of phosphatidylinositol-3 kinase (PI3K) and the serine/threonine protein kinase B (Akt) activity." SIGNOR-255492 CHEK1 protein O14757 UNIPROT TP53 protein P04637 UNIPROT "up-regulates activity" phosphorylation Ser37 NVLSPLPsQAMDDLM 9606 BTO:0001321 15659650 t lperfetto "CHK1 and CHK2 phosphorylate the p53 N terminus at Ser15, Thr18, Ser20, and Ser37" SIGNOR-217799 AMPK complex SIGNOR-C15 SIGNOR FOXO3 protein O43524 UNIPROT "up-regulates activity" phosphorylation Ser555 RALSNSVsNMGLSES -1 17711846 t done miannu "Here, we find that AMPK directly regulates mammalian FOXO3, a member of the FOXO family of Forkhead transcription factors known to promote resistance to oxidative stress, tumor suppression, and longevity. We show that AMPK phosphorylates human FOXO3 at six previously unidentified regulatory sites.Phosphorylation by AMPK leads to the activation of FOXO3 transcriptional activity without affecting FOXO3 subcellular localization.Taken together, these results indicate that AMPK phosphorylates at least six residues of FOXO3 in vitro (Thr179, Ser399, Ser413, Ser555, Ser588, and Ser626)." SIGNOR-274093 NRF1 protein Q16656 UNIPROT TFB2M protein Q9H5Q4 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 15684387 f lperfetto "Here, we establish that the expression of human TFB1M and TFB2M promoters is governed by nuclear respiratory factors (NRF-1 and NRF-2), key transcription factors implicated in mitochondrial biogenesis. In addition, we show that NRF recognition sites within both TFB promoters are required for maximal trans activation by the PGC-1 family coactivators, PGC-1alpha and PRC" SIGNOR-268999 AVPR2 protein P30518 UNIPROT GNAL protein P38405 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-256897 SRC protein P12931 UNIPROT ACLY protein P53396 UNIPROT "up-regulates activity" phosphorylation Tyr1006 PATPLLDyALEVEKI 9606 BTO:0000007 32420483 t done miannu " We demonstrate the binding of PIP2 to the CoA-binding domain of ACLY and identify the six tyrosine residues of ACLY that are phosphorylated by Lyn. Three of them (Y682, Y252, Y227) can be also phosphorylated by Src and they are located in catalytic, citrate binding and ATP binding domains, respectively. PI3K and Lyn inhibitors reduce the ACLY enzyme activity, ACLY-mediated Acetyl-CoA synthesis, phospholipid synthesis, histone acetylation and cell growth. Thus, PIP2/PIP3 binding and Src tyrosine kinases-mediated stimulation of ACLY links oncogenic pathways to Acetyl-CoA-dependent pro-growth and survival metabolic pathways in cancer cells." SIGNOR-274107 NFIX protein Q14938 UNIPROT RBFOX3 protein A6NFN3 UNIPROT "up-regulates quantity" "transcriptional regulation" 10090 31838646 t Gianni "For example, within the NFI targetome, we identified 6 collagen genes, 13 genes encoding potassium channel or glutamate receptor subunits and a range of factors related to axon guidance (e.g. Slit1, Robo1, Epha4, Epha5, Epha8)" SIGNOR-268913 "CHEVI complex" complex SIGNOR-C269 SIGNOR SEC22B protein O75396 UNIPROT "up-regulates activity" relocalization 9606 27319744 t lperfetto "VPS33B association with VIPAS39, α-tubulin, and SEC22B was identified by co-immunoprecipitation, mass spectra, and immunoblotting in human embryonic kidney 293T (HEK293T) cells. Also, pull-down experiments revealed that VIPAS39 bound to intact VPS33B; in contrast, α-tubulin and SEC22B separately interacted with the sec1-like domains of VPS33B. Vps33b deficiency in megakaryocytes disturbs the redistribution of Vipas39 and Sec22b to proplatelets, and interrupted the co-localization of Sec22b with Vwf-positive vesicles" SIGNOR-261832 ADSS2 protein P30520 UNIPROT GDP smallmolecule CHEBI:17552 ChEBI "up-regulates quantity" "chemical modification" 9606 10496970 t miannu "Adenylosuccinate synthetase catalyzes the first committed step in the de novo biosynthesis of AMP, thermodynamically coupling the hydrolysis of GTP to the formation of adenylosuccinate from l-aspartate and IMP." SIGNOR-267349 regorafenib chemical CHEBI:68647 ChEBI ABCB1 protein P08183 UNIPROT "down-regulates activity" "chemical inhibition" 9606 26254357 t miannu "It is suggested that in vitro, regorafenib is an inhibitor of ABCB1 and ABCG2, but not a substrate, and that its active metabolites, M2 (N-Oxide metabolite) and M5 (N-Oxide/N-desmethyl metabolite), are substrates of ABCB1 and ABCG2" SIGNOR-259182 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR AR protein P10275 UNIPROT down-regulates phosphorylation Ser516 VSRVPYPsPTCVKSE 9606 BTO:0001130 18511414 t lperfetto "Map kinase-dependent phosphorylation at ar ser-515 was supported by the decrease in intensity of the slower migrating 23-kda band after treatment with both egf and increasing concentrations of the map kinase inhibitor, u0126" SIGNOR-244606 PRKAA1 protein Q13131 UNIPROT DDIT3 protein P35638 UNIPROT "down-regulates activity" phosphorylation Ser30 EDLQEVLsSDENGGT 10090 27650555 t Luana "Here, we report that phosphorylation of CHOP at Ser30 by AMPKα1 triggers CHOP degradation resulting in reduced macrophage apoptosis and subsequent ameliorated plaque vulnerability in vivo." SIGNOR-259864 SPI1 protein P17947 UNIPROT MEIS1 protein O00470 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 26622774 f miannu "In the present study, PU.1 siRNA was demonstrated to efficiently inhibit the transcription level of oncogene MEIS1 in the human acute myeloid non-MLL leukemia U937 cell line. In addition, PU.1, as a positive regulator of MEIS1, performed a crucial role in maintaining cell proliferation." SIGNOR-256002 ponatinib chemical CHEBI:78543 ChEBI RIPK1 protein Q13546 UNIPROT "down-regulates activity" "chemical inhibition" 9606 25801024 t Federica "Discovery of ponatinib as the first-in-class dual inhibitor of RIPK1 and RIPK3" SIGNOR-261082 TTC8 protein Q8TAM2 UNIPROT "BBsome complex" complex SIGNOR-C288 SIGNOR "form complex" binding 9606 BTO:0004910 19081074 t lperfetto "We recently showed that seven highly conserved BBS proteins form a stable complex, the BBSome, that functions in membrane trafficking to and inside the primary cilium.|As a first step in characterizing this protein, we investigated the biochemical properties of its binding to the core BBSome (previously defined as the BBS1, -2, -4, -5, -7, -8, and -9 complex). We subjected the native LAP-BBS4 eluate to velocity sedimentation analysis (Figure 1C). BBIP10 clearly cosedimented with BBS4 at 14S, suggesting that BBIP10 strongly associates with the core BBSome" SIGNOR-262554 GSK3B protein P49841 UNIPROT ROR2 protein Q01974 UNIPROT "down-regulates activity" phosphorylation Ser864 PKPSSHHsGSGSTST 9606 SIGNOR-C110 21078818 t gcesareni "We identify ror2 ser 864 as a critical residue phosphorylated by gsk3 and required for noncanonical receptor activation by wnt5a, analogous to the priming phosphorylation of low-density receptor-related protein 6 (lrp6) in response to wnt3a." SIGNOR-169642 MAP3K7 protein O43318 UNIPROT MAP2K7 protein O14733 UNIPROT "up-regulates activity" phosphorylation 9606 BTO:0000007 17110930 t Barakat "Upon TNFα stimulation, MEKK1, ASK1, and TAK1 phosphorylate and activate MKK7, which in turn activates JNK" SIGNOR-274146 HECW2 protein Q9P2P5 UNIPROT PI3K complex SIGNOR-C156 SIGNOR "up-regulates activity" binding 9606 BTO:0000093 27119228 t miannu "NEDL2 acts as a scaffold protein to promote GDNF-stimulated Akt activation. biochemical analysis indicated that NEDL2 appears to act like a scaffold protein to recruit SHC, Grb2, PI3K (p110 and p85), PDK1 and Akt together to promote the signaling transduction. NEDL2 binds p85, p110 and Akt with different domains" SIGNOR-269458 HBA1 protein P69905 UNIPROT TNF protein P01375 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000876 11901318 f "Regulation of expression" miannu "Free hemoglobin enhances tumor necrosis factor-alpha production in isolated human monocytes." SIGNOR-251753 FGF11 protein Q92914 UNIPROT SCN9A protein Q15858 UNIPROT "down-regulates activity" binding 9606 BTO:0000938 20679355 t miannu "Sodium channel fast inactivation is modulated by alpha subunit interaction with a family of cytoplasmic proteins termed fibroblast growth factor homologous factors (FHFs). In this paper, we report that all A-type FHFs exert rapid onset long-term inactivation on Nav1.6 and other sodium channels." SIGNOR-253426 SRC protein P12931 UNIPROT CTNND1 protein O60716 UNIPROT "up-regulates activity" phosphorylation Tyr296 MGYDDLDyGMMSDYG -1 11382764 t lperfetto "Identification of Src phosphorylation sites in the catenin p120ctn.Using selected tyrosine to phenylalanine p120 mutants as dominant negative reagents, it may now be possible to selectively block events postulated to be dependent on p120 tyrosine phosphorylation.combinations of Tyr _ Phe mutations at residues 96, 112, 228, 257, 280, 291, 296, and 302" SIGNOR-246500 SOSTDC1 protein Q6X4U4 UNIPROT WNT10B protein O00744 UNIPROT "down-regulates activity" 10090 22829579 f lperfetto "Our laboratory identified an almost twofold upregulation of sclerostin domain-containing 1 (Sostdc1; also referred to as WISE, USAG-1, ectodin), a dual Bmp/Wnt inhibitor, in postnatal day (P)1 pancreata from transgenic mice misexpressing hepatocyte nuclear factor (Hnf)6 in islet endocrine cells." SIGNOR-242698 CSNK2A1 protein P68400 UNIPROT RRAD protein P55042 UNIPROT unknown phosphorylation Ser257 QIRLRRDsKEANARR -1 9677319 t llicata "CKII phosphorylate multiple C-terminal serine residues, including Ser214, Ser257, Ser273, Ser290 and Ser299. | However, phosphorylation of Rad by PKC and CKII abolishes the interaction of Rad with calmodulin." SIGNOR-250945 CDK4 protein P11802 UNIPROT SMAD3 protein P84022 UNIPROT "down-regulates activity" phosphorylation Thr8 MSSILPFtPPIVKRL 9606 15241418 t lperfetto "We have mapped CDK4 and CDK2 phosphorylation sites to Thr 8, Thr 178 and Ser 212 in Smad3. Mutation of the CDK phosphorylation sites increases Smad3 transcriptional activity" SIGNOR-232138 thromboxane smallmolecule CHEBI:26995 ChEBI TBXA2R protein P21731 UNIPROT "up-regulates activity" "chemical activation" 19747485 t "Thromboxane plays an essential role in hemostasis, regulating platelet aggregation and vessel tone. In humans, it signals through the TPalpha and TPbeta isoforms that are transcriptionally regulated by distinct promoters Prm1 and Prm3, respectively." SIGNOR-254264 PLCG1 protein P19174 UNIPROT RAC1 protein P63000 UNIPROT up-regulates 9606 17562871 f gcesareni "We propose that the association of plcgamma1 with complexes containing git1 and beta-pix is essential for its role in integrin-mediated cell spreading and motility. As a component of this complex, plcgamma1 is also involved in the activation of cdc42 and rac1." SIGNOR-155747 TDGF1 protein P13385 UNIPROT ACVR1B protein P36896 UNIPROT "up-regulates activity" binding 9606 19874624 t Regulation miannu "Nodal effects are dependent upon interactions with Cripto, a small cysteine-rich extracellular protein that is attached to the plasma membrane through a glycosyl phosphatidyl inositol linkage. Cripto interacts with Nodal and ALK4, independently, and promotes the formation of a stable high affinity complex with activin type II receptors." SIGNOR-251938 MYC protein P01106 UNIPROT CDKN2B protein P42772 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0001271 12835716 f gcesareni "Miz1 is a zinc finger transcription factor with an n-terminal poz domain. Complexes with myc, bcl-6 or gfi-1 repress expression of genes like cdkn2b (p15(ink4)) or cdkn1a (p21(cip1))." SIGNOR-102746 BCL6 protein P41182 UNIPROT LITAF protein Q99732 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0001518 23795761 f miannu "BCL6 silencing increased LITAF expression, and chromatin immunoprecipitation and luciferase reporter assays demonstrated a direct transcriptional repression of LITAF by BCL6." SIGNOR-253758 LPCAT4 protein Q643R3 UNIPROT "coenzyme A(4-)" smallmolecule CHEBI:57287 ChEBI "up-regulates quantity" "chemical modification" 9606 21498505 t miannu "Plasma-derived fatty acids are esterified to acyl-CoA by acyl-CoA synthetases and transferred to lysophospholipids by acyl-CoA:lysophospholipid acyltransferases. We report the characterization of three lysophosphatidylcholine (lysoPC) acyltransferases (LPCATs), products of the AYTL1, -2, and -3 genes. " SIGNOR-272771 Ub:E2 complex SIGNOR-C497 SIGNOR PJA1 protein Q8NG27 UNIPROT "up-regulates activity" ubiquitination 9606 34199813 t miannu "The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t" SIGNOR-270990 PRMT1 protein Q99873 UNIPROT TAF15 protein Q92804 UNIPROT up-regulates methylation 9606 19124016 t miannu "The methylation of taf15 by prmt1 is required for the ability of taf15 to positively regulate the expression of the studied endogenous taf15-target genes." SIGNOR-183137 idarubicin chemical CHEBI:42068 ChEBI TOP2A protein P11388 UNIPROT "down-regulates activity" "chemical inhibition" 9606 20824055 t miannu "Topoisomerase II (Top2) is a nuclear enzyme involved in several metabolic processes of DNA. Chemotherapy agents that poison Top2 are known to induce persistent protein-mediated DNA double strand breaks (DSB). In this report, by using knock down experiments, we demonstrated that Top2α was largely responsible for the induction of γH2AX and cytotoxicity by the Top2 poisons idarubicin and etoposide in normal human cells." SIGNOR-259327 MAPK3 protein P27361 UNIPROT STMN1 protein P16949 UNIPROT "down-regulates activity" phosphorylation Ser25 QAFELILsPRSKESV 9606 9731215 t lperfetto "Stress-induced stathmin phosphorylation is not de- pendent on ERK. Stathmin is also known to be phos- phorylated by ERK on Ser-25 and Ser-38 (17). Thus, it is possible that ERK phosphorylates stathmin in 293 cells|In subsequent reports (28, 29) it was shown that phosphorylation of stathmin blocks its ability to destabilize MTs." SIGNOR-249482 TRIM63 protein Q969Q1 UNIPROT PSMD4 protein P55036 UNIPROT "down-regulates quantity by destabilization" polyubiquitination Lys74 DTGRILSkLHTVQPK -1 19240029 t miannu "S5a/Rpn10 is a ubiquitin (Ub)-binding protein that is a subunit of the 26S proteasome but also exists free in the cytosol. It binds poly-Ub chains through its two Ub-interacting motifs (UIMs). We discovered that, unlike typical substrates of Ub ligases (E3s), S5a can be ubiquitinated by all E3s tested including multimeric and monomeric Ring finger E3s (MuRF1, Siah2, Parkin, APC, and SCF(betaTRCP1)), the U-box E3, CHIP, and HECT domain E3s (E6AP and Nedd4) when assayed with UbcH5 or related Ub-conjugating enzymes.The short half-life of S5a presumably is because of the presence of the UIM domain and reflects the ubiquitination of free S5a by many E3s. Surprisingly, the same four Lys residues on S5a, Lys-74, Lys-122, Lys-262, and Lys-365 were ubiquitinated by MuRF1 and E6AP (Fig. 10)." SIGNOR-272738 CD79A protein P11912 UNIPROT BCR-Mk complex SIGNOR-C433 SIGNOR "form complex" binding 9606 BTO:0000776 32323266 t scontino "BCR consists of a pair of identical immunoglob- ulin heavy (IgH) and light (IgL) chains. though membrane BCR per se is not able to transduce downstream signaling, it does so by making BCR complex with CD79. The extracellular portion of the BCR is non-covalently coupled to a disulfide-linked heterodimer of the CD79A and CD79B. This association allows expression of BCR on the plasma membrane and BCR internalization after antigen recognition." SIGNOR-268188 ACP1 protein P24666 UNIPROT EPHA2 protein P29317 UNIPROT "down-regulates activity" dephosphorylation Tyr575 RQSPEDVyFSKSEQL -1 21538645 t gcesareni "The SAM domain tyrosine Y960 which has been implicated in downstream PI3K signaling is dephosphorylated exclusively by HCPTP-B. The activation loop tyrosine (Y772) which directly controls kinase activity is dephosphorylated about six times faster by HCPTP-A. In contrast, the juxtamembrane tyrosines (Y575, Y588 and Y594) which are implicated in both control of kinase activity and downstream signaling are dephosphorylated by both variants with similar rates" SIGNOR-246031 ABL1 protein P00519 UNIPROT MAP4K1 protein Q92918 UNIPROT "up-regulates activity" phosphorylation Tyr232 FLMTKSGyQPPRLKE 9606 BTO:0000007 11278340 t "C-Abl phosphorylates HPK1 in cytoplasm and stimulates HPK1 activity. the c-Abl phosphorylation site (YXXP) in HPK1 (Y232QPP; aa 232–235) is localized in HPK1-KD" SIGNOR-251429 PPARG protein P37231 UNIPROT JUN protein P05412 UNIPROT "up-regulates activity" 9606 BTO:0000801 17681149 f lperfetto "Transcriptional repression of inflammatory response genes occurs by negative interference of PPARg with the nuclear factor kB (NF-kB), signal transducer and activator of transcription (STAT), and activating protein 1 (AP-1) signaling pathways" SIGNOR-249558 GRIPAP1 protein Q4V328 UNIPROT MAP3K1 protein Q13233 UNIPROT "up-regulates activity" binding 9606 BTO:0002181 17761173 t Giulio "We investigated signal transduction pathways that might lie downstream of GRASP-1 and found that GRASP-1 potently activates JNK pathway signaling, with no effect on ERK signaling. Such JNK pathway activating activity requires binding of GRASP-1 to both JNK and the upstream JNK pathway activator MEKK-1." SIGNOR-260607 NARS1 protein O43776 UNIPROT AMP smallmolecule CHEBI:456215 ChEBI "up-regulates quantity" "chemical modification" 9606 32788587 t miannu "Asparaginyl-tRNA synthetase1 (NARS1) is a member of the ubiquitously expressed cytoplasmic Class IIa family of tRNA synthetases required for protein translation. Asparaginyl-tRNA synthetase1 (NARS1) belongs to the class IIa family, based upon a 7 beta-strand protein structure. There are two NARS genes: NARS1 functions in the cytoplasm while NARS2 functions in mitochondria, solely responsible for asparagine tRNA charging in these locations." SIGNOR-270458 MAML2 protein Q8IZL2 UNIPROT NOTCH proteinfamily SIGNOR-PF30 SIGNOR "up-regulates quantity by expression" "transcriptional regulation" 9606 12370315 f gcesareni "We recently cloned a mammalian homologue of the mastermind gene of drosophila melanogaster, maml1 (mastermind-like-1 molecule) and determined that it functions as a transcriptional coactivator for notch receptors." SIGNOR-254307 Zap70 protein P43404 UNIPROT LAT protein O43561 UNIPROT "up-regulates activity" phosphorylation "Tyr 132" DYHNPGyLVVLPD 9606 BTO:0000007 29915297 t "Isoform O43561-2" Barakat "In the presence of the catalytically inactive LckK273R, the phosphorylation of LAT Y132 and Y191 residues by Zap70K362E were considerably increased" SIGNOR-274561 Sincalide smallmolecule CID:9833444 PUBCHEM CCKAR protein P32238 UNIPROT "up-regulates activity" "chemical activation" 9606 BTO:0002524 31160049 t "Ligand-GPCR dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257466 P2RY4 protein P51582 UNIPROT GNA15 protein P30679 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257214 STT3A protein P46977 UNIPROT CD274 protein Q9NZQ7 UNIPROT "up-regulates quantity by stabilization" glycosylation 9606 BTO_0001939 29765039 t Barakat "Together, these results support a notion that the two STT3 isoforms regulate EMT-mediated PD-L1 induction through PD-L1 protein N-glycosylation and stabilization." SIGNOR-274975 STT3B protein Q8TCJ2 UNIPROT CD274 protein Q9NZQ7 UNIPROT "up-regulates quantity by stabilization" glycosylation 9606 BTO_0001939 29765039 t Barakat "Together, these results support a notion that the two STT3 isoforms regulate EMT-mediated PD-L1 induction through PD-L1 protein N-glycosylation and stabilization." SIGNOR-274976 COPS5 protein Q92905 UNIPROT CD274 protein Q9NZQ7 UNIPROT "up-regulates quantity by stabilization" deubiquitination 9606 BTO:0000007 27866850 t Barakat "The results suggested that TNF-α upregulates expression of CSN5, which interacts and deubiquitinates PD-L1 for protein stabilization." SIGNOR-274977 SPOP protein O43791 UNIPROT CD274 protein Q9NZQ7 UNIPROT "down-regulates quantity" ubiquitination 9606 BTO_0005672 29160310 t Barakat "Loss-of-function mutations in SPOP compromise ubiquitination-mediated PD-L1 degradation, leading to increased PD-L1 levels and reduced numbers of tumor-infiltrating lymphocytes (TILs) in mouse tumors and in primary human prostate cancer specimens." SIGNOR-274978 STUB1 protein Q9UNE7 UNIPROT CD274 protein Q9NZQ7 UNIPROT "down-regulates quantity by destabilization" destabilization 9606 BTO_0002806 28813410 t Barakat "Deletion of STUB1 resulted in a more profound increase in PD-L1 levels in CMTM6 deficient than in CMTM6 proficient cells, identifying STUB1 as an E3 ligase that causes destabilization of PD-L1 (Fig. 4f,g), either by direct modification of one of the lysines in the PD-L1 cytoplasmic domain or indirectly" SIGNOR-274979 NFATC1 protein O95644 UNIPROT Myotube_hypertrophy phenotype SIGNOR-PH20 SIGNOR up-regulates "transcriptional regulation" 9606 BTO:0001103 14729474 f apalma "To summarize, these two studies have generated important insights into the control of skeletal muscle hypertrophy by the calcineurin/NFATc1 signaling pathway" SIGNOR-256215 MBD1 protein Q9UIS9 UNIPROT ALOX5 protein P09917 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0001412 19781662 f "Human 5-lipoxygenase (5-LO) is the key enzyme in the formation of inflammatory leukotrienes. 5-LO gene expression is mainly restricted to B cells and cells of myeloid origin. It is known that basal 5-lipoxygenase promoter activity is regulated by DNA methylation.|Using ChIP assays, we found that the methyl-DNA binding proteins MBD1, MBD2 and MeCP2 bind to the methylated 5-LO core promoter in U937 cells. Knock down of each of the MBDs upregulates 5-LO mRNA expression in U937 cells indicating that these proteins are involved in silencing of the 5-LO gene." SIGNOR-254030 MAPK8 protein P45983 UNIPROT BCL2 protein P10415 UNIPROT "down-regulates activity" phosphorylation Ser87 AAAGPALsPVPPVVH 9606 10567572 t gcesareni "Jnk1-mediated phosphorylation of bcl-2 regulates starvation-induced autophagy." SIGNOR-48038 DUSP4 protein Q13115 UNIPROT Gbeta proteinfamily SIGNOR-PF4 SIGNOR "down-regulates activity" dephosphorylation 10116 7535768 t "inferred from 70% of family members" "Dephosphorylation and Inactivation of ERKs|ERK1 phosphorylated on either threonine (ERK1*Y204F) or tyrosine alone (ERK1*T202A) was utilized as a substrate for HVH2. Threonine 202 and tyrosine 204 in ERK1 (53) correspond to threonine 183 and tyrosine 185 in ERK2 which are the activation-phosphorylation sites by MEK(14, 15, 16). ERK1*, a kinase-deficient mutant, was phosphorylated on both threonine and tyrosine by MEK2 (Fig. 3B). ERK1*T202A, having threonine 202 substituted by an alanine, was phosphorylated only on tyrosine while ERK1*Y204F, having tyrosine 204 substituted by a phenylalanine, was phosphorylated only on threonine (Fig. 3B). GST-HVH2 dephosphorylated all three ERK1* mutants (Fig. 3A), suggesting that double phosphorylations of adjacent threonine and tyrosine were not a prerequisite for HVH2 recognition. However, HVH2 dephosphorylated ERK1* and ERK1*T202A more efficiently than ERK1*Y204F (Fig. 3A), indicating that HVH2 preferred phosphotyrosine over phosphothreonine. Interestingly, MEK also phosphorylated tyrosine residues more efficiently than threonine residues of ERK" SIGNOR-269914 FLT3 protein P36888 UNIPROT FOXO3 protein O43524 UNIPROT "down-regulates activity" 10090 14981546 f "Immunoblot analysis indicated an increased level of Foxo3a phosphorylation on residue Thr32, as shown by the appearance of additional slower-migrating phospho-species immediately after induction of FLT3-ITD4 expression" SIGNOR-261523 N-hydroxy-3-[4-[[2-hydroxyethyl-[2-(1H-indol-3-yl)ethyl]amino]methyl]phenyl]-2-propenamide chemical CHEBI:94063 ChEBI HDAC5 protein Q9UQL6 UNIPROT "down-regulates activity" "chemical inhibition" -1 20139990 t Luana "Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1)." SIGNOR-257987 DUSP1 protein P28562 UNIPROT MAPK3 protein P27361 UNIPROT down-regulates dephosphorylation 9606 10617468 t gcesareni "The mitogen-activated protein (map) kinase cascade is inactivated at the level of map kinase by members of the map kinase phosphatase (mkp) family, including mkp-1." SIGNOR-73617 MAP3K1 protein Q13233 UNIPROT MAP2K1 protein Q02750 UNIPROT "up-regulates activity" phosphorylation Ser222 LIDSMANsFVGTRSY 10090 BTO:0000944 8131746 t lperfetto "Phosphorylation at ser-218 and ser-222 by map kinase kinase kinases (raf or mekk1) positively regulates mek1 kinase activity." SIGNOR-235564 AKT proteinfamily SIGNOR-PF24 SIGNOR RARA protein P10276 UNIPROT down-regulates phosphorylation Ser96 FVCQDKSsGYHYGVS 9606 BTO:0000551 16417524 t miannu "We report that akt, which is constitutively activated in nsclc cells, phosphorylates raralpha and inhibits its transactivation. / mutation of ser96 to alanine abrogated the suppressive effect of akt." SIGNOR-143721 LPAR3 protein Q9UBY5 UNIPROT GNA15 protein P30679 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257406 CHUK protein O15111 UNIPROT CYLD protein Q9NQC7 UNIPROT "down-regulates activity" phosphorylation Ser432 KMPNTNGsIGHSPLS 9606 BTO:0000938 24614225 t lperfetto "The phosphorylation of cyld was completely abolished by the combined mutations of the entire serine cluster (m4, lane 5). Similar results were obtained with the ikk holoenzyme (fig. 4c, panel 1), recombinant ikk_ (panel 2), and recombinant ikk_cyld phosphorylation may serve as a mechanism to inactivate its traf2 deubiquitination activity." SIGNOR-204696 MAPK13 protein O15264 UNIPROT STMN1 protein P16949 UNIPROT down-regulates phosphorylation Ser38 SVPEFPLsPPKKKDL 9606 BTO:0000782 8325880 t gcesareni "Serine 25 of oncoprotein 18 is a major cytosolic target for the mitogen-activated protein kinase." SIGNOR-25826 IRAK1 protein P51617 UNIPROT IRAK1 protein P51617 UNIPROT "up-regulates activity" phosphorylation Thr209 LCEISRGtHNFSEEL 9606 BTO:0000007 14625308 t lperfetto "Sequential autophosphorylation steps in the interleukin-1 receptor-associated kinase-1 regulate its availability as an adapter in interleukin-1 signalingthis identifies irak-1 as a novel type of adapter protein, which employs its own kinase activity to introduce negative charges adjacent to the protein interaction domain, which anchors irak-1 at the active receptor complex. Thus, irak-1 regulates its own availability as an adapter molecule by sequential autophosphorylation" SIGNOR-119212 "A2/b1 integrin" complex SIGNOR-C160 SIGNOR Cell_adhesion phenotype SIGNOR-PH7 SIGNOR up-regulates 9606 25388208 f miannu "Integrin-mediated cell adhesion is important for development, immune responses, hemostasis and wound healing." SIGNOR-269009 IKBKB protein O14920 UNIPROT CDKN2A protein P42771 UNIPROT down-regulates phosphorylation Ser8 MEPAAGSsMEPSADW 9606 20152798 t lperfetto "Ikkbeta specifically binds to p16 and phosphorylates ser8 of p16 phosphorylation at ser8 of p16 brings about a significant loss of its cyclin-dependent kinase (cdk) 4-inhibitory activity" SIGNOR-163801 ATF4 protein P18848 UNIPROT TARS2 protein Q9BW92 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 33384352 t miannu "QRICH1 promotes the expression of translation-related genes. our combined ChIP-seq and RNA-seq analyses identified that QRICH1 and ATF4 were enriched at the promoters of these specific tRNA synthetases, and that ER stress positively regulated their transcription (Fig. 4I). Together, these findings suggest that QRICH1 and ATF4 modulate tRNA metabolic processes to promote secreted protein synthesis during ER stress." SIGNOR-269428 RIPK1 protein Q13546 UNIPROT FAS protein P25445 UNIPROT "up-regulates activity" binding 9606 18545270 t lperfetto "The death domain of the rip1 kinase binds to death receptors such as fas that is required for caspase 8 activation and apoptosis" SIGNOR-177949 RNA_splicing phenotype SIGNOR-PH201 SIGNOR "messenger RNA" smallmolecule CHEBI:33699 ChEBI up-regulates 9606 32140746 f lperfetto "The splicing of introns from nuclear precursors of message RNA (pre-mRNA) is executed by the spliceosome, a ribonucleoprotein (RNP) apparatus that first surfaced in the literature in 1985 " SIGNOR-268402 venetoclax chemical CHEBI:133021 ChEBI BCL2 protein P10415 UNIPROT "down-regulates activity" "chemical inhibition" 9606 23291630 t miannu "Here we report the re-engineering of navitoclax to create a highly potent, orally bioavailable and BCL-2-selective inhibitor, ABT-199. This compound inhibits the growth of BCL-2-dependent tumors in vivo and spares human platelets. These data indicate that selective pharmacological inhibition of BCL-2 shows promise for the treatment of BCL-2-dependent hematological cancers." SIGNOR-261938 AKT proteinfamily SIGNOR-PF24 SIGNOR RAC1 protein P63000 UNIPROT "down-regulates activity" phosphorylation Ser71 YDRLRPLsYPQTDVF 9606 BTO:0003476 10617634 t gcesareni "The results suggest that Akt kinase of the phosphoinositide 3-kinase signal transduction pathway phosphorylates serine 71 of Rac1 as one of its authentic substrates and modulates the Rac1 signal transduction pathway through phosphorylation." SIGNOR-248036 PRKAG1 protein P54619 UNIPROT PRKAA2 protein P54646 UNIPROT up-regulates binding 9606 16054041 t gcesareni "Gamma non-catalytic subunit mediates binding to amp, adp and atp, leading to activate or inhibit ampk: amp-binding results in allosteric activation of alpha catalytic subunit (prkaa1 or prkaa2) both by inducing phosphorylation and preventing dephosphorylation of catalytic subunits." SIGNOR-139173 WNT11 protein O96014 UNIPROT LRP6 protein O75581 UNIPROT "up-regulates activity" binding 9606 15578921 t gcesareni "Wnt proteins bind to the frizzled receptors and lrp5/6 co-receptors, and through stabilizing the critical mediator betBeta-catenin, initiate a complex signaling cascade that plays an important role in regulating cell proliferation and differentiation." SIGNOR-131637 PTPN12 protein Q05209 UNIPROT INSR protein P06213 UNIPROT down-regulates dephosphorylation Tyr999 YASSNPEyLSASDVF 9606 10734133 t gcesareni "Autophosphorylated on tyrosine residues in response to insulin. Dephosphorylated by ptpreand ptpn1 at tyr-999, tyr-1185, tyr-1189 and tyr-1190." SIGNOR-75906 NR0B2 protein Q15466 UNIPROT NR5A2 protein O00482 UNIPROT down-regulates binding 9606 15723037 t gcesareni "Modulation of human nuclear receptor lrh-1 activity by phospholipids and shpthe human nuclear receptor liver receptor homolog 1 (hlrh-1) plays an important role in the development of breast carcinomas. This orphan receptor is efficiently downregulated by the unusual co-repressor shp" SIGNOR-134202 ANGPTL1 protein O95841 UNIPROT TEK protein Q02763 UNIPROT up-regulates binding 9606 10051567 t gcesareni "Ang3 and ang4 are agonists of tie2, but mouse ang3 has strong activity only on endothelial cells of its own species." SIGNOR-65110 GRK2 protein P25098 UNIPROT OPRM1 protein P35372 UNIPROT "down-regulates activity" phosphorylation Thr356 FREFCIPtSSNIEQQ 9606 BTO:0000007 12123746 t gcesareni "These results suggest that two C-terminal amino acids, Ser(355) and Thr(357), are required for short-term homologous desensitization and agonist-induced phosphorylation of mu-opioid receptors expressed in HEK 293 cells" SIGNOR-247782 CDKN1A protein P38936 UNIPROT PCNA protein P12004 UNIPROT down-regulates binding 9606 22911014 t gcesareni "P21 exerts its effect on the cell cycle not only by inhibiting cyclin/cdk complexes, but also by inhibiting proliferating cell nuclear antigen (pcna)" SIGNOR-191939 Scribble_complex_DLG3-LLGL2_variant complex SIGNOR-C504 SIGNOR Cell_polarity phenotype SIGNOR-PH213 SIGNOR up-regulates 9606 23397623 f miannu "The Scribble polarity complex or module is one of the three polarity modules that regulate cell polarity in multiple epithelia including blood-tissue barriers. This protein complex is composed of Scribble, Lethal giant larvae (Lgl) and Discs large (Dlg), which are well conserved across species from fruitflies and worms to mammals." SIGNOR-270886 ATF4 protein P18848 UNIPROT ASNS protein P08243 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0002182 18940792 f miannu "C/EBP homology protein (CHOP) interacts with activating transcription factor 4 (ATF4) and negatively regulates the stress-dependent induction of the asparagine synthetase gene." SIGNOR-253838 NEK2 protein P51955 UNIPROT NEK2 protein P51955 UNIPROT up-regulates phosphorylation Thr170 ARILNHDtSFAKTFV 9606 17197699 t gcesareni "Thus, it appears that autophosphorylation of thr-170 and/or ser-171 in nek2 may fine-tune overall activity of nek2 in vivo. regardless, the importance of thr-175 suggested by its conservation in many other kinases is underlined by the t175a mutant that shows reduced kinase activity and a significant reduction in efficiency of cs." SIGNOR-151759 NARS2 protein Q96I59 UNIPROT diphosphate(3-) smallmolecule CHEBI:33019 ChEBI "up-regulates quantity" "chemical modification" 9606 32788587 t miannu "Asparaginyl-tRNA synthetase1 (NARS1) is a member of the ubiquitously expressed cytoplasmic Class IIa family of tRNA synthetases required for protein translation. Asparaginyl-tRNA synthetase1 (NARS1) belongs to the class IIa family, based upon a 7 beta-strand protein structure. There are two NARS genes: NARS1 functions in the cytoplasm while NARS2 functions in mitochondria, solely responsible for asparagine tRNA charging in these locations." SIGNOR-270465 TNF protein P01375 UNIPROT Demyelination phenotype SIGNOR-PH155 SIGNOR up-regulates 9606 24507514 f miannu "TNF-a is the most comprehensively studied cytokine in both EAE and MS. Most TNF-a overexpressing transgenic animals showed spontaneous pathology, characterized by progressive demyelination and macrophage infiltration" SIGNOR-263834 GNAL protein P38405 UNIPROT Adenylate_cyclase proteinfamily SIGNOR-PF92 SIGNOR "up-regulates activity" binding 9606 BTO:0004032 21303898 t miannu "D1-class dopamine receptors (D1 and D5) activate the G s/olf family of G proteins to stimulate cAMP produc tion by AC and are found exclusively postsynaptically on dopamine-receptive cells, such as GABA-ergic medium spiny neurons (MSNs) in the striatum." SIGNOR-267852 CHEK2 protein O96017 UNIPROT AATF protein Q9NY61 UNIPROT "up-regulates quantity by stabilization" phosphorylation Ser510 KKVDRKAsKGRKLRF 9606 BTO:0001109 17157788 t lperfetto "Three putative Chk2 phosphorylation sites (Stevens et al., 2003) are present in Che-1 at resides Ser141, Ser474, and Ser508. Thus, we performed in vitro Chk2 kinase assays utilizing the GST-Che-1 fusion peptides spanning these residues as substrates.| Taken together, these results indicate that Chk2 phosphorylates Che-1 and this phosphorylation contributes to increase Che-1 stability." SIGNOR-264418 EGFR protein P00533 UNIPROT STAT5A protein P42229 UNIPROT up-regulates binding 9606 BTO:0000017 10358079 t gcesareni "We identified stat5 as a direct binding partner to egfr and erbb4 and discovered new recognition motifs for shc and stat5.Egf stimulation and subsequent phosphorylation of egfr at tyrosine y978, y998 and y869 would then subsequently lead to recruitment and activation of stat5." SIGNOR-68159 PERP protein Q96FX8 UNIPROT NFKB1 protein P19838 UNIPROT "down-regulates quantity" ubiquitination 9606 25860612 t "We identify KPC1 as the Ub ligase (E3) that binds to the ankyrin repeats domain of p105, ubiquitinates it, and mediates its processing both under basal conditions and following signaling" SIGNOR-255843 Dinaciclib chemical CID:46926350 PUBCHEM CDK9 protein P50750 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-191331 MAPK3 protein P27361 UNIPROT KLC1 protein Q07866 UNIPROT down-regulates phosphorylation Ser460 YKACKVDsPTVTTTL 9606 21385839 t gcesareni "Phosphorylation of kinesin light chain 1 at serine 460 modulates binding and trafficking of calsyntenin-1mutation of klc1ser460 to an alanine residue, to preclude phosphorylation, increased the binding of calsyntenin-1, whereas mutation to an aspartate residueklc1ser460 is a predicted mitogen-activated protein kinase (mapk) target site, and we show that extracellular-signal-regulated kinase (erk) phosphorylates this residue in vitro." SIGNOR-172642 DVL1 protein O14640 UNIPROT APC protein P25054 UNIPROT "down-regulates activity" binding 9606 10330181 t amattioni "Dvl-1 inhibits Axin-promoted GSK-3_-dependent phosphorylation of _-catenin and APC, leading to beta-catenin stabilization." SIGNOR-167951 CAMK2A protein Q9UQM7 UNIPROT ANKS1B protein Q7Z6G8 UNIPROT "down-regulates activity" phosphorylation 9606 BTO:0000938 27477489 t miannu "CaMKII-mediated displacement of AIDA-1 out of the postsynaptic density core. The present study indicates that CaMKII activation is necessary for the NMDA-induced movement of AIDA-1 out of the PSD core." SIGNOR-264231 PEX12 protein O00623 UNIPROT PEX5 protein P50542 UNIPROT "up-regulates activity" ubiquitination -1 19687296 t miannu "Here we report on the identification of the protein-ubiquitin ligases that are responsible for the ubiquitination of the peroxisomal protein import receptor Pex5. It is demonstrated that each of the three RING peroxins Pex2, Pex10, and Pex12 exhibits ubiquitin-protein isopeptide ligase activity. Our results show that Pex2 mediates the Ubc4-dependent polyubiquitination whereas Pex12 facilitates the Pex4-dependent monoubiquitination of Pex5.While polyubiquitinated Pex5 is degraded by the proteasome, monoubiquitinated Pex5 is destined for a new round of the receptor cycle." SIGNOR-253020 calcium(2+) smallmolecule CHEBI:29108 ChEBI FLNA protein P21333 UNIPROT "down-regulates activity" "chemical inhibition" 9606 BTO:0000132 27871158 t lperfetto "Gelsolin is an actin binding protein that severs and caps the barbed-end actin filaments to prevent actin monomer exchange upon intracellular calcium increase in the initial step. Cofilin also binds to actin and contributes to the disassembly of actin filaments and the subsequent release of actin monomers. The actin cross-linking complex, GP1b/IX-filamin, translocates from the plasma membrane to the cytoskeleton during this step." SIGNOR-261845 PRKDC protein P78527 UNIPROT HSP90AA1 protein P07900 UNIPROT unknown phosphorylation Thr5 tQTQDQPM 9606 BTO:0000567 2507541 t lperfetto "Here we show that the dsDNA-activated protein kinase from human HeLa cells phosphorylates 2 threonine residues in the sequence PEETQTQDQPME at the amino terminus of human hsp90 alpha." SIGNOR-248887 REST protein Q13127 UNIPROT REST-CoREST complex SIGNOR-C111 SIGNOR "form complex" binding 9606 20080105 t 1 miannu "Transcriptional repression of neural-specific genes in nonneuronal cells is dependent on the REST (RE1-silencing transcription factor)–CoREST complex." SIGNOR-239217 COPS8 protein Q99627 UNIPROT "COP9 signalosome variant 1" complex SIGNOR-C489 SIGNOR "form complex" binding 9606 18850735 t miannu "The COP9 signalosome (CSN) is a multiprotein complex that plays a critical role in diverse cellular and developmental processes in various eukaryotic organisms. we have performed a comprehensive proteomic analysis of the human CSN complex using a new purification method and quantitative mass spectrometry. Purification of the human CSN complex from a stable 293 cell line expressing N-terminal HBTH-tagged CSN5 subunit was achieved by high-affinity streptavidin binding with TEV cleavage elution." SIGNOR-270770 PRKCA protein P17252 UNIPROT GSK3A protein P49840 UNIPROT down-regulates phosphorylation Ser21 SGRARTSsFAEPGGG 9606 11884598 t lperfetto "Convergence of multiple signaling cascades at glycogen synthase kinase 3: edg receptor-mediated phosphorylation and inactivation by lysophosphatidic acid through a protein kinase c-dependent intracellular pathway." SIGNOR-115714 atomoxetine chemical CHEBI:127342 ChEBI SLC6A4 protein P31645 UNIPROT "down-regulates activity" "chemical inhibition" -1 9871604 t miannu "The gamma-amino alcohol/ether unit contained in venlafaxine, 2 fluoxetine, 3 and tomoxetine 3 has been prepared by a sequence of nitrile aldol reaction and nitrile reduction. Equilibrium dissociation constants KD for binding of (_+)-2 and (_+)-3 to hSERT, hNET, and hDAT are given in Table 2." SIGNOR-259067 MAPK12 protein P53778 UNIPROT MAPT protein P10636 UNIPROT "down-regulates activity" phosphorylation Ser519 SGYSSPGsPGTPGSR -1 9199504 t miannu "Phosphorylation of tau by SAPK3 and SAPK4 markedly reduced the ability of tau to promote microtubule assembly. SAPK3 (also called ERK6 and p38) and SAPK4 phosphorylate recombinant tau protein at multiple Ser/Thr-Pro sites that are hyperphosphorylated in PHF-tau, with SAPK4 and SAPK3 being the most effective." SIGNOR-250084 SLC36A4 protein Q6YBV0 UNIPROT tryptophan smallmolecule CHEBI:27897 ChEBI "up-regulates quantity" relocalization 8355 21097500 t lperfetto "HPAT4 in Xenopus oocytes mediated sodium-independent, electroneutral uptake of [(3)H]proline, with the highest rate of uptake when the uptake medium pH was 7.4 and an affinity of 3.13 μM. Tryptophan was also an excellently transported substrate with a similarly high affinity (1.72 μM)." SIGNOR-264735 MUSK protein O15146 UNIPROT DOK7 protein Q18PE1 UNIPROT "up-regulates activity" phosphorylation Tyr395 CLPGTVEyQVPTSLR 10090 20603078 t miannu "Here, we demonstrate that Dok-7 also functions downstream from MuSK, and we identify the proteins that are recruited to the C-terminal domain of Dok-7. We show that Agrin stimulates phosphorylation of two tyrosine residues in the C-terminal domain of Dok-7, which leads to recruitment of two adapter proteins: Crk and Crk-L. Y396 and Y406 are the major tyrosine phosphorylation sites in Dok-7 expressed in C2 myotubes." SIGNOR-273845 MTOR protein P42345 UNIPROT IRS1 protein P35568 UNIPROT "down-regulates activity" phosphorylation Ser639 YMPMSPKsVSAPQQI 10116 BTO:0000452 11287630 t lperfetto "Mtor induced the serine phosphorylation of irs-1 (ser-636/639), and such phosphorylation was inhibited by rapamycin. These results suggest that tnf impairs insulin signaling through irs-1 by activation of a pi 3-kinase/akt/mtor pathway, which is antagonized by pten" SIGNOR-106590 NRXN3 protein Q9HDB5 UNIPROT NLGN2 protein Q8NFZ4 UNIPROT "up-regulates activity" binding 9606 BTO:0000142 22626546 t miannu "The neurexin–NL2 interaction is sufficient to induce GABAergic differentiation and clustering of GABAARs at postsynaptic sites" SIGNOR-265456 POLR1F protein Q3B726 UNIPROT "RNA Polymerase I" complex SIGNOR-C390 SIGNOR "form complex" binding 22260999 t lperfetto "In eukaryotic cells, the RNA polymerase Pol I synthesizes the rRNA precursor, Pol II transcribes mRNAs and small non-coding RNAs (such as small nuclear RNAs), and Pol III produces tRNAs and other small RNAs. Pol I, II and II contain 14, 12 and 17 polypeptide subunits, respectively (Table 1). " SIGNOR-266157 FUS protein P35637 UNIPROT ADARB1 protein P78563 UNIPROT "down-regulates quantity by repression" "post transcriptional regulation" 10090 BTO:0001279 28515487 f "This conclusion is also supported by the analysis of alternative splicing events in hFUS+/+; Smn+/− mice. As shown in Fig. 6b, the splicing of Dusp22, Mphosph9, Adarb1, hnRNP A2/B1, Gria4, Vps16, Atxn2 and Agrin, which are significantly affected in hFUS+/+ mice, is not further modified by SMN decrease" SIGNOR-262805 AMPK complex SIGNOR-C15 SIGNOR GBF1 protein Q92538 UNIPROT down-regulates phosphorylation Thr1337 GKIHRSAtDADVVNS 9606 18063581 t lperfetto "These results indicate that gbf1 is a novel ampk substrate and that the ampk-mediated phosphorylation of gbf1 at thr(1337) has a critical role, presumably by attenuating the function of gbf1, in the disassembly of the golgi apparatus induced under stress conditions that lower the intracellular atp concentration." SIGNOR-216588 TPSAB1 protein Q15661 UNIPROT F2RL1 protein P55085 UNIPROT "up-regulates activity" binding 10116 21999702 t lperfetto "Mast cells contribute to tissue repair in fibrous tissues by stimulating proliferation of fibroblasts through the release of tryptase which activates protease-activated receptor-2 (PAR-2).|Taken together, our data show that tryptase can stimulate myoblast proliferation and this effect is part of a signaling cascade dependent on PAR-2 activation and on the downstream activation of COX-2." SIGNOR-251744 OMG protein P23515 UNIPROT LINGO1 protein Q96FE5 UNIPROT up-regulates binding 9606 BTO:0000938 15694321 t flangone "Nogo-a, myelin-associated glycoprotein (mag), and oligodendrocyte myelin glycoprotein (omgp)...signal through a common receptor complex in neurons, which includes the ligand binding nogo-66 receptor (ngr), and two signal-transducing binding partners, p75 and lingo-1..." SIGNOR-133640 HSPB1 protein P04792 UNIPROT GCH1 protein P30793 UNIPROT "up-regulates quantity by stabilization" binding 9606 18241680 t miannu "GTP cyclohydrolase I (GCH), an oligomeric protein composed of 10 identical subunits, is required for the synthesis of neurotransmitters; mutations in GCH are associated with dopa-responsive dystonia (DRD) and hyperphenylalaninemia. Mutated GCH proteins are unstable and prone to dominant-negative effect. We show herein that expression of the GCH mutant GCH-201E or the splicing variant GCH-II caused intracellular inclusion bodies. When Hsp27 was expressed together with the GCH mutants, Hsp27 expression decreased the formation of inclusion bodies by GCH (as assessed by immunofluorescence) and decreased the amount of insoluble GCH mutant proteins (as assessed by Western blot). we demonstrated that Hsp27 increases the expression of the wild-type GCH protein, causes the appearance of the soluble GCH-II protein, and decreases the quantities of insoluble mutated GCH protein. Therefore, it is likely that Hsp27 improves the folding of mutated GCH proteins, so they can stay in free cytosolic compartment." SIGNOR-252222 NFE2L2 protein Q16236 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 BTO:0000599 26194347 f irozzo "Nrf2 was up-regulated in HCC, and expression of Nrf2 was correlated with tumor differentiation, metastasis, and tumor size. Further studies demonstrated that inhibition of Nrf2 expression inhibited proliferation by inducing apoptosis and repressed invasion, and up-regulation of Nrf2 expression resulted in opposite phenotypes." SIGNOR-256262 PRKCA protein P17252 UNIPROT GRM5 protein P41594 UNIPROT "up-regulates activity" phosphorylation Ser840 VRSAFTTsTVVRMHV -1 15894802 t lperfetto "Thus, we showed that it is phosphorylation of Ser-839, not Thr-840, that is absolutely required for the unique Ca2+ oscillations produced by mGluR5 activation. The Thr-840 residue is important only in that it is permissive for the PKC-dependent phosphorylation of Ser-839." SIGNOR-249278 ATP13A1 protein Q9HD20 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 BTO:0004093 29650961 f doi.org/10.1101/185272 francesca "Loss of ATP13A3 led to marked inhibition of serum-stimulated proliferation of BOECs, and increased apoptosis in serum-deprived conditions" SIGNOR-261216 NAB2 protein Q15742 UNIPROT TNFSF10 protein P50591 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0000782 22128144 f miannu "In the present study, we investigated the molecular basis for the differential regulation of TRAIL in helped versus helpless CD8(+) T cells by comparing their transcriptional profiles, and have identified a transcriptional corepressor, NGFI-A binding protein 2 (Nab2), that is selectively induced in helped CD8(+) T cells. Enforced expression of Nab2 prevents TRAIL induction after restimulation of primary helpless CD8(+) T cells, and expression of a dominant-negative form of Nab2 in helped CD8(+) T cells impairs their secondary proliferative response that is reversible by TRAIL blockade." SIGNOR-253893 AIFM2 protein Q9BRQ8 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR up-regulates 9606 BTO:0003000 12135761 f miannu "The PRG3 gene is a potential p53 target gene in a p53‐dependent apoptosis pathway. These results clearly indicate that the ectopic expression of PRG3 induces apoptosis." SIGNOR-261809 GOLGB1 protein Q14789 UNIPROT GOLGA2 protein Q08379 UNIPROT "up-regulates activity" binding 9606 23555793 t miannu "The “cis-golgin tether” is one of the most well-characterized golgin tether complexes. It is composed of the COPI vesicle-associated golgin giantin linked to Golgi membrane-associated GM130 via p115. GM130 is in turn linked to GRASP65 via a PDZ-like domain. GRASP65 is anchored to the Golgi membrane through N-terminal myristoylation as well as through binding to other Golgi proteins [10]. Together, these proteins appear to mediate vesicle tethering at the cis-Golgi membrane." SIGNOR-261238 SETD2 protein Q9BYW2 UNIPROT STAT1 protein P42224 UNIPROT "up-regulates activity" methylation Lys525 QLNMLGEkLLGPNAS 9606 BTO:0000007 28753426 t Gianni "SETD2 enhances antiviral immunity by directly methylating STAT1 on K525. Mechanistically, SETD2 directly mediates STAT1 methylation on lysine 525 via its methyltransferase activity, which reinforces IFN-activated STAT1 phosphorylation and antiviral cellular response." SIGNOR-269091 CDK5 protein Q00535 UNIPROT TPPP protein O94811 UNIPROT "down-regulates activity" phosphorylation Thr14 PAKAANRtPPKSPGD -1 17693641 t miannu "Here we show that TPPP induces tubulin self-assembly into intact frequently bundled microtubules, and that the phosphorylation of specific sites distinctly affects the function of TPPP. The phosphorylation sites Thr(14), Ser(18), Ser(160) for Cdk5; Ser(18), Ser(160) for ERK2, and Ser(32) for PKA were identified by mass spectrometry. The phosphorylation by ERK2 or Cdk5 resulted in the loss of microtubule-assembling activity of TPPP." SIGNOR-262933 ENO1 protein P06733 UNIPROT MYC protein P01106 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9534 BTO:0000318 2005901 t Luana "This result suggests that MBP-1 in vivo acts as a sequence-specific repressor." SIGNOR-261594 MYOD1 protein P15172 UNIPROT "SWI/SNF complex" complex SIGNOR-C92 SIGNOR up-regulates binding 9606 BTO:0001103 17194702 t lperfetto "Myod targets brg1 to the myogenin promoter during the initiation of myogenesis in tissue culture models for skeletal muscle differentiation /initiation of myogenin transcription is dependent upon myod, the pbx homeodomain factor, and swi/snf chromatin-remodeling enzymes" SIGNOR-217737 SRC protein P12931 UNIPROT TERT protein O14746 UNIPROT down-regulates phosphorylation Tyr707 QDPPPELyFVKVDVT 9606 12808100 t lperfetto "Hydrogen peroxide triggers nuclear export of telomerase reverse transcriptase via src kinase family-dependent phosphorylation of tyrosine 707" SIGNOR-102097 SCF-betaTRCP complex SIGNOR-C5 SIGNOR WEE1 protein P30291 UNIPROT down-regulates binding 9606 15340381 t lperfetto "Scfb-trcp continues to have a role in this phase, however, through its induced degradation of the cdk1 inhibitor, wee1." SIGNOR-217184 G8RGG88B68 smallmolecule SID:135317436 ChEBI IFNAR2 protein P48551 UNIPROT "up-regulates activity" "chemical activation" -1 15898717 t miannu "To significantly improve the pharmacological properties of the drug, a pegylated form of IFNalpha(2a) was developed (PEGASYS). This 40 kDa PEG-conjugated IFNalpha(2a) ((40)PEG-IFNalpha(2a)) is obtained by the covalent binding of one 40 kDa branched PEG-polymer to a lysine side-chain of IFNalpha(2a). Here, we report the detailed structural, kinetic, and thermodynamic analysis of the binding to the extracellular domain of the receptor IFNAR2 of (40)PEG-IFNalpha(2a) and its isolated positional isomers modified at K31, K134, K131, K121, K164, and K70, respectively, in comparison with unmodified IFNalpha(2a)." SIGNOR-259391 1-[6-(2-hydroxypropan-2-yl)-2-pyridinyl]-6-[4-(4-methyl-1-piperazinyl)anilino]-2-prop-2-enyl-3-pyrazolo[3,4-d]pyrimidinone chemical CHEBI:91414 ChEBI WEE1 protein P30291 UNIPROT down-regulates "chemical inhibition" 9606 20068082 t gcesareni "Mk-1775 (merck). This wee1 inhibitor (ic50, 5.2nm) potentiates the activity of dna-damaging agents (e.g., gemcitabine, cisplatin, carboplatin) in vitro and in vivo, particularly in p53-negative cancers" SIGNOR-163173 SYK protein P43405 UNIPROT IKZF1 protein Q13422 UNIPROT up-regulates phosphorylation Ser364 GTPRSNHsAQDSAVE 9606 BTO:0001271 23071339 t miannu "Syk phoshorylatesikarosat unique c-terminal serine phosphorylation sites s358 and s361, thereby augmenting its nuclear localization and sequence-specific dna binding activity. Mechanistically, we establish that syk-inducedikarosactivation is essential for its nuclear localization and optimal transcription factor function." SIGNOR-199100 edrophonium chemical CHEBI:251408 ChEBI ACHE protein P22303 UNIPROT "down-regulates activity" "chemical inhibition" -1 9301662 t miannu "With the aim of performing a rigorous test of the anti-AChE properties of our compounds, the kinetics of enzyme inhibition were studied in purified enzyme preparations. The inhibition data are shown in Table 1. Additionally, known competitive inhibitors of AChE (procainamide and edrophonium) were included in the study for comparative purposes." SIGNOR-258667 IL15RA protein Q13261 UNIPROT TYK2 protein P29597 UNIPROT up-regulates 9606 30029643 t "Since Jak-STAT pathway primarily activated in IL-15-me- diated cell proliferation, we tested whether it is also participates in IL-15-mediated proliferation of FAPs. Interestingly, we found the expression of phospho-Jak3 and phospho-Tyk2, as well as their downstream, phospho- STAT3 and phospho-STAT5, was significantly upregulated" SIGNOR-256253 PLPPR1 protein Q8TBJ4 UNIPROT RASGEF1A protein Q8N9B8 UNIPROT "up-regulates activity" binding 9606 BTO:0002036 27058420 t miannu "Oncogenic effects of imbalanced PRG3 are mediated via PRG3-RasGEF1 interaction and Ras activation. PRG3 interacts with RasGEF1 in vivo.We could further show that PRG3 executes the binding to RasGEF1 predominantly via its C-terminal domain (CT) and in the consequence causes Ras activation." SIGNOR-261807 BCS1L protein Q9Y276 UNIPROT LETM1 protein O95202 UNIPROT "up-regulates activity" binding 9606 BTO:0000567 18628306 t lperfetto "LETM1 was co-precipitated with BCS1L and formation of the LETM1 complex depended on BCS1L levels, suggesting that BCS1L stimulates the assembly of the LETM1 complex." SIGNOR-262543 LMO1 protein P25800 UNIPROT TAL1 protein P17542 UNIPROT up-regulates binding 9606 BTO:0000782;BTO:0001271 9020185 t miannu "Transcriptional activity of tal1 in t cell acute lymphoblastic leukemia (t-all) requires rbtn1 or -2" SIGNOR-46114 CDK5 protein Q00535 UNIPROT TP53 protein P04637 UNIPROT up-regulates phosphorylation Ser15 PSVEPPLsQETFSDL 9606 BTO:0000938 17591690 t gcesareni "Here, we demonstrate for the first time that cdk5 interacts with p53 and increases its stability through posttranslational regulation, leading to accumulation of p53, particularly in the nucleus. We show that cdk5 phosphorylates p53 on ser15, ser33 and ser46 in vitro," SIGNOR-156414 PPP2CA protein P67775 UNIPROT CHEK1 protein O14757 UNIPROT "down-regulates activity" dephosphorylation Ser317 ENVKYSSsQPEPRTG 9606 17015476 t "Phosphorylation of Chk1 by ATR is antagonized by a Chk1-regulated protein phosphatase 2A circuit|In response to genotoxic stress, Chk1 is phosphorylated on serines 317 (S317) and 345 (S345) by the ataxia-telangiectasia-related (ATR) protein kinase. Phosphorylation of Chk1 on these C-terminal serine residues is used as an indicator of Chk1 activation in vivo." SIGNOR-248616 ITGB4 protein P16144 UNIPROT PIK3CD protein O00329 UNIPROT up-regulates binding 9606 9428518 t gcesareni "Stable expression of alpha6beta4 increased carcinoma invasion in a pi3k-dependent manner, and transient expression of a constitutively active pi3k increased invasion in the absence of alpha6beta4. Ligation of alpha6beta4 stimulated significantly more pi3k activity than ligation of beta1 integrins, establishing specificity among integrins for pi3k activation." SIGNOR-54700 DCC protein P43146 UNIPROT CACNA1A protein O00555 UNIPROT "up-regulates activity" 9606 12827203 t miannu "DCC activation by a netrin-1 gradient creates a high-level [Ca2+]i gradient by triggering LCC activity and by stimulating the cAMP–PKA pathway, which further activates LCC in the plasma membrane (PM) and Ca2+ channels in the ER." SIGNOR-268293 JAK1 protein P23458 UNIPROT STAT3 protein P40763 UNIPROT "up-regulates activity" binding 9606 24710148 t lperfetto "The binding of lif to the lifr induces its heterodimerization with gp130. The formation of this complex results in the activation of the receptor-associated janus kinases (jaks), in the phosphorylation of receptor docking sites, and finally in the recruitment of src homology-2 (sh2) domain containing proteins such as stat3 (signal transducer and activator of transcription 3)." SIGNOR-236369 KAT2B protein Q92831 UNIPROT H3C15 protein Q71DI3 UNIPROT "down-regulates activity" acetylation Lys10 RTKQTARkSTGGKAP 9606 SIGNOR-C465 34811519 t "Acetlyation of H3 causes transcriptional activation, thus has an inhibitory role on H3" lperfetto "The HAT module within the SAGA and ADA complexes acetylates histone H3, mainly on residues K9 and K14." SIGNOR-269618 PRKDC protein P78527 UNIPROT HNRNPU protein Q00839 UNIPROT up-regulates phosphorylation Ser59 AMEPGNGsLDLGGDS 9606 19351595 t lperfetto "We identify heterogeneous nuclear ribonucleoprotein u (hnrnp-u), also termed scaffold attachment factor a (saf-a), as a specific substrate for dna-pk. We show that hnrnp-u is phosphorylated at ser59 by dna-pk in vitro and in cells in response to dna double-strand breaks" SIGNOR-185058 AURKB protein Q96GD4 UNIPROT "Histone H3" proteinfamily SIGNOR-PF69 SIGNOR up-regulates phosphorylation 9606 10464286 t gcesareni "Phosphorylation at ser-11 (h3s10ph) by aurkb is crucial for chromosome condensation and cell-cycle progression during mitosis and meiosis." SIGNOR-265321 CSNK2A2 protein P19784 UNIPROT PTPN1 protein P18031 UNIPROT unknown phosphorylation -1 9600099 t llicata "In this study, we demonstrate that HPTP1B are multiple phosphorylated on threonine and tyrosine as well as serine near its N-terminus by CKII and p60c-src in vitro." SIGNOR-251028 CHEK1 protein O14757 UNIPROT MDM4 protein O15151 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser367 PDCRRTIsAPVVRPK 9606 18356162 t lperfetto "The chk1 and chk2 kinases have also been shown to phosphorylate ser367, leading to 14-3-3 binding (34_36, 38, 44). In both cases, the outcome differed: in chk1-mediated phosphorylation, mdmx was translocated to the cytoplasm;in chk2-mediated phosphorylation, mdmx was degraded (34_36, 38, 44). It is possible that the damage response is mediated through additional phosphorylation sites other than ser367 and that, depending on the type of damage, certain sites will be modified, leading to different outcomes." SIGNOR-178067 FOS protein P01100 UNIPROT STAR protein P49675 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 19022561 t miannu "We found that both SF1 and LRH1 can transcriptionally cooperate with the AP-1 family members c-JUN and c-FOS, known to be associated with enhanced proliferation of endometrial carcinoma cells, to further enhance activation of the STAR, HSD3B2, and CYP19A1 PII promoters." SIGNOR-254878 IRX2 protein Q9BZI1 UNIPROT CXCL10 protein P02778 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0003885 26560478 f Luana "Our results imply that the IRX2 transcription factor might represent a novel metastasis associated protein that acts as a negative regulator of cellular motility and as a repressor of chemokine expression. " SIGNOR-266042 TIRAP protein P58753 UNIPROT MYD88 protein Q99836 UNIPROT "up-regulates activity" binding 9606 25948473 t lperfetto "Stimulation of Toll-like receptor (TLR) 4 leads to the activation of both MyD88-dependent and MyD88-independent pathways through the recruitment of adaptors TIRAP/MyD88 and TRIF/TRAM, respectively." SIGNOR-110215 CSNK2A1 protein P68400 UNIPROT IRS1 protein P35568 UNIPROT unknown phosphorylation Thr502 TPGTGLGtSPALAGD -1 8349691 t llicata "These data suggest that casein kinase II mediates a portion of the insulin-stimulated serine/threonine phosphorylation of overexpressed IRS-1 in vivo. | Thr-502 was identified as the major casein kinase II-catalyzed phosphorylation site in rat IRS-1." SIGNOR-250906 CSNK2A2 protein P19784 UNIPROT PPP1R2 protein P41236 UNIPROT "up-regulates activity" phosphorylation Ser87 GDDEDACsDTEATEA -1 8288648 t llicata "Recombinant wild-type I-2 and the Ala-120/121 mutant were phosphorylated synergistically by GSK-3 and casein kinase II. The Thr-72 and Ser-86 mutants, however, did not undergo this synergistic phosphorylation. Our studies indicate that Thr-72 is the only GSK-3 site and that Ser-86 is the casein kinase II site required for the potentiation of GSK-3 action." SIGNOR-251022 CSNK2A1 protein P68400 UNIPROT AQP4 protein P55087 UNIPROT "down-regulates activity" phosphorylation Ser285 MEVEDNRsQVETDDL 9615 BTO:0000837 11742978 t llicata "We found that the stress-induced kinase casein kinase (CK)II phosphorylates the Ser276 immediately preceding the tyrosine motif, increasing AQP4-mu 3A interaction and enhancing AQP4-lysosomal targeting and degradation. AQP4 phosphorylation by CKII may thus provide a mechanism that regulates AQP4 cell surface expression. | To determine whether Ser276 is an actual CKII substrate, we used GST–AQP4-Cter proteins in which only one out of the three C-terminal CKII consensus sites was sequentially conserved (Ser276, Ser285 and Ser315, respectively). Figure 7B (right panel) shows that the three serine residues, including Ser276, were indeed efficiently phosphorylated by CKII." SIGNOR-250827 PKN1 protein Q16512 UNIPROT RAF1 protein P04049 UNIPROT up-regulates phosphorylation Ser339 PRGQRDSsYYWEIEA 9606 15849194 t llicata "P21-activated kinase 1 (pak1)-dependent phosphorylation of raf-1 regulates its mitochondrial localization, phosphorylation of bad, and bcl-2 association. moreover, the mitochondrial translocation of raf-1 and the interaction between raf-1 and bcl-2 are regulated by raf-1 phosphorylation at ser-338/ser-339." SIGNOR-135679 SMAD7 protein O15105 UNIPROT BMPR1B protein O00238 UNIPROT down-regulates 10090 10564272 f gcesareni "We found that both smad6 and smad7 inhibit the activation of smad1 and smad5 by bmpr-ia/alk-3 and bmpr-ib/alk-6, as well as that by alk-2" SIGNOR-236864 CAMK4 protein Q16566 UNIPROT NOS1 protein P29475 UNIPROT "down-regulates activity" phosphorylation Ser852 SYKVRFNsVSSYSDS 10400690 t llicata "It was found that purified recombinant nNOS was phosphorylated by CaM-K Ialpha, CaM-K IIalpha, and CaM-K IV at Ser847 in vitro. Replacement of Ser847 with Ala (S847A) prevented phosphorylation by CaM kinases. Phosphorylated recombinant wild-type nNOS at Ser847 (approximately 0.5 mol of phosphate incorporation into nNOS) exhibited a 30% decrease of Vmax with little change of both the Km for L-arginine and Kact for CaM relative to unphosphorylated enzyme. The activity of mutant S847D was decreased to a level 50-60% as much as the wild-type enzyme. The decreased NOS enzyme activity of phosphorylated nNOS at Ser847 and mutant S847D was partially due to suppression of CaM binding, but not to impairment of dimer formation which is thought to be essential for enzyme activation." SIGNOR-250713 NFKBIZ protein Q9BYH8 UNIPROT IL17A protein Q16552 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 BTO:0000782 20383124 t Luana "In cooperation with RORγt and RORα, IκBζ enhances Il17a expression by binding directly to the regulatory region of the Il17a gene. " SIGNOR-266210 ABL1 protein P00519 UNIPROT PRKN protein O60260 UNIPROT down-regulates phosphorylation Tyr143 SPAGRSIyNSFYVYC 9606 BTO:0000142 20823226 t llicata "Here we show that the nonreceptor tyrosine kinase c-abl phosphorylates tyrosine 143 of parkin, inhibiting parkin's ubiquitin e3 ligase activity and protective function." SIGNOR-167853 ITGB1 protein P05556 UNIPROT "A11/b1 integrin" complex SIGNOR-C168 SIGNOR "form complex" binding 16988024 t lperfetto "Integrins are one of the major families of cell adhesion receptors (Humphries, 2000; Hynes, 2002). All integrins are non-covalently-linked, heterodimeric molecules containing an α and a β subunit. Both subunits are type I transmembrane proteins, containing large extracellular domains and mostly short cytoplasmic domains (Springer and Wang, 2004; Arnaout et al., 2005). Mammalian genomes contain 18 α subunit and 8 β subunit genes, and to date 24 different α,β combinations have been identified at the protein level. Although some subunits only appear in a single heterodimer, twelve integrins contain the β1 subunit, and five contain αV." SIGNOR-253188 glutaryl-CoA(5-) smallmolecule CHEBI:57378 ChEBI "coenzyme A(4-)" smallmolecule CHEBI:57287 ChEBI "up-regulates quantity" "precursor of" 33148467 t lperfetto "The acyl-CoA thioesterase (ACOT) family catalyses the hydrolysis of acyl-CoA thioesters to their corresponding non-esterified fatty acid and coenzyme A (CoA)." SIGNOR-271816 FADS3 protein Q9Y5Q0 UNIPROT "long-chain fatty acyl-CoA(4-)" smallmolecule CHEBI:83139 ChEBI "down-regulates quantity" "chemical modification" 9606 15189125 t miannu "Fatty acid desaturases introduce a double bond in a specific position of long-chain fatty acids, and are conserved across kingdoms. Three desaturases, Delta9, Delta6, and Delta5, are present in humans. Delta-9 catalyzes synthesis of monounsaturated fatty acids. Oleic acid, a main product of Delta9 desaturase, is the major fatty acid in mammalian adipose triglycerides, and is also used for phospholipid and cholesteryl ester synthesis. Delta-6 and Delta5 desaturases are required for the synthesis of highly unsaturated fatty acids (HUFAs), which are mainly esterified into phospholipids and contribute to maintaining membrane fluidity." SIGNOR-267909 NFATC3 protein Q12968 UNIPROT GPC6 protein Q9Y625 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000150 21871017 t miannu "NFAT transcriptionally regulates GPC6 induction in breast cancer cells and binds to three regulatory elements in the GPC6 proximal promoter. Expression of GPC6 in response to NFAT signalling promotes invasive migration, whereas GPC6 silencing with shRNA (small-hairpin RNA) potently blocks this phenotype." SIGNOR-264024 CSNK2A1 protein P68400 UNIPROT SPIB protein Q01892 UNIPROT down-regulates phosphorylation Ser129 PYPSPVLsEEEDLPL 9606 10618498 t lperfetto "Serine residues 37 in the transactivation domain and 129, 144 and 146 in the pest domain of spi-b are phosphorylated by ckii in vitro. The ckii phosphorylation sites mapped in vitro are phosphorylated in vivo. Mutations of the ckii phosphorylation sites increase the ability of spi-b to transactivate. Spi-b phosphorylation by ckii reduces its stability" SIGNOR-73879 AKT proteinfamily SIGNOR-PF24 SIGNOR STK3 protein Q13188 UNIPROT down-regulates phosphorylation Thr384 GTMKRNAtSPQVQRP 9606 20086174 t lperfetto "We determined that mst2 phosphorylation by akt limits mst2 activity in two ways: first, by blocking its binding to rassf1a and by promoting its association into the raf-1 inhibitory complex, and second, by preventing homodimerization of mst2, which is needed for its activation. we identified t117 and t384 as akt phosphorylation sites in mst2." SIGNOR-244349 N-(2,3-dihydro-1,4-benzodioxin-2-ylmethyl)-2-(2,6-dimethoxyphenoxy)ethanamine chemical CHEBI:64098 ChEBI ADRA1B protein P35368 UNIPROT "down-regulates activity" "chemical inhibition" 10029 BTO:0000246 7651358 t miannu "Membrane preparations from CHO cells stably transfected with the cloned human a1-AR genes showed saturable binding of [‘251]HEAT; Bm,,ı values were 1.3 ± 0.2, 5.5 ± 0.1, and 1.1 ± 0.1 pmol/mg of protein, with Kd values of 110 ± 21, 60 ± 1, and 300 ± 26 ıM (three experiments each), for the ala-, alb-, and ald-ARS, respectively. The potencies of a1-AR agonists and antagonists at the cloned human a1-ARs are shown in Table 1." SIGNOR-258466 tRNA(His) smallmolecule CHEBI:29178 ChEBI His-tRNA(His) smallmolecule CHEBI:29155 ChEBI "up-regulates quantity" "precursor of" 9606 10430027 t miannu "Histidyl-tRNA synthetase (HisRS) is responsible for the synthesis of histidyl-transfer RNA, which is essential for the incorporation of histidine into proteins. This amino acid has uniquely moderate basic properties and is an important group in many catalytic functions of enzymes." SIGNOR-270491 ABL1 protein P00519 UNIPROT LGALS3 protein P17931 UNIPROT unknown phosphorylation Tyr79 GAPAPGVyPGPPSGP 9606 20600357 t llicata "In this report we have identified novel tyrosine phosphorylation sites in galectin-3 as well as the kinase responsible for its phosphorylation. Our results demonstrate that tyrosines at positions 79, 107 and 118 can be phosphorylated in vitro and in vivo by c-abl kinase. our results demonstrate that cells expressing galectin-3 y107f variant showed reduced migration in wound healing assay ( fig. 5). This result confirms the role of galectin-3 tyrosine phosphorylation in cell motility." SIGNOR-166501 "CCT365623 (hydrochloride)" chemical CID:139266765 PUBCHEM LOX protein P28300 UNIPROT "down-regulates activity" "chemical inhibition" 9606 BTO:0000195 31070916 t "Simone Vumbaca" "Further SAR optimization yielded the orally bioavailable LOX inhibitor CCT365623 with good anti-LOX potency, selectivity, pharmacokinetic properties, as well as anti-metastatic efficacy." SIGNOR-261121 TFIIE complex SIGNOR-C458 SIGNOR TFIIH complex SIGNOR-C457 SIGNOR "up-regulates activity" relocalization 9606 31064989 t lperfetto "The heterodimer TFIIE (composed of the TFIIEα and TFIIEβ subunits) seems to play a pivotal role in transcription by directly influencing the transition from initiation to elongation3,4. TFIIE interacts with different factors within the PIC, including Pol II5,6 as well as with DNA immediately upstream of the transcription bubble region7,8. Furthermore, TFIIE seems to influence TFIIH activity9, although it is not clear how this molecular process can occur." SIGNOR-269362 KLF15 protein Q9UIH9 UNIPROT RBP3 protein P10745 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0000007 15277472 f miannu "KLF15 repressed transactivation of rhodopsin and IRBP promoters alone and in combination with the transcriptional activators Crx and/or Nrl." SIGNOR-253816 MRPS2 protein Q9Y399 UNIPROT "28S mitochondrial small ribosomal subunit" complex SIGNOR-C266 SIGNOR "form complex" binding P82664 9606 25838379 t miannu "The mammalian mitochondrial ribosome (mitoribosome) has a highly protein-rich composition with a small sedimentation coefficient of 55 S, consisting of 39 S large and 28 S small subunits. . We report here the identification of 28 S small subunit proteins." SIGNOR-261449 NFYB protein P25208 UNIPROT NFY complex SIGNOR-C1 SIGNOR "form complex" binding 9606 9885213 t lperfetto "Nf-y is one of the best characterized ccaat binding proteins, and its unique structure and evolutionary conservation suggest that it plays a crucial role in transcription of eukaryotic genes.It Is a ubiquitous heteromeric transcription factor, composed of three subunits, nf-ya, nf-yb, and nf-yc, all necessary for dna binding." SIGNOR-63016 GSK3A protein P49840 UNIPROT MAFA protein Q8NHW3 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser49 CHRLPPGsLSSTPLS 9606 18042454 t miannu "We also demonstrate that gsk-3 triggers mafa sequential phosphorylation on residues s61, t57, t53, and s49 /we demonstrated that phosphorylation by gsk-3 is conserved among the large maf proteins. It couples ubiquitination/degradation and transcriptional activation and modulates maf biological activity./ Taken together, these results suggest that, in contrast to what can be expected from ubiquitination/degradation, gsk-3-mediated mafa phosphorylation increases its transactivating ability, thereby controlling its biological activity." SIGNOR-159381 FOXO proteinfamily SIGNOR-PF27 SIGNOR CDKN2D protein P55273 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 17873901 f gcesareni "Foxo1a strongly activated p15ink4b transcription and p19ink4d transcription, while foxo3a showed higher p19ink4d transcription activity than p15ink4b transcription activity" SIGNOR-252918 METTL3 protein Q86U44 UNIPROT WWTR1 protein Q9GZV5 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000007;BTO:0000567 27117702 t miannu "Here we find that METTL3 promotes translation of certain mRNAs including epidermal growth factor receptor (EGFR) and the Hippo pathway effector TAZ in human cancer cells. " SIGNOR-265955 AMFR protein Q9UKV5 UNIPROT MFN2 protein O95140 UNIPROT "down-regulates quantity by destabilization" polyubiquitination 9534 BTO:0000298 23427266 t miannu "Gp78 induces ubiquitylation and proteasomal degradation of Mfn1 and Mfn2." SIGNOR-272887 TAOK3 protein Q9H2K8 UNIPROT STK3 protein Q13188 UNIPROT up-regulates phosphorylation 9606 23431053 t gcesareni "In addition, the thousand-and-one (tao) amino acids kinase or taok1 3 has been shown to directly phosphorylate and activate hpo or mst1/2" SIGNOR-201333 TRAPPC9 protein Q96Q05 UNIPROT IKBKB protein O14920 UNIPROT "up-regulates activity" binding 9606 BTO:0000007 15951441 t miannu "We demonstrated by immunohistochemistry that NIBP expression in the brain is localized to neurons. NIBP physically interacts with NIK, IKK(beta), but not IKK(alpha) or IKK(gamma). NIBP overexpression potentiates tumor necrosis factor-alpha-induced NF-kappaB activation through increased phosphorylation of the IKK complex and its downstream I(kappa)B(alpha) and p65 substrates." SIGNOR-269673 ADIPOQ protein Q15848 UNIPROT ADIPOR2 protein Q86V24 UNIPROT up-regulates binding 9606 16622416 t milica "Two adiponectin receptors, adipor1 and adipor2, have recently been identified." SIGNOR-146173 SLC24A3 protein Q9HC58 UNIPROT calcium(2+) smallmolecule CHEBI:29108 ChEBI "down-regulates quantity" relocalization 9606 30173760 t miannu "K+-dependent Na+-Ca2+ Exchangers (NCKX) are bi-directional plasma membrane Ca2+ transporters which belong to the Solute Carrier Family 24 A (SLC24 A) of membrane transporters. NCKXs operate via the alternating access model and mediate the extrusion of one Ca2+ ion coupled with one K+ ion in exchange for four Na+ ions (4Na+↔ 1Ca2+ + 1 K+)" SIGNOR-264391 GAPDHS protein O14556 UNIPROT "3-phosphonato-D-glyceroyl phosphate(4-)" smallmolecule CHEBI:57604 ChEBI "up-regulates quantity" "chemical modification" 9606 11724794 t miannu "GAPDH is commonly known as a key enzyme in glycolysis (GAPDH catalyzes the NAD-mediated oxidative phosphorylation of glyceraldehyde 3-phosphate to 1,3-diphosphoglycerate), a number of intriguing intracellular roles have been reported including modulation of the cytoskeleton, kinase activity, and the promotion of vesicle fusion" SIGNOR-266497 PLK1 protein P53350 UNIPROT VIM protein P08670 UNIPROT up-regulates phosphorylation Ser83 GVRLLQDsVDFSLAD 9606 BTO:0000150 18056432 t gcesareni "We observed that plk1 phosphorylates vimentin on ser82, which in turn regulates cell surface levels of 1 integrin." SIGNOR-159386 SLIT2 protein O94813 UNIPROT ROBO4 protein Q8WZ75 UNIPROT up-regulates binding 9606 BTO:0000938 12941633 t gcesareni "We show that robo4 binds slit and inhibits cellular migration in a heterologous expression system, analogous to the role of known robo receptors in the nervous system." SIGNOR-86380 PRKACA protein P17612 UNIPROT SRSF1 protein Q07955 UNIPROT up-regulates phosphorylation Ser119 YGPPSRRsENRVVVS 9606 22393468 t llicata "Here, we show that pka phosphorylates srsf1 on serine 119 in vitro. Phosphorylation of srsf1 on this site enhanced the rna binding capacity of srsf1 in vivo" SIGNOR-196397 CSNK1A1 protein P48729 UNIPROT TUT1 protein Q9H6E5 UNIPROT "up-regulates activity" phosphorylation Ser6 sDVESLPR 9606 BTO:0000007 26138484 t done miannu "We identified a phosphorylated residue (serine 6, S6) on Star-PAP in the zinc finger region, the domain required for PIPKIα interaction. We show that S6 is phosphorylated by CKIα within the nucleus which is required for Star-PAP nuclear retention and interaction with PIPKIα. " SIGNOR-273619 FUBP1 protein Q96AE4 UNIPROT CCND2 protein P30279 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 19637194 f irozzo "A positive cell cycle regulator that we found down-regulated in Hep3B cells upon FBP1 inactivation was cyclin D2. In addition, Cyclin D2 mRNA levels were diminished in the FBP1 knockdown cells, whereas the amount of Cyclin D1 mRNA remained unaffected. Numerous studies have classified D-type cyclins as cell cycle–promoting oncoproteins important for cellular transformation, and our results suggest that cyclin D2 is a candidate FBP1-regulated oncoprotein in HCC." SIGNOR-259124 MRPL37 protein Q9BZE1 UNIPROT "39S mitochondrial large ribosomal subunit" complex SIGNOR-C285 SIGNOR "form complex" binding -1 25838379 t lperfetto "We have determined the structure of the intact mitoribosome to 3.5 angstrom resolution by single-particle electron cryo-microscopy. It reveals 80 extensively interconnected proteins, 36 of which are specific to mitochondria, and three rRNA molecules" SIGNOR-262360 dothiepin chemical CHEBI:36798 ChEBI CHRM4 protein P08173 UNIPROT "down-regulates activity" "chemical inhibition" 10029 BTO:0000246 8100134 t miannu "Antagonism of the five cloned human muscarinic cholinergic receptors expressed in CHO-K1 cells by antidepressants and antihistaminics. Competition between [‘H]QNB and the antidepressant compounds (Table 1) showed that at the ml subtype the most potent drugs were amitriptyline > dothiepin > doxepin = nortriptyline; at the m2 receptor, amitriptyline > imipramine > nortriptyline = dothiepin; at the m3 recep- tor, amitriptyline > dothiepin > nortriptyline; at the m4 receptor, amitriptyline > dothiepin > doxepin = nortrip- tyline; and at the m5 receptor, amitriptyline > doxepin > imipramine." SIGNOR-258698 AMER1 protein Q5JTC6 UNIPROT AXIN1 protein O15169 UNIPROT "up-regulates activity" relocalization 9606 SIGNOR-C110 21304492 t gcesareni "Amer1 binds ck1gamma, recruits axin and gsk3beta to the plasma membrane and promotes complex formation between axin and lrp6." SIGNOR-171886 DVL1P1 protein P54792 UNIPROT CCDC88C protein Q9P219 UNIPROT up-regulates binding 9606 23151663 t gcesareni "Daple binds to dvl and functions as a negative regulator of the wnt signalling pathway." SIGNOR-199448 SRGAP1 protein Q7Z6B7 UNIPROT RAC1 protein P63000 UNIPROT "down-regulates activity" "gtpase-activating protein" 9606 BTO:0000007 32203420 t Luana "We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2)." SIGNOR-260515 CyclinK/CDK13 complex SIGNOR-C38 SIGNOR POLR2A protein P24928 UNIPROT "up-regulates activity" phosphorylation Ser1917 SPTSPTYsPTSPKYS 9606 BTO:0006413 32917631 t "Ser2 in CTD of PolII" lperfetto "Together, these studies demonstrate the important, yet largely redundant, role for CDK12 and CDK13 for the regulation of POLII CTD phosphorylation at multiple residues, as well as the global role for both of these kinases in regulating POLII occupancy across the genome.|CDK12 and CDK13 are thus evolutionarily related and structurally similar kinases, and biochemical assays have demonstrated that both have POLII C-terminal domain (CTD) kinase activity and the ability to phosphorylate the Ser2 residue of the repetitive CTD heptad sequence" SIGNOR-273075 "perfluorooctane-1-sulfonic acid" chemical CHEBI:39421 ChEBI AR protein P10275 UNIPROT "down-regulates activity" "chemical inhibition" -1 23764977 t miannu "Seven PFCs [perfluorohexane sulfonate (PFHxS), perfluorooctane sulfonate (PFOS), perfluorooctanoate (PFOA), perfluorononanoate (PFNA), perfluorodecanoate (PFDA), perfluoroundecanoate (PFUnA), and perfluorododecanoate (PFDoA)] were analyzed in vitro for their potential to affect estrogen receptor (ER) and androgen receptor (AR) transactivity as well as aromatase enzyme activity. The PFCs were assessed as single compounds and in an equimolar mixture. PFHxS, PFOS and PFOA significantly induced the ER transactivity, whereas PFHxS, PFOS, PFOA, PFNA and PFDA significantly antagonized the AR activity in a concentration-dependent manner. " SIGNOR-268767 CDK1 protein P06493 UNIPROT BRCA1 protein P38398 UNIPROT up-regulates phosphorylation Ser1189 QKGELSRsPSPFTHT 9606 BTO:0000551 19683496 t gcesareni "However, shrna-mediated depletion of cdk1 alone or small molecule cdk1 inhibition abrogated s phase cell-cycle arrest and the phosphorylation of a subset of atr/atm targets after dna damage. Loss of dna damage-induced checkpoint control was caused by a reduction in formation of brca1-containing foci. Mutation of brca1 at s1497 and s1189/s1191 resulted in loss of cdk1-mediated phosphorylation and also compromised formation of brca1-containing foci." SIGNOR-187595 ipilimumab antibody DB06186 DRUGBANK CTLA4 protein P16410 UNIPROT "down-regulates activity" binding 9606 BTO:0005594 18049334 t miannu "The inhibitory receptor CTLA4 has a key role in peripheral tolerance of T cells for both normal and tumor-associated antigens. CTLA4 blockade with ipilimumab induces cancer regression in some patients with metastatic clear cell renal cancer, even if they have not responded to other immunotherapies." SIGNOR-259894 PTK2 protein Q05397 UNIPROT GRB2 protein P62993 UNIPROT "up-regulates activity" binding 15688067 t miannu "Src-mediated phosphorylation of FAK at Tyr925 creates an SH2 binding site for the growth-factor-receptor-bound protein 2 (GRB2) adaptor protein, which leads to the activation of Ras and the extracellular signal-regulated kinase-2 (ERK2) cascade." SIGNOR-257733 MAPKAPK2 protein P49137 UNIPROT HSPA1L protein P34931 UNIPROT "up-regulates activity" phosphorylation Ser241 DFDNRLVsHFVEEFK -1 31642047 t done miannu " We demonstrate that MK2 phosphorylates HspA1L solely on Ser241, a residue within the N-terminal nucleotide-binding domain of the enzyme. This phosphorylation event enhances the chaperone activity of HspA1L in vitro and renders male germ cells more resistant to heat stress-induced apoptosis." SIGNOR-273674 Dihydromorphine chemical CHEBI:4575 ChEBI OPRD1 protein P41143 UNIPROT "up-regulates activity" "chemical activation" 10029 BTO:0000246 9686407 t miannu "Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors." SIGNOR-258788 CDC5L protein Q99459 UNIPROT HNRNPM protein P52272 UNIPROT "up-regulates activity" binding 9606 BTO:0000567 20467437 t 1 miannu "hnRNP-M interacts directly with CDC5L and PLRG1 in vivo. we investigated whether the function of hnRNP-M in alternative splicing was affected by the central region mapped as essential for binding to the CDC5L/PLRG1 proteins. We conclude that loss of the CDC5L/PLRG1 interaction domain in hnRNP-M correlates with a loss of ability to modulate alternative splice site selection in this assay." SIGNOR-239410 NFE2L2 protein Q16236 UNIPROT TBXAS1 protein P24557 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 14565864 f lperfetto "Ecotopic expression of NF-E2 related factors showed that Nrf2, but not Nrf1, Nrf3, or Bach1, activated TXAS promoter in a dose-dependent manner." SIGNOR-268993 "gamma-aminobutyric acid" smallmolecule CHEBI:16865 ChEBI GABA-A proteinfamily SIGNOR-PF61 SIGNOR "up-regulates activity" "chemical activation" 9606 BTO:0000227 18790874 t miannu "Gamma-Aminobutyric acid (GABA1), the major inhibitory neurotransmitter in the brain, exerts its action via ionotropic GABAA and metabotropic GABAB receptors. GABAA receptors (GABAA-Rs) are the major inhibitory receptors in the central nervous system (CNS)." SIGNOR-264963 RNF7 protein Q9UBF6 UNIPROT HIF1A protein Q16665 UNIPROT "down-regulates activity" ubiquitination 9606 23136067 t miannu "SAG (Sensitive to Apoptosis Gene), also known as RBX2 (RING box protein 2), ROC2 (Regulator of Cullins 2), or RNF7 (RING Finger Protein 7), was originally cloned in our laboratory as a redox inducible antioxidant protein and later characterized as the second member of the RBX/ROC RING component of the SCF (SKP1-CUL-F-box Proteins) E3 ubiquitin ligase.  by forming a complex with other components of the SCF E3 ligase, SAG promotes ubiquitination and degradation of a number of protein substrates, including c-JUN, DEPTOR, HIF-1α, IκBα, NF1, NOXA, p27, and procaspase-3, thus regulating various signaling pathways and biological processes." SIGNOR-271450 "GABA-A (a4-b1-g2) receptor" complex SIGNOR-C333 SIGNOR chloride smallmolecule CHEBI:17996 ChEBI "up-regulates quantity" relocalization 9606 18790874 t brain lperfetto "GABAA receptors (GABAA-Rs) are the major inhibitory receptors in the central nervous system (CNS). |Mammalian GABAA-Rs are all anion-selective channels. Increased chloride permeability generally reduces neuronal excitability (inhibition)" SIGNOR-263813 ITGB4 protein P16144 UNIPROT PIK3CB protein P42338 UNIPROT up-regulates binding 9606 9428518 t gcesareni "Stable expression of alpha6beta4 increased carcinoma invasion in a pi3k-dependent manner, and transient expression of a constitutively active pi3k increased invasion in the absence of alpha6beta4. Ligation of alpha6beta4 stimulated significantly more pi3k activity than ligation of beta1 integrins, establishing specificity among integrins for pi3k activation." SIGNOR-54615 CDC14A protein Q9UNH5 UNIPROT MAPK6 protein Q16659 UNIPROT "down-regulates quantity by destabilization" dephosphorylation Ser684 IGIPQFHsPVGSPLK 9606 20236090 t "Reciprocally, we found that the phosphatases Cdc14A and Cdc14B (Cdc is cell-division cycle) bind to ERK3 and reverse its C-terminal phosphorylation in mitosis. Importantly, alanine substitution of the four C-terminal phosphorylation sites markedly decreased the half-life of ERK3 in mitosis, thereby linking phosphorylation to the stabilization of the kinase.|In vitro phosphorylation of a series of ERK3-deletion mutants by mitotic cell extracts revealed that phosphorylation is confined to the unique C-terminal extension of the protein. Using MS analysis, we identified four novel phosphorylation sites, Ser684, Ser688, Thr698 and Ser705, located at the extreme C-terminus of ERK3." SIGNOR-248830 MARCHF5 protein Q9NX47 UNIPROT MARCHF5 protein Q9NX47 UNIPROT "down-regulates quantity by destabilization" polyubiquitination 9606 BTO:0000567 16874301 t miannu "Rapid degradation of MITOL by autoubiquitination activity. Taken together, these results suggested that MITOL strictly controls its protein expression level by rapid degradation of MITOL through the PHD-dependent autoubiquitination activity." SIGNOR-271895 CSNK2A2 protein P19784 UNIPROT TCF7L2 protein Q9NQB0 UNIPROT "up-regulates activity" phosphorylation Ser58 ESETNQNsSSDSEAE -1 11711551 t llicata "We show here that Tcf-4 can be phosphorylated in vitro by protein kinase CK2 stoichiometrically in amino acids Ser-58-Ser-59-Ser-60. Phosphorylation of these residues does not modify the interaction of Tcf-4 with beta-catenin but reduces its association to plakoglobin. | Experiments performed using a Tcf-4 mutant with decreased interaction to plakoglobin demonstrated that binding to this protein negatively affected the transcriptional activity of Tcf-4." SIGNOR-251044 CSNK2A1 protein P68400 UNIPROT GTF2A1 protein P52655 UNIPROT "up-regulates activity" phosphorylation Ser281 DGTGDTSsEEDEDEE -1 11278496 t llicata "We now show that human TFIIA is phosphorylated in vivo on serine residues that are partially conserved between yeast and human TFIIA large subunits. Alanine substitution mutation of serine residues 316 and 321 in TFIIA alphabeta reduced TFIIA phosphorylation significantly in vivo. Additional alanine substitutions at serines 280 and 281 reduced phosphorylation to undetectable levels. Mutation of all four serine residues reduced the ability of TFIIA to stimulate transcription in transient transfection assays with various activators and promoters, indicating that TFIIA phosphorylation is required globally for optimal function." SIGNOR-250875 Mob1 proteinfamily SIGNOR-PF42 SIGNOR LATS2 protein Q9NRM7 UNIPROT up-regulates binding 9606 21084559 t "Lats1 and Lats2 are nuclear Dbf2-related (NDR) family protein kinases." gcesareni "Lats1/2 are activated by association with the highly homologous scaffold proteins mps one binder kinase activator-like 1a (mobkl1a) and 1b (mobkl1b), which are collectively referred to as mob1." SIGNOR-269957 PRKCA protein P17252 UNIPROT PTPN11 protein Q06124 UNIPROT unknown phosphorylation Ser595 GLMQQQKsFR 9606 11781100 t lperfetto " In summary, SHP2 is phosphorylated on serine residues 576 and 591 by PKC isoforms alpha, beta 1, beta 2, and eta." SIGNOR-249138 quizartinib chemical CHEBI:90217 ChEBI FLT3 protein P36888 UNIPROT "down-regulates activity" "chemical inhibition" -1 22037378 t Luana "Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here." SIGNOR-258270 pictrelisib chemical CHEBI:65326 ChEBI PI3K complex SIGNOR-C156 SIGNOR down-regulates "chemical inhibition" 9606 BTO:0000149 21876152 t gcesareni "Currently, several pi3k inhibitors, including gdc0941 (genentech) and bez235 (novartis pharmaceuticals), have entered phase i clinical trials, and in addition, isoform-specific compounds are being developed" SIGNOR-252664 TRAF6 protein Q9Y4K3 UNIPROT MAP3K7 protein O43318 UNIPROT "up-regulates activity" ubiquitination Lys34 NFEEIDYkEIEVEEV 9606 18758450 t lperfetto "Intriguingly, TGF-beta-induced TRAF6-mediated Lys 63-linked polyubiquitylation of TAK1 Lys 34 correlates with TAK1 activation. Our data show that TGF-beta specifically activates TAK1 through interaction of TbetaRI with TRAF6, whereas activation of Smad2 is not dependent on TRAF6." SIGNOR-236071 PRKACA protein P17612 UNIPROT GSK3B protein P49841 UNIPROT "down-regulates activity" phosphorylation Ser9 SGRPRTTsFAESCKP 9606 BTO:0000782 19836308 t lperfetto "Gsk3 is different from most kinases in that it is constitutively partially active and the most common regulatory mechanism is inhibition by phosphorylation of ser21 in gsk3alpha or ser9 in gsk3beta. This inhibitory phosphorylation can be mediated by several kinases, such as akt/protein kinase b (pkb), protein kinase c (pkc) and protein kinase a (pka)." SIGNOR-188577 PTGER2 protein P43116 UNIPROT EGFR protein P00533 UNIPROT up-regulates 9606 BTO:0000586 17251915 f gcesareni "Ep2 can also promote the transactivation of epidermal growth factor receptor (egfr) expressed in colon cancer cells through src, which activates the proteolytic release of the egfr ligands amphiregulin (ar) and transforming growth factor-alfa (tgfalfa)." SIGNOR-152805 "Elongator complex" complex SIGNOR-C466 SIGNOR RAB3IL1 protein Q8TBN0 UNIPROT "up-regulates activity" binding -1 15780940 t miannu "Our results raise the possibility that regulation of polarized exocytosis is an evolutionarily conserved function of the entire Elongator complex and that FD results from a dysregulation of neuronal exocytosis. Our results raise the possibility that regulation of polarized exocytosis is an evolutionarily conserved function of the entire Elongator complex and that FD results from a dysregulation of neuronal exocytosis. We show that elp1Δ suppression of sec2ts is not a result of reduced transcriptional elongation and that Elp1p physically associates with Sec2p. The Sec2p interaction domain of Elp1p is necessary for both Elp1p function and for the polarized localization of Sec2p. Mutations in human Elp1p (IKAP) are a known cause of familial dysautonomia (FD)." SIGNOR-269714 AKT proteinfamily SIGNOR-PF24 SIGNOR NIBAN1 protein Q9BZQ8 UNIPROT unknown phosphorylation Ser602 ASPARRAsAILPGVL 9606 22510990 t llicata "We demonstrate here that ultraviolet irradiation induces phosphorylation of niban at s602 by akt, which increases the association of niban with nucleophosmin and disassociation of nucleophosmin from the mdm2 complex." SIGNOR-197053 NEFL protein P07196 UNIPROT "Neurofilament L/H" complex SIGNOR-C208 SIGNOR "form complex" binding 9606 BTO:0000938 19468066 t miannu "Neurofilaments are obligate heteropolymers that are minimally comprised of the low molecular neurofilament protein L (NFL) plus the medium and/or high molecular weight proteins neurofilament protein M (NFM) and neurofilament protein H" SIGNOR-255272 MYOD1 protein P15172 UNIPROT MYOG protein P15173 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" BTO:0001103 12694204 t "Simone Vumbaca" "We conclude that MyoD is the major MRF that binds to the E-box from the myogenin promoter during differentiation." SIGNOR-255640 FZD4 protein Q9ULV1 UNIPROT DVL2 protein O14641 UNIPROT "up-regulates activity" binding 9606 27096005 t areggio "Through study of FZD4 and its associated ligand Norrin, we report that a minimum of three residues distal to the KTXXXW motif in the C-terminal tail of Frizzled-4 are essential for DVL recruitment and robust Lef/Tcf-dependent transcriptional activation in response to Norrin." SIGNOR-258958 NCAPG protein Q9BPX3 UNIPROT "Condensin I" complex SIGNOR-C341 SIGNOR "form complex" binding 9606 32445620 t miannu "The majority of higher eukaryotes, including humans, have two condensins, condensin I (CI) and II (CII) Although sharing the same SMC subunits (SMC2 and SMC4), condensin I and II have distinct non-SMC regulatory subunits, including the kleisin subunit (CAP-H and CAP-H2, respectively) and a pair of HEAT repeat subunits (CAP-D2/G and CAP-D3/G2, respectively; Figure 1B). the combined actions of both condensins contribute to formation of a nested-loop architecture necessary to achieve the highest level of chromosome compaction." SIGNOR-263902 AKT1 protein P31749 UNIPROT FOXO1 protein Q12778 UNIPROT "down-regulates activity" phosphorylation 10090 BTO:0002572 18423396 t lperfetto "Akt1/PKBalpha was found to be the major regulator of phosphorylation and nuclear export ofFoxO1, whose presence in the nucleus strongly attenuates adipocyte differentiation." SIGNOR-236206 ATP smallmolecule CHEBI:15422 ChEBI PRKAG1 protein P54619 UNIPROT down-regulates "chemical inhibition" 9606 SIGNOR-C15 21680840 t gcesareni "AMPK is an ___ heterotrimer activated by decreasing concentrations of adenosine triphosphate (ATP) and increasing AMP concentrations." SIGNOR-228607 JNK proteinfamily SIGNOR-PF15 SIGNOR KIF5C protein O60282 UNIPROT "up-regulates activity" phosphorylation Ser176 CTERFVSsPEEVMDV 9606 BTO:0000142 27013971 t miannu "JNK phosphorylates KIF5C on S176 in the motor domain; a site that we show is phosphorylated in brain. In the peroxisome cargo-bound state, S176 phosphorylated KIF5C(1-560) transports to microtubule plus ends, whereas dephosphorylated KIF5C(1-560) is bound tightly to microtubules resulting in an immobile state. As a consequence, phosphorylation of S176 can facilitate plus-end cargo transport by KIF5C(1-560)." SIGNOR-264063 ACVR1B protein P36896 UNIPROT SMAD2 protein Q15796 UNIPROT "up-regulates activity" phosphorylation 9606 11389842 t "Indirect_regulation of phosphorylation" miannu "Nodal Induces Smad Phosphorylation through ALK4 in a Cripto-Dependent Manner" SIGNOR-251943 CBL protein P22681 UNIPROT MYCBPAP protein Q8TBZ2 UNIPROT "up-regulates activity" monoubiquitination 9606 BTO:0000007 17255943 t miannu "We moreover found that AMAP1 is monoubiquitinated, rather than polyubiquitinated, by virtue of Cbl and provide evidence that the ability of AMAP1 to be monoubiquitinated is important for its involvement in invasion. " SIGNOR-272627 SRC protein P12931 UNIPROT MUC1 protein P15941 UNIPROT up-regulates phosphorylation Tyr1229 SSTDRSPyEKVSAGN 9606 11152665 t lperfetto "The c-src tyrosine kinase regulates signaling of the human df3/muc1 carcinoma-associated antigen with gsk3 beta and betBeta-catenin c-src phosphorylates the muc1 cytoplasmic domain at a yekv motif c-src-mediated phosphorylation of muc1 increases binding of muc1 and betBeta-catenin" SIGNOR-85938 CSNK2A1 protein P68400 UNIPROT MYF5 protein P13349 UNIPROT "up-regulates activity" phosphorylation Ser49 HKAELQGsDEDEHVR -1 9461343 t llicata "Here, we report that Myf-5 protein constitutes a substrate for phosphorylation in vitro by protein kinase CK2. We identified two potential phosphorylation sites at serine49 and serine133, both of which seem to be necessary for Myf-5 activity. " SIGNOR-250923 "MBD2/NuRD complex" complex SIGNOR-C337 SIGNOR Chromatine_condensation phenotype SIGNOR-PH21 SIGNOR up-regulates 9606 27098840 f miannu "The NuRD complex is a multi-protein transcriptional corepressor that couples histone deacetylase and ATP-dependent chromatin remodelling activities.In humans, an assembly of proteins called the NuRD complex makes chromatin more compact by removing acetyl groups from nucleosomes." SIGNOR-263859 clobetasol chemical CHEBI:205919 ChEBI NR3C1 protein P04150 UNIPROT "up-regulates activity" "chemical activation" 9606 4594577 t SimoneGraziosi "The clinical evaluation of a new topical corticosteroid, clobetasol propionate. An international controlled trial." SIGNOR-269217 ING2 protein Q9H160 UNIPROT MMP13 protein P45452 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0001913 19437536 f miannu "ING2 is upregulated in colon cancer and increases invasion by enhanced MMP13 expression." SIGNOR-254491 RIPK3 protein Q9Y572 UNIPROT MLKL protein Q8NB16 UNIPROT "up-regulates activity" phosphorylation Thr357 FELRKTQtSMSLGTT 10090 24012422 t gianni "MLKL comprises a four-helical bundle tethered to the pseudokinase domain, which contains an unusual pseudoactive site. Although the pseudokinase domain binds ATP, it is catalytically inactive and its essential nonenzymatic role in necroptotic signaling is induced by receptor-interacting serine-threonine kinase 3 (RIPK3)-mediated phosphorylation.[...]S345, S347, and T349 in the MLKL activation loop were phosphorylated by RIPK3 in in vitro kinase assays" SIGNOR-266429 CyclinA2/CDK2 complex SIGNOR-C83 SIGNOR CEP76 protein Q8TAP6 UNIPROT "down-regulates activity" phosphorylation Ser83 VEQELPSsPKQPICF 9606 BTO:0001938 27065328 t miannu "Mechanistically, Cep76 phosphorylation inhibits activation of polo-like kinase 1 (Plk1), thereby blocking premature centriole disengagement and subsequent amplification. we conclude that Cep76 inhibits centriole disengagement and consequently amplification by blocking Plk1 activation at the centrosome." SIGNOR-262730 BRCA1 protein P38398 UNIPROT FOXC2 protein Q99958 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0000150 22120723 f miannu "We show that the BRCA1-GATA3 interaction is important for the repression of genes associated with triple-negative and basal-like breast cancer (BLBCs) including FOXC1, and that GATA3 interacts with a C-terminal region of BRCA1. We demonstrate that this BRCA1-GATA3 repression complex is not a FOXC1-specific phenomenon as a number of other genes associated with BLBCs such as FOXC2, CXCL1 and p-cadherin were also repressed in a similar manner." SIGNOR-253760 CSNK2A2 protein P19784 UNIPROT EIF4EBP1 protein Q13541 UNIPROT "down-regulates activity" phosphorylation Ser112 KRAGGEEsQFEMDI 9606 BTO:0000007 9806882 t lperfetto "The kinase is quite distinct from casein kinase 2, which also phosphorylates Ser-111 of 4E-BP1. The possible importance of these kinases in the phosphorylation of 4E-BP1 in fat cells is discussed. It is suggested that the phosphorylation of Ser-111 might be a priming event that facilitates the subsequent phosphorylation of Thr-36, Thr-45, Ser-64 and Thr69 by a rapamycin-sensitive process that initiates the dissociation of 4E-BP1 from eIF4E and hence the formation of the eIF4F complex." SIGNOR-249334 PAX3 protein P23760 UNIPROT MEOX2 protein P50222 UNIPROT "up-regulates activity" binding -1 11423130 t miannu "We show that Mox1 and Mox2 proteins are capable of interacting with Pax1 and Pax3. We propose that the Mox family of homeodomain proteins participates in the molecular signaling network regulating the diverse events of somite development through the physical interaction with the Pax1 and Pax3 members of the Pax family." SIGNOR-222238 ABL1 protein P00519 UNIPROT TP63 protein Q9H3D4 UNIPROT "up-regulates quantity by stabilization" phosphorylation Tyr149 SVTAPSPyAQPSSTF 9606 19783996 t Manara "In cell lines, upon cisplatin treatment, c-Abl phosphorylates TAp63 on specific tyrosine residues. Such modifications affect p63 stability and induce a p63-dependent activation of proapoptotic promoters." SIGNOR-260934 miR-23a mirna URS00001CC864_9606 RNAcentral GLS protein O94925 UNIPROT "down-regulates quantity" "post transcriptional regulation" 10090 20060380 t "These results suggest that miR-27a would suppress adipocyte differentiation through targeting PPARgamma and thereby down-regulation of miR-27a might be associated with adipose tissue dysregulation in obesity." SIGNOR-255929 CDK1 protein P06493 UNIPROT NPM1 protein P06748 UNIPROT "down-regulates activity" phosphorylation Thr237 KQEKTPKtPKGPSSV 9606 14670079 t gcesareni "We further demonstrate that phospho-mkk1/mkk2 antibodies recognize npm on the c-terminal region, which is phosphorylated by cdc2 (cell division control kinase-2) during g2/m-phase. biochemical and immunocytochemistry analyses verified that the phospho-mkk1/mkk2 antibodies cross-reacted with npm that was phosphorylated at thr234 and thr237 during g2/m-phase, which are the same sites that are targeted by cdc2 (cell division cycle protein-2) during mitosis." SIGNOR-120334 SSTR5 protein P35346 UNIPROT GNAO1 protein P09471 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-256969 SMARCE1 protein Q969G3 UNIPROT "Brain-specific SWI/SNF SMARCA2 variant" complex SIGNOR-C485 SIGNOR "form complex" binding 9606 BTO:0000142 11790558 t miannu " Whereas chromatin-remodeling complexes are generally thought to promote gene expression, recent genetic and biochemical studies suggest that the SWI/SNF complex may also be involved in transcriptional repression . The subunit composition of the different human complexes that belong to this family is listed in Table 1. Several of the subunits, including SNF5/INI1, are common to all complexes and may constitute its core." SIGNOR-270744 DIABLO protein Q9NR28 UNIPROT BIRC3 protein Q13489 UNIPROT "down-regulates quantity" binding 9606 14960576 t amattioni "Smac/diablo selectively causes the rapid degradation of c-iap1 and c-iap2 in hela cells. Smac binding to c-iap via its n-terminal iap-binding motif is the prerequisite for this effect" SIGNOR-121886 SOX9 protein P48436 UNIPROT COL11A2 protein P13942 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 10980415 f miannu "Since Sox9 also contains a potent transcription activation domain, it is a typical transcription factor. Sox9 which binds and activates this enhancer element, is required for chondrocyte differentiation and for expression of a series of chondrocyte-specific marker genes including Col2a1, Col9a2, Col11a2 and Aggrecan." SIGNOR-251758 MDK protein P21741 UNIPROT NOTCH2 protein Q04721 UNIPROT up-regulates binding 9606 18469519 t gcesareni "We showed that mk binds to the notch2 receptor in hacat keratinocytes. We further found that mk activates notch2" SIGNOR-161427 POLR2J protein P52435 UNIPROT "RNA Polymerase II" complex SIGNOR-C391 SIGNOR "form complex" binding 9606 BTO:0000567 9852112 t lperfetto "Pol II is composed of 10–12 polypeptides ranging in size from 220 to 7 kDa, depending on the source of purification (11, 12, 13). The subunits of human pol II (or RNA polymerase B) have been defined as RPB1 (220 kDa), RPB2 (140 kDa), RPB3 (33 kDa), RPB4 (18 kDa), RPB5 (28 kDa), RPB6 (19 kDa), RPB7 (27 kDa), RPB8 (17 kDa), RPB9 (14.5 kDa), RPB10alpha (or RPB12, 7.0 kDa), RPB10beta (or RPB10, 7.6 kDa), and RPB11 (14 kDa) (3,11, 12, 13). RPB5, RPB6, RPB8, RPB10alpha, and RPB10beta are shared by all three eukaryotic RNA polymerases, whereas the rest of the RPB components are unique to pol II" SIGNOR-266161 KCNQ3 protein O43525 UNIPROT potassium(1+) smallmolecule CHEBI:29103 ChEBI "up-regulates quantity" relocalization 9606 19298256 t miannu "KCNQ genes encode five Kv7 K+ channel subunits (Kv7.1–Kv7.5). Four of these (Kv7.2–Kv7.5) are expressed in the nervous system. Kv7.2 and Kv7.3 are the principal molecular components of the slow voltage-gated M-channel, which widely regulates neuronal excitability, although other subunits may contribute to M-like currents in some locations." SIGNOR-265984 DRD1 protein P21728 UNIPROT GNA14 protein O95837 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257391 APH1A protein Q96BI3 UNIPROT NCSTN protein Q92542 UNIPROT up-regulates binding 9606 BTO:0000142 12297508 t gcesareni "By using co-immunoprecipitation and nickel affinity pull-down approaches, we now show that mammalian aph-1 (maph-1), a conserved multipass membrane protein, physically associates with nicastrin and the heterodimers of the presenilin amino- and carboxyl-terminal fragments in human cell lines and in rat brain." SIGNOR-93259 (R)-noradrenaline smallmolecule CHEBI:18357 ChEBI ADRA1D protein P25100 UNIPROT "up-regulates activity" "chemical activation" 9606 BTO:0002524 31160049 t "Ligand-GPCR dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257452 TIAM2 protein Q8IVF5 UNIPROT RAC1 protein P63000 UNIPROT "up-regulates activity" "guanine nucleotide exchange factor" 9606 BTO:0000007 32203420 t Luana "We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2)." SIGNOR-260578 TIMP1 protein P01033 UNIPROT Angiogenesis phenotype SIGNOR-PH46 SIGNOR down-regulates 17326328 f lperfetto "There are many naturally occurring proteins that can inhibit angiogenesis, including angiostatin, endostatin, interferon, platelet factor 4, thorombospondin, prolactin 16 kd fragment, and tissue inhibitor of metalloproteinase-1, -2, and -3" SIGNOR-252272 PRKCA protein P17252 UNIPROT CD5 protein P06127 UNIPROT unknown phosphorylation Thr436 FHRNHTAtVRSHAEN 9606 BTO:0000661 11123317 t lperfetto "Here, we present a selective mutagenesis analysis of two conserved threonine residues (T410 and T412) located at the membrane-proximal cytoplasmic region of CD5. These residues are contained within consensus phosphorylation motifs for protein kinase C and are shown here to be critical for in vivo protein kinase C-mediated phosphorylation of CD5. " SIGNOR-249071 CYP19A1 protein P11511 UNIPROT 17beta-estradiol smallmolecule CHEBI:16469 ChEBI "up-regulates quantity" "chemical modification" 9606 395188 t lperfetto "Studies show that aromatization (a reaction sequence unique in steroid biosynthesis) of androgens to estrogens is not limited to the female reproductive organs but also occurs in extragonadal tissue. Aromatization involves the loss of the angular C-19 methyl group and cis elimination of the 1beta and 2beta hydrogens from the androgen precursors, androstenedione and testosterone, to yield estrone and estradiol, respectively. In men, the production of estrone is 18 ug/day and is mainly extraglandular. Aromatase activity has also been shown in a variety of tissues in mammalian and other species." SIGNOR-251528 PCDH9 protein Q9HC56 UNIPROT ITGB1 protein P05556 UNIPROT "up-regulates activity" binding 9606 BTO:0000227 16697637 t miannu "The clustered protocadherins comprise the largest subfamily of the cadherin superfamily and are predominantly expressed in the nervous system. Pcdh-alpha proteins interact with beta1-integrin to promote cell adhesion." SIGNOR-269035 MYD88 protein Q99836 UNIPROT IRAK4 protein Q9NWZ3 UNIPROT "up-regulates activity" binding 9606 12297423 t "Signaling between MyD88 and TRAF6 is mediated by members of the IL-1R-associated kinase (IRAK) family; however, the exact function of each IRAK protein remains controversial. IRAK-1 is required for the optimal transduction of IL-1R- and TLR-mediated signals, but IRAK-1 can be replaced by other IRAKs. Surprisingly, gene targeting studies show that the newest IRAK protein, IRAK-4, has an essential role in mediating signals initiated by IL-1R and TLR engagement." SIGNOR-252097 STAT3 protein P40763 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 BTO:0002314 25194572 f lperfetto "STAT3 signaling controls satellite cell expansion and skeletal muscle repair" SIGNOR-245048 threonine smallmolecule CHEBI:26986 ChEBI AminoAcids stimulus SIGNOR-ST5 SIGNOR "up-regulates quantity" 29259120 t lperfetto "All extant life employs the same 20 amino acids for protein biosynthesis" SIGNOR-264761 CAPN2 protein P17655 UNIPROT CDK5R1 protein Q15078 UNIPROT "up-regulates activity" cleavage 9606 BTO:0000590 25969760 t lperfetto "Calpains also modulate the activity of CDK5. Physiologically, CDK 5 is activated by p35 and its cleaved product p25. The latter has a longer half life than p35 and therefore it is a more potent activator of CDK5. The cleavage of p35 to p25 is mediated by calpain" SIGNOR-251610 XXYLT1 protein Q8NBI6 UNIPROT NOTCH proteinfamily SIGNOR-PF30 SIGNOR up-regulates binding 9606 22117070 t "Xylosylation in ER membrane" gcesareni "Xxylt1 acts on the xyl1,3glc-o-linked glycan of notch egf domains." SIGNOR-254333 17beta-estradiol smallmolecule CHEBI:16469 ChEBI ESR1 protein P03372 UNIPROT "up-regulates activity" "chemical activation" -1 9048584 t miannu "In total 37 substances were tested for both ER subtypes (Fig. 3 and Table 1). In Fig. 3 several examples of typical competitor curves obtained are shown. In all cases monophasic curves were obtained for compounds with significant affinity. . The present study is the first in which the ligand binding properties of both ER subtypes are measured separately, and caution is needed when comparing RBAs from this study with the previous studies involving mixtures of ER subtypes." SIGNOR-258591 GRIK4 protein Q16099 UNIPROT Excitatory_synaptic_transmission phenotype SIGNOR-PH133 SIGNOR up-regulates 9606 BTO:0000938 24564659 f miannu "Excitatory synaptic transmission in the mammalian brain is mediated primarily by the amino acid glutamate, activating two different groups of glutamate receptors: ionotropic and metabotropic." SIGNOR-264345 KDM4B protein O94953 UNIPROT "Histone H3" proteinfamily SIGNOR-PF69 SIGNOR "down-regulates activity" demethylation 9606 30759871 t miannu "The KDM4 family of Jumonj domain histone demethylases specifically target di- and tri-methylated lysine 9 on histone H3 (H3K9me3), removing a modification central to defining heterochromatin and gene repression. The majority of studies regarding its function describe it as an activator that removes repressive H3K9me3 and H3K9me2 at or near regulated promoters in order to facilitate expression of the indicated pathways." SIGNOR-265359 AGTR1 protein P30556 UNIPROT GNA13 protein Q14344 UNIPROT up-regulates binding 9606 21289285 t gcesareni "These results indicate that ang ii increases endothelial arginase activity/expression through galfa12/13 g proteins coupled to at(1) receptors and subsequent activation of rhoa/rock/p38 mapk pathways leading to endothelial dysfunction." SIGNOR-171760 ATG4B protein Q9Y4P1 UNIPROT GABARAP protein O95166 UNIPROT "up-regulates activity" cleavage -1 16303767 t lperfetto "In vivo and in vitro biochemical analyses have shown that human atg4b is an authentic cysteine protease essential for cleavage of the c terminus of each atg8 homolog to expose the c-terminal gly" SIGNOR-141929 PRKCD protein Q05655 UNIPROT ADD2 protein P35612 UNIPROT unknown phosphorylation Ser713 KKKFRTPsFLKKSKK -1 8810272 t lperfetto "Ser-726 and Ser-713 in the C-terminal MARCKS-related domains of alpha- and beta-adducin, respectively, were identified as the major phosphorylation sites for PKC." SIGNOR-248952 CSNK2B protein P67870 UNIPROT IRS1 protein P35568 UNIPROT unknown phosphorylation Ser99 HFAIAADsEAEQDSW -1 8349691 t llicata "These data suggest that casein kinase II mediates a portion of the insulin-stimulated serine/threonine phosphorylation of overexpressed IRS-1 in vivo. | Thr-502 was identified as the major casein kinase II-catalyzed phosphorylation site in rat IRS-1." SIGNOR-251074 SMC1A protein Q14683 UNIPROT "Cohesin complex" complex SIGNOR-C304 SIGNOR "form complex" binding 28430577 t lperfetto "Cohesin is an evolutionarily conserved complex composed of four core proteins (SMC1A, SMC3, RAD21 and either STAG2 or STAG1) that form a ring-shaped structure able to encircle chromatin" SIGNOR-263313 AXIN1 protein O15169 UNIPROT GSK3B/Axin/APC complex SIGNOR-C110 SIGNOR "form complex" binding 9606 BTO:0000586 9734785 t lperfetto "Axin, an inhibitor of the wnt pathway, interacts with beta-catenin, gsk-3beta and apc and reduces the beta-catenin level." SIGNOR-227292 SF3A2 protein Q15428 UNIPROT "U2 snRNP complex" complex SIGNOR-C479 SIGNOR "form complex" binding 9606 30765414 t lperfetto "The major spliceosomal building blocks are the U1, U2, U4/U6, and U5 small nuclear ribonucleoproteins (snRNPs). Each consists of a small nuclear RNA (snRNA) (or two, in the case of U4/U6), seven Sm proteins that form a ring (or seven Lsm proteins in the case of U6), and a variable number of snRNP-specific proteins (Fig. 1F) (Will and Lührmann 2011). Under splicing conditions, the U4/U6 and U5 snRNPs form a 25S U4/U6.U5 tri-snRNP, in which the U4 and U6 snRNAs are base-paired, forming a three-way junction." SIGNOR-270667 N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridinyl)cyclohexanecarboxamide chemical CHEBI:125619 ChEBI HTR1A protein P08908 UNIPROT "down-regulates activity" "chemical inhibition" 10029 BTO:0000246 9550290 t miannu "Together, these data show that (i) [3H]-S 15535 is a highly selective 5-HT1A receptor ligand which labels both G-protein-coupled and uncoupled 5-HT1A receptors, (ii) antagonists, such as WAY 100,635, which yield monophasic isotherms in competition with both [3H]-agonists and [3H]-antagonists, are not sensitive to the G-protein coupling state of the receptor, but (iii) spiperone and methiothepin behaved as inverse agonists, their competition isotherms with [3H]-S 15535 being modulated in an opposite manner to those of agonists." SIGNOR-258887 PRKCQ protein Q04759 UNIPROT NOS3 protein P29474 UNIPROT "down-regulates activity" phosphorylation Thr495 TGITRKKtFKEVANA 9606 BTO:0001853 24379783 t lperfetto "The phosphorylation of both S617 and S635 have also been shown to promote increased eNOS-derived NO release (Michell et al., 2002). The phosphorylaiton of S617 can be induced by PKA or Akt activity, and may serve to sensitize eNOS to calmodulin binding and modulate the phosphorylation of other eNOS sites" SIGNOR-251636 CSNK1E protein P49674 UNIPROT BID protein P55957 UNIPROT "up-regulates activity" phosphorylation Ser64 LQTDGNRsSHSRLGR 9606 BTO:0000567 11583622 t llicata "Here we report that Bid is phosphorylated by casein kinase I (CKI) and casein kinase II (CKII). Inhibition of CKI and CKII accelerated Fas-mediated apoptosis and Bid cleavage, whereas hyperactivity of the kinases delayed apoptosis. | These results suggest that residues S61, S64, and to a much lesser extent T58 are sites of phosphorylation of Bid." SIGNOR-250805 CHUK protein O15111 UNIPROT CYLD protein Q9NQC7 UNIPROT "down-regulates activity" phosphorylation Ser418 TTENRFHsLPFSLTK 9606 BTO:0000938 24614225 t lperfetto "Thus, serine 418 is phosphorylated in vivo. Cyld phosphorylation may serve as a mechanism to inactivate its traf2 deubiquitination activity." SIGNOR-204688 PCK1 protein P35558 UNIPROT phosphonatoenolpyruvate smallmolecule CHEBI:58702 ChEBI "up-regulates quantity" "chemical modification" 9606 30193097 t miannu "¬†PCK1 regulates an essential rate-limiting step by catalyzing the reversible conversion of oxaloacetate (OAA) into phosphoenolpyruvate (PEP).¬†" SIGNOR-266587 CDK2 protein P24941 UNIPROT CCP110 protein O43303 UNIPROT "down-regulates activity" phosphorylation Thr566 NTRQQMDtPMVSCGN -1 12361598 t miannu "GST-tagged recombinant CP110 (GST-wt) was robustly phosphorylated by cyclin E/CDK2 (Figure 2A). Expression of a mutant derivative of CP110 refractory to CDK phosphorylation provokes marked polyploidy. We localized the majority (nine of ten) of potential CDK2 phosphorylation sites in CP110 to an amino-terminal fragment (GST-ΔN1; Figure 1B)" SIGNOR-265959 creatine smallmolecule CHEBI:16919 ChEBI CKB protein P12277 UNIPROT "up-regulates activity" "chemical activation" 9606 18502307 t miannu "Creatine kinase catalyses the reversible transphosphorylation of creatine by ATP. In the cell, creatine kinase isoenzymes are specifically localized at strategic sites of ATP consumption to efficiently regenerate ATP in situ via phosphocreatine or at sites of ATP generation to build-up a phosphocreatine pool." SIGNOR-265809 RELA protein Q04206 UNIPROT CREBBP protein Q92793 UNIPROT up-regulates binding 9606 SIGNOR-C6 10207072 t gcesareni "Both p53 and rela(p65) interact with the transcriptional coactivator proteins p300 and creb-binding protein (cbp), and we demonstrate that these results are consistent with competition for a limiting pool of p300/cbp complexes in vivo." SIGNOR-66953 SLBP protein Q14493 UNIPROT H2BC14 protein Q99879 UNIPROT "up-regulates quantity by expression" "translation regulation" 9606 BTO:0001938 19155325 t lperfetto "Synthesis of mature histone mRNA requires only a single processing reaction: an endonucleolytic cleavage between a conserved stem-loop and a purine-rich downstream element to form the 3' end. The stem-loop binding protein (SLBP) is required for processing, and following processing, histone mRNA is transported to the cytoplasm, where SLBP participates in translation of the histone mRNA|We used radiolabeled probes generated by PCR targeting the open reading frame (ORF) to detect histones H2A, H2B, H3, H4, and H1 and used 7SK snRNA as a loading control (Fig. 2A). The abundance of histone H2A, H2B, H3, and H4 mRNAs is reduced to 37% to 70% of control levels in the SLBP knockdown cells when compared to the C2 control." SIGNOR-265390 TTK protein P33981 UNIPROT TTK protein P33981 UNIPROT up-regulates phosphorylation Thr676 NQMQPDTtSVVKDSQ 9606 19120698 t llicata "Autophosphorylation appears to be a priming event for kinase activation. We identified mps1 autophosphorylation sites in the activation and the p+1 loops. Whereas activation loop autophosphorylation enhances kinase activity" SIGNOR-183026 AGT protein P01019 UNIPROT AGTR2 protein P50052 UNIPROT up-regulates 9606 BTO:0001130 16597412 f gcesareni "Endothelin-1 (et-1) and angiotensin ii (angii), two potent vasoactive peptides involved in the regulation of cardiovascular homeostasis, also induce mitogenic and pro-angiogenic responses in vitro and in vivo. Both peptides are produced by cleavage of inactive precursors by metalloproteases (endothelin-converting enzyme and angiotensin-converting enzyme, respectively) and activate two subtypes of membrane receptors (eta-r and etb-r for et-1, at1r and at2r for angii) that all belong to the superfamily of g-protein coupled receptors." SIGNOR-145680 EGR2 protein P11161 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR down-regulates 9606 11494141 f miannu "Flow cytometry suggested that over-expression of BPOZ inhibited progression of the cell cycle at the G1/S transition. Anti-sense oligonucleotides for BPOZ or EGR2 effectively inhibited their expression, and cell growth was accelerated." SIGNOR-260048 TFIIH complex SIGNOR-C457 SIGNOR POLR2A protein P24928 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser1766 SPSYSPTsPSYSPTS 9606 14662762 t lperfetto "Although there is some inconsistency in the literature, it is generally thought that cdk7, a component of the transcription factor (tf) iih, is a major ser-5 kinase, whereas cdk9, a component of positive transcription elongation factor (p-tef) b, is a major ser-2 kinase within cells. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination." SIGNOR-269350 ACTB protein P60709 UNIPROT "Muscle cell-specific SWI/SNF SMARCA4 variant" complex SIGNOR-C483 SIGNOR "form complex" binding 9606 BTO:0000887 11073988 t miannu "We have also found that, of the two human SWI/2/SNF2 family-related ATPases, the PBAF complex contains only BRG1 but not hbrm (Xue et al., submitted). In contrast, the BAF complex isolated by BAF250 can include either BRG1 or hbrm (Fig. ​(Fig.4b).4b). These data underscore the distinctness of the two human complexes and suggest that BAF250 is a signature subunit that may confer specificity to the BAF complex." SIGNOR-270739 tiagabine chemical CHEBI:9586 ChEBI SLC6A1 protein P30531 UNIPROT "down-regulates activity" "chemical inhibition" -1 7851497 t miannu "Recently, a number of lipophilic GABA transport inhibitors have been designed and synthesized, which are capable of crossing the blood brain barrier, and which display anticonvulsive activity. We have now determined the potency of four of these compounds, SK&F 89976-A (N-(4,4-diphenyl-3-butenyl)-3-piperidinecarboxylic acid), tiagabine ((R)-1-[4,4-bis(3-methyl-2-thienyl)-3-butenyl]-3- piperidencarboxylic acid), CI-966 ([1-[2-[bis 4-(trifluoromethyl)phenyl]methoxy]ethyl]-1,2,5,6-tetrahydro-3- pyridinecarboxylic acid), and NNC-711 (1-(2-(((diphenylmethylene)amino)oxy)ethyl)-1,2,4,6-tetrahydro-3- pyridinecarboxylic acid hydrochloride), at each of the four cloned GABA transporters, and find them to be highly selective for GAT-1." SIGNOR-258477 "AE/b7 integrin" complex SIGNOR-C186 SIGNOR Cell_adhesion phenotype SIGNOR-PH7 SIGNOR up-regulates 9606 25388208 f miannu "Integrin-mediated cell adhesion is important for development, immune responses, hemostasis and wound healing." SIGNOR-269030 SPI1 protein P17947 UNIPROT GATA1 protein P15976 UNIPROT "down-regulates activity" binding 10090 10364157 t irozzo "We find that PU.1 interacts directly with GATA-1, a zinc finger transcription factor required for erythroid differentiation. Interaction between PU.1 and GATA-1 requires intact DNA-binding domains in both proteins. PU.1 represses GATA-1-mediated transcriptional activation." SIGNOR-256049 CDK1 protein P06493 UNIPROT AKAP12 protein Q02952 UNIPROT "up-regulates activity" phosphorylation Thr767 ESFKRLVtPRKKSKS 9606 BTO:0000007 23063527 t lperfetto "Mass spectrometry, molecular, and cellular approaches show that CDK1/Cyclin B1 phosphorylates Gravin on threonine 766 to prime the recruitment of the polo-like kinase Plk1 at defined phases of mitosis." SIGNOR-271839 ZNF365 protein Q70YC5 UNIPROT PARP1 protein P09874 UNIPROT "up-regulates activity" binding 9606 23966166 t "We identified ZNF365 as a necessary component of the HR repair pathway. ZNF365 interacts with PARP1 and tethers MRE11 to the nucleolytic resection sites for replication fork recovery" SIGNOR-272477 "HLA2 beta chain" proteinfamily SIGNOR-PF90 SIGNOR "Class II MHC" complex SIGNOR-C428 SIGNOR "form complex" binding 9606 1311249 t scontino "The biosynthesis of MHC Class II molecules starts with the assembly of the alpha and beta subunits." SIGNOR-267869 wortmannin chemical CHEBI:52289 ChEBI PI3K complex SIGNOR-C156 SIGNOR down-regulates "chemical inhibition" 9606 8162590 t gcesareni "The microbial product wortmannin and some of its analogues have been shown to be potent inhibitors of phosphatidylinositol-3-kinase." SIGNOR-252666 SLC2A4 protein P14672 UNIPROT glucose chemical CHEBI:17234 ChEBI "up-regulates quantity" relocalization 9606 17403369 t "Skeletal muscle both stores glucose as glycogen and oxidizes it to produce energy following the transport step. The principal glucose transporter protein that mediates this uptake is GLUT4, which plays a key role in regulating whole body glucose homeostasis" SIGNOR-267288 CDK5 protein Q00535 UNIPROT ERBB3 protein P21860 UNIPROT "up-regulates activity" phosphorylation Ser1123 RSRSRSRsPRPRGDS 10116 BTO:0004102 12824184 t llicata "We demonstrated that Cdk5 phosphorylated Ser-1176 in the neuregulin receptor ErbB2 and phosphorylated Thr-871 and Ser-1120 in the ErbB3 receptor. We identified the Ser-1120 sequence RSRSPR in ErbB3 as a novel phosphorylation consensus sequence of Cdk5. Finally, we found that Cdk5 activity is involved in neuregulin-induced Akt activity and neuregulin-mediated neuronal survival. " SIGNOR-250663 OGG1 protein O15527 UNIPROT DNA_repair phenotype SIGNOR-PH57 SIGNOR up-regulates 10090 26221032 f miannu "Cut repeats from the CUX1 protein were recently shown to stimulate 8-oxoguanine DNA glycosylase 1 (OGG1), an enzyme that removes oxidized purines from DNA and introduces a single strand break through its apurinic/apyrimidinic lyase activity to initiate base excision repair." SIGNOR-263959 Ub:E2 complex SIGNOR-C497 SIGNOR RSPRY1 protein Q96DX4 UNIPROT "up-regulates activity" ubiquitination 9606 34199813 t miannu "The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t" SIGNOR-271210 MAPK1 protein P28482 UNIPROT ARRB1 protein P49407 UNIPROT down-regulates phosphorylation Ser412 EEEDGTGsPQLNNR 9606 15456867 t gcesareni "Erk1 and erk2 phosphorylate beta-arrestin1 at ser-412 in vitro. . in the resting state, cytosolic arrestin1 proteins are constitutively phosphorylated by extracellular signal-regulated kinase (erk) at ser412, located within their distal c terminus. erk-phosphorylated arrestin1 is unable to associate with clathrin cages, whereas this constraint is removed upon its dephosphorylation" SIGNOR-129585 CDK1 protein P06493 UNIPROT NUP98 protein P52948 UNIPROT "down-regulates activity" phosphorylation Ser612 LNNSNLFsPVNRDSE 9606 21335236 t gcesareni "We show that npc disassembly is a phosphorylation-driven process, dependent on cdk1 activity and supported by members of the nima-related kinase (nek) family. mitotic hyperphosphorylation of nup98 is accomplished by multiple kinases, including cdk1 and neks." SIGNOR-172217 RARG protein P13631 UNIPROT THR proteinfamily SIGNOR-PF84 SIGNOR "up-regulates activity" binding 9606 15650024 t "inferred from family member" lperfetto "We report that the retinoic acid receptors (rars), a distinct class of nuclear receptors, are also efficient heterodimer partners for trs" SIGNOR-267804 SBF1 protein O95248 UNIPROT Myelination phenotype SIGNOR-PH206 SIGNOR up-regulates 10090 20937701 f miannu "Reduced sciatic nerve axons and normal myelination in the absence of Mtmr5. However, Mtmr5−/− mice had significantly fewer total myelinated axons in sciatic nerves than wild-type controls (Fig. 5G)." SIGNOR-269812 NFE2L2 protein Q16236 UNIPROT TBXAS1 protein P24557 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 14565864 t miannu "Ecotopic expression of NF-E2 related factors showed that Nrf2, but not Nrf1, Nrf3, or Bach1, activated TXAS promoter in a dose-dependent manner." SIGNOR-253907 DVL1 protein O14640 UNIPROT JUN protein P05412 UNIPROT up-regulates binding 9606 BTO:0000007 18347071 t gcesareni "In this study, we discovered two novel interactions between dvl and c-jun and between dvl and beta-catenin in the nucleus that mediate the formation of a dvlc-junbeta-catenintcf functional complex." SIGNOR-178038 regorafenib chemical CHEBI:68647 ChEBI RET protein P07949 UNIPROT "down-regulates activity" "chemical inhibition" 9606 26254357 t miannu "A novel multi-kinase inhibitor, regorafenib (Figure 1), inhibits vascular endothelial growth factor receptor (VEGFR) 1, VEGFR2, and VEGFR3, that play key roles in angiogenesis, and fibroblast growth factor receptor (FGFR) 1, platelet-derived growth factor receptor-β (PDGFR-β), tyrosine kinase with immunoglobulin and epidermal growth factor homology domain 2 (TIE2) and the mutant oncogenic kinase KIT, RET, B-RAF" SIGNOR-259181 PRKCA protein P17252 UNIPROT CHAT protein P28329 UNIPROT up-regulates phosphorylation Ser558 VPTYESAsIRRFQEG 9606 BTO:0000938 15381704 t "The effect has been demonstrated using P28329-3" gcesareni "We show that chat is differentially phosphorylated by protein kinase c (pkc) isoforms on four serines (ser-440, ser-346, ser-347, and ser-476) and one threonine (thr-255). This phosphorylation is hierarchical, with phosphorylation at ser-476 required for phosphorylation at other serines. Phosphorylation at some, but not all, sites regulates basal catalysis and activation." SIGNOR-129268 ITGB1 protein P05556 UNIPROT "A8/b1 integrin" complex SIGNOR-C165 SIGNOR "form complex" binding 16988024 t lperfetto "Integrins are one of the major families of cell adhesion receptors (Humphries, 2000; Hynes, 2002). All integrins are non-covalently-linked, heterodimeric molecules containing an α and a β subunit. Both subunits are type I transmembrane proteins, containing large extracellular domains and mostly short cytoplasmic domains (Springer and Wang, 2004; Arnaout et al., 2005). Mammalian genomes contain 18 α subunit and 8 β subunit genes, and to date 24 different α,β combinations have been identified at the protein level. Although some subunits only appear in a single heterodimer, twelve integrins contain the β1 subunit, and five contain αV." SIGNOR-253182 DUSP16 protein Q9BY84 UNIPROT MAPK8IP1 protein Q9UQF2 UNIPROT up-regulates binding 9606 BTO:0000938 12524447 t gcesareni "Here we report that jip-1 also binds the dual-specificity phosphatases mkp7 and m3/6 via a region independent of its jnk binding domain. when mkp7 is bound to jip-1 it reduces jnk activation leading to reduced phosphorylation of the jnk target c-jun" SIGNOR-97173 AKT1 protein P31749 UNIPROT YAP1 protein P46937 UNIPROT down-regulates phosphorylation Ser127 PQHVRAHsSPASLQL 9606 12535517 t gcesareni "One protein that associates with 14-3-3 in an akt-dependent manner is shown here to be the yes-associated protein (yap), which is phosphorylated by akt at serine 127, leading to binding to 14-3-3. Akt promotes yap localization to the cytoplasm, resulting in loss from the nucleus where it functions as a coactivator of transcription factors including p73." SIGNOR-252593 SIK1 protein P57059 UNIPROT CRTC2 protein Q53ET0 UNIPROT down-regulates phosphorylation Ser171 SALNRTSsDSALHTS 9606 16817901 t miannu "These results suggested that sik1 could phosphorylate all torcs and thereby repress their transactivation activities." SIGNOR-147707 SRC protein P12931 UNIPROT PRKD1 protein Q15139 UNIPROT up-regulates phosphorylation Tyr95 KFPECGFyGMYDKIL 9606 17804414 t llicata "Critical for the regulation of pkd1 activity in response to oxidative stress are src- and abl-mediated tyrosine phosphorylations that eventually lead to protein kinase cdelta (pkcdelta)-mediated activation of pkd1. our data suggest that pkd1 phosphorylation at tyr95 generates a binding motif for pkcdelta, and that oxidative stress-mediated pkcdelta/pkd interaction results in pkd1 activation loop phosphorylation and activation." SIGNOR-157716 INSR protein P06213 UNIPROT ADRB2 protein P07550 UNIPROT "down-regulates activity" phosphorylation Tyr141 AITSPFKyQSLLTKN 10029 BTO:0000246 8557631 t "Insulin (10 nM)-stimulated rIR-catalyzed phosphorylation of β2-adrenergic receptor peptides was found prominently in peptides L339 (Tyr350 and Tyr354), T362 (Tyr364), and to a lesser extent peptides Y132 (Tyr132 and Tyr141), and I135 (Tyr141). G-protein-linked receptors and intrinsic tyrosine-kinase growth receptors represent two prominent modalities in cell signaling. Cross-regulation among members of both receptor superfamilies has been reported, including the counter-regulatory effects of insulin on β-adrenergic catecholamine action. Cells stimulated by insulin show loss of function and increased phosphotyrosine content of β2-adrenergic receptors." SIGNOR-251300 PPM1D protein O15297 UNIPROT MAPK14 protein Q16539 UNIPROT "down-regulates activity" dephosphorylation 9606 11101524 t lperfetto "Wip1 selectively inactivates p38 by specific dephosphorylation of its conserved threonine residue" SIGNOR-84793 AKT proteinfamily SIGNOR-PF24 SIGNOR AKT1S1 protein Q96B36 UNIPROT "down-regulates activity" phosphorylation Thr246 LPRPRLNtSDFQKLK 9606 BTO:0000007 12524439 t gcesareni "Treatment of these cells with 4-hydroxytamoxifen stimulated the phosphorylation of wt PRAS40 but not the mutant PRAS40 in which Thr-246 was mutated. These results demonstrate that activation of Akt alone is sufficient to induce phosphorylation of PRAS40" SIGNOR-236929 ACP1 protein P24666 UNIPROT EPHA2 protein P29317 UNIPROT "down-regulates activity" dephosphorylation Tyr960 GHQKRIAySLLGLKD -1 21538645 t gcesareni "The SAM domain tyrosine Y960 which has been implicated in downstream PI3K signaling is dephosphorylated exclusively by HCPTP-B. The activation loop tyrosine (Y772) which directly controls kinase activity is dephosphorylated about six times faster by HCPTP-A. In contrast, the juxtamembrane tyrosines (Y575, Y588 and Y594) which are implicated in both control of kinase activity and downstream signaling are dephosphorylated by both variants with similar rates" SIGNOR-246023 CCL3 protein P10147 UNIPROT CCR1 protein P32246 UNIPROT "up-regulates activity" binding 9606 20219869 t areggio "The investigators showed that myoblasts constitutively express receptors for CCL2 (CCR2), CCL3 (CCR1 and CCR5), and CCL4 (CCR5), and that stimulation with either CCL2 or CCL4 was sufficient to promote myoblast proliferation. " SIGNOR-255114 "D-glyceraldehyde 3-phosphate(2-)" smallmolecule CHEBI:59776 ChEBI "D-erythrose 4-phosphate(2-)" smallmolecule CHEBI:16897 ChEBI "up-regulates quantity" "precursor of" 9606 19401148 t miannu "Transaldolase (TAL, sedoheptulose 7-phosphate: d-glyceraldehyde 3-phosphate dihydroxyacetone transferase; EC number 2.2.1.2) is a cofactor-less enzyme of the pentose phosphate pathway (PPP) (Fig. 1A and B). It catalyzes the reversible transfer of a three carbon unit (“dihydroxyacetone”) between various sugar phosphates (from 3 to 8 carbon atoms in length). Physiological donor compounds are ketose sugar phosphates as fructose 6-phosphate or sedoheptulose 7-phosphate. Acceptor compounds are aldose sugar phosphates as glyceraldehyde 3-phosphate and erythrose 4-phosphate." SIGNOR-268132 AKT1 protein P31749 UNIPROT PPARGC1A protein Q9UBK2 UNIPROT "down-regulates activity" phosphorylation Ser571 RMRSRSRsFSRHRSC 9606 BTO:0000759 17554339 t lperfetto "Here we describe a mechanism by which insulin, through the intermediary protein kinase akt2/protein kinase b (pkb)-beta, elicits the phosphorylation and inhibition of the transcriptional coactivator peroxisome proliferator-activated receptor-coactivator 1alpha (pgc-1alpha), a global regulator of hepatic metabolism during fasting / phosphorylation of pgc-1alpha At ser570 Is required for akt to inhibit recruitment of pgc-1alpha To chromatin." SIGNOR-252502 SERPINA1 protein P01009 UNIPROT F12 protein P00748 UNIPROT "down-regulates activity" binding 9606 BTO:0000131 26707513 t lperfetto "C1INH is a serine protease inhibitor (serpin) that acts on both the complement pathway and the contact system and is the main inhibitor of the contact system by targeting both FXIIa and PK 9. Additionally, FXIIa can be inhibited by α1‐antitrypsin and plasminogen activator inhibitor‐1 (PAI‐1)." SIGNOR-263515 HDAC3 protein O15379 UNIPROT E2F1 protein Q01094 UNIPROT up-regulates binding 9606 23213415 t gcesareni "Furthermore, smad7 caused hdac-1 bind to e2f-1 to form a ternary complex on chromosomal dna containing an e2f-binding motif and leading to repression in the activity of the e2f target genes." SIGNOR-199961 ROCK1 protein Q13464 UNIPROT PPP1R12A protein O14974 UNIPROT down-regulates phosphorylation Thr696 ARQSRRStQGVTLTD 9606 8662509 t "Rho-associated kinase (Rho-kinase) is activated by GTP-RhoA" gcesareni "Rho-associated kinase (rho-kinase) phosphorylated mbs and consequently inactivated myosin phosphatase. Rho appears to inhibit myosin phosphatase through the action of rho-kinase." SIGNOR-42354 MOB1B protein Q7L9L4 UNIPROT LATS2 protein Q9NRM7 UNIPROT up-regulates binding 9606 21084559 t "Lats1 and Lats2 are nuclear Dbf2-related (NDR) family protein kinases." gcesareni "Lats1/2 are activated by association with the highly homologous scaffold proteins mps one binder kinase activator-like 1a (mobkl1a) and 1b (mobkl1b), which are collectively referred to as mob1." SIGNOR-169798 RAD51C protein O43502 UNIPROT RAD51B/RAD51C complex SIGNOR-C65 SIGNOR "form complex" binding 9606 11751636 t miannu "We show that two of them, rad51b and rad51c, are associated in a stable complex. Rad51b-rad51c complex has ssdna binding and ssdna-stimulated atpase activities." SIGNOR-113388 ATR protein Q13535 UNIPROT XPC protein Q01831 UNIPROT up-regulates binding 9606 23422745 t gcesareni "Atrand atm physically interacted with xpc and promptly localized to the uv damage sites." SIGNOR-201112 CTNNB1 protein P35222 UNIPROT "Histone H3" proteinfamily SIGNOR-PF69 SIGNOR "down-regulates activity" 9606 16510874 f Luana "Beta-cat promotes h3k4 trimethylation at the c-myc gene in vivo. H3k4 trimethylation in vivo requires prior ubiquitination of h2b, and we find that ubiquitin is necessary for transcription initiation on chromatin but not nonchromatin templates in vitro. Chromatin immunoprecipitation experiments reveal that beta-cat recruits pygopus, bcl-9/legless, and mll/set1-type complexes to the c-myc enhancertogether with the negative wnt regulators, apc, and betatrcp." SIGNOR-265358 PRKAR1B protein P31321 UNIPROT PRKACA protein P17612 UNIPROT "down-regulates activity" binding 9606 26687711 t "Inactive PKA exists as a holoenzyme, comprised of two regulatory (R) subunits and two catalytic subunits . In the presence of cAMP, the holoenzyme becomes active by binding two cAMP molecules cooperatively to each R subunit, resulting in a conformational change in the R subunits, thus releasing the two C subunits to phosphorylate downstream targets" SIGNOR-258753 HACD proteinfamily SIGNOR-PF86 SIGNOR ELOVL proteinfamily SIGNOR-PF93 SIGNOR "up-regulates activity" binding 18554506 t miannu "Very long-chain fatty acids are produced through a four-step cycle. Mammals have four candidates, HACD1-4, based on sequence similarities to the recently identified yeast Phs1, although HACD3 and HACD4 share relatively weak similarity. We demonstrate that all four of these human proteins are indeed 3-hydroxyacyl-CoA dehydratases.We also established that the HACD proteins interact with ELOVL proteins. Our analyses have completed the identification of mammalian enzymes responsible for the entire VLCFA elongation cycle." SIGNOR-267915 GRK5 protein P34947 UNIPROT GRK5 protein P34947 UNIPROT "up-regulates activity" phosphorylation Thr485 LDIEQFStVKGVNLD -1 8144599 t "Autophosphorylation of GRK5 occurs primarily at residues Ser-484 and Thr-485. Phospholipid-stimulated autophosphorylation activates the G protein-coupled receptor kinase GRK5." SIGNOR-251202 PRKCB protein P05771 UNIPROT GSK3A protein P49840 UNIPROT down-regulates phosphorylation Ser21 SGRARTSsFAEPGGG 9606 11884598 t gcesareni "Convergence of multiple signaling cascades at glycogen synthase kinase 3: edg receptor-mediated phosphorylation and inactivation by lysophosphatidic acid through a protein kinase c-dependent intracellular pathway." SIGNOR-115718 EIF2S1 protein P05198 UNIPROT Ternary_GTP_eIF2_tRNA_complex complex SIGNOR-C452 SIGNOR "form complex" binding 9606 32955564 t lperfetto "In eukaryotes, translation initiation generally occurs by a cap-dependent scanning mechanism, wherein the small (40S) subunit of the ribosome recruits methionyl initiator tRNA (Met-tRNAi) in a ternary complex (TC) with GTP-bound eukaryotic initiation factor 2 (eIF2), in a reaction stimulated by factors eIF1, eIF1A and eIF3." SIGNOR-269114 HCK protein P08631 UNIPROT PLCG2 protein P16885 UNIPROT "up-regulates activity" phosphorylation Tyr759 LYDVSRMyVDPSEIN -1 7682059 t lperfetto "The phosphorylation of purified phospholipase C-gamma 1 (PLC-gamma 1) and PLC-gamma 2 by src-family-protein tyrosine kinases (PTKs) P56lck, p53/56lyn, p59hck, p59fyn, and p60src was studied in vitro. All five PTKs phosphorylated PLC-gamma 1 and PLC-gamma 2, suggesting that both PLC-gamma isozymes can be phosphorylated in cells by any of the src-family PTKs in response to the activation of cell surface receptors." SIGNOR-249364 glycine smallmolecule CHEBI:15428 ChEBI GLRB protein P48167 UNIPROT "up-regulates activity" "chemical activation" 9606 BTO:0001175;BTO:0001279;BTO:0000146 18721822 t miannu "The glycine receptor chloride channel (GlyR), a member of the pentameric Cys-loop ion channel receptor family, mediates inhibitory neurotransmission in the spinal cord, brainstem and retina." SIGNOR-264983 ATM protein Q13315 UNIPROT RNF20 protein Q5VTR2 UNIPROT up-regulates phosphorylation 9606 21763684 t gcesareni "E3 ubiquitin ligase, a heterodimeric complex of the ringfinger rfn20/rfn40 is phosphorylated by atm." SIGNOR-174949 GRK5 protein P34947 UNIPROT ADRB2 protein P07550 UNIPROT unknown phosphorylation Ser396 GHQGTVPsDNIDSQG -1 8662852 t "we report the identification of the sites of GRK2- and GRK5-mediated beta2AR phosphorylation. six are phosphorylated by GRK5 (Thr-384, Thr-393, Ser-396, Ser-401, Ser-407, and Ser-411)." SIGNOR-251195 GDP smallmolecule CHEBI:17552 ChEBI PRPS1 protein P60891 UNIPROT "down-regulates activity" "chemical inhibition" 29074724 t lperfetto "PRPS1 is inhibited by the nucleotide biosynthesis products ADP, AMP, and GDP" SIGNOR-265738 MAPK1 protein P28482 UNIPROT NEFH protein P12036 UNIPROT "up-regulates activity" phosphorylation Ser518 SPEKEAKsPVKEEAK 10116 BTO:0000938 9592082 t lperfetto "The fraction containing Erk2, as well as bacterially expressed Erk1 and Erk2, phosphorylated all types of KSP motifs in peptides (KSPXK, KSPXXK, KSPXXXK, and KSPXXXXK) derived from NF-M and NF-H. They also phosphorylated an expressed 24 KSPXXXK repeat NF-H polypeptide, an expressed NF-H as well as dephosphorylated native rat NF-H, and NF-M proteins with accompanying decreases in their respective electrophoretic mobilities. |Our data on primary hippocampal cells also showed an inhibition of neurite outgrowth by the drug that was accompanied by inhibition of MAP, NF-H, and NF-M phosphorylation." SIGNOR-249423 AGRP protein O00253 UNIPROT MC2R protein Q01718 UNIPROT "down-regulates activity" binding 9606 20371771 t lperfetto "The melanocortin (MC) receptor family consists of five Gs-coupled receptors that control various physiological functions in response to four distinct agonists, adrenocorticotropic hormone (ACTH, also known as corticotrophin) and α, β, and γ melanocyte–stimulating hormone (MSH), which are derived from the proopiomelanocortin precursor protein, and two inverse agonists, agouti and agouti-related proteins" SIGNOR-268696 RPS6KB1 protein P23443 UNIPROT MRE11 protein P49959 UNIPROT "down-regulates quantity by destabilization" phosphorylation Thr597 SQRGRADtGLETSTR -1 28967905 t miannu "MRE11 is highly unstable in PTEN-deficient cells but stability can be significantly restored by inhibiting mTORC1 or p70S6 kinase (p70S6K), downstream kinases whose activities are stimulated by AKT, or by mutating a residue in MRE11 that we show is phosphorylated by p70S6K in vitro." SIGNOR-265944 APBA3 protein O96018 UNIPROT STXBP1 protein P61764 UNIPROT "up-regulates activity" binding 10116 9395480 t miannu "Munc18-1 is a neuronal protein that interacts with syntaxin 1 and is required for synaptic vesicle exocytosis. We have now identified two Munc18-1-interacting proteins called Mint1 and Mint2 that may mediate the function of Munc18-1." SIGNOR-264036 malonyl-CoA smallmolecule CHEBI:15531 ChEBI CPT1B protein Q92523 UNIPROT "down-regulates activity" binding 9606 14517221 t miannu "Carnitine palmitoyltransferase 1A (CPT1A) is the key regulatory enzyme of hepatic long-chain fatty acid beta-oxidation. The first component of this system is CPT1, an integral mitochondrial outer membrane protein, which catalyzes the transfer of long-chain acyl group of the acyl-CoA ester to carnitine. CPT1 is tightly regulated by its physiological inhibitor malonyl-CoA, the first intermediate in fatty acid biosynthesis. Three CPT1 isoforms with various tissue distribution and encoded by distinct genes have been identified (1., 2.): a liver (CPT1A or L-CPT1) (8.), a muscle (CPT1B or M-CPT1) (9.), and a brain isoform (CPT1C)." SIGNOR-267115 ATG3 protein Q9NT62 UNIPROT GABARAP protein O95166 UNIPROT "up-regulates activity" binding -1 16303767 t lperfetto "Three human atg8 (hatg8) homologs, lc3, gabarap, and gate-16, have been characterized as modifiers in reactions mediated by hatg7 (an e1-like enzyme) and hatg3 (an e2-like enzyme)" SIGNOR-141868 SMARCA4 protein P51532 UNIPROT "Brain-specific SWI/SNF SMARCA4 variant" complex SIGNOR-C486 SIGNOR "form complex" binding 9606 BTO:0000142 11790558 t miannu " Whereas chromatin-remodeling complexes are generally thought to promote gene expression, recent genetic and biochemical studies suggest that the SWI/SNF complex may also be involved in transcriptional repression . The subunit composition of the different human complexes that belong to this family is listed in Table 1. Several of the subunits, including SNF5/INI1, are common to all complexes and may constitute its core." SIGNOR-270756 AUTS2 protein Q8WXX7 UNIPROT DOCK1 protein Q14185 UNIPROT "up-regulates activity" binding 10090 BTO:0001909 25533347 t miannu "Mutations in the Autism susceptibility candidate 2 gene (AUTS2), whose protein is believed to act in neuronal cell nuclei, have been associated with multiple psychiatric illnesses, including autism spectrum disorders, intellectual disability, and schizophrenia. Here we show that cytoplasmic AUTS2 is involved in the regulation of the cytoskeleton and neural development.  AUTS2 activates Rac1 to induce lamellipodia but downregulates Cdc42 to suppress filopodia. Our loss-of-function and rescue experiments show that a cytoplasmic AUTS2-Rac1 pathway is involved in cortical neuronal migration and neuritogenesis in the developing brain. These results suggest that FL-AUTS2 can activate Rac1 via interaction with P-Rex1 and the Elmo2/Dock180 complex to regulate actin dynamics in N1E-115 cells." SIGNOR-266820 SRC protein P12931 UNIPROT GRIN2A protein Q12879 UNIPROT "up-regulates activity" phosphorylation Tyr1387 GRCPSDPyKHSLPSQ -1 10195142 t lperfetto "To gain further insight into the roles of Src and Fyn in the phosphorylation and regulation of the NMDA receptor, we have characterized the tyrosine phosphorylation of NR2A and NR2B by exogenous Src and FynIn the case of NR2A, three potential tyrosine phosphorylation sites have been proposed: Tyr1105, Tyr1267 and Tyr1387 (Zheng et al. 1998; Bi et al. 2000), all of which are similarly located in the C-terminal, cytoplasmic domain." SIGNOR-247171 CSNK2A1 protein P68400 UNIPROT HMOX2 protein P30519 UNIPROT "up-regulates activity" phosphorylation Ser79 TALYFTYsALEEEME 10116 BTO:0003036 14527438 t llicata "Carbon monoxide neurotransmission activated by CK2 phosphorylation of heme oxygenase-2. | CK2 activation is abolished by the S79A mutation but preserved in S179A and T248A mutations, indicating that S79 is the target of CK2-dependent activation of HO2" SIGNOR-250895 GSK3B protein P49841 UNIPROT EIF4EBP1 protein Q13541 UNIPROT "down-regulates activity" phosphorylation Thr46 GGTLFSTtPGGTRII 9606 BTO:0000671 18701453 t lperfetto "We found that gsk-3Beta phosphorylates and inactivates 4e-bp1, thereby increasing eif4e-dependent protein synthesis. upon stimulation, 4e-bp1 is phosphorylated on several threonine and serine residues, including thr-37/46 (36). This results in dissolution of the complex, freeing eif4e to bind with mrna cap to promote translation initiation." SIGNOR-236660 tamoxifen chemical CHEBI:41774 ChEBI ESR1 protein P03372 UNIPROT "down-regulates activity" "chemical inhibition" 9606 20512796 t miannu "Estrogen receptor-alpha (ER) antagonists have been widely used for breast cancer therapy. Despite initial responsiveness, hormone-sensitive ER-positive cancer cells eventually develop resistance to ER antagonists. It has been shown that in most of these resistant tumor cells, the ER is expressed and continues to regulate tumor growth. Recent studies indicate that tamoxifen initially acts as an antagonist, but later functions as an ER agonist, promoting tumor growth." SIGNOR-258587 HDAC2 protein Q92769 UNIPROT "MECP2/SIN3A/HDAC complex" complex SIGNOR-C360 SIGNOR "form complex" binding 9606 BTO:0000567 9620804 t Luana "We show that a region of MeCP2 that localizes with the TRD associates with a corepressor complex containing the transcriptional repressor mSin3A and histone deacetylases." SIGNOR-267736 SMC4 protein Q9NTJ3 UNIPROT "Condensin II" complex SIGNOR-C342 SIGNOR "form complex" binding 9606 32445620 t miannu "The majority of higher eukaryotes, including humans, have two condensins, condensin I (CI) and II (CII) Although sharing the same SMC subunits (SMC2 and SMC4), condensin I and II have distinct non-SMC regulatory subunits, including the kleisin subunit (CAP-H and CAP-H2, respectively) and a pair of HEAT repeat subunits (CAP-D2/G and CAP-D3/G2, respectively; Figure 1B). the combined actions of both condensins contribute to formation of a nested-loop architecture necessary to achieve the highest level of chromosome compaction." SIGNOR-263909 MC4R protein P32245 UNIPROT GNA14 protein O95837 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257392 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR SMAD2 protein Q15796 UNIPROT up-regulates phosphorylation Ser255 ELSPTTLsPVNHSLD 9606 26194464 t "MARCO ROSINA" "Taken together, ERK-mediated Smad2 linker phosphorylation is responsible for TH17 differentiation" SIGNOR-255020 STK3/4 proteinfamily SIGNOR-PF41 SIGNOR MOB1A protein Q9H8S9 UNIPROT up-regulates phosphorylation 9606 BTO:0000007 18362890 t "inferred from 70% family members" gcesareni "These findings indicate that the phosphorylation of mob1 at thr74 by mst2 is essential to make a complex of mob1, mst2 and ndr1, and to fully activate ndr1" SIGNOR-270220 PRKCD protein Q05655 UNIPROT PLD2 protein O14939 UNIPROT up-regulates phosphorylation Thr566 FIQRWNFtKTTKAKY 9606 20733000 t "Translocation from Cytoplasm to the Edge of Lamellipodia" gcesareni "Finally, we show that thr566 of pld2 is directly phosphorylated by pkc and that pld2 mutation in this region prevents pld2 activation, pld2 translocation to the edge of lamellipodia, rac translocation, and cell spreading after integrin activation" SIGNOR-167577 PPM1A protein P35813 UNIPROT MAPK14 protein Q16539 UNIPROT "down-regulates activity" dephosphorylation 9606 9707433 t lperfetto "Moreover, when expressed in mammalian cells, pp2ca inhibited the activation of the p38 and jnk cascades induced by environmental stresses. Both in vivo and in vitro observations indicated that pp2ca dephosphorylated and inactivated mapkks (mkk6 and sek1) and a mapk (p38) in the stress-responsive mapk cascades. Furthermore, a direct interaction of pp2ca and p38 was demonstrated by a co-immunoprecipitation assay" SIGNOR-59618 "R2TP core co-chaperone" complex SIGNOR-C515 SIGNOR "PAQosome co-chaperone complex" complex SIGNOR-C516 SIGNOR "form complex" binding 9606 30484152 t miannu "The PAQosome (Particle for Arrangement of Quaternary structure) is a large multisubunit chaperone complex that is essential for the assembly and stabilization of other macromolecular complexes. It also interacts with several chaperones including Hsp90, Hsp70, and CCT. The PAQosome is comprised of the R2TP complex, the URI1 prefoldin complex (also known as the non-canonical prefoldin-like complex), the RNA polymerase subunit RPB5, and the WD40 repeat protein WDR92. " SIGNOR-270925 PHF2 protein O75151 UNIPROT "Histone H3" proteinfamily SIGNOR-PF69 SIGNOR "down-regulates activity" demethylation 9606 21532585 t miannu "PHF2, a jmjC demethylase, is enzymatically inactive by itself, but becomes an active H3K9Me2 demethylase through PKA-mediated phosphorylation. This modification leads to targeting of the PHF2‚ÄìARID5B complex to its target promoters, where it removes the repressive H3K9Me2 mark." SIGNOR-265343 PAK1 protein Q13153 UNIPROT ILK protein Q13418 UNIPROT up-regulates phosphorylation Ser246 CPRLRIFsHPNVLPV 9606 17420447 t lperfetto "We found that pak1 phosphorylates ilk at threonine-173 and serine-246 in vitro and in vivo. together, these results suggest that ilk is a pak1 substrate, undergoes phosphorylation-dependent shuttling between the cell nucleus and cytoplasm, and interacts with gene-regulatory chromatin." SIGNOR-154303 PPP3CA protein Q08209 UNIPROT NFATC2 protein Q13469 UNIPROT up-regulates dephosphorylation 9606 18676376 t lperfetto "Calcineurin dephosphorylates members of the nuclear factor of activated T cells (NFAT)2 transcription factor family, allowing NFAT to translocate to the nucleus where it cooperates with other transcription factors to induce transcription of target genes." SIGNOR-233435 PRKCA protein P17252 UNIPROT SNAP25 protein P60880 UNIPROT unknown phosphorylation Ser187 RIMEKADsNKTRIDE 9606 12459461 t lperfetto "This study establishes that SNAP-25 is differentially phosphorylated by protein kinase C and protein kinase A in neuroendocrine PC12 cells. Using phosphopeptide mapping and site-directed mutagenesis we identified both Thr138 and Ser187 as the targets of SNAP-25 phosphorylation by protein kinase C" SIGNOR-249178 GLI2 protein P10070 UNIPROT GLI1/GLI2 complex SIGNOR-C450 SIGNOR "form complex" binding 9606 BTO:0000304 32766732 t "GLI2 and GLI1 heterodimerize via the Zn-finger domain" SimoneGraziosi "GLI1 and GLI2 were shown to co-immunoprecipitate in PANC1 pancreatic cancer cells and RMS13 rhabdomyosarcoma cells.|Chromatin immunoprecipitation showed that GLI1 and GLI2 occupied the same regions at the BCL2, MYCN and CCND1 promoters. Furthermore, depletion of GLI1 inhibited GLI2 occupancy at these promoters, suggesting that GLI1/GLI2 interaction is required for the recruitment of GLI2 to these sites." SIGNOR-269210 PRKCA protein P17252 UNIPROT CBL protein P22681 UNIPROT "down-regulates quantity" phosphorylation Ser619 RELTNRHsLPFSLPS 9606 BTO:0000782 11024037 t lperfetto "However, under normal conditions, PKC activation resulting from CD43 engagement was required to activate the MAPK pathway, suggesting that phosphorylation of Cbl on serine residues by PKC and its association with 14-3-3 molecules may play a role in preventing the Cbl inhibitory effect on the Ras-MAPK pathway. " SIGNOR-249054 STAT4 protein Q14765 UNIPROT S100A4 protein P26447 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000150 22740693 f miannu "It suggests that HBXIP is able to activate S100A4 promoter via interacting with STAT4 in breast cancer cells, leading to the up-regulation of S100A4." SIGNOR-255246 RNF182 protein Q8N6D2 UNIPROT ATP6V0C protein P27449 UNIPROT "down-regulates quantity by destabilization" polyubiquitination 9606 BTO:0002574 18298843 t miannu "The data indicated that RNF182 targeted ATP6V0C for degradation by the ubiquitin-proteosome pathway." SIGNOR-271771 EIF4E2 protein O60573 UNIPROT "EIF4E2/GIGYF2 complex" complex SIGNOR-C257 SIGNOR "form complex" binding 9606 BTO:0000568 22751931 t SARA "A Novel 4EHP-GIGYF2 Translational Repressor Complex Is Essential for Mammalian Development|GIGYF2 interacts specifically with m4EHP. The stabilities of m4EHP and GIGYF2 proteins are coregulated." SIGNOR-261008 EEF1A2 protein Q05639 UNIPROT Thr-tRNA(Thr) smallmolecule CHEBI:29163 ChEBI up-regulates relocalization 9606 23699257 t lperfetto "During protein synthesis, eEF1A binds to and delivers aminoacylated tRNAs (aa-tRNAs) to the elongating ribosome (Fig. 1). GTP bound to eEF1A is hydrolyzed upon codon-anticodon match between an aa-tRNA in the A site of the ribosome and mRNA bound to the ribosome." SIGNOR-269536 BMP2 protein P12643 UNIPROT SHH protein Q15465 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 19855020 f gcesareni "On the other hand, bmp activity negatively regulates shh transcription and a bmp-shh nega-tive-feedback loop serves to confine shh expression during limb development." SIGNOR-188853 SCN4A protein P35499 UNIPROT sodium(1+) chemical CHEBI:29101 ChEBI "up-regulates quantity" relocalization 9606 27262167 t miannu "Voltage-gated Na1 channels (NaV channels) drive the rapid upstroke of action potentials in cardiac and skeletal muscle and in most neurons, thereby serving as initiators of electrical activity in excitable tissue. Nine genes encode a family of homologous of NaV channel pore-forming a subunits. While channels are open, Na1 ions flux through the central pore down an electrochemical gradient, further depolarizing the membrane and triggering an action potential." SIGNOR-253405 "MYOD1/SWI/SNF complex" complex SIGNOR-C93 SIGNOR DYSF protein O75923 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000887 15870273 f miannu "Swi/snf enzymes are necessary for myod to activate muscle gene transcription / myod increased the expression of 94 genes and decreased that of 70 genes /these 94 genes (represented by 96 array features) were analyzed for their dependence on a functional brg1-based swi/snf complex. In the presence of dominant-negative brg1, 29 genes did not achieve full activation by myod, as determined by statistical criteria (q 0.05) and a twofold or more decrease in expression level (table 1; see also table s1 in the supplemental material)" SIGNOR-136497 cabazitaxel chemical CHEBI:63584 ChEBI TUBB1 protein Q9H4B7 UNIPROT "down-regulates activity" "chemical inhibition" 9606 21770474 t miannu "Among these, larotaxel (XRP9881, formerly RPR109881A)[3,4] and cabazitaxel (XRP6258, TXD258, RPR116258A)[5] share a mechanism of action unique to taxanes, promoting tubulin assembly and stabilizing microtubules against cold-induced depolymerization" SIGNOR-259341 PTPRE protein P23469 UNIPROT MAPK1 protein P28482 UNIPROT "down-regulates activity" dephosphorylation Thr185 HDHTGFLtEYVATRW 9606 12754301 t llicata "The effect of PTP epsilon on ERKs is at least in part indirect because phosphorylation of the threonine residue in the ERK activation loop is reduced in the presence of PTP epsilon. Nonetheless, PTP epsilon is present in a molecular complex with ERK, providing PTP epsilon with opportunity to act on ERK proteins also directly. We conclude that PTP epsilon is a physiological inhibitor of ERK signaling|These enzymes are joined by the large family of dual-specificity phosphatases, which are structurally similar to tyrosine phosphatases but which can dephosphorylate both residues of the activation loop" SIGNOR-248449 CSNK2A1 protein P68400 UNIPROT ATF1 protein P18846 UNIPROT up-regulates phosphorylation Ser63 GILARRPsYRKILKD 9606 8663317 t lperfetto "Camk ii phosphorylates only ser63 (corresponding to ser133 of creb), which is essential for the activation, and not ser72 (corresponding to ser142 of creb), which is a negative regulation site" SIGNOR-42565 3-isobutyl-1-methyl-7H-xanthine smallmolecule CHEBI:34795 ChEBI PDE1A protein P54750 UNIPROT "down-regulates activity" "chemical inhibition" 9606 22014080 t "Until now, very few inhibitors of PDE1 were available for evaluating the contribution of PDE1 in tissue and cell function. Vinpocetine (Ahn et al., 1989) and 8-methoxymethyl-IBMX (Ahn et al., 1997) are common PDE1 inhibitors." SIGNOR-256274 PPP3CC protein P48454 UNIPROT NFATC2 protein Q13469 UNIPROT up-regulates relocalization 9606 BTO:0001103 11062529 t gcesareni "The ca2+ dependent phosphatase calcineurin induces cardiac and skeletal muscle hypertrophy by a process that involves nf-at nuclear translocation, and activation of mef2c." SIGNOR-84056 MAPK3 protein P27361 UNIPROT GSK3B protein P49841 UNIPROT "down-regulates activity" phosphorylation Ser9 SGRPRTTsFAESCKP 10090 BTO:0002572 28646232 t Gianni "We demonstrate that insulin-mediated activation of ERK1/2 results in phosphorylation of GSK3β at S9 independently of Akt/mTORC1 activity in Tsc2 null mouse embryonic fibroblasts. In addition, we show that inhibition of ERK1/2 rescues GSK3β activity and restores protein synthesis in Tsc2 −/− MEFs to normal levels" SIGNOR-262523 SP1 protein P08047 UNIPROT SOD1 protein P00441 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 8921911 f miannu "Studies using two mutant versions of this promoter, in which the Sp1 and C/EBP-related factor binding sites were deleted, respectively, revealed that Sp1 and C/EBP-related factors activate the transcription of SOD1 gene. the binding of Sp1 to the proximal upstream region of the Cu/Zn SOD might explain the expression of Cu/Zn SOD in a wide variety of cells." SIGNOR-253899 EPHA3 protein P29320 UNIPROT EPHA3 protein P29320 UNIPROT "up-regulates activity" phosphorylation Tyr596 KLPGLRTyVDPHTYE 9606 11870224 t "Eph receptor activation leads to tyrosine phosphorylation of three major autophosphorylation sites. these residues function to regulate kinase activity, their phosphorylation being required for full intrinsic enzyme activity. these tyrosines (EphA3 Y596, Y602 and Y779) as the prominent autophosphorylation sites of EphA3" SIGNOR-251115 ACVR1 protein Q04771 UNIPROT ACVR1/BMPR2 complex SIGNOR-C30 SIGNOR "form complex" binding 9606 7791754 t lperfetto "Bmpr-ii is a transmembrane serine/threonine kinase that binds bmp-2 and bmp-7 in association with multiple type i receptors, including bmpr-ia/brk1, bmpr-ib, and actr-i, which is also an activin type i receptor." SIGNOR-33287 HNF1A protein P20823 UNIPROT UGT1A10 protein Q9HAW8 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000195 15044625 t "Using gel shift and functional assays, HNF1alpha was demonstrated to bind to and activate the UGT1A8, -1A9, and -1A10 promoters. In contrast, Cdx2 bound to and activated the UGT1A8 and -1A10 promoters but could not activate the UGT1A9 promoter." SIGNOR-253971 AKT1 protein P31749 UNIPROT MDM2 protein Q00987 UNIPROT "up-regulates quantity by stabilization" phosphorylation Ser166 SSRRRAIsETEENSD 9606 15169778 t gcesareni "Stabilization of mdm2 via decreased ubiquitination is mediated by protein kinase b/akt-dependent phosphorylation." SIGNOR-124949 LRIG1 protein Q96JA1 UNIPROT CBLC protein Q9ULV8 UNIPROT up-regulates binding 9606 BTO:0001253 15282549 t gcesareni "Upregulation of lrig1 is followed by enhanced ubiquitylation and degradation of egfr. The underlying mechanism involves recruitment of c-cbl, an e3 ubiquitin ligase that simultaneously ubiquitylates egfr and lrig1 and sorts them for degradation" SIGNOR-127301 CDC25A protein P30304 UNIPROT RAF1 protein P04049 UNIPROT down-regulates dephosphorylation 9606 7744247 t gcesareni "Cdc25a can act on substrates other than cdks, since it dephosphorylates the homeodomain transcription factor cut and interacts with and dephosphorylates the proto-oncogene raf-1, resulting in a significant decrease in raf-1 kinase activity" SIGNOR-32548 PSMA6 protein P60900 UNIPROT "26S Proteasome" complex SIGNOR-C307 SIGNOR "form complex" binding 9606 29636472 t lperfetto "Here, we report near-atomic resolution cryo-EM structures of the activated human proteasome|The proteasome is composed of a 28-subunit barrel-shaped core particle (CP) and two 19- subunit regulatory particles (RP)5–8 capped at both sides of the CP|Human proteasomes were purified through affinity chromatography on a large scale from a stable HEK293 cell line" SIGNOR-263368 SRC protein P12931 UNIPROT IKBKB protein O14920 UNIPROT "up-regulates activity" phosphorylation Tyr188 SFVGTLQyLAPELLE 9606 SIGNOR-C14 12707358 t lperfetto "These results indicate that c-src can associate with ikkbeta and phosphorylate its tyrosine residues after tnf-alfa or tpa stimulation." SIGNOR-100784 ZBTB20 protein Q9HC78 UNIPROT AFP protein P02771 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0000007 23776228 t miannu "Zinc finger and BTB domain-containing 20 (ZBTB20), a member of BTB/POZ family, functions in neurogenesis and represses α-fetoprotein gene transcription in liver." SIGNOR-266867 PRKCD protein Q05655 UNIPROT HDAC5 protein Q9UQL6 UNIPROT "down-regulates activity" phosphorylation Ser498 RHRPLSRtQSSPLPQ 9606 18332134 t Manara "In this report, we show that VEGF stimulates PKD-dependent phosphorylation of HDAC5 at Ser259/498residues in ECs, which leads to HDAC5 nuclear exclusion and myocyte enhancer factor-2 (MEF2) transcriptional activation." SIGNOR-260876 "Caspase 1 complex" complex SIGNOR-C220 SIGNOR IL18 protein Q14116 UNIPROT "up-regulates activity" cleavage Asp36 DDENLESdYFGKLES 9606 BTO:0001370 9334240 t lperfetto "We also found two precursor hIL-18 (prohIL-18)-processing activities in the cytosol of THP.1 cells. These activities were blocked separately by the caspase inhibitors Ac-YVAD-CHO and Ac-DEVD-CHO. Further analyses of the partially purified enzymes revealed that one is caspase-1, which cleaves prohIL-18 at the Asp36-Tyr37 site to generate the mature hIL-18, and the other is caspase-3, which cleaves both precursor and mature hIL-18 at Asp71-Ser72 and Asp76-Asn77 to generate biologically inactive products." SIGNOR-256377 AKT1 protein P31749 UNIPROT USP14 protein P54578 UNIPROT "up-regulates activity" phosphorylation Ser432 THQGRSSsSGHYVSW 9606 26523394 t lperfetto "Phosphorylation and activation of ubiquitin-specific protease-14 by Akt regulates the ubiquitin-proteasome system|These results suggested S432 as a major and S143 as a minor phosphorylation site of Akt." SIGNOR-265056 KLHL15 protein Q96M94 UNIPROT "Cullin 3-RBX1-Skp1" complex SIGNOR-C526 SIGNOR "up-regulates activity" binding 9606 BTO:0001938 27561354 t miannu " Here, we identify the Cullin3 E3 ligase substrate adaptor Kelch-like protein 15 (KLHL15) as a new interaction partner of CtIP and show that KLHL15 promotes CtIP protein turnover via the ubiquitin-proteasome pathway." SIGNOR-272411 TGFBRAP1 protein Q8WUH2 UNIPROT "CORVET tethering complex" complex SIGNOR-C550 SIGNOR "form complex" binding 9606 23351085 t miannu "The two Vps-C complexes CORVET (class C core vacuole/endosome tethering) and HOPS (homotypic fusion and vacuole protein sorting) perform diverse biochemical functions in endocytosis: they tether membranes, interact with Rab GTPases, activate and proof-read SNARE assembly to drive membrane fusion, and possibly attach endosomes to the cytoskeleton. The core subunits Vps11, Vps16 and Vps18 present the SNARE-interacting Vps33 subunit on one side and bind the Rab GTPase interaction module through Vps3/Vps8 (in CORVET) or Vps39/Vps41 (in HOPS) on the other side (Fig. 3A) The core subunits Vps11, Vps16 and Vps18 present the SNARE-interacting Vps33 subunit on one side and bind the Rab GTPase interaction module through Vps3/Vps8 (in CORVET) or Vps39/Vps41 (in HOPS) on the other side (Fig. 3A)" SIGNOR-273695 PKA proteinfamily SIGNOR-PF17 SIGNOR IQGAP2 protein Q13576 UNIPROT "up-regulates activity" phosphorylation Thr716 EYMHRRQtFIDNTDS 9606 21776420 t miannu "We show that IQGAP2 is regulated by an interaction with the A-kinase anchoring protein AKAP220. Phosphorylation of IQGAP2 via AKAP220-anchored PKA leads to enhanced Rac binding. Since AKAPs function to direct PKA toward specific substrates, we proposed that the formation of an IQGAP2/AKAP220/PKA ternary complex sharpens the response to cAMP." SIGNOR-273742 BCL2L11 protein O43521 UNIPROT BAX protein Q07812 UNIPROT "up-regulates activity" binding 9606 BTO:0000007 11997495 t lperfetto "We have shown that the interaction of the bims and bimad isoforms with bax leads to a conformational change in this protein analogous to that triggered by the bh3-only protein bid.We find short peptides representing the alpha-helical bh3 domains of bid or bim are capable of inducing oligomerization of bak and bax to release cytochrome." SIGNOR-87280 FAM83H protein Q6ZRV2 UNIPROT CSNK1E protein P49674 UNIPROT "up-regulates quantity" binding 9606 BTO:0000007 29789297 t miannu "We identified members of the FAM83 family of proteins as partners of CK1 in cells. All eight members of the FAM83 family (FAM83A–H) interacted with the α and α-like isoforms of CK1; FAM83A, -B, -E, and -H also interacted with the δ and ε isoforms of CK1. The intrinsic catalytic activity of CK1 is not affected by or required for the association of CK1 with FAM83 proteins. Our findings imply that the DUF1669 domains of FAM83 proteins anchor CK1 α, α-like, δ, and ε isoforms in specific subcellular compartments and potentially mediate their association with substrates." SIGNOR-273764 RARA protein P10276 UNIPROT RXRG protein P48443 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 1310351 f gcesareni "Here we report that the transcriptional activity of rar and rxr can be reciprocally modulated by direct interactions between the two proteins" SIGNOR-16469 AURKB protein Q96GD4 UNIPROT KIF4A protein O95239 UNIPROT "up-regulates activity" phosphorylation Thr799 PPKLRRRtFSLTEVR -1 28992084 t miannu "Using in vitro kinase assays, we found that active AMPK and Aurora B phosphorylated KIF4A at Ser801 and Thr799 respectively in a time-dependent manner (Figure 5D). KIF4A is phosphoregulated by AMPK and Aurora B. Although AMPK phosphorylation increased the ATPase activity of KIF4A, Aurora B phosphorylation resulted in a stronger increase (Figure 5I), which might be consistent with the more powerful kinase function of Aurora B during mitosis." SIGNOR-265992 CLK1 protein P49759 UNIPROT SRSF1 protein Q07955 UNIPROT "up-regulates activity" phosphorylation -1 8617202 t miannu "In vitro, Clk/Sty efficiently phosphorylated the SR family member ASF/SF2 on serine residues located within its serine/arginine-rich region (the RS domain). Overexpression of the active Clk/Sty kinase caused a redistribution of SR proteins within the nucleus. These results suggest that Clk/Sty kinase directly regulates the activity and compartmentalization of SR splicing factors." SIGNOR-273857 CLK2 protein P49760 UNIPROT SRSF1 protein Q07955 UNIPROT "up-regulates activity" phosphorylation -1 8617202 t miannu "In vitro, Clk/Sty efficiently phosphorylated the SR family member ASF/SF2 on serine residues located within its serine/arginine-rich region (the RS domain). Overexpression of the active Clk/Sty kinase caused a redistribution of SR proteins within the nucleus. These results suggest that Clk/Sty kinase directly regulates the activity and compartmentalization of SR splicing factors." SIGNOR-273858 SRSF1 protein Q07955 UNIPROT Alternative_Splicing_Regulation phenotype SIGNOR-PH204 SIGNOR up-regulates 9606 26273603 f miannu "In particular, SRSF1 recognizes SREs in its own transcripts, leading to alternative splicing, with some transcript forms being degraded by nonsense-mediated mRNA decay (NMD)." SIGNOR-273861 LRP4 protein O75096 UNIPROT MUSK protein O15146 UNIPROT "up-regulates activity" binding 9606 BTO:0000887 23458718 t miannu "AGRN is released by the nerve and binds to LRP4, which then binds to MuSK. This interaction leads to MuSK autophosphorylation and activation of its kinase function, leading to anterograde signalling by subsequent phosphorylation of DOK7 (not shown), which binds MuSK as a dimer." SIGNOR-273850 GAN protein Q9H2C0 UNIPROT CUL3 protein Q13618 UNIPROT "up-regulates activity" binding 10090 BTO:0000142 18680552 t miannu "Gigaxonin is the substrate-specific adaptor for a new Cul3-E3-ubiquitin ligase family that promotes the proteasome dependent degradation of its partners MAP1B, MAP8 and tubulin cofactor B." SIGNOR-268944 MAPK14 protein Q16539 UNIPROT ATF2 protein P15336 UNIPROT up-regulates phosphorylation Thr69 SVIVADQtPTPTRFL 9606 20068231 t gcesareni "Phosphorylation of thr-69 by mapk14 and mapk11, and at thr-71 by mapk1/erk2, mapk3/erk1, mapk11, mapk12 and mapk14 in response to external stimulus like insulin causes increased transcriptional activity." SIGNOR-163246 DMTF1 protein Q9Y222 UNIPROT GAS1 protein P54826 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 10090 BTO:0004532 19816943 f Luana " Notably, amphiregulin (Areg), thrombospondin-1 (Tsp-1), JunB, Egr1, adrenomedullin (Adm), Bcl-3 and methyl-CpG binding domain protein 1 (Mbd1) were downregulated in the lungs from Dmp1-null mice while Gas1 and Ect2 genes were upregulated. " SIGNOR-261588 CDC7 protein O00311 UNIPROT DTD1 protein Q8TEA8 UNIPROT "up-regulates activity" phosphorylation Ser194 TPRKEDRsASSGAEG -1 25258324 t done miannu " Here we show that DUE-B is de-phosphorylated in M phase and phosphorylated in G1/S phase. Phosphorylated DUE-B forms homodimers, whereas de-phosphorylated DUE-B interacts with the Mcm2–7 complex and aminoacyl-tRNA synthetases. We find that CKII can prime DUE-B for Cdc7 phosphorylation. Confirming the importance of DUE-B phosphorylation in replication initiation, a C-terminal Ser/Thr to Ala mutant blocks Cdc45 and RPA loading on sperm chromatin and inhibits DNA replication. DUE-B C-terminal phosphorylation sites (serine 179, 181, 182, 194, 196, 197, 204, 205, and threonine 187) were mutated to unphosphorylatable alanine (DUE-B(S/T)-A) or phosphomimic aspartic acid (DUE-B(S/T)-D)." SIGNOR-273961 SMO protein Q99835 UNIPROT ARRB2 protein P32121 UNIPROT up-regulates binding 9606 23074268 t "The binding occours if Smo is phosphorylated" gcesareni "Grk2-mediated phosphorylation of vertebrate smo allows smo to bind to beta-arrestins 1 or 2" SIGNOR-199153 SRC protein P12931 UNIPROT CORO7 protein P57737 UNIPROT "up-regulates activity" phosphorylation Tyr758 GDTRVFLyELLPESP -1 18581049 t done miannu "We establish that Src activity is indispensable for the interaction of Crn7 with Golgi membranes. Crn7 binds Src in vivo and can be phosphorylated by recombinant Src in vitro. We demonstrate that tyrosine-758 is the major Src phosphorylation site. " SIGNOR-274005 NR3C1 protein P04150 UNIPROT PER1 protein O15534 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 19805059 t miannu "GR directly regulates transcription of circadian clock components in mouse and human primary MSCs. Per2, E4bp4, Per1, and Timeless rapidly respond to glucocorticoid stimulation. Primary glucocorticoid receptor (GR) target genes are those at which GR occupies a nearby genomic glucocorticoid response element (GRE) and regulates target gene transcription" SIGNOR-268050 "SWI/SNF complex" complex SIGNOR-C92 SIGNOR "MYOD1/SWI/SNF complex" complex SIGNOR-C93 SIGNOR "form complex" binding 9606 BTO:0001103 17194702 t miannu "Myod targets brg1 to the myogenin promoter during the initiation of myogenesis in tissue culture models for skeletal muscle differentiation /initiation of myogenin transcription is dependent upon myod, the pbx homeodomain factor, and swi/snf chromatin-remodeling enzymes" SIGNOR-151703 ULK1 protein O75385 UNIPROT FBP1 protein P09467 UNIPROT "down-regulates activity" phosphorylation Ser63 HLYGIAGsTNVTGDQ 9606 BTO:0000007 27153534 t done miannu "Here, we demonstrate that, during deprivation of amino acid and growth factors, ULK1/2 directly phosphorylate key glycolytic enzymes including hexokinase (HK), phosphofructokinase 1 (PFK1), enolase 1 (ENO1), and the gluconeogenic enzyme fructose-1,6-bisphosphatase (FBP1).Phosphorylation of these enzymes leads to enhanced HK activity to sustain glucose uptake but reduced activity of FBP1 to block the gluconeogenic route and reduced activity of PFK1 and ENO1 to moderate drop of glucose-6-phosphate and to repartition more carbon flux to pentose phosphate pathway (PPP), maintaining cellular energy and redox homeostasis at cellular and organismal levels.Similar results were also obtained using ULK2 as the kinase (data not shown)." SIGNOR-274032 SMARCA2 protein P51531 UNIPROT CERF complex SIGNOR-C340 SIGNOR "form complex" binding 9606 BTO:0000227 15640247 t miannu "Biochemical isolation of CECR2 revealed the presence of this protein as a component of a novel heterodimeric complex termed CECR2-containing remodeling factor (CERF). CERF comprises CECR2 and the ATP-dependent chromatin remodeler SNF2L, a mammalian ISWI ortholog expressed predominantly in the central nervous system. CERF is capable of remodeling chromatin in vitro and displays an ATP hydrolyzing activity that is stimulated by nucleosomes. Together, these data identify a novel chromatin remodeling complex with a critical role in neurulation." SIGNOR-263890 MAML1 protein Q92585 UNIPROT NOTCH4 protein Q99466 UNIPROT up-regulates binding 9606 11101851 t gcesareni "Maml1 binds to the ankyrin repeat domain of all four mammalian notch receptors, forms a dna-binding complex with icn and rbp-jkappa, and amplifies notch-induced transcription of hes4" SIGNOR-84916 "RNA Polymerase III" complex SIGNOR-C389 SIGNOR tRNA(Gly) smallmolecule CHEBI:29176 ChEBI "up-regulates quantity" "chemical modification" 9606 27911719 t lperfetto "RNAPIII is specialized for transcription of short, abundant nonprotein-coding RNA transcripts. In addition to all tRNAs, RNAPIII transcribes the 5S rRNA and other essential RNAs, including the U6 small nuclear RNA (snRNA), the snR52 small nucleolar RNA and the RNA components of the signal recognition particle (SRP1) and RNase P (RPR1)" SIGNOR-269487 CSNK2A1 protein P68400 UNIPROT SSRP1 protein Q08945 UNIPROT "down-regulates activity" phosphorylation Ser510 SSSNEGDsDRDEKKR 9606 BTO:0000007 15659405 t llicata "CK2 phosphorylates SSRP1 and inhibits its DNA-binding activity. | we identified serines 510, 657, and 688 as phosphorylation targets of CK2 in vitro. Mutagenesis of the three serines revealed that serine 510 was more important for the regulation of SSRP1 DNA-binding activity." SIGNOR-250959 GNAI1 protein P63096 UNIPROT PLD2 protein O14939 UNIPROT down-regulates binding 9606 9148895 t gcesareni "The results of this study suggest that membrane phospholipase d activity can be negatively regulated via gi" SIGNOR-48256 CAMK2B protein Q13554 UNIPROT ETS1 protein P14921 UNIPROT "down-regulates activity" phosphorylation Ser257 DSFESIEsYDSCDRL BTO:0003637 12475968 t llicata "Increased Transactivation of the GM-CSF Promoter/Enhancer by Ets1 with Mutated CaMK II Sites | Significantly, phosphorylation of Ets1 by Ca2+-dependent pathways is thought to inhibit DNA binding in vitro. To analyze the role of these four serines, S251, S257, S282, and S285, in transcription, we constructed three mutant derivatives of human Ets1 " SIGNOR-250685 HCK protein P08631 UNIPROT RAPGEF1 protein Q13905 UNIPROT up-regulates phosphorylation Tyr504 APIPSVPyAPFAAIL 9606 24396067 t llicata "We also showed that ctla-4 receptor signaling mediates tyrosine phosphorylation in the c3g protein, and that this is required for augmented activation of rap1 and increased adhesion mediated by leukocyte function-associated antigen type 1 (lfa-1). ctla-4 signaling leads to phosphorylation of c3g tyrosine 504. the src family member hck phosphorylates c3g downstream of ctla-4." SIGNOR-203613 PINK1 protein Q9BXM7 UNIPROT MFN2 protein O95140 UNIPROT "down-regulates quantity" ubiquitination 9606 BTO:0000793 20871098 f Barakat "Ubiquitination of MFN-1 or MFN-2 was induced in untransfected cells and cells transfected with control siRNA. However, ubiquitination of MFN-1 and MFN-2 was significantly reduced when treated with either PINK1 siRNA combination. These results suggest that PINK1 is required for the ubiquitination of MFN-1 and MFN-2." SIGNOR-274136 CDC14A protein Q9UNH5 UNIPROT MAPK6 protein Q16659 UNIPROT down-regulates dephosphorylation Ser684 IGIPQFHsPVGSPLK 9606 20236090 t lperfetto "Using ms analysis, we identified four novel phosphorylation sites, ser684, ser688, thr698 and ser705, located at the extreme c-terminus of erk3.alanine substitution of the four c-terminal phosphorylation sites markedly decreased the half-life of erk3 in mitosis, thereby linking phosphorylation to the stabilization of the kinase.we found that the phosphatases cdc14a and cdc14b (cdc is cell-division cycle) bind to erk3 and reverse its c-terminal phosphorylation in mitosis." SIGNOR-164404 MAPK9 protein P45984 UNIPROT NFATC3 protein Q12968 UNIPROT down-regulates phosphorylation Ser163 SYRESSLsPSPASSI 9606 BTO:0000782 9374467 t lperfetto "Ser163 and ser165 represent the major sites of in vitro phosphorylation of nfat4 by jnk. / the negative regulation of nfat4 nuclear accumulation caused by jnk provides a mechanism for cell type?specific Responses to extracellular stimulation" SIGNOR-53364 "2-Hydroxy-3-[N-[4-[methyl-[2-(4-methylpiperazin-1-yl)acetyl]amino]phenyl]-C-phenylcarbonimidoyl]-1H-indole-6-carboxylic acid" chemical CID:135461425 PUBCHEM FGFR1 protein P11362 UNIPROT "down-regulates activity" "chemical inhibition" -1 22037378 t llicata "Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here." SIGNOR-258183 SRC protein P12931 UNIPROT TXK protein P42681 UNIPROT "up-regulates activity" phosphorylation Tyr420 RYVLDDEyVSSFGAK 9606 11353545 t lperfetto "We further demonstrate that Rlk can be phosphorylated and activated by Src kinases, leading to a decrease in its half-life. A specific tyrosine in the activation loop of Rlk, Y420, is required for phosphorylation and activation, as well as for decreased stability, but is not required for lipid RAFT association." SIGNOR-247346 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR ADAM17 protein P78536 UNIPROT up-regulates phosphorylation Thr735 KPFPAPQtPGRLQPA 9606 12058067 t lperfetto "We report that the cytosolic tail of the tumor necrosis factor alpha-converting enzyme (tace) is phosphorylated by erk at threonine 735.These results demonstrate that secretases are able to discriminate between the different stimuli that trigger membrane protein ectodomain cleavage and indicate that phosphorylation by mapks may regulate the proteolytic function of membrane secretases." SIGNOR-89614 TLN1 protein Q9Y490 UNIPROT "AL/b2 integrin" complex SIGNOR-C169 SIGNOR "up-regulates activity" binding 10090 BTO:0000132 19118207 t miannu "Over the past 10 years, the binding of talin to the cytoplasmic tail of integrin-β subunits has been established to have a key role in integrin activation. Binding of the phosphotyrosinebinding (PTB)-domain-like subdomain of the protein 4.1, ezrin, radixin, moesin (FERM) domain of talin to the conserved WxxxNP(I/L)Y motif of the β-integrin tail permits additional weaker interactions between talin and the membrane-proximal region of the tail that trigger integrin activation, probably through the disruption of inhibitory interactions between α- and β-subunit cytoplasmic tails." SIGNOR-257619 Ub:E2 complex SIGNOR-C497 SIGNOR HECTD3 protein Q5T447 UNIPROT "up-regulates activity" ubiquitination 9606 34199813 t miannu "The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t" SIGNOR-271280 EIF2AK2 protein P19525 UNIPROT TP53 protein P04637 UNIPROT up-regulates phosphorylation Ser392 FKTEGPDsD 9606 10348343 t gcesareni "The double-stranded rna activated protein kinase pkr physically associates with the tumor suppressor p53 protein and phosphorylates human p53 on serine 392 in vitro." SIGNOR-68033 DOT1L protein Q8TEK3 UNIPROT MCL1 protein Q07820 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 27856324 f irozzo "Previously, we found that MLL-AF4 binds to the BCL-2 gene and directly activates it through DOT1L recruitment and increased H3K79me2/3 levels. MLL-AF4 directly controls the active transcription of both BCL-2 and MCL-1 […]. Of all the BCL-2 family members, only BCL-2 and MCL-1 are directly activated by MLL-AF4." SIGNOR-255881 nintedanib chemical CHEBI:85164 ChEBI FGFR3 protein P22607 UNIPROT "down-regulates activity" "chemical inhibition" -1 18559524 t Luana "In this report, we describe the preclinical profile of BIBF 1120, a combined VEGFR, FGFR, and PDGFR inhibitor currently entering phase III clinical studies in non–small cell lung carcinoma and other cancers." SIGNOR-257798 DLGAP5 protein Q15398 UNIPROT DLG4 protein P78352 UNIPROT "up-regulates activity" binding 9606 BTO:0000938 9115257 t miannu "SAPAPs are specifically expressed in neuronal cells and enriched in the PSD fraction. SAPAPs induce the enrichment of PSD-95/SAP90 to the plasma membrane in transfected cells. Thus, SAPAPs may have a potential activity to maintain the structure of PSD by concentrating its components to the membrane area." SIGNOR-264213 MK-2206 chemical CHEBI:67271 ChEBI AKT1 protein P31749 UNIPROT down-regulates "chemical inhibition" 9606 BTO:0001286 21841310 t gcesareni "Treatment with the pi3k inhibitor ly294002 or the akt inhibitor mk2206 diminished s473 phosphorylation." SIGNOR-252461 PRKCD protein Q05655 UNIPROT DAB2 protein P98082 UNIPROT down-regulates phosphorylation Ser24 QAAPKAPsKKEKKKG 9606 BTO:0000782 15280374 t gcesareni "Mutational analysis revealed that a dab2 ser(24) phosphorylation mutant (s24a) abrogated the inhibitory function of dab2." SIGNOR-127198 DZIP3 protein Q86Y13 UNIPROT H2AC6 protein Q93077 UNIPROT "up-regulates activity" monoubiquitination Lys119 IQAVLLPkKTESHHK 9606 BTO:0000007 18206970 t miannu " 2A-HUB catalyzes monoubiquitination of H2A at lysine 119, functioning as a combinatoric component of the repression machinery required for specific gene regulation programs. Thus, 2A-HUB mediates a selective repression of a specific set of chemokine genes in macrophages, critically modulating migratory responses to TLR activation. H2A monoubiquitination acts to prevent FACT recruitment at the transcriptional promoter region, blocking RNA polymerase II release at the early stage of elongation." SIGNOR-271759 paliperidone chemical CHEBI:82978 ChEBI HTR1D protein P28221 UNIPROT "down-regulates activity" "chemical inhibition" 10116 BTO:0000529 8935801 t miannu "Risperidone and its active metabolite 9-OH-risperidone were compared to reference antipsychotic drugs (haloperidol, pipamperone, fluspirilene, clozapine, zotepine) and compounds under development (olanzapine, seroquel, sertindole, ORG-5222, ziprasidone) for in vitro binding to neurotransmitter receptors in brain tissue and on membranes of recombinant cells expressing cloned human receptors and for in vivo occupancy of neurotransmitter receptors in rat and guinea-pig brain following acute treatment (2 h., s.c.). The binding affinities of the compounds for various neurotransmitter receptors were measured using membrane preparations of animal brain regions and of recombinant cells expressing cloned, mostly human receptors. Receptors, tissues and cells are indicated in Table I; results are shown in Table 4A-B." SIGNOR-258562 SLC6A8 protein P48029 UNIPROT creatine smallmolecule CHEBI:16919 ChEBI "up-regulates quantity" relocalization 9606 18652074 t miannu "CRT is essential for normal brain function as mutations in the CRT gene (SLC6A8) result in X-linked mental retardation, associated with the almost complete lack of creatine in the brain, severe speech and language delay, epilepsy, and autistic behaviour." SIGNOR-265782 BTRC protein Q9Y297 UNIPROT NFKB1 protein P19838 UNIPROT "down-regulates quantity by destabilization" polyubiquitination -1 10835356 t miannu "Here we demonstrate that following IkappaB kinase (IkappaK)-mediated phosphorylation, the C-terminal domain of p105 (residues 918-934) serves as a recognition motif for the SCF(beta)(-TrCP) ubiquitin ligase.In vitro, SCF(beta)(-TrCP) specifically conjugates and promotes processing of phosphorylated p105." SIGNOR-272570 EGLN3 protein Q9H6Z9 UNIPROT PK proteinfamily SIGNOR-PF80 SIGNOR "up-regulates activity" hydroxylation 9606 BTO:0000567 21620138 t "inferred from family member" "Interaction of PKM2 with prolyl hydroxylase 3 (PHD3) enhances PKM2 binding to HIF-1Œ± and PKM2 coactivator function. Mass spectrometry and anti-hydroxyproline antibody assays demonstrate PKM2 hydroxylation on proline-403/408. PHD3 knockdown inhibits PKM2 coactivator function, reduces glucose uptake and lactate production, and increases O(2) consumption in cancer cells." SIGNOR-270290 MYC protein P01106 UNIPROT SLC2A1 protein P11166 UNIPROT "up-regulates quantity" "transcriptional regulation" 10116 10823814 t "C-Myc directly transactivates genes encoding GLUT1, phosphofructokinase, and enolase and increases glucose uptake in Rat1 fibroblasts. Nuclear run-on studies confirmed that the GLUT1 transcriptional rate is elevated by c-Myc. Our findings suggest that overexpression of the c-Myc oncoprotein deregulates glycolysis through the activation of several components of the glucose metabolic pathway." SIGNOR-259987 MAP2K4 protein P45985 UNIPROT MAPK14 protein Q16539 UNIPROT "up-regulates activity" phosphorylation Thr180 RHTDDEMtGYVATRW 9606 7535770 t lperfetto "Recently, two MAP kinase kinases (MKK3 and MKK4) that activate p38 MAP kinase have been identified. The mechanism of p38 activation is mediated by dual phosphorylation on Thr-180 and Tyr-182" SIGNOR-27973 NADPH(4-) smallmolecule CHEBI:57783 ChEBI FASN protein P49327 UNIPROT "up-regulates activity" binding 9606 34765544 t miannu "We determined that FASN inhibitor treatment resulted in NADPH accumulation and inhibition of PGDH enzyme activity. NADPH is a cofactor utilized by FASN, also a known allosteric inhibitor of PGDH." SIGNOR-267371 IRF3 protein Q14653 UNIPROT Interferon-type-I proteinfamily SIGNOR-PF50 SIGNOR "up-regulates quantity by expression" "transcriptional regulation" 10090 20610653 f miannu "Type 1 IFNs are induced in a cell type-specific manner through Toll-like receptor and RIG-I-like receptor pathways, both of which activate interferon regulatory factors (IRFs) and nuclear factor _B (NF-_B) transcription factors." SIGNOR-260330 ATXN7L3 protein Q14CW9 UNIPROT "SAGA complex" complex SIGNOR-C465 SIGNOR "form complex" binding 9606 34811519 t lperfetto "Here we present the cryogenic-electron microscopy (cryo-EM) structure of human SAGA (hSAGA)|Human SAGA is a 20-subunit, 1.4-MDa complex with five functional modules (Fig. ​(Fig.1a):1a): a scaffolding core that includes TBP-associated factors (TAFs); a TRRAP (Transformation/Transcription domain Associated Protein) containing a phosphoinositide-3-kinase (PI3K)-related pseudoprotein kinase (ΨPIKK); a histone acetyltransferase (HAT); a deubiquitinase (DUB) and a metazoan-specific splicing (SPL) module" SIGNOR-269579 MTOR protein P42345 UNIPROT RPS6KB1 protein P23443 UNIPROT "up-regulates activity" phosphorylation Thr412 NQVFLGFtYVAPSVL 10090 BTO:0002572 12782654 t lperfetto "S6K1 is a positive regulator of protein synthesis, and its activity is induced by mTOR-mediated phosphorylation." SIGNOR-101336 PPP1CA protein P62136 UNIPROT CDC25C protein P30307 UNIPROT up-regulates binding 9606 14592972 t gcesareni "Pp1 recognizes cdc25 directly by interacting with a pp1-binding motif in the cdc25 n-terminus." SIGNOR-118917 NFKB1 protein P19838 UNIPROT RELA protein Q04206 UNIPROT "up-regulates activity" binding 9606 9450761 t lperfetto "Here we report the crystal structure at 2.9 a resolution of the p50/p65 heterodimer bound to the kappab dna" SIGNOR-55378 retinal smallmolecule CHEBI:15035 ChEBI "all-trans-retinoic acid" smallmolecule CHEBI:15367 ChEBI "up-regulates quantity" "precursor of" 9606 21621639 t lperfetto "All-trans-retinoic acid (atRA) provides essential support to diverse biological systems and physiological processes.| An accrual of biochemical, physiological and genetic data have identified specific functional outcomes for the retinol dehydrogenases, RDH1, RDH10, and DHRS9, as physiological catalysts of the first step in atRA biosynthesis, and for the retinal dehydrogenases RALDH1, RALDH2, and RALDH3, as catalysts of the second and irreversible step." SIGNOR-265127 ERG protein P11308 UNIPROT PIM proteinfamily SIGNOR-PF34 SIGNOR "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0002398 22140532 t miannu "ERG deregulation induces PIM1 over-expression and aneuploidy in prostate epithelial cells. The up-regulation of PIM1 induced by tERG over-expression significantly modified Cyclin B1 levels and increased the percentage of aneuploid cells in the RWPE-1 cell line after taxane-based treatment. Here we provide the first evidence for an ERG-mediated PIM1 up-regulation in prostate cells in vitro and in vivo, suggesting a direct effect of ERG transcriptional activity in the alteration of genetic stability." SIGNOR-259408 indisulam chemical CHEBI:145431 ChEBI DCAF15 protein Q66K64 UNIPROT "up-regulates activity" "chemical activation" 9606 BTO:0001109 31819272 t miannu "Indisulam promotes an interaction between RBM39 and the DCAF15 E3 ligase substrate receptor, leading to RBM39 ubiquitination and proteasome-mediated degradation." SIGNOR-272204 CDK1 protein P06493 UNIPROT TOP2A protein P11388 UNIPROT unknown phosphorylation Ser1393 GSVPLSSsPPATHFP 9606 7635160 t llicata "We show that many of the sites phosphorylated on topoisomerase iia in vivo correspond to sites phosphorylated in vitro by both p3pdcz and mitogen-activated protein (map) kinase. phosphopeptide 1 was eliminated by replacement of ser1392" SIGNOR-30256 "prostaglandin E2" smallmolecule CHEBI:15551 ChEBI PTGER2 protein P43116 UNIPROT up-regulates "chemical activation" 9606 15299086 t gcesareni "Pge2 acts via four ep receptors termed ep1 to ep4." SIGNOR-127735 GSK3A protein P49840 UNIPROT GSK3A protein P49840 UNIPROT up-regulates phosphorylation Tyr279 RGEPNVSyICSRYYR 9606 BTO:0000527 18701488 t gcesareni "Gsk3a is activated by phosphorylation at tyr-279." SIGNOR-180035 GSK3B protein P49841 UNIPROT CTNNB1 protein P35222 UNIPROT "down-regulates activity" phosphorylation Ser37 YLDSGIHsGATTTAP 9606 BTO:0000586 SIGNOR-C110 16293724 t gcesareni "This leads to the inactivation and release of glycogen synthase kinase 3beta from its complex with axin, thereby relieving the inhibitory phosphorylation of beta-catenin and activating its signaling pathway." SIGNOR-141803 EXT1 protein Q16394 UNIPROT WNT8B protein Q93098 UNIPROT "up-regulates activity" 9606 24860992 f miannu "Decreased Ext1 was shown to reduce the level of Wnt8 and BMP4 signaling and disrupt ventral-specific gene expression. Ext1 function is required for maintenance of normal levels of BMP and wnt, as well as their target genes. In addition, expression of xbra and the establishment of ventral mesoderm depend upon normal levels of Ext1. These findings suggest that ext1-dependent synthesis of HSPG is critical for wnt and BMP signaling, mesodermal identity, and ventral pattern." SIGNOR-264020 MAPK1 protein P28482 UNIPROT RBFOX2 protein O43251 UNIPROT unknown phosphorylation Thr7 tPGYHGFP 10090 22028470 t miannu "We have optimized a chemical genetic system using analog-sensitive ERK2, a form of ERK2 engineered to use an analog of adenosine 5'-triphosphate (ATP), to tag and isolate ERK2 substrates in vitro. This approach identified 80 proteins phosphorylated by ERK2, 13 of which are known ERK2 substrates. With this improved methodology, we detected 98 sites directly phosphorylated by ERK2 on 80 proteins from NIH 3T3-L1 fibroblasts. Thirteen of these proteins are known substrates and the rest represent previously unknown kinase/substrate interactions. (table1)" SIGNOR-262761 PRKCA protein P17252 UNIPROT ADD1 protein P35611 UNIPROT up-regulates phosphorylation Ser726 KKKFRTPsFLKKSKK 9606 BTO:0000938 BTO:0000671 9679146 t gcesareni "These data demonstrate that adducin is a significant in vivo substrate for pkc or other pma-activated kinases in a variety of cells, and that phosphorylation of adducin occurs in dendritic spines that are believed to respond to external signals by changes in morphology and reorganization of cytoskeletal structures. Ser-726 and ser-713 in the c-terminal marcks-related domains of alpha- and beta-adducin, respectively, were identified as the major phosphorylation sites common for pka and pkc." SIGNOR-59229 CDK12 protein Q9NYV4 UNIPROT POLR2A protein P24928 UNIPROT up-regulates phosphorylation Ser1917 SPTSPTYsPTSPKYS 9606 22012619 t miannu "Cyck/cdk12 can activate transcription and phosphorylate ser2 in the ctd of rnapii / phosphorylation of serine at position 2 (ser2) is thought to be responsible for productive transcriptional elongation and synthesis of full-length mature mrna" SIGNOR-176825 SHMT2 protein P34897 UNIPROT (6R)-5,10-methylenetetrahydrofolate(2-) smallmolecule CHEBI:15636 ChEBI "up-regulates quantity" "chemical modification" 9606 32439610 t lperfetto "Serine catabolism initiated by serine hydroxymethyltransferase (SHMT) transfers thegamma-carbon amino acid side chain to THF, forming glycine and 5,10-methylene-THF (me-THF) (Fig. 1). The cytosolic (SHMT1) and mitochondrial (SHMT2) isoforms perform the same reactions." SIGNOR-268227 FOXM1 protein Q08050 UNIPROT SLC27A2 protein O14975 UNIPROT "up-regulates quantity by expression" 9606 31949772 f lperfetto "FOXM1 as a prognostic biomarker promotes endometrial cancer progression via transactivation of SLC27A2 expression." SIGNOR-260414 AANAT protein Q16613 UNIPROT N-acetylserotonin smallmolecule CHEBI:17697 ChEBI "up-regulates quantity" "chemical modification" -1 22775292 t miannu "Here, we present the X-ray crystal structure of human N-acetyl serotonin methyltransferase (ASMT), the last enzyme of the melatonin biosynthesis pathway. Melatonin synthesis requires serotonin, which is first acetylated by the arylalkylamine N-acetyltransferase (AA-NAT) to produce N-acetyl serotonin (NAS) (Fig. 1A). Then, acetyl serotonin methyltransferase (ASMT, also known as hydroxyindole O-methyltransferase or HIOMT) produces melatonin by transferring a methyl group from the cofactor S-adenosyl-L-methionine (SAM) to NAS." SIGNOR-265478 GSK3B protein P49841 UNIPROT MAPT protein P10636 UNIPROT down-regulates phosphorylation Ser579 NVKSKIGsTENLKHQ 9606 21215781 t "The effect has been demonstrated using P10636-8" lperfetto "Tau pseudophosphorylation at specific sites such as s262, s293, s324 and s356 was reported to induce tau conformational change and attenuate tau binding to microtubules (fischer et al., 2009). Then, newly soluble tau proteins are targeted by post-translational modifications that directly or indirectly alter tau conformation, promoting tau dimerization in an anti-parallel manner. Stable tau dimers form tau oligomers, which continue in the aggregation process" SIGNOR-171042 KLF2 protein Q9Y5W3 UNIPROT PPARG protein P37231 UNIPROT down-regulates "transcriptional regulation" 9606 12426306 f fspada "Constitutive overexpression of klf2 but not klf15 potently inhibits peroxisome proliferator-activated receptor-gamma (ppargamma) expression with no effect on the upstream regulators c/ebpbeta and c/ebpdelta." SIGNOR-210019 UTS2R protein Q9UKP6 UNIPROT GNAZ protein P19086 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257319 Ub:E2 complex SIGNOR-C497 SIGNOR TRIM73 protein Q86UV7 UNIPROT "up-regulates activity" ubiquitination 9606 34199813 t miannu "The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t" SIGNOR-271187 NfKb-p65/p50 complex SIGNOR-C13 SIGNOR EGR1 protein P18146 UNIPROT up-regulates binding 9606 10671503 t lperfetto "The early growth response transcription factor egr-1 can also interact with rela in vitro and regulate nf-kappab transcriptional activity in vivo" SIGNOR-216328 "GABA-A (a4-b3-d) receptor" complex SIGNOR-C327 SIGNOR CRHR1 protein P34998 UNIPROT down-regulates 9606 BTO:0000614 33536967 f lperfetto "OT inhibits corticotropin-releasing factor (CRF) mRNA expression at the hypothalamus, resulting in antistress and anti-anxiety effects| It has been demonstrated that the inhibitory effect of OT on CRF mRNA expression is not a direct one on CRF neurons. GABAergic neurons are present in the surroundings of the PVN (peri-PVN). These GABA-projecting neurons into the PVN inhibits CRF expression via GABAA receptors" SIGNOR-268605 SELPLG protein Q14242 UNIPROT SELP protein P16109 UNIPROT up-regulates binding 9606 BTO:0000130 23994464 t apalma "This steady-state rolling is primarily mediated by the interaction of endothelial P-selectins with their neutrophil glycoprotein counterreceptors, primarily PSGL-1." SIGNOR-255038 CSNK1A1 protein P48729 UNIPROT CREB1 protein P16220 UNIPROT up-regulates phosphorylation Ser94 QISTIAEsEDSQESV 9606 9931297 t lperfetto "Ser108, ser111 and ser114, located in a region matching the consensus sequence for the casein kinase ii target, were required.These results strongly suggest that the casein kinase ii target region is involved in cell cycle-regulated phosphorylation of the creb protein and also in transcriptional enhancement." SIGNOR-64250 PCDHA2 protein Q9Y5H9 UNIPROT PCDHGA10 protein Q9Y5H3 UNIPROT "up-regulates activity" binding 9606 BTO:0000227 16697637 t miannu "The clustered protocadherins comprise the largest subfamily of the cadherin superfamily and are predominantly expressed in the nervous system. Pcdh-alpha proteins interact with beta1-integrin to promote cell adhesion. They also form oligomers with Pcdh-gamma proteins at the same membrane sites." SIGNOR-265682 HTR4 protein Q13639 UNIPROT GNAZ protein P19086 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257309 KATNAL2 protein Q8IYT4 UNIPROT TUBD1 protein Q9UJT1 UNIPROT "down-regulates quantity by destabilization" binding 10090 BTO:0001363 29136647 t miannu "Here we show that KATNAL2 is critical for numerous aspects of this developmental process, including the initiation of the axoneme from the basal body, suppression of the spermatid centriole duplication cycle, sperm nuclear sculpting via the manchette, the attachment of the acrosome to the nucleus and the tethering of elongated spermatids to Sertoli cells via the tubulobulbar complex and ultimately sperm release via spermiation. KATNAL2 does not sever microtubules composed of α- and β-tubulin but does interact with δ- and ε-tubulin" SIGNOR-267175 SRC protein P12931 UNIPROT SH3GL1 protein Q99961 UNIPROT down-regulates phosphorylation Tyr315 QPSCKALyDFEPEND 9606 16054026 t lperfetto "Further, we identified an interaction between fak's second pro-rich motif and endophilin a2's sh3 domain. This interaction served as an autophosphorylation-dependent scaffold to allow src phosphorylation of endophilin a2 at tyr315. Tyr315 phosphorylation inhibited endophilin/dynamin interactions, and blockade of tyr315 phosphorylation promoted endocytosis of mt1-mmp. Together, these results suggest a regulatory mechanism of cell invasion whereby fak promotes cell-surface presentation of mt1-mmp by inhibiting endophilin a2-dependent endocytosis." SIGNOR-139150 ING1 protein Q9UK53 UNIPROT SIRT2 protein Q8IXJ6 UNIPROT "down-regulates activity" binding 9606 14522900 t miannu "We found that p33(ING1b) physically interacts with hSIR2, reverses its ability to induce the AFP promoter, and induces acetylation of p53 residues at Lys(373) and/or Lys(382)." SIGNOR-254486 N-hydroxy-3-[4-[[2-hydroxyethyl-[2-(1H-indol-3-yl)ethyl]amino]methyl]phenyl]-2-propenamide chemical CHEBI:94063 ChEBI HDAC4 protein P56524 UNIPROT "down-regulates activity" "chemical inhibition" -1 20139990 t Luana "Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1)." SIGNOR-257986 MAPK13 protein O15264 UNIPROT CDC25B protein P30305 UNIPROT down-regulates 9606 11333986 f gcesareni "P38 map k can also induce a g2/m checkpoint through the phosphorylation and the phosphatase cdc25b." SIGNOR-85999 PRKACA protein P17612 UNIPROT CSK protein P41240 UNIPROT "up-regulates activity" phosphorylation Ser364 ALREKKFsTKSDVWS 9606 BTO:0000782 11181701 t lperfetto "Activation of the cooh-terminal src kinase (csk) by camp-dependent protein kinase inhibits signaling through the t cell receptor.Pka phosphorylates csk at s364 in vitro and in vivo leading to a two- to fourfold increase in csk activity that is necessary for camp-mediated inhibition of tcr-induced interleukin 2 secretion." SIGNOR-105229 CAD protein P27708 UNIPROT (S)-dihydroorotate smallmolecule CHEBI:30864 ChEBI "up-regulates quantity" "chemical modification" 9606 28552578 t miannu "CAD is a 243 kDa polypeptide formed by the fusion of four enzymatic domains that initiate the de novo biosynthesis of pyrimidine nucleotides . The first two domains, glutaminase (GLN) and carbamoyl phosphate synthetase (CPS-II), initiate the pathway, catalyzing the formation of carbamoyl phosphate (CP) from bicarbonate, glutamine, and two ATP molecules. Next, the labile CP is partially channeled to the C-terminal aspartate transcarbamoylase (ATC) domain where it reacts with aspartate to form carbamoyl aspartate. Then, carbamoyl aspartate is condensated to dihydroorotate, the cyclic precursor of the pyrimidine ring, by the dihydroorotase (DHO), a Zn metalloenzyme fused between CPS and ATC domains." SIGNOR-267420 APPL1 protein Q9UKG1 UNIPROT STK11 protein Q15831 UNIPROT up-regulates binding 9606 BTO:0000887 19520843 t milica "In this study, we identified lkb1 as a new binding partner of appl1 and showed that the bar domain of appl1 is involved in this interaction.Here we show that in muscle cells adiponectin and metformin induce ampk activation by promoting appl1-dependent lkb1 cytosolic translocation. Appl1 mediates adiponectin signaling by directly interacting with adiponectin receptors and enhances lkb1 cytosolic localization by anchoring this kinase in the cytosol." SIGNOR-186065 RPS6KA1 protein Q15418 UNIPROT Translational_regulation phenotype SIGNOR-PH202 SIGNOR up-regulates 9606 17360704 f gianni "Mutation of rpS6 at Ser(235/236) reveals that phosphorylation of these sites promotes its recruitment to the 7-methylguanosine cap complex, suggesting that Ras/ERK signaling regulates assembly of the translation preinitiation complex. These data demonstrate that RSK provides an mTOR-independent pathway linking the Ras/ERK signaling cascade to the translational machinery." SIGNOR-268528 L-glutamate(1-) smallmolecule CHEBI:29985 ChEBI L-aspartate(1-) smallmolecule CHEBI:29991 ChEBI "up-regulates quantity" "precursor of" 9606 31422819 t miannu "This is a pyridoxal 5‚Ä≤-phosphate (PLP)-dependent enzyme that exists as cytosolic (GOT1) and intramitochondrial (GOT2) isoforms. Both isoforms catalyze the reversible interconversion of oxaloacetate and glutamate into aspartate and Œ±-ketoglutarate. These enzymes are part of the malate-aspartate shuttle (MAS), a key player in intracellular NAD(H) redox homeostasis (Figure 1)." SIGNOR-267512 COPS2 protein P61201 UNIPROT "COP9 signalosome variant 1" complex SIGNOR-C489 SIGNOR "form complex" binding 9606 18850735 t miannu "The COP9 signalosome (CSN) is a multiprotein complex that plays a critical role in diverse cellular and developmental processes in various eukaryotic organisms. we have performed a comprehensive proteomic analysis of the human CSN complex using a new purification method and quantitative mass spectrometry. Purification of the human CSN complex from a stable 293 cell line expressing N-terminal HBTH-tagged CSN5 subunit was achieved by high-affinity streptavidin binding with TEV cleavage elution." SIGNOR-270772 PP1 proteinfamily SIGNOR-PF54 SIGNOR SP1 protein P08047 UNIPROT "down-regulates activity" dephosphorylation 9606 12684058 t lperfetto "Transcription factors Sp1 and Sp3 activate alpha-ENaC2 transcription through a GC-rich element (Sp1-binding site) in the promoter. Sp1 and Sp3 are essential for alpha-ENaC2 transcription in lung epithelial cells and that dephosphorylation of the Sp transcription factors by PP1 suppresses alpha-ENaC2 expression." SIGNOR-264669 PRKACA protein P17612 UNIPROT ACLY protein P53396 UNIPROT "up-regulates activity" phosphorylation Ser455 PAPSRTAsFSESRAD -1 10653665 t miannu "Phosphorylation of Recombinant Human ATP:Citrate Lyase by cAMP-Dependent Protein Kinase Abolishes Homotropic Allosteric Regulation of the Enzyme by Citrate and Increases the Enzyme Activity. Ser 454, which is phosphorylated by the catalytic subunit of cAMP-dependent protein kinase (PKA)" SIGNOR-250328 CSNK2A1 protein P68400 UNIPROT PIAS1 protein O75925 UNIPROT up-regulates phosphorylation Ser466 VIDLTIDsSSDEEEE 9606 19217413 t llicata "Ck2 phosphorylates serine residues adjacent to the sim of pias1 these findings show that the phosphosim module mediates binding to free sumo and sumo conjugates in a phosphorylation-dependent mode, with ck2 being the critical kinase involvedin this process." SIGNOR-184039 "GABA-A (a6-b2-d) receptor" complex SIGNOR-C328 SIGNOR CRHR1 protein P34998 UNIPROT down-regulates 9606 BTO:0000614 33536967 f lperfetto "OT inhibits corticotropin-releasing factor (CRF) mRNA expression at the hypothalamus, resulting in antistress and anti-anxiety effects| It has been demonstrated that the inhibitory effect of OT on CRF mRNA expression is not a direct one on CRF neurons. GABAergic neurons are present in the surroundings of the PVN (peri-PVN). These GABA-projecting neurons into the PVN inhibits CRF expression via GABAA receptors" SIGNOR-268608 INSR protein P06213 UNIPROT GAB1 protein Q13480 UNIPROT "up-regulates activity" phosphorylation Tyr373 ASDTDSSyCIPTAGM 10090 10978177 t "HGab-1 was phosphorylated by IR at eight tyrosine residues (Y242, Y285, Y373, Y447, Y472, Y619, Y657, and Y689). t Gab-1 is the major binding partner of PI-3 kinase in 3T3L1 cells when stimulated with insulin" SIGNOR-251312 MIF protein P14174 UNIPROT CD74 protein P04233 UNIPROT up-regulates binding 9606 12782713 t miannu "Mif binds to the extracellular domain of cd74, and cd74 is required for mif-induced activation of the extracellular signal-regulated kinase-1/2 map kinase cascade, cell proliferation, and pge2 production." SIGNOR-101526 2-oxoglutarate(2-) smallmolecule CHEBI:16810 ChEBI RIOX1 protein Q9H6W3 UNIPROT "up-regulates activity" "chemical activation" 29981745 t lperfetto "Histone lysine demethylases (KDMs) are 2-oxoglutarate-dependent dioxygenases (2-OGDDs) that regulate gene expression by altering chromatin structure. |2-OG is a central intermediate of the Krebs cycle, where it is produced by isocitrate dehydrogenase (IDH) isoenzymes 2 and 3." SIGNOR-273475 DAB2IP protein Q5VWQ8 UNIPROT ERN1 protein O75460 UNIPROT "up-regulates activity" binding 9606 BTO:0001176 27858941 t miannu "DAB2IP binds IRE1α, and was shown to be required for activation of this signaling cascade in endothelial cells. IRE1α can trigger pro-apoptotic JNK signaling through recruitment of the TRAF2–ASK1 complex. DAB2IP facilitates IRE1α activation, and participates in a signaling complex required to induce TRAF2-dependent ASK1 activation and JNK phosphorylation." SIGNOR-254749 PDX1 protein P52945 UNIPROT SLC2A2 protein P11168 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 11309388 t "In conclusion, Pdx1 confers the expression of pancreatic β-cell-specific genes, such as genes encoding insulin, islet amyloid polypeptide, Glut2, and Nkx6.1." SIGNOR-255540 TRIP12 protein Q14669 UNIPROT NAE1 protein Q13564 UNIPROT "down-regulates quantity by destabilization" ubiquitination -1 SIGNOR-C131 18627766 t miannu "Our data suggest that that TRIP12 promotes degradation of APP-BP1 by catalyzing its ubiquitination, which in turn modulates the neddylation pathway." SIGNOR-266780 "SAGA complex" complex SIGNOR-C465 SIGNOR Chromatine_condensation phenotype SIGNOR-PH21 SIGNOR down-regulates 9606 15970593 f lperfetto "Transcription initiation is a major regulatory step in eukaryotic gene expression. Co-activators establish transcriptionally competent promoter architectures and chromatin signatures to allow the formation of the pre-initiation complex (PIC), comprising RNA polymerase II (Pol II) and general transcription factors (GTFs).|this observation appears remarkably prevalent for chromatin-modifying and remodeling complexes. Here, we use the modular organization of the evolutionary conserved Spt-Ada-Gcn5 acetyltransferase (SAGA) complex as a paradigm to illustrate how co-activators share and combine a relatively limited set of functional tools." SIGNOR-269569 CDK5 protein Q00535 UNIPROT CAMKK2 protein Q96RR4 UNIPROT down-regulates phosphorylation Ser129 ICPSLPYsPVSSPQS 9606 22778263 t lperfetto "Cdk5 and gsk3 phosphorylate ser-129, ser-133, and ser-137. Mutation of ser-129, ser-133, and ser-137 increases autonomous activity with little change in ca2 /cam-dependent activity." SIGNOR-198111 tandutinib chemical CHEBI:90237 ChEBI PDGFRA protein P16234 UNIPROT "down-regulates activity" "chemical inhibition" -1 22037378 t Luana "Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here." SIGNOR-258298 GABRD protein O14764 UNIPROT "GABA-A (a6-b2-d) receptor" complex SIGNOR-C328 SIGNOR "form complex" binding 9606 BTO:0000227 18790874 t "brain, See table 3 for identified complexes" lperfetto "The assembly of GABAA-R as heteropentamers produces complex subtype heterogeneity in structure, which is the major determinant of their pharmacological profile.|Evidence is greatly in favor of a pentameric receptor and most GABAA-R subtypes are formed from two copies of a single alpha, two copies of a single beta, and one copy of another subunit, such as gamma, delta, or epsilon." SIGNOR-263770 SRC protein P12931 UNIPROT GJA1 protein P17302 UNIPROT down-regulates phosphorylation Tyr247 VKGKSDPyHATSGAL 9606 16916748 t lperfetto "The oncogenic tyrosine kinase, v-src, phosphorylates connexin43 (cx43) on y247 and y265 and inhibits cx43 gap junctional communication (gjc), the process of intercellular exchange of ions and metabolites." SIGNOR-148913 IL1B protein P01584 UNIPROT KRT1 protein P04264 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 17982242 f "Regulation of expression" miannu "IL-1β alone decreased the expression of E-cadherin and cytokeratin" SIGNOR-251883 NFIB protein O00712 UNIPROT EPHA4 protein P54764 UNIPROT "up-regulates quantity" "transcriptional regulation" 10090 31838646 t Gianni "For example, within the NFI targetome, we identified 6 collagen genes, 13 genes encoding potassium channel or glutamate receptor subunits and a range of factors related to axon guidance (e.g. Slit1, Robo1, Epha4, Epha5, Epha8)" SIGNOR-268901 AKT proteinfamily SIGNOR-PF24 SIGNOR MST1R protein Q04912 UNIPROT up-regulates phosphorylation Ser1394 VRRPRPLsEPPRPT 9606 14505491 t lperfetto "Akt/pkb phosphorylates ron ser-1394, thus providing a docking site for 14-3-3based on these results, we propose a mechanism based on msp-ron-dependent phosphorylation and 14-3-3 association, whereby the function of alpha6beta4 switches from a mechanical adhesive device into a signaling component, and might be critically involved in human epidermal wound healing" SIGNOR-118053 FBXW7 protein Q969H0 UNIPROT DAB2IP protein Q5VWQ8 UNIPROT "down-regulates quantity by destabilization" ubiquitination 9606 27858941 t miannu "DAB2IP protein levels can be negatively regulated by the activity of the E3-ubiquitin ligases Fbw7, Skp2, and Smurf1" SIGNOR-254774 trametinib chemical CHEBI:75998 ChEBI MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR "down-regulates activity" "chemical inhibition" 9606 BTO:0001950 25487801 t Luana "Inhibitors of MEK1/2 (trametinib) and/or ERK1/2 (selumetinib) had the strongest and most conserved inhibitory activities, suggesting that MEK1/2 and ERK1/2 may have unique capabilities as stand-alone or combinatorial therapies for MERS-CoV infections. " SIGNOR-262312 alvimopan chemical CHEBI:135686 ChEBI OPRD1 protein P41143 UNIPROT "down-regulates activity" "chemical inhibition" -1 18313920 t Luana "A series of N-substituted trans-3,4-dimethyl-4-(3-hydroxyphenyl)piperidines, l opioid receptor antagonists, analogs of alvimopan, were prepared using solid phase methodology. This study led to the identification of a highly selective l opioid receptor antagonist, which interacts selectively with l peripheral receptors." SIGNOR-257772 MAP3K2 protein Q9Y2U5 UNIPROT MAP2K5 protein Q13163 UNIPROT up-regulates 9606 BTO:0000007;BTO:0000782 11073940 f gcesareni "Mekk2 activated bmk1/erk5 to a greater extent, which might correlate with a higher affinity mekk2-mek5 interaction. A dominant negative form of mek5 blocked the activation of bmk1/erk5 by mekk2" SIGNOR-84184 MAPK14 protein Q16539 UNIPROT MEF2A protein Q02078 UNIPROT up-regulates phosphorylation Thr319 TPVVSVTtPSLPPQG 9606 9858528 t lperfetto "We show that mef2a, but not mef2b or mef2d, is a substrate for p38. Threonines 312 and 319 are the key regulatory phosphorylation sites by p38 in mef2a. Phosphorylation at these sites enhances transcriptional activity of mef2a" SIGNOR-62784 SETMAR protein Q53H47 UNIPROT CHEK1 protein O14757 UNIPROT "up-regulates quantity by stabilization" 9606 BTO:0000007 25024738 f miannu "We previously found that Chk1 phosphorylation of Metnase on S495 enhanced its DNA DSB repair activity but decreased its ability to re-start stalled replication forks. Here we show that phosphorylated Metnase feeds back to increase the half-life of Chk1. Chk1 half-life is regulated by DDB1 targeting it to Cul4A for ubiquitination and destruction. Metnase decreases Chk1 interaction with DDB1, and decreases Chk1 ubiquitination.  Phosphorylated Chk1 phosphorylates S495 of Metnase. Phosphorylated Metnase decreases the interaction of DDB1 with Chk1, reducing Chk1 targeting to the Cul4a E3 ubiquitin ligase, increasing Chk1 stability." SIGNOR-273609 Kindlin proteinfamily SIGNOR-PF48 SIGNOR ITGB2 protein P05107 UNIPROT "up-regulates activity" binding 9606 29544897 t miannu "Kindlins bind with β-integrin cytoplasmic tails and execute broad biological functions including directed cell migration, proliferation, differentiation and survival." SIGNOR-259023 nefazodone chemical CHEBI:7494 ChEBI SLC6A4 protein P31645 UNIPROT "down-regulates activity" "chemical inhibition" -1 9871604 t miannu "Equilibrium dissociation constants KD for binding of (_+)-2 and (_+)-3 to hSERT, hNET, and hDAT are given in Table 2. Nefazodone has similar affinities at hSERT, hNET, and hDAT, but has low potency" SIGNOR-259068 CHUK protein O15111 UNIPROT NFKB1 protein P19838 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser927 DSDSVCDsGVETSFR 9606 BTO:0000567 SIGNOR-C13 10469655 t lperfetto "All residues of p105 phosphorylated by ikka are c-terminal; the major phosphorylation region contains three serines (ser923; ser927;ser932) and two threonines (thr927 and thr391)." SIGNOR-70453 BMPR1B protein O00238 UNIPROT STAMBP protein O95630 UNIPROT "up-regulates activity" phosphorylation Ser243 SLKPGALsNSESIPT 9534 BTO:0000298 11483516 t llicata "BMP type I receptor activation stimulates AMSH phosphorylation | The exact position of phosphoserine residues in four phosphopeptides was identified by Edman degradation analysis; spot a for Ser243, Ser245 and Ser247, spot b for Ser2, and spots c and d for Ser48. To confirm the position of the phosphoserine residues, the serine residue(s) in each phosphopeptide was replaced by alanine residues. Then, each mutant as well as wild‐type AMSH was transfected into COS7 cells in the absence or presence of caALK6, and tryptic phosphopeptide mapping of each mutant was performed. As seen in Figure 7, each spot corresponding to the phosphopeptide containing phosphoserine disappeared in the tryptic phosphopeptide mapping. | Thus, AMSH promotes BMP signaling by negatively regulating the function of I‐Smads." SIGNOR-250597 RPL12 protein P30050 UNIPROT "60S cytosolic large ribosomal subunit" complex SIGNOR-C287 SIGNOR "form complex" binding -1 25901680 t lperfetto "Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins." SIGNOR-262487 RORA protein P35398 UNIPROT NPAS2 protein Q99743 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000599 20817722 t miannu "Direct Regulation of the NPAS2 Promoter by RORα and REV-ERBα. it appears in the context of the NPAS2 promoter RORα functions as a transcriptional activator, but REV-ERBα may only function as an inhibitor of RORα activity by blocking binding." SIGNOR-267980 Ub:E2 complex SIGNOR-C497 SIGNOR MARCHF5 protein Q9NX47 UNIPROT "up-regulates activity" ubiquitination 9606 34199813 t miannu "The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t" SIGNOR-271247 CSTF3 protein Q12996 UNIPROT "CSTF complex" complex SIGNOR-C441 SIGNOR "form complex" binding 9606 10669729 t lperfetto "We therefore first identified regions of the CstF subunits, CstF-77, CstF-64, and CstF-50, required for interaction with each other. " SIGNOR-268367 WNK3 protein Q9BYP7 UNIPROT SLC12A2 protein P55011 UNIPROT "up-regulates activity" phosphorylation 21613606 t lperfetto "We have shown that with-no-lysine kinase 3 (WNK3) possesses several properties that suggest it could be the Cl−/volume-sensitive regulatory kinase that, in association with protein phosphatases, reciprocally modifies the phosphorylation/dephosphorylation states of the SLC12 proteins and thus their activities|WNK3 activates NKCC1/2 and NCC and inhibits the KCCs" SIGNOR-264625 FHIT protein P49789 UNIPROT CTNNB1 protein P35222 UNIPROT down-regulates binding 9606 18077326 t miannu "Fhit interacts with _-catenin in vitro and in vivo / the tumor suppressor fhit acts as a repressor of _-catenin transcriptional activity" SIGNOR-159873 AMPK complex SIGNOR-C15 SIGNOR TSC complex SIGNOR-C101 SIGNOR "up-regulates activity" phosphorylation 10090 BTO:0002572 SIGNOR-C15 16959574 t lperfetto "GSK3 inhibits the mTOR pathway by phosphorylating TSC2 in a manner dependent on AMPK-priming phosphorylation" SIGNOR-217749 MAPK3 protein P27361 UNIPROT GAB1 protein Q13480 UNIPROT "up-regulates activity" phosphorylation Thr476 EANYVPMtPGTFDFS 10029 BTO:0000246 15379552 t lperfetto "Our results demonstrate that ERK1/2 phosphorylate Gab1 at six serine/threonine residues (T312, S381, S454, T476, S581, S597) in consensus motifs for MAP kinase phosphorylation. |serine and threonine phosphorylation are capable of modulating the initial signal" SIGNOR-249464 CDK5 protein Q00535 UNIPROT EPRS1 protein P07814 UNIPROT down-regulates phosphorylation Ser886 LSQSSDSsPTRNSEP 9606 19647514 t lperfetto "Ser(886) phosphorylation is required for the interaction of nsap1, which blocks eprs binding to target mrnas. The same phosphorylation event induces subsequent binding of ribosomal protein l13a and gapdh and restores mrna binding. Ifn-_ activates cdk5 to phosphorylate ser(886) in the linker domain of glutamyl-prolyl trna synthetase (eprs), the initial event in assembly of the gait complex. Cdk5/p35 also induces, albeit indirectly via a distinct kinase, phosphorylation of ser(999), the second essential event in gait pathway activation" SIGNOR-187383 ZNF267 protein Q14586 UNIPROT MMP10 protein P09238 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0000007 16054593 t Luana "Furthermore, ZNF267 binds to the MMP-10 promoter region as demonstrated by chromatin immunoprecipitation assays. In conclusion, our results suggest that ZNF267 as a negative transcriptional regulator of MMP-10 " SIGNOR-266211 "Condensin II" complex SIGNOR-C342 SIGNOR Chromatine_condensation phenotype SIGNOR-PH21 SIGNOR up-regulates 9606 32445620 f miannu "Human Condensin I and II Drive Extensive ATP-Dependent Compaction of Nucleosome-Bound DNA. the combined actions of both condensins contribute to formation of a nested-loop architecture necessary to achieve the highest level of chromosome compaction." SIGNOR-263913 SOS2 protein Q07890 UNIPROT KRAS protein P01116 UNIPROT up-regulates "guanine nucleotide exchange factor" 9606 21779497 t gcesareni "Grb2 binds and activates sos, which then activates ras, and this activates p110 independently of p85." SIGNOR-175265 GRIK3 protein Q13003 UNIPROT Excitatory_synaptic_transmission phenotype SIGNOR-PH133 SIGNOR up-regulates 9606 BTO:0000938 24564659 f miannu "Excitatory synaptic transmission in the mammalian brain is mediated primarily by the amino acid glutamate, activating two different groups of glutamate receptors: ionotropic and metabotropic." SIGNOR-264344 SOX4 protein Q06945 UNIPROT CTNNB1 protein P35222 UNIPROT "up-regulates activity" binding 9606 BTO:0003104 24970928 t irozzo "The findings in this study raise the possibility that Sox4 may also antagonize Lef1 (Tcf1 is not expressed in pro-B lymphocytes) function by controlling the stability of β-catenin in pro-B lymphocytes." SIGNOR-256139 CSNK2A2 protein P19784 UNIPROT STX1A protein Q16623 UNIPROT unknown phosphorylation Ser14 ELRTAKDsDDDDDVA 10116 BTO:0000142 10844023 t llicata "We generated an antibody that specifically recognizes a casein kinase II-mediated phosphorylation on serine-14 of syntaxin 1. In this report we show that this phosphorylation occurs in vivo and is developmentally regulated in the rat brain | Phosphorylated syntaxin is preferentially associated with SNAP-25 and localizes to discrete domains of the axonal plasma membrane that do not colocalize with pools of synaptic vesicles." SIGNOR-251043 AURKB protein Q96GD4 UNIPROT H3-3A protein P84243 UNIPROT "up-regulates activity" phosphorylation Ser11 TKQTARKsTGGKAPR 9606 10464286 t "Ser 11 phosphorylation of H3 is either activatory and inhibitory as promotes DNA condensation (activatory) and induce transcription (inhibitory)." gcesareni "Phosphorylation at ser-11 (h3s10ph) by aurkb is crucial for chromosome condensation and cell-cycle progression during mitosis and meiosis." SIGNOR-70420 PIK3CA protein P42336 UNIPROT AKT1 protein P31749 UNIPROT "up-regulates activity" 9606 BTO:0000586 16293724 f lperfetto "We show that PGE2 stimulates colon cancer cell growth through its heterotrimeric guanine nucleotide-binding protein;G protein)-coupled receptor, EP2, by a signaling route that involves the activation of phosphoinositide 3-kinase and the protein kinase Akt" SIGNOR-235914 BAX protein Q07812 UNIPROT BAX protein Q07812 UNIPROT "up-regulates activity" binding 9606 10629050 t "Following Bid-induced conformational change" lperfetto "Following bid-induced conformational change, bax oligomerizes and inserts tightly within the outer mitochondrial membrane. The integration of bax in the outer mitochondrial membrane is followed by cytochrome crelease" SIGNOR-73895 GPCR proteinfamily SIGNOR-PF33 SIGNOR GNAI1 protein P63096 UNIPROT up-regulates 9606 23994464 t apalma "Activation of those receptors triggers the dissociation of the GPCR-specific GŒ± subunit from the shared GŒ≤Œ≥ dimer and concomitant activation of various signal transduction pathways by both G-protein fragments" SIGNOR-255009 SYK protein P43405 UNIPROT FCGR2A protein P12318 UNIPROT "up-regulates activity" phosphorylation Tyr281 LEETNNDyETADGGY -1 8756631 t lperfetto "To identify the FcgammaRII-phosphorylating protein tyrosine kinase (PTK), we used the combination of an in vitro and an in vivo approach. In an in vitro assay using recombinant cytoplasmic tails of the different FcgammaRII isoforms as well as tyrosine exchange mutants, we show that each of the BCR-associated PTKs (Lyn, Blk, Fyn, and Syk) shows different phosphorylation patterns with regard to the different FcgammaR isoforms and pointFyn and Blk definitely phosphorylate Y-282 in the ITAM of Fc_RIIa/c, whereas the non-ITAM tyrosine residue (Y-275) becomes phosphorylated by Syk, as the phosphorylation of double point mutants shows. In addi-tion to these tyrosine residues, Fyn, Blk, and Syk might phosphorylate the most C-terminal tyrosine residue (Y-298) because altering this tyrosine residue together with one of the tyrosine residues clearly shown to be phosphorylated by the respective PTK results in the abrogation of phosphorylation." SIGNOR-247590 HNF4G protein Q14541 UNIPROT AKR1C4 protein P17516 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0003846 2044952 f 2 miannu "Hepatocyte nuclear factor (HNF)-4_/_, HNF-1_, and vHNF-1 regulate the cell-specific expression of the human dihydrodiol dehydrogenase (DD)4/AKR1C4 gene. HNF-4_ is a necessary factor for the activation of the human DD4 gene. is much higher than that of vHNF-1-C." SIGNOR-240013 LRRK2 protein Q5S007 UNIPROT LRRK2 protein Q5S007 UNIPROT down-regulates phosphorylation Thr1491 DYHFVNAtEESDALA 9606 BTO:0000938 19824698 t lperfetto "We identified ser1403, thr1404, thr1410, thr1491 located within the roc domain, as well as thr1967 and thr1969 in the kinase domain, as the autophosphorylation sites. eduction in the gtp-bound form of lrrk2 caused by t1491d mutation might have lowered the kinase activity, implicating the autophosphorylation of the roc domain in a negative feedback regulation of the kinase activity of lrrk2." SIGNOR-188425 CHEK2 protein O96017 UNIPROT TP53 protein P04637 UNIPROT "up-regulates quantity by stabilization" phosphorylation Ser366 PGGSRAHsSHLKSKK 9606 BTO:0000567 10673501 t gcesareni "Chk1/chk2 and atm/atr also phosphorylate the effector p53, increasing its stability.We Have demonstrated that the human homologs of the checkpoint kinases, chk1 and chk2/hcds1, phosphorylate at least three dna damage-inducible phosphorylation sites in p53." SIGNOR-75013 TUBA1A protein Q71U36 UNIPROT Neuron_migration phenotype SIGNOR-PH67 SIGNOR up-regulates 9606 BTO:0000007 19185337 f miannu "We show here that Elongator regulates corticogenesis because an acute disruption of its activity in dorsal progenitors results in radial migration delays and defective terminal branching of projection neurons that come with a reduction in α-tubulin acetylation. Importantly, this complex interacts with the microtubule cytoskeleton, where Elp3 may directly acetylate α-tubulin, a posttranslational modification known to regulate the intracellular trafficking that is critical for cell shape remodeling during migration and terminal branching." SIGNOR-269725 SIRT5 protein Q9NXA8 UNIPROT HMGCS2 protein P54868 UNIPROT "up-regulates activity" "post translational modification" Lys83 YNNVEAGkYTVGLGQ 9606 BTO:0000007 24315375 t desuccinylation lperfetto "We demonstrate that SIRT5 regu-lates succinylation of the rate-limiting ketogenicenzyme 3-hydroxy-3-methylglutaryl-CoA synthase 2(HMGCS2) both in vivo and in vitro.|Succinylation of Lysine Residues within the SubstrateBinding Pocket Inhibits HMGCS2 Activity|Here, we use a label-freequantitative proteomic approach to characterizethe lysine succinylome in liver mitochondria and itsregulation by the desuccinylase SIRT5" SIGNOR-267641 EGR1 protein P18146 UNIPROT PPARG protein P37231 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0003336 29212876 t miannu "Previous studies have reported that the PPARγ proximal promoter contains an overlapping binding site for Egr-1, which is involved in the down-regulation of PPARγ. In the present study, we have provided direct evidence that leptin causes PPARγ reduction in primary cultured PASMC; this effect is coupled to leptin-induced ERK1/2 activation and subsequent induction of Egr-1, which further down-regulates PPARγ expression and results in PASMC proliferation. The present study confirmed that ERK1/2 signaling cascade mediated leptin-induced PPARγ reduction by up-regulation of Egr-1 in PASMC." SIGNOR-263508 PPM1B protein O75688 UNIPROT IKBKB protein O14920 UNIPROT "down-regulates activity" dephosphorylation Ser177 AKELDQGsLCTSFVG 9606 18930133 t "PPM1A and PPM1B act as IKKbeta phosphatases to terminate TNFalpha-induced IKKbeta-NF-kappaB activation|Overexpression of PPM1A or PPM1B results in dephosphorylation of IKKbeta at Ser177 and Ser181 and termination of IKKbeta-induced NF-kappaB activation." SIGNOR-248343 BCR-ABL "fusion protein" SIGNOR-FP6 SIGNOR "Caspase 3 complex" complex SIGNOR-C221 SIGNOR "down-regulates activity" 9606 BTO:0002882 11684015 f lperfetto "BCR/ABL Tyrosine Kinase Enhances Expression of RAD51 by Stimulation of STAT5-Mediated Transactivation and Inhibition of Caspase-3-Dependent Degradation|" SIGNOR-271705 PRKCE protein Q02156 UNIPROT GRM5 protein P41594 UNIPROT "up-regulates activity" phosphorylation Ser840 VRSAFTTsTVVRMHV -1 15894802 t lperfetto "Thus, we showed that it is phosphorylation of Ser-839, not Thr-840, that is absolutely required for the unique Ca2+ oscillations produced by mGluR5 activation. The Thr-840 residue is important only in that it is permissive for the PKC-dependent phosphorylation of Ser-839." SIGNOR-249281 PTPRJ protein Q12913 UNIPROT RET protein P07949 UNIPROT "down-regulates activity" dephosphorylation Tyr1062 TWIENKLyGMSDPNW 9606 16778204 t "The receptor-type protein tyrosine phosphatase J antagonizes the biochemical and biological effects of RET-derived oncoproteins.|PTPRJ expression induces dephosphorylation of the RET(C634R) and, probably via an indirect mechanism, RET/PTC1 oncoproteins on two key RET autophosphorylation sites (Tyr1062 and Tyr905). This results in a significant decrease of RET-induced Shc and extracellular signal-regulated kinase 1/2 phosphorylation levels" SIGNOR-248700 "ErbB receptor family" proteinfamily SIGNOR-PF36 SIGNOR SHC3 protein Q92529 UNIPROT up-regulates relocalization 9606 16729043 t "inferred from 70% family members" gcesareni "Like erbb1, erbb4 recruits grb2, shc and stat5." SIGNOR-269962 PRKAR2A protein P13861 UNIPROT PRKAR2A protein P13861 UNIPROT "up-regulates activity" phosphorylation Ser99 SRFNRRVsVCAETYN -1 6293815 t miannu "RII subunit containing the 'autophosphorylation' site (Ser-95)" SIGNOR-250073 Oxytocin protein P01178-PRO_0000020495 UNIPROT OXTR protein P30559 UNIPROT up-regulates binding 9606 1313946 t gcesareni "The oxytocin receptor, expressed in xenopus oocytes, specifically responds to oxytocin and induces an inward membrane current" SIGNOR-16758 AMPK complex SIGNOR-C15 SIGNOR CRY1 protein Q16526 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser280 YKKVKKNsSPPLSLY 9606 19833968 t miannu "We demonstrated that the nutrient-responsive adenosine monophosphate-activated protein kinase (AMPK) phosphorylates and destabilizes the clock component cryptochrome 1 (CRY1). In mouse livers, AMPK activity and nuclear localization were rhythmic and inversely correlated with CRY1 nuclear protein abundance. Stimulation of AMPK destabilized cryptochromes and altered circadian rhythms, and mice in which the AMPK pathway was genetically disrupted showed alterations in peripheral clocks. Phosphorylation of S71 or S280 by AMPK destabilizes CRY1" SIGNOR-268047 CyclinE/CDK2 complex SIGNOR-C16 SIGNOR PARP10 protein Q53GL7 UNIPROT "up-regulates activity" phosphorylation Thr101 QGLPPGTtPQRLEQH -1 16455663 t miannu "The PARP activity of PARP10 depends on phosphorylation by CDK2-cyclin E in vitro. CDK-phosphorylated PARP10 is absent in growth-arrested cells. These results suggest that PARP10 functions in cell proliferation and may serve as a marker for proliferating cells.our results suggest that nucleolar PARP10 acquires CDK2-cyclin E-dependent phosphorylation at the Thr-101 residue." SIGNOR-273594 N-(3-aminopropyl)-N-[(1R)-1-[7-chloro-4-oxo-3-(phenylmethyl)-2-quinazolinyl]-2-methylpropyl]-4-methylbenzamide chemical CHEBI:94692 ChEBI KIF11 protein P52732 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-193483 LAMA3 protein Q16787 UNIPROT Laminin-5 complex SIGNOR-C184 SIGNOR "form complex" binding 9211848 t lperfetto "Like the other laminins (3), Ln-5 comprises three disul- fide-bonded subunits: a3, b3, and g2." SIGNOR-253235 ATM protein Q13315 UNIPROT TTC5 protein Q8N0Z6 UNIPROT "up-regulates activity" phosphorylation Ser203 TGQNPKIsQQALSAY 9606 15448695 t miannu "Here we report a new pathway in which ATM kinase signals the DNA damage response by targeting the transcriptional cofactor Strap. ATM phosphorylates Strap at a serine residue, stabilizing nuclear Strap and facilitating formation of a stress-responsive co-activator complex." SIGNOR-262645 BCR-ABL "fusion protein" SIGNOR-FP6 SIGNOR BCR protein P11274 UNIPROT "down-regulates activity" phosphorylation Tyr177 ADAEKPFyVNVEFHH 9606 8622703 t lperfetto "We have previously demonstrated that the bcr protein is tyrosine phosphorylated within first-exon sequences by the bcr-abl oncoprotein. Here we report that in addition to tyrosine 177 (y-177), y-360 and y283 are phosphorylated in bcr-abl proteins in vitro. Tyrosine-phosphorylated bcr, phosphorylated in vitro by bcr-abl, was greatly inhibited in its serine/threonine kinase activity, impairing both auto- and transkinase activities of bcr." SIGNOR-40611 mTORC1 complex SIGNOR-C3 SIGNOR RPS6KB1 protein P23443 UNIPROT up-regulates phosphorylation Thr412 NQVFLGFtYVAPSVL 9606 15809305 t lperfetto "Mtorc1 promotes protein synthesis by phosphorylating the eukaryotic initiation factor 4e (eif4e)- binding protein 1 (4e-bp1) and the p70 ribosomal s6 kinase 1 (s6k1). In vitro activation of p70alfa by mtor-catalyzed phosphorylation involving p70alfa thr-412. Mtor-catalyzed p70alfa phosphorylation in vitro is accompanied by a substantial restoration in p70alfa kinase activity toward its physiologic substrate, the 40 s ribosomal protein s6. In response to insulin and nutrients, mtorc1, consisting of mtor, raptor (regulatory-associated protein of mtor), and mlst8, is activated and phosphorylates eukaryotic initiation factor 4e-binding protein (4ebp) and p70 s6 kinase to promote protein synthesis and cell size." SIGNOR-217067 CyclinK/CDK12 complex SIGNOR-C37 SIGNOR POLR2A protein P24928 UNIPROT "up-regulates activity" phosphorylation Ser1784 TPTSPNYsPTSPSYS 9606 BTO:0006413 32917631 t "Ser2 in CTD of PolII" lperfetto "Together, these studies demonstrate the important, yet largely redundant, role for CDK12 and CDK13 for the regulation of POLII CTD phosphorylation at multiple residues, as well as the global role for both of these kinases in regulating POLII occupancy across the genome.|CDK12 and CDK13 are thus evolutionarily related and structurally similar kinases, and biochemical assays have demonstrated that both have POLII C-terminal domain (CTD) kinase activity and the ability to phosphorylate the Ser2 residue of the repetitive CTD heptad sequence" SIGNOR-273107 HEY1 protein Q9Y5J3 UNIPROT RBPJ protein Q06330 UNIPROT down-regulates binding 9606 16682003 t gcesareni "These findings suggest a novel mechanism for negative feedback on notch signaling that requires rbp-jkappa to interact physically with hrt and hes." SIGNOR-146687 MIR1-1 mirna URS000075CF56_9606 RNAcentral IGF1 protein P05019 UNIPROT "down-regulates quantity" "post transcriptional regulation" 9606 25477897 t miannu "The down-regulation of miR-29b is thought to promote DNA hypermethylation in AML since miR-29b can directly target DNMT3A, DNMT3B, and Sp1 (a transcriptional regulator of DNMT1" SIGNOR-255793 PAM16 protein Q9Y3D7 UNIPROT "TIM23 complex" complex SIGNOR-C423 SIGNOR "form complex" binding 32074073 t lperfetto "The human TIM23 complex is formed by the core components TIM50 (50), TIM23 (23) and TIM17A/B (17A/B). The sorting elements are TIM21 (21) and ROMO1, and the motor elements include TIM44 (44), PAM18 (18; DNAJC15 and DNAJC19), PAM16 (16; MAGMAS), mtHSP70 (Mortalin) and GrpE." SIGNOR-267699 CHRM3 protein P20309 UNIPROT GNAI1 protein P63096 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-256739 DNMT3B protein Q9UBC3 UNIPROT BAG1 protein Q99933 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0001109 18413740 f lperfetto "DNA methyltransferase 1 and 3B activate BAG-1 expression via recruitment of CTCFL/BORIS and modulation of promoter histone methylation" SIGNOR-254109 SDC4 protein P31431 UNIPROT DVL2 protein O14641 UNIPROT up-regulates binding 9606 23151663 t gcesareni "Like other wnt co receptors, syndecan 4 directly interacts with dvl during pcp." SIGNOR-199635 CARM1 protein Q86X55 UNIPROT PAX7 protein P23759 UNIPROT up-regulates methylation 9606 BTO:0002314 BTO:0000887;BTO:0001103 22863532 t miannu "Carm1 specifically methylates multiple arginines in the n-terminus of pax7. Methylated pax7 directly binds the c-terminal cleavage forms of the trithorax proteins mll1/2 resulting in the recruitment of the ash2l:mll1/2:wdr5:rbbp5 histone h3k4 methyltransferase complex to regulatory enhancers and the proximal promoter of myf5." SIGNOR-198617 GFI1 protein Q99684 UNIPROT SPI1 protein P17947 UNIPROT "down-regulates activity" binding 10090 BTO:0000725 17197705 t miannu "Our data demonstrate that GFI-1 physically interacts with PU.1, repressing PU.1-dependent transcription. This repression is functionally significant, as GFI-1 blocked PU.1-induced macrophage differentiation of a multipotential hematopoietic progenitor cell line." SIGNOR-256043 PRKACA protein P17612 UNIPROT IMMT protein Q16891 UNIPROT "down-regulates activity" phosphorylation Ser528 ELQFRRLsQEQVDNF -1 27153535 t miannu "PKA directly phosphorylated the Ser528 residue of MIC60. Phosphorylation of MIC60 Interrupts Parkin Recruitment and Formation of the MICOS Complex" SIGNOR-266302 RNF31 protein Q96EP0 UNIPROT LUBAC complex SIGNOR-C527 SIGNOR "form complex" binding 9606 BTO:0000567 17006537 t miannu "Here, we report that a protein complex consisting of two RING finger proteins, HOIL-1L and HOIP, exhibits ubiquitin polymerization activity by recognizing ubiquitin moieties of proteins. The polyubiquitin chain generated by the complex is not formed by Lys linkages, but by linkages between the C- and N-termini of ubiquitin, indicating that the ligase complex possesses a unique feature to assemble a novel head-to-tail linear polyubiquitin chain." SIGNOR-271616 IL15RA protein Q13261 UNIPROT JAK1 protein P23458 UNIPROT up-regulates BTO:0000782 30029643 t areggio "Since Jak-STAT pathway primarily activated in IL-15-me- diated cell proliferation, we tested whether it is also participates in IL-15-mediated proliferation of FAPs. Interestingly, we found the expression of phospho-Jak3 and phospho-Tyk2, as well as their downstream, phospho- STAT3 and phospho-STAT5, was significantly upregulated" SIGNOR-256227 "SNS-314 Mesylate" chemical CID:24995523 PUBCHEM AURKA protein O14965 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-207099 SNAI2 protein O43623 UNIPROT CCND1 protein P24385 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000356 21044962 f miannu "knockdown of SLUG in SLUG-high breast cancer cells elevated the levels of UbcH5c while decreasing the level of cyclin D1 protein. SLUG is recruited at the E2-box sequence at the UbcH5c gene promoter along with the corepressor CtBP1 and the effector HDAC1 to silence the expression of this gene." SIGNOR-255176 PRKACA protein P17612 UNIPROT ADD1 protein P35611 UNIPROT "down-regulates activity" phosphorylation Ser436 TCSPLRHsFQKQQRE -1 8810272 t miannu "Protein kinase A phosphorylates -adducin at three sites in the neck domain (Ser-408, ’436, and ’481) in addition to the MARCKS-related domain of both subunits. Phosphorylation by PKA, in contrast to PKC, reduced affinity of erythrocyte adducin for spectrin-F-actin complexes as well as activity of adducin in promoting binding of spectrin to F-actin." SIGNOR-250330 RHOA protein P61586 UNIPROT PFN1 protein P07737 UNIPROT "up-regulates activity" 9606 BTO:0000815 22820501 t lperfetto "We find that the small GTPase Rho regulates R-cadherin adherens junction formation via Dia1 (also known as p140mDia) and profilin-1-mediated signaling pathway. The role played by Rho in regulating R-cadherin is underscored by the fact that constitutively active RhoA(Q63L) induces R-cadherin junction formation in MDA-MB-231 cells.|Data presented thus far demonstrated that Rho, Dia1, and profilin-1 were required for R-cadherin junction formation in N480 cells." SIGNOR-253109 MAML1 protein Q92585 UNIPROT EP300 protein Q09472 UNIPROT up-regulates relocalization 9606 19304754 t gcesareni "We show that maml1 potentiates p300 autoacetylation and p300 transcriptional activation. Maml1 directly enhances p300 hat activity, and this coincides with the translocation of maml1, p300 and acetylated histones to nuclear bodies." SIGNOR-184853 CyclinA2/CDK2 complex SIGNOR-C83 SIGNOR CEP76 protein Q8TAP6 UNIPROT "down-regulates activity" phosphorylation Ser83 VEQELPSsPKQPICF 9606 BTO:0000007 27065328 t miannu "Cep76 is phosphorylated by cyclin A/CDK2 at a single site S83. These data suggest that the phosphomimetic mutant is functional and that phosphorylation at S83 is critical for Cep76 to suppress centriole amplification." SIGNOR-262603 CSNK1E protein P49674 UNIPROT EIF4EBP1 protein Q13541 UNIPROT down-regulates phosphorylation Thr50 FSTTPGGtRIIYDRK 9606 BTO:0000150 24247720 t lperfetto "Mechanistic investigations showed that ck1_ interacted with and phosphorylated 4e-bp1 at two novel sites t41 and t50, which were essential for 4e-bp1 inactivation along with increased mrna translation and cell proliferation." SIGNOR-203276 TP53 protein P04637 UNIPROT NFKB2 protein Q00653 UNIPROT up-regulates binding 9606 16990795 t gcesareni "P52 cooperates with p53 to regulate other known p53 target genes." SIGNOR-149811 TBK1 protein Q9UHD2 UNIPROT IRF3 protein Q14653 UNIPROT "up-regulates activity" phosphorylation Ser398 VDLHISNsHPLSLTS -1 18440553 t lperfetto "Virus-induced phosphoactivation of irf-3, thought to be mediated directly or indirectly by ikk? And/or tbk1 occurs in the c-terminal region of irf-3 at seven ser/thr residues, 385sslentvdlhisnshplslts405 (fig. 1a).Within This region, irf-3 has two phosphorylation sites: site 1 includes ser385 and ser386, whereas site 2 includes ser396, ser398, ser402, ser405, and thr404." SIGNOR-178403 EEF1A2 protein Q05639 UNIPROT Gly-tRNA(Gly) smallmolecule CHEBI:29156 ChEBI up-regulates relocalization 9606 23699257 t lperfetto "During protein synthesis, eEF1A binds to and delivers aminoacylated tRNAs (aa-tRNAs) to the elongating ribosome (Fig. 1). GTP bound to eEF1A is hydrolyzed upon codon-anticodon match between an aa-tRNA in the A site of the ribosome and mRNA bound to the ribosome." SIGNOR-269541 AKT proteinfamily SIGNOR-PF24 SIGNOR BAD protein Q92934 UNIPROT "down-regulates activity" phosphorylation Ser99 PFRGRSRsAPPNLWA 9606 BTO:0000007 9381178 t "Active Akt induced a significant increase in BAD phosphorylation. mutant BAD with alanine substitutions at Ser112 and Ser136 was not phosphorylated by active Akt . phosphorylation of BAD by Akt will preclude its binding to membrane-anchored Bcl-xL, leading to increased cell survival." SIGNOR-251470 ITGB1 protein P05556 UNIPROT "A1/b1 integrin" complex SIGNOR-C159 SIGNOR "form complex" binding 16988024 t lperfetto "Integrins are one of the major families of cell adhesion receptors (Humphries, 2000; Hynes, 2002). All integrins are non-covalently-linked, heterodimeric molecules containing an α and a β subunit. Both subunits are type I transmembrane proteins, containing large extracellular domains and mostly short cytoplasmic domains (Springer and Wang, 2004; Arnaout et al., 2005). Mammalian genomes contain 18 α subunit and 8 β subunit genes, and to date 24 different α,β combinations have been identified at the protein level. Although some subunits only appear in a single heterodimer, twelve integrins contain the β1 subunit, and five contain αV." SIGNOR-253170 CREB1 protein P16220 UNIPROT Survival phenotype SIGNOR-PH13 SIGNOR up-regulates 9606 20660310 f amattioni "beta-catenin/CBP-driven transcription is critical for maintenance of an undifferentiated/proliferative state" SIGNOR-229777 CTCF protein P49711 UNIPROT RARRES1 protein P49788 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000356 22615834 f miannu "Epigenetic repression of RARRES1 is mediated by methylation of a proximal promoter and a loss of CTCF binding. knocking-down CTCF expression hampered RARRES1 expression, suggesting CTCF positively regulated RARRES1 transcription presumably by binding to unmethylated promoter poised at transcription-ready state." SIGNOR-253831 Ubiquitin proteinfamily SIGNOR-PF89 SIGNOR Ub:RBR_E3 complex SIGNOR-C520 SIGNOR "form complex" binding 9606 34199813 t miannu "The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5′-triphosphate (ATP)-dependent manner to form a thioester-linked E1‒Ub conjugate. The activated Ub is then delivered to an E2 enzyme via a transthiolation reaction. Finally, an E3 enzyme, which can bind both a substrate and an E2‒Ub conjugate, mediates the covalent linkage of Ub to the target protein as a tag." SIGNOR-271381 PCSK6 protein P29122 UNIPROT VWF protein P04275 UNIPROT "up-regulates activity" cleavage 8218226 t Giorgia "Like PACE,PACE4 was able to process pro-vWF to its mature form, and efficient cleavage required both the P4 arginine and the P2 lysine" SIGNOR-260367 EP300 protein Q09472 UNIPROT KRT16 protein P08779 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 12954631 f miannu "these results suggest that Sp1 and AP1 sites in the essential promoter region are critical for EGF response, and Sp1 showed a functional cooperation with c-Jun and coactivators p300/CBP in driving the transcriptional regulation of EGF-induced keratin 16 gene expression. The coactivators p300/CBP could collaborate with Sp1 and c-Jun in the activation of keratin 16 promoter." SIGNOR-253904 regorafenib chemical CHEBI:68647 ChEBI EPHA2 protein P29317 UNIPROT "down-regulates activity" "chemical inhibition" 9606 24756792 t miannu "In biochemical in vitro or cell-based assays, Regorafenib or its major human active metabolites M-2 and M-5 inhibited the activity of RET,VEGFR 1-3, KIT, PDGFR-alpha, PDGFR-beta, FGFR1, FGFR2, TIE2, DDR2, TrkA, Eph2A, RAF-1, BRAF, BRAFV600E, SAPK2, PTK5, and Abl at concentrations that can be achieved clinically." SIGNOR-259210 CUL2 protein Q13617 UNIPROT "BAF250b E3 ligase" complex SIGNOR-C522 SIGNOR "form complex" binding 9606 BTO:0000567 20086098 t miannu "In the present work, we show that BAF250 associates with elongin C (Elo C), cullin 2 (Cul2), and Roc1 to form an E3 ubiquitin ligase. BAF250 forms an E3 ubiquitin ligase with Elo B/C, Cul2, and Roc1 that targets histone H2B. H2B-Ub has been shown to be required for transcriptional activation in vitro" SIGNOR-271440 SRC protein P12931 UNIPROT DDR2 protein Q16832 UNIPROT up-regulates phosphorylation Tyr741 NLYSGDYyRIQGRAV 9606 16186108 t gcesareni "Here, using baculoviral co-expression of the ddr2 cytosolic domain and src, we show that src targets three tyrosine residues (tyr-736, tyr-740, and tyr-741) in the activation loop of ddr2 for phosphorylation. This phosphorylation by src stimulates ddr2 cis-autophosphorylation of additional tyrosine residues." SIGNOR-140767 PYGL protein P06737 UNIPROT glycogen smallmolecule CHEBI:28087 ChEBI "down-regulates quantity" "chemical modification" 9606 3346228 t "Mammalian glycogen phosphorylases are found in at least three isozymic forms that can be distinguished by functional and structural properties as well as by the tissues in which they are preferentially expressed [√¢‚Ǩ¬¶] Each phosphorylase isozyme fulfills different physiological requirements even though all forms of the enzyme catalyze the same reaction, the phosphorolysis of glycogen to yield glucose 1-phosphate." SIGNOR-267949 MAP4K1 protein Q92918 UNIPROT MAPK8 protein P45983 UNIPROT up-regulates 9606 8824585 f gcesareni "These results demonstrated that the observed jnk1 activation was from hpk1 and not from other hpkl-associated kinases or from cross-reactive kinases precipitated by anti-hpk1 antibody." SIGNOR-43999 "CAK complex" complex SIGNOR-C456 SIGNOR CDK4 protein P11802 UNIPROT up-regulates phosphorylation Thr172 YSYQMALtPVVVTLW 9606 8139570 t lperfetto "Phosphorylation of cdk4 on threonine 172 by a cdk-activating kinase (cak).  therefore, formation of the cyclin d-cdk4 complex and phosphorylation of the bound catalytic subunit are independently regulated, and in addition to the requirement for cak activity, serum stimulation is required to promote assembly of the complexes in mammalian cells." SIGNOR-269329 GSK3B/Axin/APC complex SIGNOR-C110 SIGNOR CTNNB1 protein P35222 UNIPROT "down-regulates activity" phosphorylation Ser33 QQQSYLDsGIHSGAT 9606 11955436 t lperfetto "Wnt regulation of beta-catenin degradation is essential for development and carcinogenesis. beta-catenin degradation is initiated upon amino-terminal serine/threonine phosphorylation, which is believed to be performed by glycogen synthase kinase-3 (GSK-3) in complex with tumor suppressor proteins Axin and adnomatous polyposis coli (APC)." SIGNOR-227897 LRRC45 protein Q96CN5 UNIPROT CROCC protein Q5TZA2 UNIPROT "up-regulates activity" binding 9606 BTO:0000567 24035387 t miannu "Here, we show that LRRC45 is a centrosome linker that localizes at the proximal ends of the centrioles and forms fiber-like structures between them. Depletion of LRRC45 results in centrosome splitting during interphase. LRRC45 interacts with C-Nap1 and rootletin" SIGNOR-273704 MAPK3 protein P27361 UNIPROT PCBP2 protein Q15366 UNIPROT "up-regulates quantity by stabilization" phosphorylation Ser173 MLETLSQsPPKGVTI 9606 BTO:0000664 17475908 t miannu "We also identified 4 hnRNP-E2 MAPKERK1/2 phosphorylation sites and demonstrated that hnRNP-E2 is a bona fide MAPKERK1/2 substrate and that MAPKERK1/2-dependent phosphorylation of hnRNP-E2 at these amino acid residues is essential for increased hnRNP-E2 expression in BCR/ABL-expressing cells. Serine/threonine to alanine substitution abolishes hnRNP-E2 phosphorylation and markedly decreases its stability in BCR/ABL-expressing myeloid precursors. Consistent with the existence of a BCR/ABL-MAPK pathway that posttranslationally regulates hnRNP-E2 expression, sequence analysis of hnRNP-E2 revealed the presence of 4 consensus ERK phosphorylation sites (S/T-P)35,36 at amino acid residues 173, 189, 213, and 272 (Figure 2B)." SIGNOR-262914 ALDH1A2 protein O94788 UNIPROT retinal smallmolecule CHEBI:15035 ChEBI "down-regulates quantity" "chemical modification" 9606 21621639 t lperfetto "All-trans-retinoic acid (atRA) provides essential support to diverse biological systems and physiological processes.| An accrual of biochemical, physiological and genetic data have identified specific functional outcomes for the retinol dehydrogenases, RDH1, RDH10, and DHRS9, as physiological catalysts of the first step in atRA biosynthesis, and for the retinal dehydrogenases RALDH1, RALDH2, and RALDH3, as catalysts of the second and irreversible step." SIGNOR-265125 PRKCA protein P17252 UNIPROT GSK3B protein P49841 UNIPROT down-regulates phosphorylation Ser9 SGRPRTTsFAESCKP 9606 BTO:0000782 19836308 t lperfetto "Gsk3 is different from most kinases in that it is constitutively partially active and the most common regulatory mechanism is inhibition by phosphorylation of ser21 in gsk3_ or ser9 in gsk3_. This inhibitory phosphorylation can be mediated by several kinases, such as akt/protein kinase b (pkb), protein kinase c (pkc) and protein kinase a (pka)." SIGNOR-188581 ESR1 protein P03372 UNIPROT AR protein P10275 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 11000528 f gcesareni "Inhibition of ar-induced transactivation that was er cdna dose-responsive and estradiol dependent" SIGNOR-82158 CBFA2T3/ZNF651 complex SIGNOR-C197 SIGNOR ZNF652 protein Q9Y2D9 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0000007 20116376 t "Previously we reported that a classical C2H2 zinc finger DNA binding protein ZNF652 functionally interacts with CBFA2T3 to repress transcription of genes containing ZNF652 consensus DNA binding sequence within the promoters of these target genes. Here we show that ZNF651 is a ZNF652 paralogue that shares a common DNA binding sequence with ZNF652 and represses target gene expression through the formation of a CBFA2T3-ZNF651 corepressor complex." SIGNOR-253955 USP9X protein Q93008 UNIPROT SMAD4 protein Q13485 UNIPROT up-regulates deubiquitination Lys519 DYPRQSIkETPCWIE 10090 BTO:0000165 20016939 t gcesareni "Smad4 is monoubiquitinated in lysine 519 in vivo, a modification that inhibits smad4 by impeding association with phospho-smad2. Fam reverts this negative modification, re-empowering smad4 function;control of smad4 is a good way to regulate bone formation. Fam and ectodermin/tif1gamma (ecto) were reported to respectively regulate the de-ubiquitination and ubiquitination of smad4." SIGNOR-236855 NDUFB5 protein O43674 UNIPROT "Mitochondrial respiratory chain complex I" complex SIGNOR-C277 SIGNOR "form complex" binding 30030361 t lperfetto "Thus, we now know the complete mammalian cI structure [22,23] and how the subunits are organized in six modules (N, Q, ND1, ND2, ND4 and |The main ND4-module intermediate binds NDUFB1, NDUFB4, NDUFB5, NDUFB6, NDUFB10, NDUFB11 and MT-ND4" SIGNOR-262168 RBPJ protein Q06330 UNIPROT HES1 protein Q14469 UNIPROT "up-regulates quantity" "transcriptional regulation" 10090 BTO:0000165 10066785 t gcesareni "ligand-induced Notch signaling up-regulated HES1 mRNA expression within 1h and subsequently reduced expression of MyoD mRNA" SIGNOR-243178 FOXO1 protein Q12778 UNIPROT G6PC1 protein P35575 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 18805788 f gcesareni "In the gk gene regulation, foxo1 represses hnf-4-potentiated transcription of the gene, whereas it synergizes with hnf-4 in activating the g6pase gene transcription." SIGNOR-181195 DNMT3A protein Q9Y6K1 UNIPROT TIMP2 protein P16035 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 19786833 f irozzo "Based on one of these publications, we here showed that the interaction of Dnmt3a with c-myc promote the specific methylation of CG dinucleotides localized in c-myc boxes of promoter regions of CDKN2a, CCND1 and TIMP2 genes. Acellular experiments corroborated and complemented these results by revealing that the specificity of consensus sequence for DNA methylation of Dnmt3a is increased in presence of c-myc." SIGNOR-255807 LPAR6 protein P43657 UNIPROT GNAO1 protein P09471 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257004 TTK protein P33981 UNIPROT TTK protein P33981 UNIPROT down-regulates phosphorylation Thr806 NQMAKGTtEEMKYVL 9606 18680479 t miannu "We have identified 16 sites of mps1 autophosphorylation in vitro, several of which are required for catalytic activity / t806d mps1 was significantly less active than t806a, demonstrating a potential negative correlation between phosphorylation and activity at this site." SIGNOR-179908 PRKCA protein P17252 UNIPROT EGLN2 protein Q96KS0 UNIPROT down-regulates phosphorylation Ser234 QRAIPPRsIRGDQIA 9606 18710826 t tpavlidou "Thus, recombinant phd1 was examined for in vitro phosphorylation using protein kinase a, protein kinase calpha, casein kinase i and ii and erk2. The protein was most strongly phosphorylated by protein kinase calpha, and the phosphorylation sites were found to be ser-132, ser-226 and ser-234.Mutation Of ser-132 or ser-234 to asp or glu diminished the enzymatic activity to 25-60%, while mutation of ser-226 scarcely influenced the activity." SIGNOR-180203 MYC protein P01106 UNIPROT PFKM protein P08237 UNIPROT "up-regulates quantity" "transcriptional regulation" 10116 10823814 t "C-Myc directly transactivates genes encoding GLUT1, phosphofructokinase, and enolase and increases glucose uptake in Rat1 fibroblasts. Nuclear run-on studies confirmed that the GLUT1 transcriptional rate is elevated by c-Myc. Our findings suggest that overexpression of the c-Myc oncoprotein deregulates glycolysis through the activation of several components of the glucose metabolic pathway." SIGNOR-259988 PF-04691502 chemical CID:25033539 PUBCHEM AKT proteinfamily SIGNOR-PF24 SIGNOR down-regulates "chemical inhibition" 9606 Other t "Selleck;inhibitor of phosphorylation of AktT308 and AktS473" gcesareni SIGNOR-205977 MAPKAPK2 protein P49137 UNIPROT HNRNPA0 protein Q13151 UNIPROT "up-regulates activity" phosphorylation Ser84 VELKRAVsREDSARP 10090 BTO:0000801 12456657 t miannu "MAPKAP-K2 phosphorylated hnRNP A0 at Ser84 in vitro and this residue became phosphorylated in LPS-stimulated cells. The simplest explanation for these findings is that the phosphorylation of hnRNP A0 at Ser84 by MAPKAP-K2 enhances binding to the AREs of these mRNAs or allows hnRNP A0 to displace another protein(s) from the AREs." SIGNOR-262951 PRKACA protein P17612 UNIPROT KCNH2 protein Q12809 UNIPROT up-regulates phosphorylation Thr895 KLSFRRRtDKDTEQP 9606 10488078 t lperfetto "Deletion of protein kinase a phosphorylation sites in the herg potassium channel inhibits activation shift by protein kinase afour consensus pka phosphorylation sites (s283a, s890a, t895a, s1137a)" SIGNOR-70730 "MLL2 complex" complex SIGNOR-C88 SIGNOR KDM6A protein O15550 UNIPROT "up-regulates quantity by stabilization" binding 9606 28669924 t miannu "KMT2D associates with WRAD (WDR5, RbBP5, ASH2L, and DPY30), NCOA6, PTIP, PA1, and H3K27 demethylase UTX in one protein complex. It acts as a scaffold protein within the complex and is responsible for maintaining the stability of UTX. UTX is the complex’s H3K27 demethylase." SIGNOR-268813 AKT1 protein P31749 UNIPROT TKT protein P29401 UNIPROT "up-regulates activity" phosphorylation Thr382 GCATRNRtVPFCSTF 9606 BTO:0000567 24981175 t lperfetto "Akt phosphorylates TKT on Thr382, markedly enhancing enzyme activity and increasing carbon flow through the nonoxidative PPP, thereby increasing purine synthesis." SIGNOR-265101 MAPK3 protein P27361 UNIPROT MYB protein P10242 UNIPROT down-regulates phosphorylation Ser532 KIKQEVEsPTDKSGN 9606 8798443 t llicata "Here we describe that human c-myb can be phosphorylated by mitogen-activated protein kinases (mapk's) at serine 532 of the carboxy (c-) terminal regulatory domain in vitro. expression of a constitutively active form of ras together with c-myb in transient transfection experiments had no effect on the transcriptional activity of c-myb, while expression of a polypeptide containing the c-myb c-terminal domain stimulated c-myb activity. This effect is reduced upon mapk-dependent phosphorylation of serine 532." SIGNOR-43558 PKA proteinfamily SIGNOR-PF17 SIGNOR CREB1 protein P16220 UNIPROT "up-regulates activity" phosphorylation Ser119 EILSRRPsYRKILND 9606 8386317 t miannu "CREB is phosphorylated on Ser133 by PKA (protein kinase A), promoting the recruitment of the co-activator proteins CBP (CREB-binding protein) and p300; this has been proposed to increase the transcription of CREB-dependent genes." SIGNOR-263653 SRC protein P12931 UNIPROT PTK2 protein Q05397 UNIPROT up-regulates phosphorylation Tyr407 IIDEEDTyTMPSTRD 9606 15735019 t miannu "Surprisingly, we found that expression of SrcMF or Src251 resulted in increased tyrosine phosphorylation of FAK on Tyr(407), Tyr(576), Tyr(577), and Tyr(861), which are considered to be Src kinase substrates" SIGNOR-150480 PTBP2 protein Q9UKA9 UNIPROT SRC protein P12931 UNIPROT "down-regulates quantity by repression" "post transcriptional regulation" 9606 BTO:0000567 11003644 t lperfetto "Splicing of the c-src N1 exon in neuronal cells depends in part on an intronic cluster of RNA regulatory elements called the downstream control sequence (DCS). |nPTB binds more stably to the DCS RNA than PTB does but is a weaker repressor of splicing in vitro. nPTB also greatly enhances the binding of two other proteins, hnRNP H and KSRP, to the DCS RNA." SIGNOR-261267 NFIA protein Q12857 UNIPROT ROBO1 protein Q9Y6N7 UNIPROT "up-regulates quantity" "transcriptional regulation" 10090 31838646 t Gianni "For example, within the NFI targetome, we identified 6 collagen genes, 13 genes encoding potassium channel or glutamate receptor subunits and a range of factors related to axon guidance (e.g. Slit1, Robo1, Epha4, Epha5, Epha8)" SIGNOR-268893 NMI protein Q13287 UNIPROT SOX10 protein P56693 UNIPROT "down-regulates activity" binding 9606 16214168 t miannu "We identify an association of Sox10 with the N-myc interactor Nmi. Nmi modulated the transcriptional activity of Sox10 in reporter gene assays. Nmi effects varied between different Sox10 target gene promoters, indicating that Nmi function in vivo may be promoter-specific." SIGNOR-225602 LUBAC complex SIGNOR-C527 SIGNOR DDX58 protein O95786 UNIPROT "down-regulates activity" binding 9606 BTO:0000007 21292167 t miannu "HOIL-1L/HOIP LUBAC induces TRIM25 ubiquitination and degradation Upon detection of viral RNA, retinoic acid-inducible gene I (RIG-I) undergoes TRIM25-mediated K63-linked ubiquitination, leading to type I interferon (IFN) production. In this study, we demonstrate that the linear ubiquitin assembly complex (LUBAC), comprised of two RING-IBR-RING (RBR)-containing E3 ligases, HOIL-1L and HOIP, independently targets TRIM25 and RIG-I to effectively suppress virus-induced IFN production. RBR E3 ligase domains of HOIL-1L and HOIP bind and induce proteasomal degradation of TRIM25, whereas the NZF domain of HOIL-1L competes with TRIM25 for RIG-I binding. Consequently, both actions by the HOIL-1L/HOIP LUBAC potently inhibit RIG-I ubiquitination and antiviral activity, but in a mechanistically separate manner." SIGNOR-271860 UGP2 protein Q16851 UNIPROT UDP-alpha-D-glucose(2-) chemical CHEBI:58885 ChEBI "up-regulates quantity" "chemical modification" 9606 8631325 t miannu "UDP-Glc pyrophosphorylase (EC 2.7.7.9) catalyses the interconversion of MgUTP plus Glc1P and UDP-Glc plus MgPPi." SIGNOR-267928 Ub:E2 complex SIGNOR-C497 SIGNOR RNF130 protein Q86XS8 UNIPROT "up-regulates activity" ubiquitination 9606 34199813 t miannu "The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t" SIGNOR-271031 ABL1 protein P00519 UNIPROT WASL protein O00401 UNIPROT "up-regulates activity" phosphorylation Tyr256 RETSKVIyDFIEKTG -1 16199863 t "Abl phosphorylates N-WASP on tyrosines 175 and 256. Phosphorylation at this site stabilizes the active conformation of N-WASP, resulting in comet tail elongation." SIGNOR-251437 CDK1 protein P06493 UNIPROT TP53 protein P04637 UNIPROT "up-regulates activity" phosphorylation Ser315 LPNNTSSsPQPKKKP 9606 24173284 t lperfetto "The N-terminus of E2F1 can interact directly with a region towards the C-terminus of p53, resulting in increased nuclear retention of p53 and p53-mediated transcription and apoptosis. This is inhibited by competition between p53 and cyclin A at the binding site within E2F19,10. The interaction between p53 and E2F1 is enhanced by phosphorylation of p53 on Ser315, a residue within the E2F1 binding region that is phosphorylated by cell cycle kinases such as cdk1, cdk2, cdk9 and Aurora kinase A" SIGNOR-84256 PRKAA1 protein Q13131 UNIPROT NOS3 protein P29474 UNIPROT up-regulates phosphorylation Ser1177 TSRIRTQsFSLQERQ 9606 BTO:0000567 SIGNOR-C15 18303014 t gcesareni "The central finding of this report is that rosiglitazone rapidly stimulates no production and enos ser-1177 phosphorylation in an ampk-dependent manner" SIGNOR-160838 ID1 protein P41134 UNIPROT MYOD1 protein P15172 UNIPROT "down-regulates activity" binding 10090 BTO:0000222 8380166 t 2 miannu "Id1 and Id2 interacted strongly with MyoD and Myf-5.Each Id was able to disrupt the ability of E protein-MyoD complexes to transactivate from a muscle creatine kinase reporter construct in vivo." SIGNOR-240265 FNTB protein P49356 UNIPROT MRAS protein O14807 UNIPROT "up-regulates activity" 9606 24294527 t lperfetto "Major investments have been made to target Ras through indirect routes. Inhibition of farnesyl transferase to block Ras maturation has failed in large clinical trials." SIGNOR-242562 GRM6 protein O15303 UNIPROT calcium(2+) smallmolecule CHEBI:29108 ChEBI "up-regulates quantity" relocalization 9606 BTO:0000938 29953871 t miannu "Ca2+ is arguably the most important second messenger in the brain because of its pivotal roles in presynaptic neurotransmitter release, postsynaptic responses, and plasticity induction. iGluRs and mGluRs can generate intracellular Ca2+ signals, albeit by different mechanisms, whose crosstalk has not been thoroughly explored (Figure 2C). iGluRs allow the influx of extracellular Ca2+ upon pore opening." SIGNOR-264937 MARCHF8 protein Q5T0T0 UNIPROT HLA-DRA protein P01903 UNIPROT "down-regulates quantity by destabilization" polyubiquitination Lys244 FIIKGLRkSNAAERR 9606 19117940 t miannu "Two E3 ligases, MARCH I and MARCH VIII, have been shown to polyubiquitinate lysine residue 225 in the cytoplasmic tail of I-Abeta and HLA-DRbeta. We show that lysine residue 219 in the cytoplasmic tail of DRalpha is also subject to polyubiquitination." SIGNOR-271411 PRKAA1 protein Q13131 UNIPROT EEF2K protein O00418 UNIPROT up-regulates phosphorylation Ser398 DSLPSSPsSATPHSQ 9606 SIGNOR-C15 22669845 t gcesareni "In response to genotoxic stress, eef2k was activated by ampk (adenosine monophosphate-activated protein kinase)-mediated phosphorylation on serine 398. Activated eef2k phosphorylated eef2 and induced a temporary ribosomal slowdown at the stage of elongation" SIGNOR-197734 ELOVL6 protein Q9H5J4 UNIPROT palmitoyl-CoA smallmolecule CHEBI:15525 ChEBI "down-regulates quantity" "chemical modification" 9606 31616255 t miannu "The ELOVL family of enzymes in mammals is comprised of seven members that all reside in the endoplasmic reticulum (ER) and are thought to form a multimeric complex. Together, the ELOVL family is responsible for the elongation of saturated and unsaturated fatty acids.Fatty acid elongation occurs by cycling through a four step process (condensation, reduction, dehydration, and reduction), with two carbon atoms added through each cycle." SIGNOR-267887 SLC4A10 protein Q6U841 UNIPROT chloride smallmolecule CHEBI:17996 ChEBI "down-regulates quantity" relocalization 9606 23056253 t miannu "The sodium-driven chloride bicarbonate exchanger NCBE (Slc4a10), a member of the SLC4 family of bicarbonate transporters, uses the transmembrane gradient of sodium to drive cellular net uptake of bicarbonate and to extrude chloride, thereby modulating both intracellular pH (pH(i)) and chloride concentration ([Cl(-)](i)) in neurons. " SIGNOR-264686 ATG12 protein O94817 UNIPROT Autophagosome_formation phenotype SIGNOR-PH36 SIGNOR up-regulates 4932 23321721 f lperfetto "Dissecting the role of the Atg12-Atg5-Atg16 complex during autophagosome formation" SIGNOR-219396 DHFR2 protein Q86XF0 UNIPROT dihydrofolate(2-) smallmolecule CHEBI:57451 ChEBI "down-regulates quantity" "chemical modification" 9606 21876184 t lperfetto "Human dihydrofolate reductase (DHFR) was previously thought to be the only enzyme capable of the reduction of dihydrofolate to tetrahydrofolate; an essential reaction necessary to ensure a continuous supply of biologically active folate. |We demonstrate that the DHFRP4, or dihydrofolate reductase-like 1 (DHFRL1), gene is expressed and shares some commonalities with DHFR." SIGNOR-268260 PP121 chemical CHEBI:50915 ChEBI PRKDC protein P78527 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-206304 PRKDC protein P78527 UNIPROT LIG4 protein P49917 UNIPROT down-regulates phosphorylation Ser672 CVMSGTDsQPKPDLE 9606 15194694 t lperfetto "Using tandem mass spectrometry, we identified a dna-pk phosphorylation site at thr-650 in human lig4 and a potential second phosphorylation site at ser-668 or ser-672. Phosphorylation of lig4 per se was not required for lig4 dna end joining activity. Substitution of these amino acids with alanine, individually or in combination, led to changes in lig4 protein stability of mouse lig4. The phosphomimetic mutation s650d returned lig4 stability to that of the wild-type protein. Furthermore dna-pk was found to negatively regulate lig4 protein stability." SIGNOR-125873 PLG protein P00747 UNIPROT F2R protein P25116 UNIPROT "up-regulates activity" cleavage Arg41 TNATLDPrSFLLRNP -1 10978167 t lperfetto "Plasmin mediates the lysis of fibrin clots and could in different studies activate platelets or inhibit the responses induced by thrombin (41-43). Our study favors a net inactivating effect on PAR1 despite minor cleavage at Arg41, on the basis of preferential cleavage at positions Arg70 and Lys76, COOH-terminal to the Arg41-Ser42 activation site." SIGNOR-263571 Riluzole chemical CHEBI:8863 ChEBI KCNN3 protein Q9UGI6 UNIPROT "up-regulates activity" "chemical activation" 9534 BTO:0000298 18955585 t Luana "Here, we used the neuroprotectant riluzole as a template for the design of KCa2/3 channel activators that are potent enough for in vivo studies. Of a library of 41 benzothiazoles, we identified 2 compounds, anthra[2,1-d]thiazol-2-ylamine (SKA-20) and naphtho[1,2-d]thiazol-2-ylamine (SKA-31), which are 10 to 20 times more potent than riluzole and activate KCa2.1 with EC50 values of 430 nM and 2.9 μM, KCa2.2 with an EC50 value of 1.9 μM, KCa2.3 with EC50 values of 1.2 and 2.9 μM, and KCa3.1 with EC50 values of 115 and 260 nM. " SIGNOR-258019 MAPK3 protein P27361 UNIPROT KRT8 protein P05787 UNIPROT unknown phosphorylation Ser432 SAYGGLTsPGLSYSL 9606 22344252 t llicata "Our data suggested a close relationship between k8(s431) phosphorylation and keratin reorganization in epithelial tumor cells." SIGNOR-196141 CEBPA protein P49715 UNIPROT PER2 protein O15055 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 22260161 f apalma "We have previously shown that PER2 is a downstream CCAAT-enhancer-binding protein (C/EBP)-target gene, and its disruption might be involved in the initiation and progression of acute myelogenous leukemia (AML)" SIGNOR-256369 ESR1 protein P03372 UNIPROT CDKN1A protein P38936 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000356 11517191 f "ER beta and ER alpha induced the expression of several endogenous genes such as pS2, TGF alpha, or the cyclin kinase inhibitor p21 but, in contrast to ER alpha, ER beta was unable to regulate c-myc proto-oncogene expression" SIGNOR-253940 NEK2 protein P51955 UNIPROT SGO1 protein Q5FBB7 UNIPROT up-regulates phosphorylation Ser14 LKKSFQDsLEDIKKR 9606 17621308 t lperfetto "Here we show that nek2a phosphorylates human sgo1 and such phosphorylation is essential for faithful chromosome congression in mitosis. phosphorylation sites were mapped to ser(14) and ser(507)" SIGNOR-156878 "Multiaminoacyl-tRNA synthetase" complex SIGNOR-C472 SIGNOR ATP(4-) smallmolecule CHEBI:30616 ChEBI "down-regulates quantity" "chemical modification" 9606 28271488 t miannu "Aminoacyl-tRNA synthetases (AARSs) are essential enzymes that specifically aminoacylate one tRNA molecule by the cognate amino acid. In mammals, nine synthetases, those specific for amino acids Arg, Asp, Gln, Glu, Ile, Leu, Lys, Met and Pro, associate into a multi-aminoacyl-tRNA synthetase complex, an association which is believed to play a key role in the cellular organization of translation, but also in the regulation of the translational and nontranslational functions of these enzymes." SIGNOR-270372 PLK1 protein P53350 UNIPROT NEDD1 protein Q8NHV4 UNIPROT "up-regulates activity" phosphorylation Ser426 VNKGSDEsIGKGDGF 9606 BTO:0000567 19509060 t lperfetto "Here we report that the function of Nedd1 is regulated by Cdk1 and Plk1. During mitosis, Nedd1 is firstly phosphorylated at T550 by Cdk1, which creates a binding site for the polo-box domain of Plk1. Then, Nedd1 is further phosphorylated by Plk1 at four sites: T382, S397, S637 and S426. The sequential phosphorylation of Nedd1 by Cdk1 and Plk1 promotes its interaction with gamma-tubulin for targeting the gammaTuRC to the centrosome and is important for spindle formation." SIGNOR-272992 FZR1 protein Q9UM11 UNIPROT DTYMK protein P23919 UNIPROT "down-regulates quantity by destabilization" binding 9606 BTO:0000567 16103219 t miannu "We demonstrate that TMPK is recognized and degraded by APC/C-Cdc20/Cdh1-mediated pathways from mitosis to the early G1 phase, whereas TK1 is targeted for degradation by APC/C-Cdh1 after mitotic exit. " SIGNOR-272652 PLK1 protein P53350 UNIPROT NINL protein Q9Y2I6 UNIPROT "down-regulates activity" phosphorylation Ser87 VRPSDEDsSSLESAA -1 12852856 t lperfetto "Here, we identify a centrosomal plk1 substrate, termed nlp (ninein-like protein), whose properties suggest an important role in microtubule organization. Nlp interacts with two components of the gamma-tubulin ring complex and stimulates microtubule nucleation. Plk1 phosphorylates nlp and disrupts both its centrosome association and its gamma-tubulin interaction" SIGNOR-103352 PTPRE protein P23469 UNIPROT KCNB1 protein Q14721 UNIPROT "down-regulates activity" dephosphorylation Tyr128 YWGIDEIyLESCCQA 9606 BTO:0000007 10921884 t "Hypomyelination and increased activity of voltage-gated K(+) channels in mice lacking protein tyrosine phosphatase epsilon" SIGNOR-248450 PPP2R3C protein Q969Q6 UNIPROT PPP5C protein P53041 UNIPROT "up-regulates activity" binding 9606 BTO:0000007 24333728 t "Protein phosphatase complex PP5/PPP2R3C dephosphorylates P-glycoprotein/ABCB1 and down-regulates the expression and function" SIGNOR-272480 FBXW12 protein Q6X9E4 UNIPROT IL22RA1 protein Q8N6P7 UNIPROT "down-regulates quantity by destabilization" binding -1 26171402 t miannu "FBXW12 causes depletion of endogenous and plasmid-derived IL-22R in lung epithelia, binds the E3 ligase constituent Skp-1, and facilitates ubiquitination of IL-22R in vitro." SIGNOR-272426 PAK2 protein Q13177 UNIPROT JUN protein P05412 UNIPROT up-regulates phosphorylation Thr2 tAKMETTF 9606 BTO:0000848 21177766 t lperfetto "P21-activated protein kinase (pak2)-mediated c-jun phosphorylation at 5 threonine sites promotes cell transformationour data showed that pak2 binds and phosphorylates c-jun at five threonine sites (thr2, thr8, thr89, thr93 and thr286)" SIGNOR-170760 FBXO22 protein Q8NEZ5 UNIPROT TP53 protein P04637 UNIPROT "down-regulates quantity by destabilization" ubiquitination 9606 BTO:0003031 26868148 t "methylated tp53" lperfetto "We demonstrate here that SCFFbxo22-KDM4A is a senescence-associated E3 ligase targeting methylated p53 for degradation. We find that Fbxo22 is highly expressed in senescent cells in a p53-dependent manner, and that SCFFbxo22 ubiquitylated p53 and formed a complex with a lysine demethylase, KDM4A. |SCFFbxo22 forms a ternary complex with p53 and KDM4A that targets methylated p53 for degradation." SIGNOR-273448 EGFR protein P00533 UNIPROT EGFR protein P00533 UNIPROT "up-regulates activity" phosphorylation Tyr1110 GSVQNPVyHNQPLNP 10090 BTO:0002882 16122376 t "Dimerization mediated by a beta hairpin, which protudes from the S1 domains of each ligand bound monomer" lperfetto "EGFR possesses three major and two minor tyrosine autophosphorylation sites located at Y1068, Y1148, Y1173, and at Y992 and Y1086 respectively. In addition, EGFR Y1114 is preceded by glutamic acid (Figure 1), which should be preferred by the EGFR kinase as indicated in previous work" SIGNOR-236516 2-oxoglutarate(2-) smallmolecule CHEBI:16810 ChEBI PHF2 protein O75151 UNIPROT "up-regulates activity" "chemical activation" 29981745 t lperfetto "Histone lysine demethylases (KDMs) are 2-oxoglutarate-dependent dioxygenases (2-OGDDs) that regulate gene expression by altering chromatin structure. |2-OG is a central intermediate of the Krebs cycle, where it is produced by isocitrate dehydrogenase (IDH) isoenzymes 2 and 3." SIGNOR-273464 MTOR protein P42345 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 BTO:0000007 20508131 f "The mammalian target of rapamycin complex 1 (mTORC1) integrates mitogen and nutrient signals to control cell proliferation and cell size." SIGNOR-255944 ZNF143 protein P52747 UNIPROT TCP1 protein P17987 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 10893243 t Luana "The transcription from the minimalCcta promoter was up-regulated 3-fold by ZNF143 and 6-fold by ZNF76 when full-length proteins were co-expressed, indicating that both ZNF143 and ZNF76 can enhance Ccta transcription." SIGNOR-266220 terazosin chemical CHEBI:9445 ChEBI ADRA1A protein P35348 UNIPROT "down-regulates activity" "chemical inhibition" 9606 BTO:0001260 9379432 t miannu "Pharmacological management of benign prostatic hyperplasia (BPH) has most successfully been achieved by administration of α1 antagonists, which function via relaxation of prostatic smooth muscle. Terazosin2 (2), doxazosin3 (3), and alfuzosin4 (4), agents currently approved for this indication" SIGNOR-258671 PAX2 protein Q02962 UNIPROT WT1 protein P19544 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 16631587 t "Cotransfection of Pax2 with the Wt1 reporter construct led to moderate activation of the Wt1 promoter." SIGNOR-252290 SMO protein Q99835 UNIPROT SRC protein P12931 UNIPROT up-regulates phosphorylation 9606 18455992 t gcesareni "Instead, shh rapidly and locally stimulated phosphorylation of the src family kinase (sfk) members src and fyn in a smo-dependent fashion." SIGNOR-178610 TGFB1 protein P01137 UNIPROT SFTPB protein P07988 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0004299 18003659 f miannu "TGF-beta represses transcription of pulmonary surfactant protein-B gene in lung epithelial cells." SIGNOR-254170 "SWI/SNF complex" complex SIGNOR-C92 SIGNOR CDKN2B protein P42772 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 18332116 f irozzo "HSNF5 reexpression in MRT cells caused SWI/SNF recruitment and activation of p15INK4b and p16INK4a, but not of p14ARF.Reexpression of hSNF5 in MRT cells overcomes epigenetic silencing and mediates transcriptional activation of p15INK4b and p16INK4a" SIGNOR-256300 MECOM protein Q03112 UNIPROT ANGPT1 protein Q15389 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 15889140 t Luana "We finally observed that the forced expression of Evi1 induced GATA-2 expression in a hematopoietic cell line, EML C1, along with GATA-1, Ang-1, Ang-2 and Tie2 " SIGNOR-266059 PRKACA protein P17612 UNIPROT VIM protein P08670 UNIPROT "down-regulates activity" phosphorylation Ser39 TTSTRTYsLGSALRP -1 2500966 t miannu "Ser-46 was phosphorylated preferentially by cAMP-dependent protein kinase. Both kinases reacted with Ser-6, Ser-24, Ser-38, Ser-50, and Ser-65. Domain- and sequence-specific phosphorylation of vimentin induces disassembly of the filament structure." SIGNOR-250067 NFIA protein Q12857 UNIPROT NEUROD1 protein Q13562 UNIPROT "up-regulates quantity" "transcriptional regulation" 10090 31838646 t Gianni "For example, within the NFI targetome, we identified 6 collagen genes, 13 genes encoding potassium channel or glutamate receptor subunits and a range of factors related to axon guidance (e.g. Slit1, Robo1, Epha4, Epha5, Epha8)" SIGNOR-268890 L-glutamate(1-) smallmolecule CHEBI:29985 ChEBI "gamma-aminobutyric acid" smallmolecule CHEBI:16865 ChEBI "up-regulates quantity" "precursor of" 9606 32041144 t miannu "Glutamate decarboxylase (GAD; EC 4.1.1.15) is a unique pyridoxal 5-phosphate (PLP)-dependent enzyme that specifically catalyzes the decarboxylation of L-glutamic acid to produce Œ≥-aminobutyric acid (GABA), which exhibits several well-known physiological functions." SIGNOR-267550 CyclinA2/CDK2 complex SIGNOR-C83 SIGNOR CDC7 protein O00311 UNIPROT "up-regulates activity" phosphorylation Thr376 QVAPRAGtPGFRAPE 10846177 t llicata "Among four possible Cdk phosphorylation sites of huCdc7, replacement of Thr-376, corresponding to the activating threonine of Cdk, with alanine (T376A mutant) dramatically reduces kinase activity, indicative of kinase activation by phosphorylation of this residue. In vitro, Cdk2-Cyclin E, Cdk2-Cyclin A, and Cdc2-Cyclin B, but not Cdk4-Cyclin D1, phosphorylates the Thr-376 residue of huCdc7, suggesting possible regulation of huCdc7 by Cdks." SIGNOR-250725 ROCK1 protein Q13464 UNIPROT MPRIP protein Q6WCQ1 UNIPROT down-regulates phosphorylation 9606 17761936 t gcesareni "Enhanced rho kinase activity induces endothelial barrier dysfunction by a contractile mechanism via inactivation of myosin phosphatase (mp).." SIGNOR-157593 MECP2 protein P51608 UNIPROT SGK1 protein O00141 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 10090 16002417 t Luana "These results are compatible with the hypothesis that MeCP2 associates with the Sgk and Fkbp5 promoters and has a repressive effect that is over-ridden by elevated glucocorticoids in response to stress." SIGNOR-264543 CYSLTR1 protein Q9Y271 UNIPROT GNAQ protein P50148 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257019 TRIB3 protein Q96RU7 UNIPROT ACACA protein Q13085 UNIPROT "down-regulates quantity by destabilization" binding 9606 BTO:0000007 16794074 t miannu "TRB3 appears to inhibit ACC activity by functioning as an adaptor for COP1.  Taken together, these results suggest that TRB3 may promote loss of fat by mediating the COP1-dependent ubiquitination and inactivation of ACC. Taking these results together, we propose that TRB3 may protect against diet-induced obesity by stimulating fatty acid oxidation in adipose during fasting through the COP1-mediated ubiquitination and degradation of ACC (Fig. 4D)." SIGNOR-271600 CARS1 protein P49589 UNIPROT tRNA(Cys) smallmolecule CHEBI:29167 ChEBI "down-regulates quantity" "chemical modification" 9606 11347887 t miannu "Cysteinyl-tRNA synthetase catalyzes the addition of cysteine to its cognate tRNA. Here we report the isolation of a fulllength cDNA that encodes a protein of 748 amino acids. The predicted protein sequence shows considerable similarity to other eukaryotic cysteinyltRNA synthetases in the carboxylterminus. Expression of the fulllength and alternative forms of the enzyme in E. coli generated functional proteins that were active in aminoacylation of human cytoplasmic tRNA with cysteine." SIGNOR-270469 GSK3B protein P49841 UNIPROT EIF2B2 protein P49770 UNIPROT down-regulates binding 9606 21798082 t gcesareni "Akt also promotes protein synthesis by phosphorylating and inactivating gsk3b, thus releasing the gsk3b-dependent inhibition of the eukariotic translation initiation factor 2b (eif2b)." SIGNOR-175475 NLGN4Y protein Q8NFZ3 UNIPROT NRXN2 protein Q9P2S2 UNIPROT "up-regulates activity" binding 9606 BTO:0000938 18923512 t brain lperfetto "Pre- and postsynaptic plasma membranes are always precisely aligned, and are separated by a synaptic cleft of ~20 nm. The cleft contains an undefined proteinaceous material in the middle, and is presumably bridged by synaptic cell-adhesion molecules such as Nrxns and Nlgns that align the pre- and postsynaptic elements and mediate trans-synaptic signaling.|Nlgns bind to both alpha- and beta-Nrxns with nanomolar affinities; binding involves the sixth LNS-domain of alpha-Nrxns which corresponds to the only LNS-domain of beta-Nrxns52. The binding affinities differ characteristically between various pairs of Nlgns and Nrxns, and are controlled by alternative splicing of both Nrxns and Nlgns (Figure 1c)" SIGNOR-264153 NKX3-1 protein Q99801 UNIPROT NKX3-1/SRF complex SIGNOR-C25 SIGNOR "form complex" binding 9606 BTO:0000887;BTO:0001260 10993896 t lperfetto "A novel complex element containing a juxtaposed nkx-binding site (nke) and an srf-binding element (sre) in the proximal promoter region was found to be necessary for the nkx3-1/srf coactivation of smga transcription." SIGNOR-82087 NR2F2 protein P24468 UNIPROT NR2F1 protein P10589 UNIPROT up-regulates binding 9606 10900149 t gcesareni "Arp-1/rxr, coup-tfi/rxr, and arp-1/coup-tfi heterodimers bound the fp330-3' site." SIGNOR-79443 PRKCA protein P17252 UNIPROT CTPS1 protein P17812 UNIPROT up-regulates phosphorylation Ser462 TLFQTKNsVMRKLYG 9606 17463002 t llicata "These data indicated that protein kinase c phosphorylation at ser(462) stimulates human ctp synthetase 1 activity, whereas phosphorylation at thr(455) inhibits activity." SIGNOR-154617 TGFB1 protein P01137 UNIPROT MEF2D protein Q14814 UNIPROT down-regulates 10090 14739161 f lperfetto "Tgf-beta was shown to inhibit myogenin and mef2d expression and myotube formation in c2c12." SIGNOR-235602 SCN10A protein Q9Y5Y9 UNIPROT sodium(1+) chemical CHEBI:29101 ChEBI "up-regulates quantity" relocalization 9606 27262167 t miannu "Voltage-gated Na1 channels (NaV channels) drive the rapid upstroke of action potentials in cardiac and skeletal muscle and in most neurons, thereby serving as initiators of electrical activity in excitable tissue. Nine genes encode a family of homologous of NaV channel pore-forming a subunits. While channels are open, Na1 ions flux through the central pore down an electrochemical gradient, further depolarizing the membrane and triggering an action potential." SIGNOR-253408 ITGAV protein P06756 UNIPROT "Av/b2 integrin" complex SIGNOR-C176 SIGNOR "form complex" binding 16988024 t lperfetto "Integrins are one of the major families of cell adhesion receptors (Humphries, 2000; Hynes, 2002). All integrins are non-covalently-linked, heterodimeric molecules containing an α and a β subunit. Both subunits are type I transmembrane proteins, containing large extracellular domains and mostly short cytoplasmic domains (Springer and Wang, 2004; Arnaout et al., 2005). Mammalian genomes contain 18 α subunit and 8 β subunit genes, and to date 24 different α,β combinations have been identified at the protein level. Although some subunits only appear in a single heterodimer, twelve integrins contain the β1 subunit, and five contain αV." SIGNOR-253203 PRKCQ protein Q04759 UNIPROT ARHGEF6 protein Q15052 UNIPROT "up-regulates activity" phosphorylation Ser225 KSSERPLsPKAVKGF 25694429 t lperfetto "Recently, we have reported that the active form of Rac 1 GTPase binds to the glycogen phosphorylase muscle isoform (PYGM) and modulates its enzymatic activity leading to T cell proliferation.|More specifically, αPIX, a known guanine nucleotide exchange factor for the small GTPases of the Rho family, preferentially Rac 1, mediates PYGM activation in Kit 225 T cells stimulated with IL-2. Using directed mutagenesis, phosphorylation of αPIX Rho-GEF serines 225 and 488 is required for activation of the Rac 1/PYGM pathway." SIGNOR-272169 RIMS1 protein Q86UR5 UNIPROT RAB3A protein P20336 UNIPROT "up-regulates activity" relocalization 9606 BTO:0000938 31679900 t miannu "N-terminal interactions of RIMs with RAB3 and MUNC13 regulate DCV fusion. Through N-terminal interactions, RIMs position MUNC13 and recruit DCVs via RAB3, which is located on the vesicle" SIGNOR-264381 PCDHA4 protein Q9UN74 UNIPROT ITGB1 protein P05556 UNIPROT "up-regulates activity" binding 9606 BTO:0000227 16697637 t miannu "The clustered protocadherins comprise the largest subfamily of the cadherin superfamily and are predominantly expressed in the nervous system. Pcdh-alpha proteins interact with beta1-integrin to promote cell adhesion." SIGNOR-265665 MAPK3 protein P27361 UNIPROT SMAD2 protein Q15796 UNIPROT up-regulates phosphorylation Thr8 MSSILPFtPPVVKRL 9606 19115199 t gcesareni "These results suggest that oncogenic ras, acting through mek1 and erk kinases, induces the phosphorylation of smad2 and smad3 .we show that phosphorylation of smad2, a mediator of the activin/transforming growth factor-beta signal, by activated extracellular signal-regulated kinase 1 (erk1) increases the amount of smad2 protein and leads to enhanced transcriptional activity" SIGNOR-183004 HERC2 protein O95714 UNIPROT XPA protein P23025 UNIPROT down-regulates ubiquitination 9606 20304803 t miannu "Herc2 may ubiquitinate xpa and thus target it for proteolytic degradation" SIGNOR-164595 TAB3 protein Q8N5C8 UNIPROT p38 proteinfamily SIGNOR-PF16 SIGNOR up-regulates binding 9606 25290089 t lperfetto "The irak1/traf6 complex can also activate jnk and p38 signalling through assembly of a catalytically active tab2-tab3-tak1 complex." SIGNOR-205452 PKN1 protein Q16512 UNIPROT MARCKS protein P29966 UNIPROT unknown phosphorylation Ser159 KKKKKRFsFKKSFKL 9534 BTO:0000298 8557118 t lperfetto "PRK1 phosphorylates MARCKS at the PKC sites: serine 152, serine 156 and serine 163." SIGNOR-248937 FADS3 protein Q9Y5Q0 UNIPROT arachidonoyl-CoA smallmolecule CHEBI:15514 ChEBI "up-regulates quantity" "chemical modification" 9606 15189125 t miannu "Fatty acid desaturases introduce a double bond in a specific position of long-chain fatty acids, and are conserved across kingdoms. Three desaturases, Delta9, Delta6, and Delta5, are present in humans. Delta-9 catalyzes synthesis of monounsaturated fatty acids. Oleic acid, a main product of Delta9 desaturase, is the major fatty acid in mammalian adipose triglycerides, and is also used for phospholipid and cholesteryl ester synthesis. Delta-6 and Delta5 desaturases are required for the synthesis of highly unsaturated fatty acids (HUFAs), which are mainly esterified into phospholipids and contribute to maintaining membrane fluidity." SIGNOR-267913 "CFI complex" complex SIGNOR-C388 SIGNOR "messenger RNA" smallmolecule CHEBI:33699 ChEBI "up-regulates quantity" cleavage 9606 8626397 t lperfetto "Purification and characterization of human cleavage factor Im involved in the 3' end processing of messenger RNA precursors|Gel retardation experiments confirmed the results obtained by UV cross-linking. In addition, we could show that CF Im stabilizes the binding of the cleavage and polyadenylation specificity factor (CPSF) to pre-mRNA and that CPSF and CF Im together form a slower migrating complex with pre-mRNA than the single protein factors." SIGNOR-266125 PRKCZ protein Q05513 UNIPROT BAX protein Q07812 UNIPROT "down-regulates activity" phosphorylation Ser184 VAGVLTAsLTIWKKM 9606 17525161 t lperfetto "Protein kinase czeta abrogates the proapoptotic function of bax through phosphorylation. Overexpression of wild type or the constitutively active a119d but not the dominant negative k281w pkczeta mutant results in bax phosphorylation at serine 184." SIGNOR-155111 PPP1R1B protein Q9UD71 UNIPROT PPP1CA protein P62136 UNIPROT "down-regulates activity" binding 9606 BTO:0000938 10604473 t miannu "DARPP-32 (dopamine and cyclic AMP-regulated phospho-protein, relative molecular mass 32,000) is converted into an inhibitor of protein phosphatase 1 when it is phosphorylated by protein kinase A (PKA) at threonine 34.‚ " SIGNOR-264957 IFNG protein P01579 UNIPROT MYOD1 protein P15172 UNIPROT down-regulates 9606 BTO:0001760 11009425 f gcesareni "In contrast, in differentiated myotubes, tnf plus interferon-gamma (ifn-gamma) signaling was required for nf-kappab-dependent down-regulation of myod and dysfunction of skeletal myofibers." SIGNOR-82467 CYP19A1 protein P11511 UNIPROT estrone smallmolecule CHEBI:17263 ChEBI "up-regulates quantity" "chemical modification" 9606 BTO:0000975 27702664 t lperfetto "The cytochrome P450 aromatase is involved in the last step of sex hormones biosynthesis by converting androgens into estrogens. |Human aromatase (CYP19A1) is a membrane-bound class II cytochrome P450 that converts androgens into estrogens [1], [2], [3], [4]. Specifically, the enzyme is involved sex hormones biosynthesis where it is responsible for the conversion of androstenedione, testosterone and 16alpha-hydroxytestosterone into estrone, estradiol and estriol, respectively" SIGNOR-268670 MAPK3 protein P27361 UNIPROT PPP2R5C protein Q13362 UNIPROT down-regulates phosphorylation Ser337 QLAKCVSsPHFQVAE 9606 16456541 t gcesareni "Iex-1 binds to b56 subunits and perk independently, enhances b56 phosphorylation by erk at a conserved ser/pro site in this complex and triggers dissociation from the catalytic subunit." SIGNOR-144317 MAPK1 protein P28482 UNIPROT DAPK1 protein P53355 UNIPROT up-regulates phosphorylation Ser734 NSSRFPPsPLASKPT 9606 15616583 t gcesareni "Dapk interacts with erk through a docking sequence within its death domain and is a substrate of erk. Phosphorylation of dapk at ser 735 by erk increases the catalytic activity of dapk both in vitro and in vivo" SIGNOR-132614 "CAK complex" complex SIGNOR-C456 SIGNOR TP53 protein P04637 UNIPROT up-regulates phosphorylation Ser392 FKTEGPDsD 9606 9315650 t llicata "The cdk7-cych-p36 complex of transcription factor iih phosphorylates p53, enhancing its sequence-specific dna binding activity in vitro.  serines 371, 376, 378, and 392 may be the potential sites for this kinase." SIGNOR-269324 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR XPO5 protein Q9HAV4 UNIPROT "down-regulates activity" phosphorylation Ser416 GFPSKTDsPSCEYSR 9606 BTO:0000007 27846390 t lperfetto "Here we show that ERK suppresses pre-miRNA export from the nucleus through phosphorylation of exportin-5 (XPO5) at T345/S416/S497. After phosphorylation by ERK, conformation of XPO5 is altered by prolyl isomerase Pin1, resulting in reduction of pre-miRNA loading. " SIGNOR-262980 MAPK8 protein P45983 UNIPROT BCL2L11 protein O43521 UNIPROT "up-regulates activity" phosphorylation Ser77 PGPFATRsPLFIFMR 10090 12818176 t miannu "Mitochondrially localized JNKs but not their upstream activators MLKs or MKKs phosphorylated BIMEL at Ser65, potentiating its cytotoxicity without altering its subcellular distribution or integration into mitochondrial membranes. JNKs specifically phosphorylate BIMEL at Ser55, 65, and/or 73" SIGNOR-250133 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR BRAF protein P15056 UNIPROT "down-regulates activity" phosphorylation Ser151 VARSNPKsPQKPIVR 9606 BTO:0000848 21478863 t "We show that overactivation of the MAPK pathway, induced by the oncogenic Ras in melanoma, induces constitutive phosphorylation of BRAF on Ser151 by ERK, which inhibits NRAS-BRAF interaction" SIGNOR-259919 LSM4 protein Q9Y4Z0 UNIPROT "U4/U6.U5 snRNP complex" complex SIGNOR-C478 SIGNOR "form complex" binding 9606 30765414 t lperfetto "The major spliceosomal building blocks are the U1, U2, U4/U6, and U5 small nuclear ribonucleoproteins (snRNPs). Each consists of a small nuclear RNA (snRNA) (or two, in the case of U4/U6), seven Sm proteins that form a ring (or seven Lsm proteins in the case of U6), and a variable number of snRNP-specific proteins (Fig. 1F) (Will and Lührmann 2011). Under splicing conditions, the U4/U6 and U5 snRNPs form a 25S U4/U6.U5 tri-snRNP, in which the U4 and U6 snRNAs are base-paired, forming a three-way junction." SIGNOR-270650 CASP6 protein P55212 UNIPROT PSEN2 protein P49810 UNIPROT "up-regulates activity" cleavage Asp329 EMEEDSYdSFGEPSY -1 10069390 t lperfetto "In decreasing order of activity, caspase-8, -3, -1, -6 and -7 proteolysed PS2 at the recognition site D326SYD329." SIGNOR-261750 2-(2-amino-3-methoxyphenyl)chromen-4-one chemical CHEBI:77954 ChEBI MAP2K2 protein P36507 UNIPROT down-regulates "chemical inhibition" 9606 BTO:0000938 BTO:0000142 11160424 t gcesareni "The mek1/2 inhibitors pd98059, sl327, and u0126 have been extensively used to implicate erk1/2 in neuroplasticity." SIGNOR-104921 FFAR1 protein O14842 UNIPROT GNAL protein P38405 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-256942 beta-alanine smallmolecule CHEBI:16958 ChEBI GlyR proteinfamily SIGNOR-PF62 SIGNOR "up-regulates activity" "chemical activation" 9606 BTO:0000007 9009272 t "inferred from family member" miannu "For each mutant GlyR we examined the agonist efficacies of taurine and Œ≤-alanine relative to glycine, the concentration of each agonist required for half-maximal current activation (EC50) and, in mutant GlyRs where Œ≤-alanine and taurine exhibited partial or no agonist efficacy, the concentration required for half-maximal inhibition of glycine-gated currents (IC50).experiments described in this report were performed on human Œ±1 homomeric GlyRs recombinantly expressed in mammalian HEK 293 cells. Taurine and Œ≤-alanine act as full agonists of human Œ±1 GlyRs when expressed in this system." SIGNOR-270261 CSNK2A2 protein P19784 UNIPROT MYF5 protein P13349 UNIPROT "up-regulates activity" phosphorylation Ser49 HKAELQGsDEDEHVR -1 9461343 t llicata "Here, we report that Myf-5 protein constitutes a substrate for phosphorylation in vitro by protein kinase CK2. We identified two potential phosphorylation sites at serine49 and serine133, both of which seem to be necessary for Myf-5 activity. " SIGNOR-251017 SUFU protein Q9UMX1 UNIPROT GLIS3 protein Q8NEA6 UNIPROT down-regulates binding 9606 21543335 t fspada "These data indicate that the inhibition of glis3-mediated transactivation by sufu appears to rely on the interaction with glis3 through the ygh motif and is not related to an effect on the general transcriptional machinery" SIGNOR-173573 QRICH1 protein Q2TAL8 UNIPROT YARS1 protein P54577 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 33384352 t miannu "QRICH1 promotes the expression of translation-related genes. our combined ChIP-seq and RNA-seq analyses identified that QRICH1 and ATF4 were enriched at the promoters of these specific tRNA synthetases, and that ER stress positively regulated their transcription (Fig. 4I). Together, these findings suggest that QRICH1 and ATF4 modulate tRNA metabolic processes to promote secreted protein synthesis during ER stress." SIGNOR-269412 serotonin(1+) smallmolecule CHEBI:350546 ChEBI HTR6 protein P50406 UNIPROT "up-regulates activity" "chemical activation" 9606 BTO:0002524 31160049 t "Ligand-GPCR dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257525 zolpidem chemical CHEBI:10125 ChEBI "GABA-A (a1-b1-g2) receptor" complex SIGNOR-C330 SIGNOR "up-regulates activity" "chemical activation" 9606 BTO:0000227 18790874 t brain lperfetto "The BZ-sensitive GABAA-Rs can be further subdivided, in that receptors containing the alpha1 subunit have a higher sensitivity to a subpopulation of BZ site ligands, the benzodiazepines quazepam and cinolazepam (Sieghart, 1989) or nonbenzodiazepines such as zolpidem (an imidazopyridine) and a few others, including CL218-872 (triazolopyridazine), zaleplon, and indiplon, and abecarnil (β-carboline), (Olsen and Gordey, 2000; Korpi et al., 2002; Sieghart and Ernst, 2005)." SIGNOR-263802 (2S)-2-hydroxy-3-methyl-N-[(2S)-1-[[(5S)-3-methyl-4-oxo-2,5-dihydro-1H-3-benzazepin-5-yl]amino]-1-oxopropan-2-yl]butanamide chemical CHEBI:131158 ChEBI APP protein P05067 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-206850 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR PARP1 protein P09874 UNIPROT up-regulates phosphorylation Thr373 AATPPPStASAPAAV 9606 BTO:0000938 BTO:0000142 16627622 t lperfetto "Parp1 phosphorylation by erk1/2 is required for maximal parp-1 activation after dna damage. S372a and t373a mutations impaired parp-1 activation." SIGNOR-244673 PRKN protein O60260 UNIPROT GPR37 protein O15354 UNIPROT "down-regulates quantity by destabilization" ubiquitination 9606 12666095 t lperfetto "Parkin is a protein of 465 amino acids, and its structure includes a ubiquitin homologous domain in its N terminus and two RING finger domains in its C terminus. Molecular studies have determined that parkin is an E3 ubiquitin ligase function, implicating parkin in the ubiquitin-proteasome system, and raising the possibility that mutations in the gene lead to loss or diminished function. Three substrates for the ubiquitin-ligase function of parkin have been identified to date.1. A 22kDa glycosolated form of alpha-synuclei|2. Parkin-associated endothelin receptor-like receptor (Pael-R)." SIGNOR-249706 CDK6 protein Q00534 UNIPROT RBL2 protein Q08999 UNIPROT unknown phosphorylation Thr401 SKALRIStPLTGVRY 9606 BTO:0001938 11157749 t llicata "We now identify 22 in vivo phosphorylation sites of p130, targeted by diverse kinases, and present evidence for three cyclin-dependent kinase 4(6) [cdk4(6)] specific phosphorylations, which appear critical for controlling the growth-restraining activity of p130. all three residues selectively targeted by cdk4(6), t401 (n-terminus), s672 (spacer region) and s1035 (c-terminus)" SIGNOR-104719 "Caspase 8 complex" complex SIGNOR-C231 SIGNOR CASP3 protein P42574 UNIPROT "up-regulates activity" cleavage 10090 BTO:0002572 10988287 t amattioni "The temporal pattern of caspase-8 cleavage is consistent with the possibility that it may function upstream of caspase-3 during p53-dependent apoptosis." SIGNOR-256451 PRKCA protein P17252 UNIPROT GRM1 protein Q13255 UNIPROT "down-regulates activity" phosphorylation Thr695 GSKKKICtRKPRFMS 9606 10823959 t lperfetto "Furthermore, we demonstrate that the selectivity of PKC action on receptor signaling rests on phosphorylation of a threonine residue located in the G protein-interacting domain of the receptor. Modification at Thr(695) selectively disrupts mGluR1alpha-G(q/11) interaction without affecting signaling through G(s)." SIGNOR-249043 EIF2AK1 protein Q9BQI3 UNIPROT HBA1 protein P69905 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 19946423 f "Regulation of expression" miannu "Translation of α- and β-globin is tightly controlled by eIF2 and downregulated by HRI." SIGNOR-251781 F10 protein P00742 UNIPROT F2 protein P00734 UNIPROT "up-regulates activity" cleavage 10090 BTO:0000131 25769543 t lperfetto "The present data point to key roles of FVIII and FIX in FX activation at the site of a platelet thrombus by supporting: (i) thrombin generation, (ii) thrombus growth and platelet phosphatidylserine exposure, and (iii) fibrin formation at the platelet surface. The likely mechanism is that tenase activity via FVIIIa and FIXa, which is confined to the sites of platelet thrombi, generates FXa that directly catalyzes the conversion of prothrombin into thrombin." SIGNOR-263539 HDAC8 protein Q9BY41 UNIPROT SMG5 protein Q9UPR3 UNIPROT "up-regulates quantity by stabilization" binding 9606 BTO:0000567 16809764 t miannu "Here, we report that the human ortholog of the yeast ever-shorter telomeres 1B (EST1B) binds HDAC8. This interaction is regulated by protein kinase A-mediated HDAC8 phosphorylation and protects human EST1B (hEST1B) from ubiquitin-mediated degradation. " SIGNOR-272650 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR SP1 protein P08047 UNIPROT "up-regulates activity" phosphorylation 9606 23616010 t lperfetto "Erk also undergoes rapid translocation into the nucleus, where it phosphorylates and activates a variety of transcription factor targets, including sp1, e2f, elk-1, and ap1." SIGNOR-233523 HTR1F protein P30939 UNIPROT GNAI1 protein P63096 UNIPROT "up-regulates activity" binding 9606 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-256673 MYOD1 protein P15172 UNIPROT CDKN1A protein P38936 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 BTO:0000165 10373569 t gcesareni "Here we report that, at the onset of differentiation, activation by MyoD of the Rb, p21, and cyclin D3 genes occurs in the absence of new protein synthesis and with the requirement of the p300 transcriptional coactivator." SIGNOR-238529 RPL9 protein P32969 UNIPROT "60S cytosolic large ribosomal subunit" complex SIGNOR-C287 SIGNOR "form complex" binding -1 25901680 t lperfetto "Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins." SIGNOR-262452 Unii-2ewn8Z05CN chemical CID:129138801 PUBCHEM EIF4A1 protein P60842 UNIPROT "down-regulates activity" "chemical inhibition" 9606 32470302 t "Simone Vumbaca" "Design of Development Candidate eFT226, a First in Class Inhibitor of Eukaryotic Initiation Factor 4A RNA Helicase" SIGNOR-261120 GSK3B protein P49841 UNIPROT CCND2 protein P30279 UNIPROT down-regulates phosphorylation Thr280 DELDQAStPTDVRDI 9606 17486076 t lperfetto "Glycogen synthase kinase-3beta and p38 phosphorylate cyclin d2 on thr280 to trigger its ubiquitin/proteasome-dependent degradation in hematopoietic cells" SIGNOR-154668 PRKCE protein Q02156 UNIPROT TRPV1 protein Q8NER1 UNIPROT "up-regulates activity" phosphorylation Ser775 EGVKRTLsFSLRSSR 9534 BTO:0000298 14523239 t lperfetto "We found that mutation of S800 to alanine significantly reduced the PMA-induced enhancement of capsaicin-evoked currents and the direct activation of TRPV1 by PMA. Mutation of S502 to alanine reduced PMA enhancement of capsaicin-evoked currents, but had no effect on direct activation of TRPV1 by PMA. Conversely, mutation of T704 to alanine had no effect on PMA enhancement of capsaicin-evoked currents but dramatically reduced direct activation of TRPV1 by PMA." SIGNOR-249231 PRKCH protein P24723 UNIPROT PTPN11 protein Q06124 UNIPROT unknown phosphorylation Ser576 CAEMREDsARVYENV 9606 11781100 t lperfetto " In summary, SHP2 is phosphorylated on serine residues 576 and 591 by PKC isoforms alpha, beta 1, beta 2, and eta" SIGNOR-249137 PPP2R5D protein Q14738 UNIPROT PP2Ca_R1A_Bd complex SIGNOR-C134 SIGNOR "form complex" binding 9606 23454242 t gcesareni "[PP2A] ... is multifarious as it is composed of catalytic, scaffold and regulatory subunits. The catalytic and scaffold subunits have two isoforms and the regulatory subunit has four different families containing different isoforms. The regulatory subunit is the most diverse with temporal and spatial specificity." SIGNOR-243439 CSNK2A1 protein P68400 UNIPROT TFAP2A protein P05549 UNIPROT up-regulates phosphorylation Ser429 TDNNAKSsDKEEKHR 9606 21777522 t lperfetto "Ck2 phosphorylates ap-2_ and increases its transcriptional activity" SIGNOR-175130 MARK1 protein Q9P0L2 UNIPROT MAP4 protein P27816 UNIPROT "down-regulates activity" phosphorylation Ser928 SRLATNTsAPDLKNV -1 8631898 t miannu "Here we show that p110mark phosphorylates analogous KXGS sites in the microtubule binding domains of the neuronal MAP2 and the ubiquitous MAP4. Phosphorylation in vitro leads to the dissociation of MAP2 and MAP4 from microtubules and to a pronounced increase in dynamic instability." SIGNOR-250170 UBE2D2 protein P62837 UNIPROT PEX5 protein P50542 UNIPROT "down-regulates quantity by destabilization" ubiquitination -1 19687296 t miannu "Here we report on the identification of the protein-ubiquitin ligases that are responsible for the ubiquitination of the peroxisomal protein import receptor Pex5. It is demonstrated that each of the three RING peroxins Pex2, Pex10, and Pex12 exhibits ubiquitin-protein isopeptide ligase activity. Our results show that Pex2 mediates the Ubc4-dependent polyubiquitination whereas Pex12 facilitates the Pex4-dependent monoubiquitination of Pex5.While polyubiquitinated Pex5 is degraded by the proteasome, monoubiquitinated Pex5 is destined for a new round of the receptor cycle." SIGNOR-253023 ABL1 protein P00519 UNIPROT CD19 protein P15391 UNIPROT "up-regulates activity" phosphorylation Tyr508 EDMRGILyAAPQLRS 10090 11120811 t gcesareni "The results revealed that only tyrosine (Y)490 of CD19 was phosphorylated by c-Abl." SIGNOR-245283 ACTB protein P60709 UNIPROT "Neural progenitor-specific SWI/SNF" complex SIGNOR-C477 SIGNOR "form complex" binding 9606 25195934 t miannu "The BAF (mammalian SWI/SNF) complexes are a family of multi-subunit ATP-dependent chromatin remodelers that use ATP hydrolysis to alter chromatin structure. Distinct BAF complex compositions are possible through combinatorial assembly of homologous subunit families and can serve non-redundant functions. In mammalian neural development, developmental stage-specific BAF assemblies are found in embryonic stem cells, neural progenitors and postmitotic neurons. In particular, the neural progenitor-specific BAF complexes are essential for controlling the kinetics and mode of neural progenitor cell division, while neuronal BAF function is necessary for the maturation of postmitotic neuronal phenotypes as well as long-term memory formation. " SIGNOR-270619 TCF4 protein P15884 UNIPROT NRXN1 protein Q9ULB1 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 22777675 f miannu "we show that TCF4 can transactivate the NRXN1β and CNTNAP2 promoters in luciferase assays." SIGNOR-255391 RUNX2 protein Q13950 UNIPROT Osteoblast_differentiation phenotype SIGNOR-PH9 SIGNOR up-regulates 10090 9182762 f gcesareni "Osf2/cbfa1 as an osteoblast-specific transcription factor and as a regulator of osteoblast differentiation" SIGNOR-48940 SRC protein P12931 UNIPROT PTTG1IP protein P53801 UNIPROT "up-regulates activity" phosphorylation Tyr174 LFKEENPyARFENN 9534 BTO:0000298 23678037 t done miannu "Src induction leads to phosphorylation at PBF residue Y174. Abrogation of this residue results in PM retention and a markedly reduced ability to bind NIS. " SIGNOR-273810 SATB1 protein Q01826 UNIPROT SPARC protein P09486 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000664 17343824 f miannu "In this study, a SATB1 eukaryotic expression plasmid was transfected into the human erythroleukemia K562 cell line and individual clones that stably over-expressed the SATB1 protein were isolated. Microarray analysis revealed that hundreds of genes were either up- or down-regulated in the SATB1 over-expressing K562 cell lines. One of these was the extra-cellular matrix glycoprotein, SPARC (human secreted protein acidic and rich in cysteine). siRNA knock-down of SATB1 also reduced SPARC expression, which was consistent with elevated SPARC levels in the SATB1 over-expressing cell line." SIGNOR-255128 Axonemal_Dynein proteinfamily SIGNOR-PF66 SIGNOR Cilium_movement phenotype SIGNOR-PH171 SIGNOR up-regulates 16440056 f lperfetto "Axonemal dyneins are responsible for the movement of cilia and flagella." SIGNOR-265021 GRIA2 protein P42262 UNIPROT Synaptic_plasticity phenotype SIGNOR-PH158 SIGNOR up-regulates -1 32527803 f Luana "AMPAR surface diffusion tunes short-term plasticity. | Accordingly, recent studies have suggested that about half of synaptic AMPARs are organized in nanoclusters that are aligned with presynaptic transmitter release sites, supporting the concept of functional nanocolumns to increase the fidelity of fast excitatory transmission. This peculiar organization might also support the proposal that we made 10 years ago that fast surface diffusion of AMPARs tunes frequency-dependent short-term plasticity (FD-STP) by allowing the fast replacement of desensitized receptors by naïve ones." SIGNOR-265796 RPS6KB1 protein P23443 UNIPROT HSPB1 protein P04792 UNIPROT down-regulates phosphorylation Ser15 FSLLRGPsWDPFRDW 9606 19593530 t "10383393: We demonstrate that both phosphorylated sHsps and the triple mutant Hsp27-S15D,S78D,S82D show significantly decreased abilities to act as molecular chaperones suppressing thermal denaturation and facilitating refolding of citrate synthase in vitro." lperfetto "Ser-15, ser-78, and ser-82 in hsp27 (ser-15 and ser-86 in hsp25) are part of the rxxs motif, a known recognition site for p70rsk." SIGNOR-186951 TGFBR1 protein P36897 UNIPROT PIK3R1 protein P27986 UNIPROT up-regulates binding 9606 BTO:0001660 9435577 t lperfetto "These studies revealed that PI 3-kinase is associated in vivo with both TGF-_ receptor subtypes and that TGF-_1 stimulation enhances PI 3-kinase activity associated with type I TGF-_ receptor in hASM cells." SIGNOR-227525 mTORC1 complex SIGNOR-C3 SIGNOR MAF1 protein Q9H063 UNIPROT down-regulates phosphorylation Ser75 SPSRLSKsQGGEEEG 9606 20516213 t lperfetto "The protein is phosphorylated mainly on residues s60, s68, and s75, and this inhibits its pol iii repression function. The responsible kinase is mtorc1, which phosphorylates maf1 directly." SIGNOR-217153 IGF1R protein P08069 UNIPROT IRS1 protein P35568 UNIPROT up-regulates phosphorylation Tyr941 EETGTEEyMKMDLGP 9606 17827393 t gcesareni "Furthermore, IGF-1 stimulates tyrosine phosphorylation of insulin receptor substrate-1 (IRS-1) and IRS-2 and their association with the p85 subunit of phosphoinositide-3 kinase (PI3K)." SIGNOR-157754 BACH1 protein O14867 UNIPROT MAFK protein O60675 UNIPROT "up-regulates activity" binding 10090 BTO:0004475 19011633 t miannu "Bach1 forms a heterodimer with the small Maf oncoproteins and binds to the Maf-recognition element (MARE) to inhibit target genes" SIGNOR-226409 mTORC1 complex SIGNOR-C3 SIGNOR EIF4EBP1 protein Q13541 UNIPROT "down-regulates activity" phosphorylation 9606 BTO:0000007 12747827 t lperfetto "Our data demonstrate that the TOS motif functions as a docking site for the mTOR/raptor complex, which is required for multisite phosphorylation of 4E-BP1, eIF4E release from 4E-BP1, and cell growth." SIGNOR-236678 MAP2K6 protein P52564 UNIPROT p38 proteinfamily SIGNOR-PF16 SIGNOR "up-regulates activity" 9606 10480932 t Luana "P38 mitogen-activated protein kinase, and its direct activator MKK6 are rapidly activated in response to TGF-beta." SIGNOR-260720 KAT2B protein Q92831 UNIPROT H3-3A protein P84243 UNIPROT "down-regulates activity" acetylation Lys10 RTKQTARkSTGGKAP 9606 SIGNOR-C465 34811519 t "Acetlyation of H3 causes transcriptional activation, thus has an inhibitory role on H3" lperfetto "The HAT module within the SAGA and ADA complexes acetylates histone H3, mainly on residues K9 and K14." SIGNOR-269612 CTDSPL protein O15194 UNIPROT SMAD3 protein P84022 UNIPROT "up-regulates activity" dephosphorylation Ser213 NLSPNPMsPAHNNLD 9606 BTO:0000007 17035229 t "Dephosphorylation of Smad2/3 Linkers by SCP2 and SCP3|MAPK-mediated linker phosphorylation appears to have a dual role in Smad2/3 regulation. Mitogens and hyperactive Ras result in extracellular signal-regulated kinase (ERK)-mediated phosphorylation of Smad3 at Ser-204, Ser-208, and Thr-179 and of Smad2 at Ser-245/250/255 and Thr-220. Mutation of these sites increases the ability of Smad3 to activate target genes, suggesting that MAPK phosphorylation of Smad3 is inhibitory (11, 12). However, in contrast, ERK-dependent phosphorylation of Smad2 at Thr-8 enhances its transcriptional activity" SIGNOR-248308 TP53 protein P04637 UNIPROT KDM4B protein O94953 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0001109 28073943 t miannu "KDM4B/JMJD2B is a p53 target gene that modulates the amplitude of p53 response after DNA damage. p53 directly regulates JMJD2B gene expression by binding to a canonical p53-consensus motif in the JMJD2B promoter." SIGNOR-263729 PML-RARalpha "fusion protein" SIGNOR-FP2 SIGNOR AP1 complex SIGNOR-C154 SIGNOR "up-regulates activity" 9606 BTO:0000093 8415704 f miannu "PML-RAR alpha chimera cooperates with c-Jun and, strikingly, with c-Fos to stimulate the transcription of both synthetic and natural reporter genes containing an AP-1 site" SIGNOR-261507 MAPK3 protein P27361 UNIPROT CAPN2 protein P17655 UNIPROT up-regulates phosphorylation Ser50 GTLFQDPsFPAIPSA 9606 14993287 t lperfetto "Epidermal growth factor activates m-calpain (calpain ii), at least in part, by extracellular signal-regulated kinase-mediated phosphorylation.We now show that erk directly phosphorylates and activates m-calpain both in vitro and in vivo. We identified serine 50 as required for epidermal growth factor (egf)-induced calpain activation in vitro and in vivo." SIGNOR-123083 "Cullin 1-RBX1-Skp1" complex SIGNOR-C529 SIGNOR RAD51 protein Q06609 UNIPROT "up-regulates activity" ubiquitination Lys58 AVAYAPKkELINIKG -1 25585578 t miannu "The F-box DNA helicase 1 (FBH1) is a 3'-5' DNA helicase with a putative function as a negative regulator of HR. It is the only known DNA helicase to contain an F-box, suggesting that one of its functions is to act as a ubiquitin ligase as part of an SCF (SKP1, CUL1 and F-box) complex. Here we report that the central player in HR, RAD51, is ubiquitylated by the SCF(FBH1) complex. Expression of an ubiquitylation-resistant form of RAD51 in human cells leads to hyperrecombination, as well as several phenotypes indicative of an altered response to DNA replication stress. However, K58/64R RAD51 was ubiquitylated much less efficiently by FBH1 in vitro than was wild-type (WT) RAD51 (Fig. 1d), confirming that the primary sites of modification by FBH1 on RAD51 are K58 and K64." SIGNOR-272453 CBL protein P22681 UNIPROT PIK3R2 protein O00459 UNIPROT down-regulates ubiquitination 9606 11526404 t lperfetto "Cbl-b, a ring-type e3 ubiquitin protein ligase, is implicated in setting the threshold of t lymphocyte activation. The p85 regulatory subunit of phosphatidylinositol 3 kinase (pi3k) was identified as a substrate for cbl-b. We have shown that cbl-b negatively regulated p85 in a proteolysis-independent manner." SIGNOR-110063 IL6ST protein P40189 UNIPROT JAK1 protein P23458 UNIPROT up-regulates 9606 BTO:0000887;BTO:0001103 23663276 t milica "Il-6 family members typically signal through the common gp130 receptor, with the janus kinase/signal transducer and activator of transcription (jak/stat) pathway being the major intracellular mediator of their effects." SIGNOR-202036 PP2Ca_R1A_Bd complex SIGNOR-C134 SIGNOR RAF1 protein P04049 UNIPROT "up-regulates activity" dephosphorylation Ser259 SQRQRSTsTPNVHMV 9606 BTO:0000007 16239230 t gcesareni "... the PP2A holoenzymes ABC and ABC act downstream of Ras and upstream of MEK1 to promote activation of this MAPK signaling cascade. Furthermore both PP2A holoenzymes were found to associate with Raf1 and catalyze dephosphorylation of inhibitory phospho-Ser-259." SIGNOR-243538 CRKL protein P46109 UNIPROT MAP4K1 protein Q92918 UNIPROT up-regulates binding 9606 BTO:0000782 9891069 t "HPK1 phosphorylated CrkL mainly on serine and weakly on threonine" gcesareni "We found that hpk1 interacted with crk and crkl adaptor proteins in vitro and in vivo and that the proline-rich motifs within hpk1 were involved in the differential interaction of hpk1 with the crk proteins and grb2. Crk and crkl not only activated hpk1 but also synergized with hpk1 in the activation of jnk." SIGNOR-63991 RB1 protein P06400 UNIPROT G1/S_transition phenotype SIGNOR-PH50 SIGNOR down-regulates 9606 21524151 f lperfetto "In its hypophosphorylated state, pRb binds transcription factors of the E2F family which are required for cell cycle progression. As the level of CyclinD/Cdk4/6 complexes increases, pRb becomes phosphorylated and progression through G1 occurs. At a critical level of phosphorylation, E2F is released from pRb. This activates the transcription of CyclinE which complexes with Cdk2 to fully release pRb repression by further phosphorylation, establishing a positive feedback loop. E2F further promotes the transcription of S-phase genes. Thus, CyclinD/Cdk4/6 and CyclinE/Cdk2 together regulate S-phase entry via phosphorylating pRb, which controls pRb binding to E2F" SIGNOR-245483 Ub:E2 complex SIGNOR-C497 SIGNOR TOPORS protein Q9NS56 UNIPROT "up-regulates activity" ubiquitination 9606 34199813 t miannu "The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t" SIGNOR-271118 Oxytocin protein P01178-PRO_0000020495 UNIPROT "GABA-A (a6-b3-d) receptor" complex SIGNOR-C329 SIGNOR up-regulates 9606 33536967 f lperfetto "OT inhibits corticotropin-releasing factor (CRF) mRNA expression at the hypothalamus, resulting in antistress and anti-anxiety effects| It has been demonstrated that the inhibitory effect of OT on CRF mRNA expression is not a direct one on CRF neurons. GABAergic neurons are present in the surroundings of the PVN (peri-PVN). These GABA-projecting neurons into the PVN inhibits CRF expression via GABAA receptors" SIGNOR-268588 NMUR2 protein Q9GZQ4 UNIPROT GNAI1 protein P63096 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-256731 MAPK10 protein P53779 UNIPROT KIF5C protein O60282 UNIPROT "down-regulates activity" phosphorylation Ser176 CTERFVSsPEEVMDV -1 19525941 t miannu "Mass spectrometry identified a residue in the kinesin-1 motor domain that was phosphorylated by JNK3 and this modification reduced kinesin-1 binding to microtubules. JNK3 phosphorylates kinesin-1 at Ser176" SIGNOR-262950 CDK5/CDK5R1 complex SIGNOR-C144 SIGNOR TP53 protein P04637 UNIPROT "up-regulates activity" phosphorylation Ser315 LPNNTSSsPQPKKKP 10116 BTO:0001009 12064478 t llicata " the present study it is shown that in apoptotic PC12 cells the levels of p53 and Cdk5 increase concomitantly. Further, Cdk5/p25 effectively phosphorylates recombinant p53 in vitro. Transient transfection of Cdk5/p25 into cells results in an increase in p53 levels, as well as the expression of the p53-responsive genes p21 and Bax. Furthermore, evidence is provided that increased Cdk5 activity increases p53 transcriptional activity significantly, suggesting that p53 is modulated in situ by Cdk5. " SIGNOR-250674 HIF1A protein Q16665 UNIPROT Glycolysis phenotype SIGNOR-PH34 SIGNOR up-regulates 9606 17415528 f "HIF-1 has been known as a major transcription factor for the induction of virtually all genes encoding glucose transporters and glycolytic enzymes, which allows hypoxic tumor cells to take up glucose more efficiently and metabolize pyruvate to lactate" SIGNOR-259381 STK4 protein Q13043 UNIPROT AR protein P10275 UNIPROT down-regulates 21512132 f lperfetto "Mst1 plays a critical role in the regulation of programmed cell death and it has been implicated in PCa development. Interestingly, MST1 has been detected in AR-chromatin complexes, and forced expression of MST1 reduces AR binding to androgen-responsive elements along the PSA promoter." SIGNOR-151712 IL3 protein P08700 UNIPROT IL3RA protein P26951 UNIPROT up-regulates binding 9606 1465408 t fspada "These results show the generation of an il-3 analog with increased biological and binding activities and support a model where the c terminus of il-3 interacts with the alpha chain of the il-3 receptor, making this region a useful focus for the development of more potent il-3 agonists or antagonists" SIGNOR-19538 AKT1 protein P31749 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR "down-regulates activity" phosphorylation 10090 BTO:0002572 18423396 t lperfetto "Akt1/PKBalpha was found to be the major regulator of phosphorylation and nuclear export ofFoxO1, whose presence in the nucleus strongly attenuates adipocyte differentiation." SIGNOR-252851 "CAK complex" complex SIGNOR-C456 SIGNOR TFIIH complex SIGNOR-C457 SIGNOR "form complex" binding 9606 30860024 t lperfetto "Transcription factor IIH (TFIIH) is a heterodecameric protein complex critical for transcription initiation by RNA polymerase II and nucleotide excision DNA repair.|The TFIIH core complex is composed of the seven subunits XPB, XPD, p62, p52, p44, p34, and p8, and is the form of TFIIH active in DNA repair|and additionally the CdK activating kinase (CAK) complex, which harbors the kinase activity of CDK7 as well as the Cyclin H and MAT1 subunits" SIGNOR-269318 PDK1 protein Q15118 UNIPROT PDHA1 protein P08559 UNIPROT "down-regulates activity" phosphorylation Ser293 TYRYHGHsMSDPGVS -1 11485553 t lperfetto "Here we report that the four isoenzymes of protein kinase responsible for the phosphorylation and inactivation of pyruvate dehydrogenase (pdk1, pdk2, pdk3 and pdk4) differ in their abilities to phosphorylate the enzyme. Pdk1 can phosphorylate all three sites (s232, s293, s300), whereas pdk2, pdk3 and pdk4 each phosphorylate only s232 and s293." SIGNOR-109551 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR CTTN protein Q14247 UNIPROT up-regulates phosphorylation 9606 BTO:0000938 20444238 t "inferred from 70% family members" gcesareni "Cortactin is regulated by multiple phosphorylation events, including phosphorylation of s405 and s418 by extracellular regulated kinases (erk)1/2. Erk1/2 phosphorylation of cortactin has emerged as an important positive regulatory modification, enabling cortactin to bind and activate the arp2/3 regulator neuronal wiskott-aldrich syndrome protein (n-wasp), promoting actin polymerization and enhancing tumor cell movement." SIGNOR-270164 MAPK3 protein P27361 UNIPROT POLR2A protein P24928 UNIPROT down-regulates phosphorylation Ser1787 SPNYSPTsPSYSPTS 9606 14662762 t lperfetto "Erk1/2 are major ser-5 kinases after h2o2 treatment. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination." SIGNOR-120216 STK4 protein Q13043 UNIPROT Mob1 proteinfamily SIGNOR-PF42 SIGNOR up-regulates phosphorylation 9606 21808241 t "MOB1a and MOB1b are near identical to each other with protein sequence homology>90%, and more importantly, both of them are putative tumor suppressors." gcesareni "Mob1, which forms a complex with lats1/2, is also phosphorylated by mst1/2, resulting in an enhanced lats1/2mob1 interaction." SIGNOR-269856 COP1 protein Q8NHY2 UNIPROT CEBPB protein P17676 UNIPROT "down-regulates quantity by destabilization" ubiquitination 10090 BTO:0000078 32795415 t Gianni "We show expression of c/EBPβ in microglia is regulated post-translationally by the ubiquitin ligase COP1 (also called RFWD2). In the absence of COP1, c/EBPβ accumulates rapidly and drives a potent pro-inflammatory and neurodegeneration-related gene program, evidenced by increased neurotoxicity in microglia-neuronal co-cultures." SIGNOR-261924 DOK1 protein Q99704 UNIPROT "A6/b4 integrin" complex SIGNOR-C174 SIGNOR "down-regulates activity" binding 9606 19118207 t miannu "Integrins also bind to many PTBdomain-containing proteins (Calderwood et al., 2003) – including Dok1 and integrincytoplasmic-domain-associated protein 1 (ICAP1) – and these can compete with talin for binding to integrin and so can impair activation" SIGNOR-257690 ESR1 protein P03372 UNIPROT F12 protein P00748 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000599 9794469 f miannu "Transcription of the FXII gene is stimulated by estrogens through specific interaction of the estrogen receptor alpha (ER alpha) with an estrogen response element present on FXII promoter." SIGNOR-254072 phentolamine chemical CHEBI:8081 ChEBI ADRA1D protein P25100 UNIPROT "down-regulates activity" "chemical inhibition" 10029 BTO:0000246 7651358 t miannu "Membrane preparations from CHO cells stably transfected with the cloned human a1-AR genes showed saturable binding of [‘251]HEAT; Bm,,ı values were 1.3 ± 0.2, 5.5 ± 0.1, and 1.1 ± 0.1 pmol/mg of protein, with Kd values of 110 ± 21, 60 ± 1, and 300 ± 26 ıM (three experiments each), for the ala-, alb-, and ald-ARS, respectively. The potencies of a1-AR agonists and antagonists at the cloned human a1-ARs are shown in Table 1." SIGNOR-258444 SRC protein P12931 UNIPROT KIT protein P10721 UNIPROT "up-regulates activity" phosphorylation Tyr900 EHAPAEMyDIMKTCW 9606 12878163 t lperfetto "C-src phosphorylates tyr900 in the second part of the kinase domain of c-kit." SIGNOR-103999 cabozantinib chemical CHEBI:72317 ChEBI FLT3 protein P36888 UNIPROT "down-regulates activity" "chemical inhibition" 9606 BTO:0000184 26536165 t miannu "Cabozantinib (XL184) is a small-molecule kinase inhibitor with potent activity toward MET and VEGF receptor 2 (VEGFR2), as well as a number of other receptor tyrosine kinases that have also been implicated in tumor pathobiology, including RET, KIT, AXL, and FLT3." SIGNOR-262242 SH3BP1 protein Q9Y3L3 UNIPROT RAC1 protein P63000 UNIPROT "down-regulates activity" "gtpase-activating protein" 9606 BTO:0000007 32203420 t Luana "We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2)." SIGNOR-260514 MSC protein O60682 UNIPROT TCF3 protein P15923 UNIPROT "down-regulates activity" binding 9606 BTO:0000776 9584154 t 2 miannu "ABF-1 contains a transcriptional repression domain and is capable of inhibiting the transactivation capability of E47 in mammalian cells." SIGNOR-241315 quetiapine chemical CHEBI:8707 ChEBI HTR1F protein P30939 UNIPROT "up-regulates activity" "chemical activation" 9534 BTO:0000298 8935801 t miannu "Risperidone and its active metabolite 9-OH-risperidone were compared to reference antipsychotic drugs (haloperidol, pipamperone, fluspirilene, clozapine, zotepine) and compounds under development (olanzapine, seroquel, sertindole, ORG-5222, ziprasidone) for in vitro binding to neurotransmitter receptors in brain tissue and on membranes of recombinant cells expressing cloned human receptors and for in vivo occupancy of neurotransmitter receptors in rat and guinea-pig brain following acute treatment (2 h., s.c.). The binding affinities of the compounds for various neurotransmitter receptors were measured using membrane preparations of animal brain regions and of recombinant cells expressing cloned, mostly human receptors. Receptors, tissues and cells are indicated in Table I; results are shown in Table 4A-B." SIGNOR-258536 AATF protein Q9NY61 UNIPROT BAX protein Q07812 UNIPROT "down-regulates quantity" "transcriptional regulation" 9606 22909821 t "We identify the transcriptional regulator apoptosis-antagonizing transcription factor (AATF)/Che-1 as a critical regulator of the cellular outcome of the p53 response. Upon genotoxic stress, AATF is phosphorylated by the checkpoint kinase MK2. Phosphorylation results in the release of AATF from cytoplasmic MRLC3 and subsequent nuclear translocation where AATF binds to the PUMA, BAX and BAK promoter regions to repress p53-driven expression of these pro-apoptotic genes." SIGNOR-259916 PTPN2 protein P17706 UNIPROT FKBP4 protein Q02790 UNIPROT down-regulates dephosphorylation 9606 BTO:0000567 12552015 t tpavlidou "We have documented that a cellular protein that binds the immunosuppressant drug fk506, termed the fk506-binding protein (fkbp52), interacts with the single-stranded d sequence within the aav inverted terminal repeats, inhibits viral second-strand dna synthesis, and consequently limits high-efficiency transgene expression. Deliberate overexpression of the murine wild-type (wt) tc-ptp gene, but not that of a cysteine-to-serine (c-s) mutant, caused tyrosine dephosphorylation of fkbp52, leading to efficient viral second-strand dna synthesis and resulting in a significant increase in aav-mediated transduction efficiency in hela cells in vitro." SIGNOR-97794 MAP2K2 protein P36507 UNIPROT PPARG protein P37231 UNIPROT up-regulates binding 9606 18596912 t gcesareni "The genomic activity of ppargamma is modulated, in addition to ligand binding, by phosphorylation of a serine residue by mapks, such as extracellular signal-regulated protein kinases-1/2 (erk-1/2), or by nucleocytoplasmic compartmentalization through the erk activators mapk kinases-1/2 (mek-1/2). These mapks phosphorylate (in humans) ser 84 in the ppargamma1 and ser 114 in ppargamma2 isoform." SIGNOR-179393 ODC1 protein P11926 UNIPROT L-ornithine smallmolecule CHEBI:15729 ChEBI "down-regulates quantity" "chemical modification" 9606 14617280 t miannu "Arginase generates ornithine, an aminoacid that can be further metabolized to proline via ornithine aminotransferase and to polyamines via ornithine decarboxylase (ODC)" SIGNOR-256037 CHGA protein P10645 UNIPROT Secretory_granule_organization phenotype SIGNOR-PH87 SIGNOR up-regulates 10090 12456801 f "CgA was initially identified as the major soluble matrix protein of secretory vesicles formed in neuroendocrine cells. Its functions include modulation of secretory granule stability, prohormone processing, and regulation of peptide sorting into secretory pathways" SIGNOR-254274 CSNK2A1 protein P68400 UNIPROT PDCL protein Q13371 UNIPROT unknown phosphorylation Ser25 SSSEDEDsDHEDKDR 9606 16717095 t lperfetto "Together, these data make a strong case for ck2 phosphorylation events within the serines 18-20 and 25 sites in vivo. hey also show that phosphorylation of ser-25 and ser-296 plays no additional role in g__ expression." SIGNOR-146837 MAPK7 protein Q13164 UNIPROT MEF2A protein Q02078 UNIPROT up-regulates phosphorylation Thr319 TPVVSVTtPSLPPQG 9606 BTO:0000567 10849446 t lperfetto "We have previously shown that bmk1 regulates c-jun gene expression through direct phosphorylation and activation of transcription factor mef2c.Here, we demonstrate that, in addition to mef2c, bmk1 phosphorylates and activates mef2a and mef2d but not mef2b.The sites phosphorylated by activated bmk1 were mapped to ser-355, thr-312, and thr-319 of mef2a and ser-179 of mef2d both in vitro and in vivo." SIGNOR-236579 SRC protein P12931 UNIPROT BCAR1 protein P56945 UNIPROT "up-regulates activity" phosphorylation Tyr115 QPQPDSVyLVPTPSK 10090 12972425 t lperfetto "Cas is a member of the focal adhesion complex. Phosphorylation of Cas by Src is an important event leading to cell transformation. Using mass spectrometry, we have mapped 11 sites in Cas that are phosphorylated by Src. These sites are all located between residues 132 and 414 of CasBased on these data, 11 tyrosine residues (132, 169, 183, 196, 238, 253, 271, 291, 301, 391, and 414) were phosphorylated by Src|the biological activity of Cas depends on its phosphorylation by Src (16–18). After phosphorylation, Cas associates with a number of proteins, including Crk, Src, phosphatidylinositol 3-kinase, Nck, and phospholipase Cgamma, via SH2 binding motifs" SIGNOR-246381 PPP3CA protein Q08209 UNIPROT DNM1L protein O00429 UNIPROT "up-regulates activity" dephosphorylation Ser637 VPVARKLsAREQRDC 9606 18838687 t "When mitochondrial depolarization is associated with sustained cytosolic Ca(2+) rise, it activates the cytosolic phosphatase calcineurin that normally interacts with Drp1. Calcineurin-dependent dephosphorylation of Drp1, and in particular of its conserved serine 637, regulates its translocation to mitochondria as substantiated by site directed mutagenesis." SIGNOR-248676 Riluzole chemical CHEBI:8863 ChEBI KCNN2 protein Q9H2S1 UNIPROT "up-regulates activity" "chemical activation" 9606 BTO:0000007 18955585 t Luana "Here, we used the neuroprotectant riluzole as a template for the design of KCa2/3 channel activators that are potent enough for in vivo studies. Of a library of 41 benzothiazoles, we identified 2 compounds, anthra[2,1-d]thiazol-2-ylamine (SKA-20) and naphtho[1,2-d]thiazol-2-ylamine (SKA-31), which are 10 to 20 times more potent than riluzole and activate KCa2.1 with EC50 values of 430 nM and 2.9 μM, KCa2.2 with an EC50 value of 1.9 μM, KCa2.3 with EC50 values of 1.2 and 2.9 μM, and KCa3.1 with EC50 values of 115 and 260 nM. " SIGNOR-258020 AZD1480 chemical CID:16659841 PUBCHEM JAK1 protein P23458 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-190164 C9orf72 protein Q96LT7 UNIPROT RAB1A protein P62820 UNIPROT "up-regulates activity" binding 9606 BTO:0000007 27334615 t miannu "C9orf72 acts as an effector of Rab1a that recruits active Rab1a to theULK1 complex to promote translocation of the ULK1 complex to thephagophore during autophagy initiation" SIGNOR-261297 GDF5 protein P43026 UNIPROT Cartilage_development phenotype SIGNOR-PH75 SIGNOR up-regulates 9606 21976273 f miannu "Growth and differentiation factor 5 (GDF5), a member of the bone morphogenetic protein (BMP) family, is essential for cartilage, bone, and joint formation." SIGNOR-252418 PTPRC protein P08575 UNIPROT JAK3 protein P52333 UNIPROT "down-regulates activity" dephosphorylation 10090 11201744 t "CD45 is a JAK phosphatase and negatively regulates cytokine receptor signalling" SIGNOR-248359 UBE3A protein Q05086 UNIPROT UBE3A protein Q05086 UNIPROT "down-regulates quantity by destabilization" ubiquitination 9606 BTO:0001968 10864652 t miannu "We show here that HPV16 E6 promotes the ubiquitination and degradation of E6AP itself. " SIGNOR-271398 ARHGEF17 protein Q96PE2 UNIPROT RHOA protein P61586 UNIPROT "up-regulates activity" "guanine nucleotide exchange factor" 9606 BTO:0000007 32203420 t Luana "We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2)." SIGNOR-260542 AP1B1 protein Q10567 UNIPROT "AP-1 complex" complex SIGNOR-C248 SIGNOR "form complex" binding 9606 21097499 t lperfetto "Key components of this system are the heterotetrameric adaptor protein (AP)4 complexes, AP-1 (gamma-beta1-mi1-sigma1), AP-2 (α-beta2-mi2-sigma2), AP-3 (delta-beta3-mi3-sigma3), and AP-4 (epsilon-beta4-mi4-sigma4) (subunit composition shown in parentheses)" SIGNOR-260685 SBF1 protein O95248 UNIPROT MTMR2 protein Q13614 UNIPROT "up-regulates activity" binding 9534 BTO:0001538 12668758 t miannu "We also demonstrate that MTMR2 interacts with MTMR5 via its coiled-coil domain and that mutations in the coiled-coil domain of either MTMR2 or MTMR5 abrogate this interaction. Through this interaction, MTMR5 increases the enzymatic activity of MTMR2 and dictates its subcellular localization. " SIGNOR-269803 GSK3B protein P49841 UNIPROT GSK3B protein P49841 UNIPROT "up-regulates activity" phosphorylation Tyr216 RGEPNVSyICSRYYR 9606 20331603 t lperfetto "Phosphorylation of the residue Tyrosine in 216 position results in the constitutive activity of GSK-3beta and believed to be important target for signal transduction." SIGNOR-217865 conivaptan chemical CHEBI:681850 ChEBI AVPR2 protein P30518 UNIPROT "down-regulates activity" "chemical inhibition" -1 20471258 t Luana "One of the targets, 13d, demonstrated improved V2-receptor binding and was further profiled for comparison with conivaptan, the program’s mixed V1a/V2 standard (Table 4). Compound 13d displayed similar V1a-receptor affinity, albeit with a 30-fold weaker V2-receptor affinity when compared to conivaptan." SIGNOR-257844 THR proteinfamily SIGNOR-PF84 SIGNOR RARB protein P10826 UNIPROT "up-regulates activity" binding 9606 15650024 t "inferred from family member" gcesareni "We report that the retinoic acid receptors (rars), a distinct class of nuclear receptors, are also efficient heterodimer partners for trs" SIGNOR-267780 CSNK2A1 protein P68400 UNIPROT PDCL protein Q13371 UNIPROT up-regulates phosphorylation Ser19 KLQYYYSsSEDEDSD 9606 16717095 t lperfetto "Phosducin-like protein (phlp) is a widely expressed binding partner of the g protein betagamma subunit complex (gbetagamma) that has been recently shown to catalyze the formation of the gbetagamma dimer from its nascent polypeptides. Phosphorylation of phlp at one or more of three consecutive serines (ser-18, ser-19, and ser-20) is necessary for gbetagamma dimer formation and is believed to be mediated by the protein kinase ck2." SIGNOR-146829 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR CDC25C protein P30307 UNIPROT up-regulates phosphorylation Thr48 VCPDVPRtPVGKFLG 9606 10864927 t lperfetto "Activation of human cdc25c at the g2/m transition occurs concomitantly with phosphorylation of five serine/threonine-proline sites: thr48, thr67, ser122, thr130, and ser214, presumably by cdc2-cyclin b." SIGNOR-216773 CDR2 protein Q01850 UNIPROT AURKA protein O14965 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 20383333 f lperfetto "Additionally, cdr2 knockdown lead to a decrease (Table 3) in four other transcripts (AURKA, CENPE, SPC25 and TTK), which are involved in kinetochore and spindle biology" SIGNOR-252023 LCK protein P06239 UNIPROT ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR up-regulates phosphorylation 9606 BTO:0000782 17998336 t "inferred from 70% of family members" gcesareni "The sh3 domain of lck modulates t-cell receptor-dependent activation of extracellular signal-regulated kinase through activation of raf-1." SIGNOR-269921 TRAF2 protein Q12933 UNIPROT BIRC3 protein Q13489 UNIPROT up-regulates binding 9606 18997792 t gcesareni "A traf2 trimer interacts with one ciap2 both in the crystal and in solution through its death domain and amino-terminal region, tradd recruits rip1 (receptor-interacting protein), traf2, and through its interaction with traf2, c-iap1 and c-iap2 (13). Traf2 recruit ciap1 and ciap2. A traf2 trimer interacts with one ciap2 both in the crystal and in solution." SIGNOR-182124 ABRAXAS1 protein Q6UWZ7 UNIPROT "BRCA1-A complex" complex SIGNOR-C296 SIGNOR "form complex" binding 9606 BTO:0000007 20656690 t lperfetto "We and others showed previously that BRCC36 is a component of the BRCA1-A complex, which consists of RAP80, CCDC98/ABRAXAS, BRCC45/BRE, MERIT40/NBA1, BRCC36, and BRCA1. " SIGNOR-263214 AGPAT4 protein Q9NRZ5 UNIPROT "1-acyl-sn-glycerol 3-phosphate(2-)" smallmolecule CHEBI:57970 ChEBI "down-regulates quantity" "chemical modification" 9606 21173190 t lperfetto "The enzyme 1-acylglycerol-3-phosphate-O-acyltransferase (AGPAT) converts lysophosphatidic acid (LPA) to phosphatidic acid (PA).¬†" SIGNOR-267015 TRAF7 protein Q6Q0C0 UNIPROT Cell_death phenotype SIGNOR-PH109 SIGNOR up-regulates 9606 15001576 f miannu "Overexpression of traf7 induced caspase-dependent apoptosis." SIGNOR-256666 MELK protein Q14680 UNIPROT MELK protein Q14680 UNIPROT up-regulates phosphorylation Thr494 TGTDKLMtGVISPER 9606 16216881 t lperfetto "We have mapped no less than 16 autophosphorylation sites including serines, threonines, and a tyrosine residue and show that the phosphorylation of thr167 and ser171 is required for the activation of melk.We have not yet explored the role of autophosphorylation of nine residues in the c-terminal, autoinhibitory domain (fig. 4c). An enticing hypothesis is that these autophosphorylations decrease the inhibitory potency of this domain and thereby contribute to the activation of the kinase." SIGNOR-141030 RPS6KA1 protein Q15418 UNIPROT L1CAM protein P32004 UNIPROT "up-regulates activity" phosphorylation Ser1152 RSKGGKYsVKDKEDT 10116 BTO:0001009 8663493 t lperfetto "Western blot analysis demonstrated that the L1 kinase activity from PC12 cells that phosphorylated this site was co-eluted with the S6 kinase, p90(rsk). Moreover, S6 kinase activity and p90(rsk) immunoreactivity co-immunoprecipitate with L1 from brain, and metabolic labeling studies have demonstrated that Ser1152 is phosphorylated in vivo in the developing rat brain. | These data demonstrate that the membrane-proximal 15 amino acids of the cytoplasmic domain of L1 are important for neurite outgrowth on L1, and the interactions it mediates may be regulated by phosphorylation of Ser1152." SIGNOR-248948 "NMDA receptor_2D" complex SIGNOR-C350 SIGNOR DLG4 protein P78352 UNIPROT "up-regulates activity" binding 9606 BTO:0000938 11052931 t miannu "Another central component of the NMDA receptor signaling complex is the scaffold protein PSD-95 (also referred to as SAP-90). The first and second PDZ domains bind tightly to the tails of the NR2 subunits of the NMDA receptor" SIGNOR-264225 DAPK1 protein P53355 UNIPROT STX1A protein Q16623 UNIPROT "down-regulates activity" phosphorylation Ser188 IIMDSSIsKQALSEI 9606 BTO:0000007;BTO:0000356 12730201 t llicata "Syntaxin-1A phosphorylation by DAP kinase or its S188D mutant, which mimics a state of complete phosphorylation, significantly decreases syntaxin binding to Munc18-1, a syntaxin-binding protein that regulates SNARE complex formation and is required for synaptic vesicle docking." SIGNOR-251083 TBK1 protein Q9UHD2 UNIPROT RELA protein Q04206 UNIPROT up-regulates phosphorylation Ser536 SGDEDFSsIADMDFS 9606 15489227 t lperfetto "Chromatographic fractionation of cell extracts allowed the identification of two distinct enzymatic activities phosphorylating ser-536. Peak 1 represents an unknown kinase, whereas peak 2 contained ikkalpha, ikkbeta, ikkepsilon, and tbk1. collectively, our results provide evidence for at least five kinases that converge on ser-536 of p65 and a novel function for this phosphorylation site in the recruitment of components of the basal transcriptional machinery to the interleukin-8 promoter." SIGNOR-129951 CDK5 protein Q00535 UNIPROT DPYSL2 protein Q16555 UNIPROT "down-regulates activity" phosphorylation Ser522 PASSAKTsPAKQQAP 9606 BTO:0000938 25040932 t lperfetto "Cdk5 and DYRK2 phosphorylate CRMP2 and CRMP4, respectively, priming these proteins at S522 before their subsequent phosphorylation by GSK-3b at T509, T516 and S518|e CRMP2 phosphorylation by GSK-3b disrupts its interaction with tubulin (Yamashita & Goshima, 2012), leading to growth inhibition" SIGNOR-264838 AKT proteinfamily SIGNOR-PF24 SIGNOR ADRB2 protein P07550 UNIPROT down-regulates phosphorylation Ser345 ELLCLRRsSLKAYGN 9606 11809767 t lperfetto "Akt mediates sequestration of the beta(2)-adrenergic receptor in response to insulin. Phosphorylation studies of the c-terminal cytoplasmic domain of the beta(2)-adrenergic receptor by akt in vitro identified ser(345) and ser(346) within a consensus motif for akt phosphorylation." SIGNOR-114466 YY1 protein P25490 UNIPROT "Polycomb repressive complex 2" complex SIGNOR-C130 SIGNOR "up-regulates quantity by expression" 17158804 t "YY1 REPO domain is necessary and sufficient for PcG transcriptional repression, Polycomb recruitment to DNA, and methylation of histone H3 on lysine 27" SIGNOR-253595 motesanib chemical CHEBI:51098 ChEBI RET protein P07949 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-194572 CDK1 protein P06493 UNIPROT RB1 protein P06400 UNIPROT down-regulates phosphorylation Thr252 PINGSPRtPRRGQNR 9606 1756735 t lperfetto "The retinoblastoma gene product (prb) is a nuclear phosphoprotein that is thought to play a key role in the negative regulation of cellular proliferation. The active form of prb is underphosphorylated. Using synthetic peptides corresponding to potential cdc2 phosphorylation sites, we have developed a strategy which has allowed the identification of five sites. S249, t252, t373, s807 and s811 are phosphorylated in vivo, and in each case these sites correspond closely to the consensus sequence for phosphorylation by p34cdc2." SIGNOR-21560 FYN protein P06241 UNIPROT TGFB1I1 protein O43294 UNIPROT "up-regulates activity" phosphorylation Tyr60 SGDKDHLySTVCKPR 9534 10838081 t miannu "Hic-5 is a CAKbeta-binding protein localized at focal adhesions. Here we show that overexpression of CAKbeta or Fyn, but not FAK, enhanced the tyrosine phosphorylation of coexpressed Hic-5 in COS-7 cells. The Y60F mutant of Hic-5 was not phosphorylated, and Hic-5 phosphorylated on tyrosine 60 was bound specifically to the SH2 domain of Csk. Specific phosphorylation of Hic-5 by CAKbeta and Fyn may activate a signaling pathway mediated by Hic-5." SIGNOR-262875 TGFB1 protein P01137 UNIPROT ITGA3 protein P26006 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0001596 1744142 f lperfetto "TGF-beta 1 decreases the biosynthesis of alpha 3 subunit but increases the production of alpha 2 subunit. IL-1 beta potentiates the effects of TGF-beta 1. Furthermore, in the presence of TGF-beta 1 the increase in the expression of alpha 1 subunit by IL-1 beta is even larger. Thus, IL-1 beta and TGF-beta 1, which usually have antagonistic functions in connective tissue, can regulate integrin expression in a synergistic way." SIGNOR-253353 OGDC complex SIGNOR-C397 SIGNOR succinyl-CoA(5-) smallmolecule CHEBI:57292 ChEBI "up-regulates quantity" "chemical modification" 9606 15953811 t miannu "The Œ±-ketoglutarate‚Äìdehydrogenase complex is a complex including multiple copies of three proteins: E1k (Œ±-ketoglutarate dehydrogenase), E2k (dihydrolipoyl succinyltransferase), and E3 (dihydrolipoamide dehydrogenase) (Fig. 2). The consecutive action of the three catalytic components of KGDHC results in oxidative decarboxylation of 2-oxoglutarate, preserving the energy in the form of succinylCoA and NADH." SIGNOR-266258 AKT2 protein P31751 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR "down-regulates quantity by destabilization" phosphorylation Ser253 APRRRAVsMDNSNKY 19951971 t lperfetto "AKT phosphorylates FOXO3a at three conserved sites (Thr32, Ser253 and Ser315), therefore creating binding sites for the 14-3-3 chaperone proteins and leading to the active export of FOXO3a to the cytoplasm where it is targeted for proteasomal degradation." SIGNOR-252863 EIF2AK2 protein P19525 UNIPROT "AIM2 inflammasome" complex SIGNOR-C222 SIGNOR "up-regulates activity" binding 9606 BTO:0000007 22801494 t miannu "Here we identify a role for double-stranded RNA-dependent protein kinase (PKR, also known as EIF2AK2) in inflammasome activation. PKR physically interacts with several inflammasome components, including NOD-like receptor (NLR) family pyrin domain-containing 3 (NLRP3), NLRP1, NLR family CARD domain-containing protein 4 (NLRC4), absent in melanoma 2 (AIM2), and broadly regulates inflammasome activation." SIGNOR-263120 MAP3K5 protein Q99683 UNIPROT ZNF622 protein Q969S3 UNIPROT up-regulates phosphorylation Ser314 WCNEKGKsFYSTEAV 9606 21771788 t gcesareni "Ask1 directly phosphorylated zpr9 at ser(314) and thr(318), suggesting that zpr9 can act as an ask1 substrate. Ask1-mediated phosphorylation of zpr9 at ser(314) and thr(318) was also responsible for zpr9-induced apoptosis." SIGNOR-175113 PPARGC1A protein Q9UBK2 UNIPROT Gluconeogenesis phenotype SIGNOR-PH35 SIGNOR up-regulates 9606 20640476 f Gianni "However, in contrast to the role of AMPK, most reports to date indicate that PGC-1a induces gluconeogenesis" SIGNOR-209932 CC2D1A protein Q6P1N0 UNIPROT RAD21 protein O60216 UNIPROT "up-regulates activity" binding 20171170 t centrosome lperfetto "Akt kinase-interacting protein 1 (Aki1)/Freud-1/CC2D1A is localized in the cytosol, nucleus, and centrosome. Aki1 plays distinct roles depending on its localization. | In the centrosome, it regulates spindle pole localization of the cohesin subunit Scc1, thereby mediating centriole cohesion during mitosis." SIGNOR-268294 COX4I1 protein P13073 UNIPROT "Mitochondrial respiratory chain complex IV" complex SIGNOR-C280 SIGNOR "form complex" binding 30030361 t lperfetto "Complex IV (EC 1.9.31) or cytochrome c oxidase (COX) catalyses the oxidation of cytochrome c and the reduction of oxygen to water, coupled to proton translocation [108]. Mammalian cIV contains 13 or 14 subunits" SIGNOR-267744 GPR35 protein Q9HC97 UNIPROT GNAI3 protein P08754 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-256860 SKI protein P12755 UNIPROT EP300 protein Q09472 UNIPROT down-regulates binding 9606 SIGNOR-C6 10575014 t gcesareni "Smad2/3 interacts with c-ski through its c-terminal mh2 domain in a tgf-beta-dependent mannerc-ski is incorporated in the smad dna binding complex, interferes with the interaction of smad3 with a transcriptional co-activator, p300, and in turn recruits hdac. c-ski is thus a transcriptional co-repressor that links smads to hdac in tgf-beta signaling." SIGNOR-72664 CDK1 protein P06493 UNIPROT HMGA1 protein P17096 UNIPROT down-regulates phosphorylation Thr78 KTRKTTTtPGRKPRG 9606 1939057 t lperfetto "Phosphorylation of the dna-binding domain of nonhistone high-mobility group i protein by cdc2 kinase: reduction of binding affinity" SIGNOR-22338 PRKCA protein P17252 UNIPROT PLD2 protein O14939 UNIPROT up-regulates phosphorylation Ser243 RWLVVKDsFLLYMCL 9606 15979581 t miannu "The phosphorylation sites in phospholipase d2 (pld2) induced by activation of protein kinase calpha (pkcalpha) in cos 7 cells were analyzed by mass spectrometry. Ser134, 146, and 243, and thr72, 99/100, and 252 were identified. These sites were mutated to ala and the double mutation of ser243 and thr252 eliminated the phosphorylation. / the s243/t252a mutant showed a partial decrease in pld2 activity" SIGNOR-138351 GSK3B protein P49841 UNIPROT CTNNB1 protein P35222 UNIPROT "down-regulates activity" phosphorylation Ser33 QQQSYLDsGIHSGAT 9606 BTO:0000938 BTO:0000142 SIGNOR-C110 19303846 t gcesareni "DISC1 inhibits GSK3beta activity through direct physical interaction, which reduces beta-catenin phosphorylation and stabilizes beta-catenin." SIGNOR-184781 BMPR1A protein P36894 UNIPROT SOST protein Q9BQB4 UNIPROT up-regulates 9606 19874086 f gcesareni "These results demonstrate that bmpria in osteoblasts negatively regulates endogenous bone mass and wnt/beta-catenin signaling and that this regulation may be mediated by the activities of sost and dkk1." SIGNOR-188958 PIK3CA protein P42336 UNIPROT AKT2 protein P31751 UNIPROT up-regulates 9606 BTO:0000586 16293724 f gcesareni "We show that pge2 stimulates colon cancer cell growth through its heterotrimeric guanine nucleotide-binding protein (g protein)coupled receptor, ep2, by a signaling route that involves the activation of phosphoinositide 3-kinase and the protein kinase akt by free g protein bg subunits and the direct association of the g protein as subunit with the regulator of g protein signaling (rgs) domain of axin." SIGNOR-141814 OGA protein O60502 UNIPROT PFK proteinfamily SIGNOR-PF79 SIGNOR "up-regulates activity" deglycosylation 9606 26399441 t lperfetto "Our previous investigation on O-GlcNAcylation of PFK1 has demonstrated that O-GlcNAcylation inhibits PFK1 enzyme activity|In cells, a single set of antagonistic enzymes-O-GlcNAc transferase (OGT) and O-GlcNAc hydrolase are responsible for the addition and removal of GlcNAc moiety, respectively." SIGNOR-267609 bevacizumab antibody DB00112 DRUGBANK VEGFA protein P15692 UNIPROT "down-regulates activity" binding 9606 BTO:0001615 15961063 t miannu "Clinical trials with VEGF inhibitors in a variety of malignancies are ongoing. Recently, a humanized anti-VEGF monoclonal antibody (bevacizumab; Avastin) has been approved by the FDA as a first-line treatment for metastatic colorectal cancer in combination with chemotherapy." SIGNOR-259884 SIRT6 protein Q8N6T7 UNIPROT SREBF1 protein P36956 UNIPROT "up-regulates activity" binding 9606 BTO:0000007 25083875 t miannu "SIRT6 directs chromatin recruitment of CLOCK:BMAL1 and SREBP1.Importantly, SIRT6 also controls SREBP-1 recruitment to target promoters, such as Fasn, and helps maintain proper cyclic transcription. In fact, circadian metabolomics analyses reveal that SIRT6 controls lipid metabolism, contributing to the regulation of pathways involved in fatty acid synthesis and beta oxidation, triglyceride storage, signaling, and cellular membrane lipids." SIGNOR-268158 GSK3B protein P49841 UNIPROT PRKCE protein Q02156 UNIPROT up-regulates phosphorylation Ser346 SEEDRSKsAPTSPCD 9606 18604201 t llicata "Specifically, we have identified three phosphorylation sites within pkcepsilon that control its association with 14-3-3.kinase (ser 350), gsk3 (ser 346) and pkc itself (ser 368)" SIGNOR-179412 TUBE1 protein Q9UJT0 UNIPROT Microtubule_polimerization phenotype SIGNOR-PH106 SIGNOR up-regulates 9606 28347630 f miannu "Microtubules are essential for the generation, migration and differentiation of neurons. Within dendrites microtubules have also been implicated in the formation and plasticity of spines. For instance, the treatment of hippocampal neurons with low doses of the microtubule destabilizing drug Nocodazole impairs BDNF induced dendritic spine formation" SIGNOR-267178 KDM6A protein O15550 UNIPROT HOXA7 protein P31268 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 24561908 t miannu "Evidence for direct involvement of UTX in regulation of HOX gene activity was demonstrated through UTX knockdown experiments in HEK293T cells in which loss of UTX induced transcriptional repression of HOXA and HOXC clusters." SIGNOR-260024 DVL1 protein O14640 UNIPROT CTNNB1 protein P35222 UNIPROT "up-regulates activity" binding 9606 15735151 t amattioni "Activated DVL binds and inhibits the phosphorylation of beta-catenin by GSK3B, blocking beta-catenin degradation so that beta catenin accumulates and translocates to the nucleus, where it interacts with the t cell specific factor (tcf)/lymphoid enhancer binding factor 1 (lef-1) transcription factor and induces the transcription of target genes such as c-jun, c-myc, and cyclin d1." SIGNOR-134285 ponatinib chemical CHEBI:78543 ChEBI FGFR1 protein P11362 UNIPROT "down-regulates activity" "chemical inhibition" 9606 BTO:0002058 23563700 t miannu "Ponatinib was able to significantly inhibit the growth of primary lung cancer cultures in vitro. Our data indicate that pharmacological inhibition of FGFR1 kinase activity with ponatinib may be effective for the treatment of lung cancer patients whose tumors overexpress FGFR1." SIGNOR-259276 CyclinK/CDK12 complex SIGNOR-C37 SIGNOR POLR2A protein P24928 UNIPROT "up-regulates activity" phosphorylation Ser1875 SPTSPKYsPTSPTYS 9606 BTO:0006413 32917631 t "Ser2 in CTD of PolII" lperfetto "Together, these studies demonstrate the important, yet largely redundant, role for CDK12 and CDK13 for the regulation of POLII CTD phosphorylation at multiple residues, as well as the global role for both of these kinases in regulating POLII occupancy across the genome.|CDK12 and CDK13 are thus evolutionarily related and structurally similar kinases, and biochemical assays have demonstrated that both have POLII C-terminal domain (CTD) kinase activity and the ability to phosphorylate the Ser2 residue of the repetitive CTD heptad sequence" SIGNOR-273089 SYN2 protein Q92777 UNIPROT Synaptic_vesicle_exocytosis phenotype SIGNOR-PH160 SIGNOR down-regulates 9606 BTO:0000938 33809712 f miannu "Synapsins are a family of peripheral proteins that bind to the SV membrane. Synapsins Maintain the SV Reserve Pool. Synapsins serve as a key protein for maintaining SVs within this reserve pool, but the mechanism that allows synapsins to do this is unclear. This mechanism is likely to involve synapsins either cross-linking SVs, thereby anchoring SVs to each other, or creating a liquid phase that allows SVs to float within a synapsin droplet." SIGNOR-264106 MAPK1 protein P28482 UNIPROT NUP50 protein Q9UKX7 UNIPROT "down-regulates activity" phosphorylation Ser221 KVAAETQsPSLFGST 9606 19767751 t gcesareni "Erk phosphorylates nup50 at ser221 and ser315 erk phosphorylation of the fg repeat region of nup50 reduced its affinity for importin-beta family proteins, importin-beta and transportin." SIGNOR-188139 WWTR1 protein Q9GZV5 UNIPROT PPARG protein P37231 UNIPROT down-regulates binding 9606 22153608 t gcesareni "Kmp also enhanced the association of taz with ppar_, thereby suppressing the gene transcription of ppar_ targets and resulting in diminished adipocyte differentiation." SIGNOR-195215 PRKDC protein P78527 UNIPROT CASP2 protein P42575 UNIPROT up-regulates phosphorylation Ser139 LSCDYDLsLPFPVCE 9606 19203584 t lperfetto "Here we show that dna damage induced by gamma-radiation triggers the phosphorylation of nuclear caspase-2 at the s122 site within its prodomain, leading to its cleavage and activation. This phosphorylation is carried out by the nuclear serine/threonine protein kinase dna-pkcs" SIGNOR-183895 452342-67-5 chemical CID:10202642 PUBCHEM TGFBR1 protein P36897 UNIPROT down-regulates "chemical inhibition" 9606 BTO:0000671 18075500 t gcesareni "Gw788388 is a new tgf-beta type i receptor inhibitor with a much improved pharmacokinetic profile compared with sb431542." SIGNOR-159863 CRH protein P06850 UNIPROT KRT14 protein P02533 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 15468147 t Regulation miannu "CRH stimulated the expression of cytokeratin 1 and involucrin, and inhibited cytokeratin 14 on both mRNA and protein levels." SIGNOR-251899 CASP2 protein P42575 UNIPROT "Caspase-2 PIDDosome" complex SIGNOR-C292 SIGNOR "form complex" binding 9606 20158568 t miannu "The PIDDosome consists of the proteins PIDD, RAIDD and caspase-2." SIGNOR-262641 P2RY2 protein P41231 UNIPROT GNA12 protein Q03113 UNIPROT "up-regulates activity" binding 9606 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257145 CBP/p300 complex SIGNOR-C6 SIGNOR SMAD1 protein Q15797 UNIPROT up-regulates binding 9606 12419246 t lperfetto "Thus, Ski/SnoN represses TGFβ signaling by multiple mechanisms. In addition to recruitment of a transcriptional repressor complex and dissociation of the transcriptional coactivator p300/CBP from the Smads" SIGNOR-217217 NR0B2 protein Q15466 UNIPROT CEBPA protein P49715 UNIPROT "down-regulates activity" binding 9606 17094771 t miannu "SHP repressed C/EBPalpha (CCAAT/enhancer-binding protein alpha)-driven transcription of PEPCK through direct interaction with C/EBPalpha protein both in vitro and in vivo. The formation of an active transcriptional complex of C/EBPalpha and its binding to DNA was inhibited by SHP, resulting in the inhibition of PEPCK gene transcription." SIGNOR-254831 BMPR1A protein P36894 UNIPROT SMAD1/4 complex SIGNOR-C85 SIGNOR "up-regulates activity" 10090 19620713 f ggiuliani "The expression of CA-BMPr1A and CA-BMPr1B mRNA was confirmed by RT-PCR using appropriate primers to distinguish expression of the constitutively active receptors from endogenous BMP receptors; specific antibodies for these receptors were not available. However, the functional effects of their expression, i.e., phosphorylation of Smad1/5/8 and p38 MAPK, verify overexpression of the constitutively active receptors (Fig. 3B). Thus, their overexpression provoked a substantial rise in the phosphorylation of Smad1/5/8 and p38 MAPK, known downstream phosphorylated intermediates in the BMP signaling pathway (Fig. 3B) (16, 17)." SIGNOR-255787 WDR83 protein Q9BRX9 UNIPROT RAF1 protein P04049 UNIPROT up-regulates binding 9606 15118098 t gcesareni "Morg1 specifically associates with several components of the erk pathway, including mp1, raf-1, mek, and erk, and stabilizes their assembly into an oligomeric complex." SIGNOR-124476 FOXS1 protein O43638 UNIPROT FOXO4 protein P98177 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9913 BTO:0004577 18288644 t Luana "Fkhl18 suppressed the transcriptional activity of FoxO3a and FoxO4." SIGNOR-261611 FGD4 protein Q96M96 UNIPROT CDC42 protein P60953 UNIPROT "up-regulates activity" "guanine nucleotide exchange factor" 9606 BTO:0000007 32203420 t Luana "We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2)." SIGNOR-260554 FUBP1 protein Q96AE4 UNIPROT MYC protein P01106 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 26490982 f irozzo "The human far upstream element (FUSE) binding protein 1 (FUBP1) belongs to an ancient family which is required for proper regulation of the c-Myc proto-oncogene. Our results indicated that FUBP1 may potentially stimulate c-Myc expression in ESCC and its expression may promote ESCC progression." SIGNOR-259123 GSK3B protein P49841 UNIPROT SNAI1 protein O95863 UNIPROT down-regulates phosphorylation Ser119 SFSSTSVsSLEAEAY 9606 15448698 t lperfetto "Snail is a well-known zn-finger transcription factor that promotes emt by repressing e-cadherin expression. It is known that snail is phosphorylated by gsk3beta and degraded by beta-trcp-mediated ubiquitination. A variant of snail (snail-6sa), which abolishes these phosphorylations, is much more stable and resides exclusively in the nucleus to induce emt" SIGNOR-129418 PRKCD protein Q05655 UNIPROT MEP1B protein Q16820 UNIPROT "down-regulates quantity" phosphorylation Ser687 KKYRERMsSNRPNLT 9534 BTO:0001538 12941954 t miannu "These findings suggest that activation of a protein kinase, presumably PKC, mediates PMA-induced hmeprinβ shedding. By labeling COS-1 cells transfected with mutant constructs lacking the potential phosphorylation sites, we identified Ser687 as the main 32P-acceptor. These data provide evidence that the cytoplasmic domain of hmeprinβ can function as a PKC substrate." SIGNOR-263171 STAT3 protein P40763 UNIPROT T_cell_activation phenotype SIGNOR-PH73 SIGNOR up-regulates 9606 32454942 f miannu "IL-1β, an inflammatory cytokine primarily expressed in activated macrophages, monocytes, and microglia, significantly contributes to MS development. IL-1β promotes differentiation of T cells into Th17 cells via the STAT3 pathway and thereby promotes and aggravates the inflammatory environment in the CNS" SIGNOR-263821 palmitoyl-CoA(4-) smallmolecule CHEBI:57379 ChEBI O-palmitoyl-L-carnitine smallmolecule CHEBI:17490 ChEBI "up-regulates quantity" "precursor of" 9606 14517221 t miannu "Carnitine palmitoyltransferase 1A (CPT1A) is the key regulatory enzyme of hepatic long-chain fatty acid beta-oxidation. The first component of this system is CPT1, an integral mitochondrial outer membrane protein, which catalyzes the transfer of long-chain acyl group of the acyl-CoA ester to carnitine. CPT1 is tightly regulated by its physiological inhibitor malonyl-CoA, the first intermediate in fatty acid biosynthesis. Three CPT1 isoforms with various tissue distribution and encoded by distinct genes have been identified (1., 2.): a liver (CPT1A or L-CPT1) (8.), a muscle (CPT1B or M-CPT1) (9.), and a brain isoform (CPT1C)." SIGNOR-267123 CTDSP1 protein Q9GZU7 UNIPROT SMAD1 protein Q15797 UNIPROT down-regulates dephosphorylation 9606 16882717 t lpetrilli "In human cells, rnai-mediated depletion of scp1 and scp2 increases the extent and duration of smad1 phosphorylation in response to bmp, the transcriptional action of smad1, and the strength of endogenous bmp gene responses. The present identification of the scp family as smad c-terminal phosphatases sheds light on the events that attenuate smad signaling and reveals unexpected links to the essential phosphatases that control rna polymerase ii in eukaryotes." SIGNOR-148396 SUN1 protein O94901 UNIPROT NUP153 protein P49790 UNIPROT "up-regulates activity" binding 9606 BTO:0000567 SIGNOR-C303 SIGNOR-C263 28831067 t lperfetto "The NXF1:NXT1 complex and NUP153 interact with the amino terminus of SUN1 |In analogy to a proposal made by Chang et al.4, Nesprins could help anchoring SUN1 near the NPC to enable it to fulfill its task in mRNA export." SIGNOR-263294 SLC4A3 protein P48751 UNIPROT hydrogencarbonate smallmolecule CHEBI:17544 ChEBI "down-regulates quantity" relocalization 9606 BTO:0000938 26136660 t miannu "Slc4a10 is a Na+-coupled Cl−-HCO3− exchanger, which is expressed in principal and inhibitory neurons as well as in choroid plexus epithelial cells of the brain. In neurons, bicarbonate transport is mainly mediated by members of the SLC4A family of proteins. While the Na+-independent anion-exchanger SLC4A3 lowers the intraneuronal bicarbonate concentration, the Na+-dependent anion exchangers SLC4A8 (NDCBE) and SLC4A10 (NCBE) use the sodium gradient to accumulate bicarbonate in exchange of chloride" SIGNOR-264917 PKN1 protein Q16512 UNIPROT AR protein P10275 UNIPROT up-regulates phosphorylation 9606 17251915 t gcesareni "Rho can sensitize the ar to low levels of circulating androgens by promoting the nuclear translocation of a transcriptional co-activator, fhl2 (four and a half lim domains 2), which binds ar, and by stimulating protein kinase n (pkn), which phosphorylates ar directly." SIGNOR-152762 DRAM2 protein Q6UX65 UNIPROT TP53 protein P04637 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 30755245 f irozzo "DRAM2 plays an oncogenic role in NSCLC via regulating p53 expression. Knockdown of DRAM2 caused an increase of p53 and p21 expression, and overexpression of p53 caused a decrease of DRAM2 expression." SIGNOR-259146 SMURF proteinfamily SIGNOR-PF29 SIGNOR SKIL protein P12757 UNIPROT "down-regulates activity" ubiquitination 9606 BTO:0002181;BTO:0005493 11389444 t lperfetto "Tgf-beta also induces the association of smurf2 with the transcriptional co-repressor snon and we show that smad2 can function to mediate this interaction. This allows smurf2 hect domain to target snon for ubiquitin-mediated degradation by the proteasome." SIGNOR-253262 HNF1A protein P20823 UNIPROT Aldolase proteinfamily SIGNOR-PF75 SIGNOR "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000599 8383844 f "inferred from family member" miannu "Contransfection experiments of aldolase B/CAT constructs and of expression vectors for different transcription factors were carried out in human hepatoma Hep G2 cells. We found that DBP and HNF-1 are strong transactivators of the aldolase B promoter while C/EBP and vHNF-1 are only weak activators" SIGNOR-270224 DLG4 protein P78352 UNIPROT TANC1 protein Q9C0D5 UNIPROT "up-regulates activity" binding 10116 BTO:0000142 21068316 t miannu "In the present study, we provide evidence that TANC1 and its close relative TANC2 regulate dendritic spines and excitatory synapses. our results indicate that TANC-dependent spine/synapse maintenance requires TANC binding to PSD-95, which promotes synaptic localization of TANC proteins. Thus, it is likely that interaction with PSD-95 concentrates TANC proteins at synapses, where they play a role in mediating PSD-95-dependent maintenance of spines and synapses." SIGNOR-266894 POLR2L protein P62875 UNIPROT "RNA Polymerase III" complex SIGNOR-C389 SIGNOR "form complex" binding 9606 12391170 t lperfetto "In this article, we use this proposed nomenclature for the S. cerevisiae subunits as the guide to refer to the human RNA polymerase III subunits, as indicated in Table ​Table1,1, and consequently the numbering of the human subunits does not always correspond to their decreasing apparent molecular weights." SIGNOR-266142 calcium(2+) smallmolecule CHEBI:29108 ChEBI Calcineurin complex SIGNOR-C155 SIGNOR "up-regulates activity" "chemical activation" 9606 21880741 t miannu "Except for nfat5, nfatc1c4 are activated upon a rise in intracellular ca2+, which stimulates the serine/threonine phosphatase activity of calcineurin the ca2+-calcineurin signal is the most important signal for regulating nfat activation, but the signal that leads to ca2+ influx during neural tube differentiation is still unclear." SIGNOR-255462 MYC protein P01106 UNIPROT VEGFA protein P15692 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 12368264 f "These defects are intrinsic to c-Myc, and are in part associated with a requirement for c-Myc for the expression of vascular endothelial growth factor (VEGF), as VEGF can partially rescue these defects." SIGNOR-259369 CDK13 protein Q14004 UNIPROT EIF4B protein P23588 UNIPROT "up-regulates activity" phosphorylation Ser422 RERSRTGsESSQTGT 9606 BTO:0001109 36882522 t lperfetto "CDK13 directly phosphorylates 4E-BP1 at Thr46 and eIF4B at Ser422; genetically or pharmacologically inhibiting CDK13 disrupts mRNA translation." SIGNOR-273115 ABL1 protein P00519 UNIPROT PDGFRB protein P09619 UNIPROT down-regulates phosphorylation Tyr970 GEGYKKKyQQVDEEF 9606 BTO:0000150;BTO:0000527 19275932 t gcesareni "These data are exciting as they indicate that abl kinases not only are activated by pdgfr and promote pdgfr-mediated proliferation and migration,but also act in an intricate negative feedback loop to turn-off pdgfr-mediated chemotaxis." SIGNOR-184556 LYN protein P07948 UNIPROT CD22 protein P20273 UNIPROT "down-regulates activity" phosphorylation 9606 BTO:0000776 32323266 t scontino "LYN is a BCR-associated SRC kinase involved in the positive regulation of BCR, but it also functions as a negative regulator by phosphorylating the immunoreceptor tyrosine-based inhibitory motifs (ITIMs) of CD22." SIGNOR-268443 TP53 protein P04637 UNIPROT ZDHHC5 protein Q9C0B5 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 28775165 t "Mechanistic investigations revealed that mutant p53 transcriptionally upregulated ZDHHC5 along with the nuclear transcription factor NF-Y" SIGNOR-261150 VEPH1 protein Q14D04 UNIPROT LATS2 protein Q9NRM7 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0000938 22055343 f "In the neuronal differentiation" lperfetto "Melted represses warts transcription to disrupt hippo pathway activity and specify rh5 fate wts and melt repress each other s transcription in a double negative, bistable feedback loop that directs robust expression of either rh5 or rh6 in r9" SIGNOR-177077 AR protein P10275 UNIPROT TMPRSS2 protein O15393 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 24505269 t miannu "Recurrent gene fusion between the androgen-regulated gene TMPRSS2 and members of the ETS transcription factor family, most commonly ERG, are present in about 50% of prostate cancer cases. Presence of this fusion gene is a critical event in the development of prostate cancer. the more aggressive phenotype that arises with the presence of TMPRSS2-ERG at least in part is caused by changes in the tumor stroma." SIGNOR-251545 HNF1A protein P20823 UNIPROT ALDOB protein P05062 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 8383844 f miannu "Contransfection experiments of aldolase B/CAT constructs and of expression vectors for different transcription factors were carried out in human hepatoma Hep G2 cells. We found that DBP and HNF-1 are strong transactivators of the aldolase B promoter while C/EBP and vHNF-1 are only weak activators" SIGNOR-253834 ATF1 protein P18846 UNIPROT EGR1 protein P18146 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10391889 t lperfetto "Phosphorylated CREB and ATF1 then bind to the CRE of the egr-1 promoter and cause a stress-dependent transcriptional activation of this gene." SIGNOR-271686 NEDD4L protein Q96PU5 UNIPROT SCN4A protein P35499 UNIPROT "down-regulates quantity by destabilization" ubiquitination 10090 BTO:0000938 23778145 t miannu "The control of Nav density at the cell membrane is crucial to ensuring normal neuronal excitability. Navs are subject to posttranslational modifications that may influence their cell membrane availability. Ubiquitylation is a key process that orchestrates the internalization and subsequent degradation or recycling of Navs. This is accomplished by ubiquitin protein ligases, such as NEDD4-2 (neuronal precursor cell expressed developmentally downregulated-4 type 2)." SIGNOR-253460 CDK9 protein P50750 UNIPROT SUPT5H protein O00267 UNIPROT up-regulates phosphorylation Thr784 MYGSGSRtPMYGSQT 9606 16427012 t lperfetto "We describe an evolutionarily conserved repetitive heptapeptide motif (consensus = g-s-r/q-t-p) in the c-terminal region (ctr) of hspt5, which, like the c-terminal domain (ctd) of rna pol ii, is highly phosphorylated by p-tefb. Thr-4 residues of the ctr repeats are functionally important phosphorylation sites. In vitro, thr-4 phosphorylation is critical for the elongation activation activity of dsif" SIGNOR-143927 MAP2 protein P11137 UNIPROT Microtubule_polimerization phenotype SIGNOR-PH106 SIGNOR "up-regulates quantity by stabilization" binding 9606 BTO:0000938 10704996 t lperfetto "MAP2 interacts with MTs through its tubulin-binding domain which mainly associates with the acidic region of the C-terminal region of tubulin|no neurite growth is observed when MAP2 expression is suppressed in neuronal cell cultures after treatment with specific antisense oligonucleotides" SIGNOR-264837 SREBF2 protein Q12772 UNIPROT NPC1L1 protein Q9UHC9 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 21123766 f miannu "Our results showed a positive correlation between changes in NPC1L1 and changes in both SREBP-2 and HNF-4α mRNA expression, a finding that supports the notion that these transcription factors stimulate intestinal NPC1L1 expression." SIGNOR-254452 POMC protein P01189 UNIPROT CDKN2A protein P42771 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 11830546 f miannu "The expression of the melanoma susceptibility gene product p16 is increased after UVR both in epidermally derived cell lines and in human skin. the increased expression of p16 after exposure to suberythemal doses of UVR is potentiated by α-MSH, a ligand for MC1R, and this effect is mimicked by cAMP, the intracellular mediator of α-MSH signaling via the MC1 receptor." SIGNOR-252377 SYN3 protein O14994 UNIPROT Actin_cytoskeleton_reorganization phenotype SIGNOR-PH84 SIGNOR "up-regulates activity" binding 9606 BTO:0000938 15265865 t miannu "Synapsins, a family of neuron-specific phosphoproteins, have been demonstrated to regulate the availability of synaptic vesicles for exocytosis by binding to both synaptic vesicles and the actin cytoskeleton in a phosphorylation-dependent manner." SIGNOR-269186 ID1 protein P41134 UNIPROT MYOD/E12E47 complex SIGNOR-C127 SIGNOR "down-regulates activity" binding 10090 9242638 t 2 miannu "All three Ids bound with high affinity to E proteins .Each Id was able to disrupt the ability of E protein-MyoD complexes to transactivate from a muscle creatine kinase reporter construct in vivo." SIGNOR-241128 CASP8 protein Q14790 UNIPROT BID protein P55957 UNIPROT "up-regulates activity" cleavage Asp60 GYDELQTdGNRSSHS 9606 BTO:0000093 9727492 t amattioni "Caspase-8 cleaves bid at aspartic acid residue 60 (asp60) cleavage of bid by casp8 releases its potent proapoptotic activity" SIGNOR-59655 LYN protein P07948 UNIPROT PAG1 protein Q9NWQ8 UNIPROT "up-regulates activity" phosphorylation Tyr417 LVPKENDyESISDLQ 9534 16920712 t miannu "Here we show that Lyn interacts with C-terminal Src kinase-binding protein (Cbp), an adaptor protein that recruits negative regulators C-terminal Src kinase (Csk)/Csk-like protein-tyrosine kinase (Ctk). Lyn phosphorylated Cbp on several tyrosine residues, including Tyr314, which recruited Csk/Ctk to suppress Lyn kinase activity.Thus, a single phosphotyrosine residue on Cbp coordinates a two-phase process involving distinct negative regulatory pathways to inactivate, then degrade, Lyn." SIGNOR-262899 PIK3R4 protein Q99570 UNIPROT "Vps34 Complex II" complex SIGNOR-C241 SIGNOR "form complex" binding -1 30397185 t lperfetto "PtdIns3P recruits specific recognition modules that are common in protein-sorting pathways, such as autophagy and endocytic sorting. It is best characterized in two heterotetramers, complexes I and II. Complex I is composed of VPS34, VPS15, Beclin 1, and autophagy-related gene (ATG)14L, whereas complex II replaces ATG14L with UVRAG. |Complexes I and II are critical for early events in autophagy and endocytic sorting, respectively." SIGNOR-260321 PRKACA protein P17612 UNIPROT WT1 protein P19544 UNIPROT down-regulates phosphorylation Ser393 KTCQRKFsRSDHLKT 9606 9366517 t llicata "Pka phosphorylated wt1 at ser-365 and ser-393 in vitro, as well as at additional sites, and this phosphorylation abolished the dna-binding activity of wt1 in vitro. Using wt1 mutants in which ser-365 and ser-393 were mutated to ala individually and in combination, we showed that phosphorylation of these sites was critical for inhibition of dna binding in vivo." SIGNOR-53176 MLL-AF4 "fusion protein" SIGNOR-FP4 SIGNOR RUNX1 protein Q01196 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 24449215 f miannu "However, the functional consequence of MLL fusions on RUNX1/CBFβ activity has not been fully understood. In this report, we show that MLL fusion proteins and the N-terminal MLL portion of MLL fusions downregulate RUNX1 and CBFβ protein expression via the MLL CXXC domain and flanking regions." SIGNOR-260126 DZIP3 protein Q86Y13 UNIPROT H2AC14 protein Q99878 UNIPROT "up-regulates activity" monoubiquitination Lys119 IQAVLLPkKTESHHK 9606 BTO:0000007 18206970 t miannu " 2A-HUB catalyzes monoubiquitination of H2A at lysine 119, functioning as a combinatoric component of the repression machinery required for specific gene regulation programs. Thus, 2A-HUB mediates a selective repression of a specific set of chemokine genes in macrophages, critically modulating migratory responses to TLR activation. H2A monoubiquitination acts to prevent FACT recruitment at the transcriptional promoter region, blocking RNA polymerase II release at the early stage of elongation." SIGNOR-271762 RAI1 protein Q7Z5J4 UNIPROT CLOCK/BMAL1 complex SIGNOR-C195 SIGNOR "up-regulates quantity by expression" "transcriptional regulation" 10090 BTO:0000614 22578325 f miannu "Data further show that haploinsufficiency of RAI1 and Rai1 in SMS fibroblasts and the mouse hypothalamus, respectively, results in the transcriptional dysregulation of the circadian clock and causes altered expression and regulation of multiple circadian genes, including PER2, PER3, CRY1, BMAL1, and others." SIGNOR-266844 AAK1 protein Q2M2I8 UNIPROT NUMB protein P49757 UNIPROT unknown phosphorylation Thr102 LRVVDEKtKDLIVDQ 9606 18657069 t llicata "Numb is phosphorylated by aak1, while little aak1-dependent phosphorylation is observed in t102a numb immunoprecipitants" SIGNOR-179610 ITCH protein Q96J02 UNIPROT CFLAR protein O15519 UNIPROT "down-regulates quantity" ubiquitination 10090 16469705 t gcesareni "Depends on JNK-mediated phosphorylation and activation of the E3 ubiquitin ligase Itch, which specifically ubiquitinates c-FLIP and induces its proteasomal degradation." SIGNOR-245307 NRBF2 protein Q96F24 UNIPROT PIK3C3 protein Q8NEB9 UNIPROT "down-regulates activity" binding 9606 BTO:0001938 phosphorylation:Ser113;Ser120 AEDAEGQsPLSQKYS;SPLSQKYsPSTEKCL 28059666 t miannu "NRBF2 S113 and S120 phosphorylation negatively regulates autophagy. Phosphorylated NRBF2 inhibits autophagy, preferentially binds a nonautophagic form of the PtdIns3K complex consisting of PIK3C3-PIK3R4 only, and this NRBF2-associated PtdIns3K complex has low lipid kinase activity. Phosphorylated NRBF2 inhibits autophagy, preferentially binds a nonautophagic form of the PtdIns3K complex consisting of PIK3C3-PIK3R4 only, and this NRBF2-associated PtdIns3K complex has low lipid kinase activity." SIGNOR-265879 DIO1 protein P49895 UNIPROT L-thyroxine smallmolecule CHEBI:18332 ChEBI "down-regulates quantity" "chemical modification" 9606 1400883 t scontino "The type I 5' iodothyronine deiodinase (5' DI) catalyzes the deiodination of T4 to the biologically active hormone T3 and accounts for a significant fraction of its production." SIGNOR-266944 HNRNPH2 protein P55795 UNIPROT TERF2 protein Q15554 UNIPROT "down-regulates quantity" "post transcriptional regulation" 10116 BTO:0001009 27117401 t miannu "During neuronal differentiation, use of an alternative splice site on the rat telomere repeat-binding factor 2 (TRF2) mRNA generates a short TRF2 protein isoform (TRF2-S) capable of derepressing neuronal genes. However, the RNA-binding proteins (RBPs) controlling this splicing event are unknown. Here, using affinity pull-down analysis, we identified heterogeneous nuclear ribonucleoproteins H1 and H2(HNRNPH) as RBPs specifically capable of interacting with the spliced RNA segment (exon 7) of Trf2 pre-mRNA. HNRNPH proteins prevent the production of the short isoform of Trf2 mRNA, as HNRNPH silencing selectively elevates TRF2-S levels." SIGNOR-266806 MAPK1 protein P28482 UNIPROT CDKN1B protein P46527 UNIPROT up-regulates phosphorylation Ser10 NVRVSNGsPSLERMD 9606 10831586 t gcesareni "Phosphorylation on ser-10 of kip1 is the major site of phosphorylation in resting cells, takes place at the g(0)-g1 phase and leads to protein stability." SIGNOR-77651 NR3C1 protein P04150 UNIPROT MAPK3 protein P27361 UNIPROT "down-regulates activity" 10090 BTO:0000944 11742987 f gcesareni "Both induction of MKP-1 expression and inhibition of its degradation are necessary for glucocorticoid-mediated inhibition of Erk-1/2 activation." SIGNOR-251677 NEK7 protein Q8TDX7 UNIPROT TERF1 protein P54274 UNIPROT "up-regulates quantity by stabilization" phosphorylation Ser114 AIIHGLSsLTACQLR 9606 BTO:0000567 28216227 t done miannu "Mechanistically, Nek7 interacts with and phosphorylates TRF1 on Ser114, which prevents TRF1 from binding to Fbx4, an Skp1-Cul1-F box E3 ligase subunit, thereby alleviating proteasomal degradation of TRF1, leading to a stable association of TRF1 with Tin2 to form a shelterin complex." SIGNOR-273903 mTORC1 complex SIGNOR-C3 SIGNOR EIF4EBP1 protein Q13541 UNIPROT "down-regulates activity" phosphorylation Thr46 GGTLFSTtPGGTRII 9606 23486913 t lperfetto "These results indicate that arg, leu, and gln act coordinately to stimulate proliferation of ptr cells through activation of the mtor-rps6k-rps6-eif4ebp1 signal transduction pathway. Specifically as part of mtorc1, mtor directly phosphorylates the ribosomal protein s6 kinases (s6k1 and s6k2) and the eukaryotic initiation factor 4e (eif4e)-binding proteins (4e-bp1 and 4e-bp2), both of which control specific steps in the initiation of cap-dependent translation" SIGNOR-217114 FGFR3 protein P22607 UNIPROT FGFR3 protein P22607 UNIPROT "up-regulates activity" phosphorylation Tyr577 RRPPGLDySFDTCKP 9606 BTO:0000007 11294897 t lperfetto "Ligand stimulation leads to autophosphorylation of fgfr3 the absence of y577 (3y-577f) or y760 (3y-760f) resulted in a modest decrease in activity." SIGNOR-106726 PTPN11 protein Q06124 UNIPROT STAT1 protein P42224 UNIPROT "down-regulates activity" dephosphorylation Tyr701 DGPKGTGyIKTELIS 9606 BTO:0000007 12270932 t "SHP-2 is a dual-specificity phosphatase involved in Stat1 dephosphorylation at both tyrosine and serine residues in nuclei|In SHP-2-/- mouse fibroblast cells, Stat1 phosphorylation at both the tyrosine residue Tyr(701) and the serine residue Ser(727) |Overexpression of SHP-2 in 293T cells inhibited IFNgamma-dependent Stat1 phosphorylation and suppressed Stat1-dependent induction of luciferase activity." SIGNOR-248672 ADIPOR2 protein Q86V24 UNIPROT APPL1 protein Q9UKG1 UNIPROT up-regulates binding 9606 16622416 t milica "Appl1 interacts with adiponectin receptors in mammalian cells and the interaction is stimulated by adiponectin." SIGNOR-146215 CDK1 protein P06493 UNIPROT RCC1 protein P18754 UNIPROT "up-regulates activity" phosphorylation Thr274 SNYHQLGtPGTESCF -1 15014043 t miannu "We show here that Cdc2 kinase phosphorylates the serines located in or near the nuclear localization signal (NLS) of hum an RCC1, the nucleotide exchange factor for Ran. This phosphorylation is necessary for RCC1 to generate RanGTP on mitotic chromosomes in mammalian cells, which in turn is required for spindle assembly and chromosome segregation. However, when both S2 and S11 were simultaneously mutated to As, the resulting 6His-RCC1S2,11A failed to be phosphorylated, whereas all of the other double mutants were phosphorylated (Fig. 1C). As expected, mutating all four sites to As (the 6His-RCC1S2,11,387A-T274A) also blocked phosphorylation (Fig. 1C)." SIGNOR-262704 MAPK14 protein Q16539 UNIPROT ATF2 protein P15336 UNIPROT up-regulates phosphorylation Thr71 IVADQTPtPTRFLKN 9606 12110590 t gcesareni "Here, we show that in fibroblasts, insulin, epidermal growth factor (egf) and serum activate atf2 via a so far unknown two-step mechanism involving two distinct ras effector pathways: the raf-mek-erk pathway induces phosphorylation of atf2 thr71, whereas subsequent atf2 thr69 phosphorylation requires the ral-ralgds-src-p38 pathway." SIGNOR-90525 Ub:E2 complex SIGNOR-C497 SIGNOR TRIM13 protein O60858 UNIPROT "up-regulates activity" ubiquitination 9606 34199813 t miannu "The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t" SIGNOR-271145 CSNK2A1 protein P68400 UNIPROT FOSB protein P53539 UNIPROT up-regulates phosphorylation Ser27 SAESQYLsSVDSFGS 9606 17241283 t lperfetto "Our findings indicate that ck2 activation increases deltafosb's transactivation potential, while ck2 inhibition decreases it. Further, we show that preventing ser27 phosphorylation by mutating the site to ala results in a significant decrease in deltafosb transactivation" SIGNOR-152403 LCMT1 protein Q9UIC8 UNIPROT PPP2CA protein P67775 UNIPROT "up-regulates activity" methylation Leu309 RRTPDYFl -1 18394995 t lperfetto "Methylation of the carboxy-terminal Leu309 in a conserved TPDYFL309 motif of the C subunit has been shown to enhance the affinity of the PP2A core enzyme for some, but not all, regulatory subunits |The PP2A core enzyme was methylated by a PP2A-specific leucine carboxyl methyltransferase (LCMT1)" SIGNOR-265749 MAPRE1 protein Q15691 UNIPROT Microtubule_polimerization phenotype SIGNOR-PH106 SIGNOR up-regulates binding 17889670 t lperfetto "Microtubule plus end binding proteins (+TIPs) localize to the dynamic plus ends of microtubules, where they stimulate microtubule growth and recruit signaling molecules. Three main +TIP classes have been identified (XMAP215, EB1, and CLIP-170)" SIGNOR-264831 MAPK1 protein P28482 UNIPROT SMAD2 protein Q15796 UNIPROT up-regulates phosphorylation Ser255 ELSPTTLsPVNHSLD 9606 BTO:0000763 12193595 t miannu "Phosphorylation of smad2 by erk increases its transcriptional activity /thr220 and ser245, ser250, and ser255 were possible phosphorylation sites. The phosphorylation of peak a peptide by erk1 is consistent with that prediction." SIGNOR-91722 dabrafenib chemical CHEBI:75045 ChEBI SIK1 protein P57059 UNIPROT "down-regulates activity" "chemical inhibition" -1 24720932 t miannu "Dabrafenib is known to inhibit V600E, V600K and V600D BRAF enzymes with in vitro IC50 values of 0.65, 0.5 and 1.84 nM, respectively. Dabrafenib can inhibit wild-type BRAF and CRAF kinases with IC50 values of 3.2 and 5.0 nM. Other kinases (SIK1, NEK111 and LIMK1) can be inhibited by dabrafenib when administered in high concentrations" SIGNOR-259219 MEIS1 protein O00470 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR down-regulates 9606 BTO:0001271 19109563 f irozzo "To discern the mechanisms by which Meis1 inhibition leads to reduced cell growth, we performed cell-cycle and apoptosis analyses.Meis1 knockdown also resulted in increased apoptosis, as evidenced by increased uptake of PI and a stain for activated caspases (CaspaTag) by M26-transduced cells compared with control cells. These results indicate that Meis1 is required for proliferation and survival of 4166 leukemia cells." SIGNOR-255860 LHX3 protein Q9UBR4 UNIPROT FSHB protein P01225 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 23766128 f miannu "we also demonstrated that LHX3 bound with greater affinity to the wild-type human FSHB promoter compared with the -211 G/T mutation and that LHX3 binding was more effectively competed with excess wild-type oligonucleotide than with the SNP. Finally, we showed that FSHB transcription was decreased in gonadotrope cells with the -211 G/T mutation compared with the wild-type FSHB promoter." SIGNOR-254557 MAP4K1 protein Q92918 UNIPROT MAP3K11 protein Q16584 UNIPROT up-regulates phosphorylation Ser281 WHKTTQMsAAGTYAW 9606 11053428 t gcesareni "Hpk1 also phosphorylated mlk-3 activation loop in vitro, and ser281 was found to be the major phosphorylation site, indicating that hpk1 also activates mlk-3 via phosphorylation of the kinase activation loop." SIGNOR-83415 AML1-ETO "fusion protein" SIGNOR-FP1 SIGNOR "Core Binding Factor complex" complex SIGNOR-C214 SIGNOR "down-regulates activity" binding 9606 15829516 t irozzo "Two classes of models can describe how AML1-ETO could interfere with normal AML1 activity. First, because AML1-ETO has the potential to interact with AML1 co-factors (such as CBFβ) through its RD, it could act as a dominant-negative molecule by competing with AML1 for these co-factors. Although AML1-ETO has been shown to interact with CBFβ and repress the expression of AML1-regulated genes in vitro and in cell culture, the available data do not distinguish between these two models." SIGNOR-256100 JUN protein P05412 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 9878062 f lperfetto "Functional data suggest that c-Jun is not merely a target for activation by many of the extracellular stimuli, but that it plays a role in mediating the cellular response. In the case of growth control, three lines of evidence suggest that the transcription factor AP-1, which is composed of Fos–Jun and Jun–Jun dimers, mediates cell proliferation in response to external growth signals in the form of peptide growth factors." SIGNOR-233467 LATS2 protein Q9NRM7 UNIPROT WWTR1 protein Q9GZV5 UNIPROT down-regulates phosphorylation Ser89 AQHVRSHsSPASLQL 9606 22658639 t "Together the YAP/TAZ-TEAD complex promotes proliferative and survival programs." milica "In response to high cell densities, activated LATS1/2 phosphorylates the WW-domain containing transcriptional co-activators YAP at Ser127 and TAZ at Ser89, promoting 14-3-3 binding and thereby inhibiting their translocation into the nucleus." SIGNOR-197651 PDPK1 protein O15530 UNIPROT RPS6KA3 protein P51812 UNIPROT up-regulates phosphorylation Ser227 DHEKKAYsFCGTVEY 9606 10480933 t gcesareni "We characterize two monoclonal antibodies raised against phosphorylated forms of the n- and c-terminal domain of rsk2 (p-s227 and p-t577, respectively). Using these two antibodies, we show that stress signals, such as uv light, induce phosphorylation and activation of the three rsks." SIGNOR-70612 SOX6 protein P35712 UNIPROT CTNNB1 protein P35222 UNIPROT "down-regulates quantity by destabilization" binding 9606 BTO:0003298 26893351 t "In adipocytes, in addition to the direct regulation of PPARγ andC/EBP expression, we showed that SOX6 inhibitsWNT signaling by binding to β-catenin, potentially leading to its degradation" SIGNOR-255825 KDM2A protein Q9Y2K7 UNIPROT NfKb-p65/p50 complex SIGNOR-C13 SIGNOR down-regulates demethylation 9606 20080798 t lperfetto "Fbxl11 and nsd1 have opposite effects on nf-kb; both bind to p65 subunit after activation of nf-kb. / nsd1 activates nf-kb and reverses the inhibitory effect of fbxl11 / these data confirm that fbxl11 and nsd1 constitute an enzyme pair that methylates and demethylates p65 on k218 and 221 in response to cytokine stimulation." SIGNOR-217415 STAT1 protein P42224 UNIPROT STAT1 protein P42224 UNIPROT "up-regulates activity" binding 9606 19041276 t lperfetto "Each STAT1 monomer becomes tyrosine phosphorylated at tyrosine 701 by the JAKs, dissociates from the receptor to form a STAT1-STAT1 homodimer which translocates to the nucleus" SIGNOR-249495 MCM7 protein P33993 UNIPROT MCM complex SIGNOR-C268 SIGNOR "form complex" binding 9606 19946136 t "The Mcm2-7 complex serves as the eukaryotic replicative helicase, the molecular motor that both unwinds duplex DNA and powers fork progression during DNA replication." SIGNOR-261677 SPOP protein O43791 UNIPROT EGLN2 protein Q96KS0 UNIPROT "down-regulates quantity by destabilization" ubiquitination 9606 BTO:0001033 28089830 t lperfetto "Tumor suppressor SPOP ubiquitinates and degrades EglN2 to compromise growth of prostate cancer cells" SIGNOR-261996 PRKCH protein P24723 UNIPROT PRKD2 protein Q9BZL6 UNIPROT up-regulates phosphorylation Ser710 GEKSFRRsVVGTPAY 9606 12058027 t gcesareni "Thus, pkd2 is likely to be a novel downstream target of specific pkcs upon the stimulation of ags-b cells with gastrin. Our data suggest a two-step mechanism of activation of pkd2 via endogenously produced diacylglycerol and the activation of pkcs." SIGNOR-89427 CBFbeta-MYH11 "fusion protein" SIGNOR-FP3 SIGNOR TP53 protein P04637 UNIPROT "down-regulates activity" binding 10090 BTO:0002882 26387755 t "Here, we show that p53 activity is inhibited in inv(16)+ AML LSCs via interactions with the CBFβ-SMMHC (CM) fusion protein and histone deacetylase 8 (HDAC8).Altogether, these results indicate that CM fusion protein binds to p53 and impairs acetylation and activation of p53." SIGNOR-255737 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR HDAC6 protein Q9UBN7 UNIPROT up-regulates phosphorylation Thr1031 ASSTDHQtPPTSPVQ 9606 24089523 t lperfetto "Histone deacetylase 6 (hdac6) is well known for its ability to promote cell migrationextracellular signal-regulated kinase (erk) phosphorylates histone deacetylase 6 (hdac6) at serine 1035 to stimulate cell migrationwe have identified two novel erk-mediated phosphorylation sites: threonine 1031 and serine 1035 in hdac6. Both sites were phosphorylated by erk1" SIGNOR-244549 Netrin proteinfamily SIGNOR-PF97 SIGNOR DSCAM protein O60469 UNIPROT "up-regulates activity" binding 10090 BTO:0001279 18585357 t miannu "Here, we report that the Down's syndrome Cell Adhesion Molecule (DSCAM), a candidate gene implicated in the mental retardation phenotype of Down's syndrome, is expressed on spinal commissural axons, binds netrin-1, and is necessary for commissural axons to grow toward and across the midline. DSCAM and DCC can each mediate a turning response of these neurons to netrin-1." SIGNOR-268173 SLC12A6 protein Q9UHW9 UNIPROT chloride smallmolecule CHEBI:17996 ChEBI "down-regulates quantity" relocalization 21613606 t lperfetto "Eukaryotic cells regulate their volume in the long term through the coordinated function of the Na+-coupled chloride (NKCC1/2 and NCC) and K+-coupled chloride (KCC1–4) cotransporters, which encompass two branches of the SLC12|The K+-Cl− cotransporters move chloride outside the cell, are inhibited by phosphorylation, and are activated by dephosphorylation. In contrast, the Na+-K+-2Cl− cotransporters introduce chloride into the cell, are inhibited by dephosphorylation, and are activated by phosphorylation gene family of solute transporters (12). " SIGNOR-264638 FBXO33 protein Q7Z6M2 UNIPROT YBX1 protein P67809 UNIPROT "down-regulates quantity by destabilization" binding 9606 BTO:0000007 16797541 t miannu "Here we identify FBX33 as a component of an SCF E3-ubiquitin ligase that targets the multifunctional regulator Y-box binding protein 1 (YB-1)/dbpB/p50 for polyubiquitination and destruction by the proteasome. By targeting YB-1 for proteasomal degradation, FBX33 negatively interferes with YB-1 mediated functions.  FBX33 recruits Skp-1/Cul1 to YB-1" SIGNOR-271604 ROCK2 protein O75116 UNIPROT PPP1R12A protein O14974 UNIPROT "down-regulates activity" phosphorylation Thr853 PREKRRStGVSFWTQ -1 12220642 t lperfetto "Rho kinase is known to control smooth muscle contractility by phosphorylating the 110 kDa myosin-targetting subunit (MYPT1) of the myosin-associated form of protein phosphatase 1 (PP1M). Phosphorylation of MYPT1 at Thr695 has previously been reported to inhibit the catalytic activity of PP1. Here, we show that the phosphorylation of Thr850 by Rho kinase dissociates PP1M from myosin, providing a second mechanism by which myosin phosphatase activity is inhibited." SIGNOR-249164 N-(1,3-benzodioxol-5-ylmethyl)-4-(4-benzofuro[3,2-d]pyrimidinyl)-1-piperazinecarbothioamide chemical CHEBI:91389 ChEBI PDGFRA protein P16234 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-189528 SOCS4 protein Q8WXH5 UNIPROT DAB1 protein O75553 UNIPROT "down-regulates quantity by destabilization" binding 9534 BTO:0000298 24210661 t miannu "SOCS7 promotes Dab1 polyubiquitylation and degradation. SOCS7-CRL5 complexes stimulate the ubiquitylation and turnover of Dab1. SOCS7, a CRL5 substrate adaptor protein, is also required for neocortical layering. SOCS7-CRL5 complexes stimulate the ubiquitylation and turnover of Dab1." SIGNOR-272139 STUB1 protein Q9UNE7 UNIPROT SMAD5 protein Q99717 UNIPROT down-regulates ubiquitination 9606 22298955 t gcesareni "In ad-dition, some proteins (e.g. Chip, carboxyl terminus of hsc70-interacting protein) inhibit the signaling activi-ties of smad1/5 by recruiting smad1/5 from the functional r-/co-smad complex and further pro-moting the ubiquitination and degradation of smad1/5 in a chaperone-independent manne" SIGNOR-195690 EP300 protein Q09472 UNIPROT Differentiation phenotype SIGNOR-PH37 SIGNOR up-regulates 9606 20660310 f amattioni "Switch to beta-catenin/p300-mediated gene expression is an essential first step in initiating normal cellular differentiation" SIGNOR-229780 VHL protein P40337 UNIPROT TP53 protein P04637 UNIPROT "up-regulates quantity by stabilization" binding 9606 BTO:0000007 16678111 t "Here we found that pVHL directly associates with and stabilizes p53 by suppressing Mdm2-mediated ubiquitination and nuclear export of p53." SIGNOR-256594 Oxytocin protein P01178-PRO_0000020495 UNIPROT "GABA-A (a1-b1-g2) receptor" complex SIGNOR-C330 SIGNOR up-regulates 9606 33536967 f lperfetto "OT inhibits corticotropin-releasing factor (CRF) mRNA expression at the hypothalamus, resulting in antistress and anti-anxiety effects| It has been demonstrated that the inhibitory effect of OT on CRF mRNA expression is not a direct one on CRF neurons. GABAergic neurons are present in the surroundings of the PVN (peri-PVN). These GABA-projecting neurons into the PVN inhibits CRF expression via GABAA receptors" SIGNOR-268579 FADD protein Q13158 UNIPROT RIPK1 protein Q13546 UNIPROT "up-regulates activity" binding 9606 21525013 t lperfetto "Rip1 is required for the formation of a rip1/fadd/caspase-8 complex that drives caspase-8 activation, cleavage of bid into tbid, mitochondrial outer membrane permeabilization, full activation of caspase-3 and caspase-dependent apoptosis. Tweak induces assembly of a death-signaling complex containing rip1, fadd, and caspase-8" SIGNOR-173429 "CKM complex" complex SIGNOR-C406 SIGNOR SMAD1 protein Q15797 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser195 PNSSYPNsPGSSSST 9606 19914168 t lpetrilli "Phosphorylation of the linker region of smad1, a receptor-activated smad (r-smad), at serine 206 (s206) and s214 induced by bmp and mediated by cdk8/9 is critical for binding of the e3 ubiquitin ligase smurf1. Binding of smurf1 leads to polyubiquitination of smad1 and its degradation by the proteasome;cdk8 and cyclint-cdk9 showed a preference for s206 and s214 but also phosphorylated s186 and s195 in the case of smad1;and t179, s208 and s213 in the case of smad3." SIGNOR-273152 CAMKK1 protein Q8N5S9 UNIPROT AKT1 protein P31749 UNIPROT "up-regulates activity" phosphorylation Thr308 KDGATMKtFCGTPEY 10833263 t llicata "Protein kinase B (PKB) was recently reported to be activated on the phosphorylation of Thr(308) by Ca(2+)/calmodulin-dependent protein kinase kinase alpha (CaM-kinase kinase alpha), suggesting that PKB was regulated through not only the phosphoinositide 3-kinase pathway but also the Ca(2+)/calmodulin protein kinase pathway." SIGNOR-252609 NAB2 protein Q15742 UNIPROT EGR3 protein Q06889 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0000414 20506119 f miannu "Our results suggest that in many cells of neuroectodermal and epithelial origin EGR1, EGR2, and EGR3 activate NAB2 transcription which is in turn repressed by NAB2, thus establishing a negative feedback loop." SIGNOR-253887 LPAR2 protein Q9HBW0 UNIPROT GNAS protein Q5JWF2 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-256784 MYOD1 protein P15172 UNIPROT FST protein P19883 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 BTO:0000165 15130492 f lperfetto "MyoD, CREB, and NFAT Mediate the Transcriptional Activation of the Follistatin Promoter Induced by TSA" SIGNOR-251727 GOPC protein Q9HD26 UNIPROT BECN1 protein Q14457 UNIPROT up-regulates binding 9606 21311563 t gcesareni "Npist binds beclin 1 by a ccd" SIGNOR-171896 PTPN1 protein P18031 UNIPROT NTRK2 protein Q16620 UNIPROT "down-regulates activity" dephosphorylation Tyr707 DVYSTDYyRVGGHTM 9606 26214522 t Luana "Collectively, these data establish a direct enzyme-substrate interaction between PTP1B and phosphorylated Y705/706 (p-Y705/706) TRKB, the critical autophosphorylation sites that mediate BDNF-induced signaling.| Therefore, the data are consistent with a role of PTP1B as an inhibitor of BDNF/TRKB signaling" SIGNOR-264553 OS9 protein Q13438 UNIPROT TRPV4 protein Q9HBA0 UNIPROT "up-regulates quantity by stabilization" binding 9606 BTO:0000007 17932042 t miannu "Here we report that OS-9, a ubiquitously expressed endoplasmic reticulum (ER)-associated protein, interacts with the cytosolic N-terminal tail of TRPV4.Thus, OS-9 regulates the secretory transport of TRPV4 and appears to protect TRPV4 subunits from the precocious ubiquitination and ER-associated degradation. Our data suggest that OS-9 functions as an auxiliary protein for TRPV4 maturation." SIGNOR-261064 CDK1 protein P06493 UNIPROT ESPL1 protein Q14674 UNIPROT down-regulates phosphorylation Ser1126 IAPSTNSsPVLKTKP 9606 11747808 t lperfetto "Both cdc2/cyclinb1 and mapk (erk2) efficiently phosphorylate separase at its major inhibitory site in vitro" SIGNOR-113126 NPNT protein Q6UXI9 UNIPROT Myoblast_fusion phenotype SIGNOR-PH98 SIGNOR up-regulates 9606 23612709 f miannu "The MEK5-dependent activation of ERK5 promotes binding of the transcription factor SP1 to the promoter of the genes encoding the transcription factors Klf2 and Klf4, leading to their increased abundance. Subsequently, Klf2 and Klf4 bind to the Npnt promoter and induce the production of nephronectin during myoblast fusion" SIGNOR-255458 HES5 protein Q5TA89 UNIPROT ASCL1 protein P50553 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 10090 BTO:0000938 30030829 f lperfetto "The basic-helixloop-helix factors HES1 and HES5 repress the expression of the proneural genes (Ascl1, Atoh1, Neurog1 and Neurog2) and thereby inhibit NSCs differentiation and neuron production" SIGNOR-265147 BMPR2 protein Q13873 UNIPROT BMPR1B protein O00238 UNIPROT up-regulates binding 9606 10712517 t gcesareni "Using several complementary approaches, we investigated the formation of homomeric and heteromeric complexes between the two known bmp type i receptors (br-ia and br-ib) and the bmp type ii receptor (br-ii)." SIGNOR-75655 mTORC2 complex SIGNOR-C2 SIGNOR mTORC2 complex SIGNOR-C2 SIGNOR "up-regulates activity" phosphorylation 10090 BTO:0000944 20022946 t lperfetto "These data suggest that mTORC1- and likely mTORC2-associated mTOR Ser-2481 autophosphorylation directly monitors intrinsic mTORC-specific catalytic activity" SIGNOR-235484 "Papain-like proteinase" protein P0C6X7-PRO_0000037311 UNIPROT IRF3 protein Q14653 UNIPROT "down-regulates activity" deubiquitination 9606 25481026 t miannu "Here we show that PLpro also inhibits IRF3 activation at a step after phosphorylation and that this inhibition is dependent on the de-ubiquitination (DUB) activity of PLpro. We found that PLpro is able to block the type I IFN induction of a constitutively active IRF3, but does not inhibit IRF3 dimerization, nuclear localization or DNA binding. However, inhibition of PLpro’s DUB activity by mutagenesis blocked the IRF3 inhibition activity of PLpro, suggesting a role for IRF3 ubiquitination in induction of a type I IFN innate immune response." SIGNOR-260249 MAPK3 protein P27361 UNIPROT NR3C1 protein P04150 UNIPROT down-regulates phosphorylation Ser226 IDENCLLsPLAGEDD -1 9199329 t lperfetto "Cyclin-dependent kinase (CDK) and mitogen-activated protein kinase (MAPK) phosphorylate the rat glucocorticoid receptor in vitro at distinct sites that together correspond to the major phosphorylated receptor residues observed in vivo; MAPK phosphorylates receptor residues threonine 171 and serine 246, whereas multiple CDK complexes modify serines 224 and 232.|MAPKs and CDKs exert opposite effects on receptor transcriptional enhancement. From our results, we speculate that activators of the MAPK pathway, such as growth factors, insulin, and certain oncoproteins, or inhibitors of CDK function, such as tumor growth factor beta (TGF_), p21, and p27, might attenuate receptor-induced transcrip- tional responses. In contrast, negative regulators of MAPK, such as pKA, as well as activators of CDK, such as the cyclins or CAKs, should potentiate receptor action." SIGNOR-154409 HTR7 protein P34969 UNIPROT GNAI1 protein P63096 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257055 STK3 protein Q13188 UNIPROT RCC1 protein P18754 UNIPROT up-regulates phosphorylation Ser11 KRIAKRRsPPADAIP 9606 BTO:0000007 19559616 t miannu "MST2 Phosphorylates RCC1 In Vitro and In Vivo. Using an antibody generated against phospho-S2/11 in RCC1 [18], we found that these two residues were also efficiently phosphorylated by MST1 and MST2 (Figure 2D), further supporting that S2 and/or S11 are genuine MST2 phosphorylation targets." SIGNOR-263145 Ub:E2 complex SIGNOR-C497 SIGNOR TRIM47 protein Q96LD4 UNIPROT "up-regulates activity" ubiquitination 9606 34199813 t miannu "The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t" SIGNOR-271001 LRRK2 protein Q5S007 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates phosphorylation 9606 BTO:0000938 21658387 t lperfetto "Lrrk2 directly phosphorylates akt1 as a possible physiological substrate. These data establish that lrrk2 can protect neurons from apoptotic insult through a survival pathway in which lrrk2 signals to activate akt. Lrrk2-mediated phosphorylation of akt1 (ser473)" SIGNOR-244410 PLK1 protein P53350 UNIPROT BRCA2 protein P51587 UNIPROT unknown phosphorylation Thr207 TPPTLSStVLIVRNE 9606 BTO:0001938 12815053 t lperfetto "Plk1 interacts with BRCA2 in vivo, and mutation of Ser193, Ser205/206, and Thr203/207 to Ala in BR-N1 abolished Plk1 phosphorylation, suggesting that BRCA2 is the substrate of Plk1. Furthermore, both the hyperphosphorylated and hypophosphorylated forms of BRCA2 bind to RAD51, whereas the M phase hyperphosphorylated form of BRCA2 no longer associates with the P/CAF, suggesting that the dissociation of P/CAF-BRCA2 complex is regulated by phosphorylation." SIGNOR-249221 bosutinib chemical CHEBI:39112 ChEBI SRC protein P12931 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-190699 Crenolanib chemical CID:10366136 PUBCHEM PDGFRA protein P16234 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-191121 IKBKB protein O14920 UNIPROT NFKB1 protein P19838 UNIPROT "down-regulates activity" phosphorylation Ser932 CDSGVETsFRKLSFT 9606 BTO:0000007 SIGNOR-C13 11158290 t lperfetto "Ikkbeta phosphorylates p105 resulting in its degradation, which releases tpl2 resulting in activation of the pro-proliferative map kinase- pathway." SIGNOR-104811 ASXL1 protein Q8IXJ9 UNIPROT PPARG protein P37231 UNIPROT "down-regulates activity" binding 9606 21047783 t miannu "Our genome-wide analysis confirmed the physiological roles of ASXL1 and ASXL2 in adipogenesis at the molecular level, supporting the hypothesis that ASXL1 is an authentic corepressor of PPARγ, whereas ASXL2 is a PPARγ coactivator, and that together ASXL1 and ASXL2 fine-tune adipogenesis via differential regulation of PPARγ. " SIGNOR-260064 CPSF3 protein Q9UKF6 UNIPROT mRNA_polyadenylation phenotype SIGNOR-PH200 SIGNOR up-regulates 9606 30507380 f lperfetto "Replication-dependent (RD) core histone mRNA produced during S-phase is the only known metazoan protein-coding mRNA presenting a 3' stem-loop instead of the otherwise universal polyA tail. A metallo β-lactamase (MBL) fold enzyme, cleavage and polyadenylation specificity factor 73 (CPSF73), is proposed to be the sole endonuclease responsible for 3' end processing of both mRNA classes." SIGNOR-268337 HOXC6 protein P09630 UNIPROT S100B protein P04271 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0002253 17488478 t Luana "HOXC6 and HOXC11 increase transcription of S100beta gene in BrdU-induced in vitro differentiation of GOTO neuroblastoma cells into Schwannian cells." SIGNOR-261646 SMAD3/SMAD4 complex SIGNOR-C9 SIGNOR JUNB protein P17275 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 9694870 f lperfetto "Here we report the identification of Smad Binding Elements (SBEs) composed of the sequence CAGACA in the promoter of the JunB gene, an immediate early gene that is potently induced by TGF-beta, activin, and bone morphogenetic protein (BMP) 2. Two JunB SBEs are arranged as an inverted repeat that is transactivated in response to Smad3 and Smad4 co-overexpression and shows inducible binding of a Smad3- and Smad4-containing complex in nuclear extracts from TGF-beta-treated cells." SIGNOR-59476 MAP1LC3B protein Q9GZQ8 UNIPROT NBR1 protein Q14596 UNIPROT down-regulates binding 9606 BTO:0000007 19250911 t gcesareni "We performed glutathione s-transferase (gst) pull-down assays using extracts from hek293 cells overexpressing an ha-tagged nbr1(d50r) mutant, which lacks the ability to bind p62 (lamark et al., 2003) (figures s1a and s1b, available online), and gst fusions of six human atg8 homologs: gabarap, gabarapl1, gabarapl2, lc3a, lc3b, and lc3c. Indeed, nbr1 interacted with all these members of the mammalian atg8 protein family. downregulation of either lc3 or gabarap (or both) family members leads to stabilization and p62-dependent aggregation of nbr1." SIGNOR-184252 ITGB2 protein P05107 UNIPROT "AM/b2 integrin" complex SIGNOR-C170 SIGNOR "form complex" binding 16988024 t lperfetto "Integrins are one of the major families of cell adhesion receptors (Humphries, 2000; Hynes, 2002). All integrins are non-covalently-linked, heterodimeric molecules containing an α and a β subunit. Both subunits are type I transmembrane proteins, containing large extracellular domains and mostly short cytoplasmic domains (Springer and Wang, 2004; Arnaout et al., 2005). Mammalian genomes contain 18 α subunit and 8 β subunit genes, and to date 24 different α,β combinations have been identified at the protein level. Although some subunits only appear in a single heterodimer, twelve integrins contain the β1 subunit, and five contain αV." SIGNOR-253192 PLK4 protein O00444 UNIPROT NEDD1 protein Q8NHV4 UNIPROT "up-regulates activity" phosphorylation Ser325 PTTVNKRsVNVNAAS 33351100 t lperfetto "We found that PLK4-mediated phosphorylation of NEDD1 at its S325 amino acid residue directly promotes both NEDD1 binding to SAS-6 and recruiting SAS-6 to the centrosome. |Collectively, our results demonstrate that PLK4-regulated NEDD1 facilitates initiation of the cartwheel assembly and of daughter centriole biogenesis in mammals." SIGNOR-272996 "Ub:E1 (UBA1 substrate)" complex SIGNOR-C495 SIGNOR UBE2E1 protein P51965 UNIPROT "up-regulates activity" ubiquitination 9606 34199813 t miannu "The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t" SIGNOR-271325 ENDOG protein Q14249 UNIPROT BAX protein Q07812 UNIPROT up-regulates 9606 21210296 f gcesareni "Permeabilization of the outer mitochondrial membrane allows the leakage of at least five apoptotic mediators from the mitochondrial intermembrane space, such as cyt c, (diablo/diablo), htra2/omi, apoptosis-inducing factors (aif), and endonuclease g. Such modifications result in their activation and translocation to outer mitochondrial membrane (omm) which helps it to interact with multidomain pro-apototic members, bax/baklike proteins, leading to their oligomerization and formation of pore." SIGNOR-170972 CDK4 protein P11802 UNIPROT RB1 protein P06400 UNIPROT down-regulates phosphorylation Ser780 STRPPTLsPIPHIPR 9606 SIGNOR-C18 23336272 t gcesareni "Cyclin d1 is known to activate cdk4, which then phosphorylates the rb protein, leading to cell cycle progression." SIGNOR-200483 PRKAB2 protein O43741 UNIPROT AMPK complex SIGNOR-C15 SIGNOR "form complex" binding 9606 16054041 t gcesareni "Gamma non-catalytic subunit mediates binding to amp, adp and atp, leading to activate or inhibit ampk: amp-binding results in allosteric activation of alpha catalytic subunit (prkaa1 or prkaa2) both by inducing phosphorylation and preventing dephosphorylation of catalytic subunits." SIGNOR-139167 SP1 protein P08047 UNIPROT RLIM protein Q9NVW2 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 23650532 t lperfetto "Thus, RLIM is a novel target of p53, and p53 exerts its inhibitory effect on RLIM expression by interfering with Sp1-mediated transcriptional activation on RLIM.|Although p53 does not directly bind to the RLIM promoter, it physically interacts with and prevents the binding of Sp1 to the RLIM promoter." SIGNOR-268980 NOTCH proteinfamily SIGNOR-PF30 SIGNOR MAML3 protein Q96JK9 UNIPROT up-regulates binding 9606 12370315 t flangone "Genetic ablation or activation of the pathway reveals that Notch signalling promotes differentiation of the hair follicle, sebaceous gland and interfollicular epidermal lineages" SIGNOR-254346 PRPF19 protein Q9UMS4 UNIPROT RPA1 protein P27694 UNIPROT "up-regulates activity" polyubiquitination 9606 BTO:0000567 24332808 t miannu "PRP19 is a ubiquitin ligase involved in pre-mRNA splicing and the DNA damage response (DDR). PRP19 ubiquitylates RPA and promotes ATRIP recruitment." SIGNOR-272076 CSNK2B protein P67870 UNIPROT HOXB6 protein P17509 UNIPROT unknown phosphorylation Ser214 LLSASQLsAEEEEEK -1 10327653 t llicata "Using two-dimensional tryptic phosphopeptide mapping and purified protein kinases, we demonstrate that Hoxb-6 is phosphorylated in vitro by casein kinase II and cAMP-dependent protein kinase. The casein kinase II phosphorylation site was mapped to serine-214. " SIGNOR-251071 ABCA7 protein Q8IZY2 UNIPROT Phagocytosis phenotype SIGNOR-PH97 SIGNOR up-regulates 9606 27472885 f miannu "Together these results indicate that ABCA7 mediates phagocytic clearance of amyloid-β in the brain, and reveal a mechanism by which loss of function of ABCA7 increases the susceptibility to AD." SIGNOR-265175 MEF2C protein Q06413 UNIPROT CDKL5 protein O76039 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 20513142 f "Mutations in MEF2C from the 5q14.3q15 microdeletion syndrome region are a frequent cause of severe mental retardation and diminish MECP2 and CDKL5 expression|In these patients we found diminished MECP2 and CDKL5 expression in vivo, and transcriptional reporter assays indicated that MEF2C mutations diminish synergistic transactivation of E-box promoters including that of MECP2 and CDKL5." SIGNOR-254031 CDK1 protein P06493 UNIPROT RAD9A protein Q99638 UNIPROT "up-regulates activity" phosphorylation Ser336 PGPQPPKsPGPHSEE 9606 BTO:0000567 12734188 t lperfetto "Here we present evidence that thr292 of hrad9 is subject to cdc2-dependent phosphorylation in mitosis. Furthermore, our data are also consistent with four other hrad9 phosphorylation sites (ser277, ser328, ser336, and thr355) being regulated in part by cdc2. We also identify ser387 as a novel site of hrad9 constitutive phosphorylation and show that phosphorylation at ser387 is a prerequisite for one form of dna damage-induced hyperphosphorylation of hrad9." SIGNOR-101051 PIM1 protein P11309 UNIPROT MDM2 protein Q00987 UNIPROT "up-regulates quantity by stabilization" phosphorylation Ser166 SSRRRAIsETEENSD 9606 18467333 t gcesareni "Additionally, the pim kinases phosphorylate mdm2 in vitro and in cultured cells at ser166 and ser186, two previously identified targets of other signaling pathways, including akt." SIGNOR-178615 EXOSC10 protein Q01780 UNIPROT Exosome_Complex complex SIGNOR-C255 SIGNOR "form complex" binding -1 24189234 t miannu "The RNA exosome is an evolutionarily conserved multi-protein complex involved in the 3' degradation of a variety of RNA transcripts. In the nucleus, the exosome participates in the maturation of structured RNAs, in the surveillance of pre-mRNAs and in the decay of a variety of noncoding transcripts. In the cytoplasm, the exosome degrades mRNAs in constitutive and regulated turnover pathways. The eukaryotic exosome, however, is composed of nine different subunits that are still somewhat related in sequence to the archaeal Rrp41-like subunits (Rrp41, Rrp46 and Mtr3), the archaeal Rrp42-like subunits (Rrp45, Rrp43 and Rrp42) and the cap proteins (Rrp4, Csl4 and Rrp40)." SIGNOR-261390 PRKCZ protein Q05513 UNIPROT NCF1 protein P14598 UNIPROT up-regulates phosphorylation Ser303 RGAPPRRsSIRNAHS 9606 BTO:0000130 12056906 t lperfetto "Phosphopeptide mapping of p47(phox) showed that, as opposed to pkc zeta, pkc alpha, beta ii, and delta are able to phosphorylate all the major pkc sites. The use of p47(phox) mutants identified serines 303, 304, 315, 320, 328, 359, 370, and 379 as targets of pkc alpha, beta ii, and delta.Taken together, these results suggest that pkc alpha, beta ii, delta, and zeta expressed in human neutrophils can individually phosphorylate p47(phox) and induce both its translocation and nadph oxidase activation." SIGNOR-89252 MEF2D protein Q14814 UNIPROT MYF6 protein P23409 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 BTO:0000165;BTO:0000222 7739551 t lperfetto "Myogenin and MEF2 function synergistically to activate the MRF4 promoter during myogenesis." SIGNOR-238715 MAPK8 protein P45983 UNIPROT HNRNPK protein P61978 UNIPROT up-regulates phosphorylation Ser353 DSAIDTWsPSEWQMA 9606 11259409 t gcesareni "The current studies demonstrate the identification of hnrnp-k as a jnk and erk substrate. The phosphoacceptor sites for jnk and erk on the k protein are different, and indeed, erk phosphorylation results in biological consequences different from those of phosphorylation by jnk (49). Whereas erk phosphorylation on aa 284 and 353 contributes to k protein nuclear export and concomitant inhibition of rna translation (49), phosphorylation by k protein on aa 216 and 353 increases the transcriptional effects of the k protein." SIGNOR-105770 "Translation release factor ERF1-ERF3" complex SIGNOR-C494 SIGNOR "protein polypeptide chain" smallmolecule CHEBI:16541 ChEBI "up-regulates quantity" "chemical modification" 9606 29735640 t miannu "Termination of mRNA translation occurs when a stop codon enters the A site of the ribosome, and in eukaryotes is mediated by release factors eRF1 and eRF3, which form a ternary eRF1/eRF3–guanosine triphosphate (GTP) complex. eRF1 recognizes the stop codon, and after hydrolysis of GTP by eRF3, mediates release of the nascent peptide. " SIGNOR-270818 FFAR4 protein Q5NUL3 UNIPROT GNAQ protein P50148 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257371 RORA protein P35398 UNIPROT PCP4 protein P48539 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 BTO:0001011 19381306 t miannu "RORα regulates the expression of several genes in Purkinje cells. RORα becomes highly expressed in postmitotic Purkinje cells. It regulates their maturation, particularly dendritic differentiation. Dendritogenesis and the expression of several genes, including Shh, Itpr1, Pcp4, Calb1, Pcp2, and Slc1a6, normally expressed in mature Purkinje cells, are inhibited in RORα-deficient mice." SIGNOR-266848 PTPRG protein P23470 UNIPROT KDR protein P35968 UNIPROT "down-regulates activity" dephosphorylation Tyr1054 FGLARDIyKDPDYVR -1 25624455 t miannu "PTPRG activation by the P1-WD peptide affected the tyrosine phosphorylation of several signaling molecules. Data analysis identified 31 molecules whose phosphorylation was modified in a statistically significant manner (Table I). inhibition of ABL1, BMX, BTK, DAB1, ITGB1, JAK2, KDR, KIT, LIMK1, MET, PDGFRB, SHC1, and VCL correlates with tyrosine dephosphorylation. In contrast, SRC inhibition correlates with hyperphosphorylation of the inhibitory Tyr530 residue and with dephosphorylation of the activatory Tyr419. Moreover, CDK2 and CTTN inhibition correlates with a hyperphosphorylation of the inhibitory Tyr15 and Tyr470, respectively. In contrast, a subgroup of 13 proteins, including BLNK, DOK2, ERBB2, GRIN2B, INSR, PDGFRA, PRKCD, PXN, STAT1, STAT2, STAT3, STAT5A, and ZAP70, appears to be activated by PTPRG activity." SIGNOR-254707 MTR protein Q99707 UNIPROT methionine smallmolecule CHEBI:16811 ChEBI "up-regulates quantity" "chemical modification" 9606 10520212 t lperfetto "Methionine synthase is a vitamin B12-dependent enzyme that catalyses the remethylation of homocysteine to methionine. Therefore, defects in this enzyme may result in elevated homocysteine levels." SIGNOR-253143 clozapine chemical CHEBI:3766 ChEBI DRD2 protein P14416 UNIPROT "down-regulates activity" "chemical inhibition" 10029 BTO:0000246 1975644 t miannu "Molecular cloning and characterization of a novel dopamine receptor (D3) as a target for neuroleptics. A dopamine receptor has been characterized which differs in its pharmacology and signalling system from the D1 or D2 receptor and represents both an autoreceptor and a postsynaptic receptor. Table1. pharmacology of D2 and D3 receptors expressed in CHO cells." SIGNOR-258368 APC-c complex SIGNOR-C150 SIGNOR Mitotic_checkpoint phenotype SIGNOR-PH28 SIGNOR up-regulates 9606 25092294 f miannu "We then found that the joint action of TRIP13 and p31comet also promotes MCC disassembly, releases APC/C from checkpoint inhibition, and inactivates the mitotic checkpoint." SIGNOR-265978 USP9X protein Q93008 UNIPROT SMAD4 protein Q13485 UNIPROT up-regulates deubiquitination Lys519 DYPRQSIkETPCWIE 9606 19135894 t gcesareni "Smad4 is monoubiquitinated in lysine 519 in vivo, a modification that inhibits smad4 by impeding association with phospho-smad2. Fam reverts this negative modification, re-empowering smad4 function;control of smad4 is a good way to regulate bone formation. Fam and ectodermin/tif1gamma (ecto) were reported to respectively regulate the de-ubiquitination and ubiquitination of smad4." SIGNOR-183285 TAF5L protein O75529 UNIPROT "SAGA complex" complex SIGNOR-C465 SIGNOR "form complex" binding 9606 34811519 t lperfetto "Here we present the cryogenic-electron microscopy (cryo-EM) structure of human SAGA (hSAGA)|Human SAGA is a 20-subunit, 1.4-MDa complex with five functional modules (Fig. ​(Fig.1a):1a): a scaffolding core that includes TBP-associated factors (TAFs); a TRRAP (Transformation/Transcription domain Associated Protein) containing a phosphoinositide-3-kinase (PI3K)-related pseudoprotein kinase (ΨPIKK); a histone acetyltransferase (HAT); a deubiquitinase (DUB) and a metazoan-specific splicing (SPL) module" SIGNOR-269586 GABRG2 protein P18507 UNIPROT "GABA-A (a6-b1-g2) receptor" complex SIGNOR-C334 SIGNOR "form complex" binding 9606 BTO:0000227 18790874 t "brain, See table 3 for identified complexes" lperfetto "The assembly of GABAA-R as heteropentamers produces complex subtype heterogeneity in structure, which is the major determinant of their pharmacological profile.|Evidence is greatly in favor of a pentameric receptor and most GABAA-R subtypes are formed from two copies of a single alpha, two copies of a single beta, and one copy of another subunit, such as gamma, delta, or epsilon." SIGNOR-263764 9-(1-Methyl-4-pyrazolyl)-1-[1-(1-oxoprop-2-enyl)-2,3-dihydroindol-6-yl]-2-benzo[h][1,6]naphthyridinone chemical CID:71748056 PUBCHEM TEC protein P42680 UNIPROT "down-regulates activity" "chemical inhibition" -1 24556163 t miannu "This analysis revealed that QL47 also potently inhibits BMX with an IC50 of 6.7 nM but impressively displays more than 100-fold selectivity against EGFR, HER2, JAK3, BLK, TEC, and ITK that possess an equivalently placed cysteine" SIGNOR-262235 tRNA(Cys) smallmolecule CHEBI:29167 ChEBI Cys-tRNA(Cys) smallmolecule CHEBI:29152 ChEBI "up-regulates quantity" "precursor of" 9606 11347887 t miannu "Cysteinyl-tRNA synthetase catalyzes the addition of cysteine to its cognate tRNA. Here we report the isolation of a fulllength cDNA that encodes a protein of 748 amino acids. The predicted protein sequence shows considerable similarity to other eukaryotic cysteinyltRNA synthetases in the carboxylterminus. Expression of the fulllength and alternative forms of the enzyme in E. coli generated functional proteins that were active in aminoacylation of human cytoplasmic tRNA with cysteine." SIGNOR-270475 DLL3 protein Q9NYJ7 UNIPROT NOTCH1 protein P46531 UNIPROT "up-regulates activity" binding 9606 BTO:0000776 16140393 t lperfetto "Notch signaling is a highly conserved pathway involved in cell fate choice during development with Delta and Jagged constituting the two evolutionary conserved families of Notch ligands. These ligands are transmembrane proteins with conserved biochemical structure that share their receptors and signal through a common mechanism. Upon ligand binding Notch receptors are proteoliticaly cleaved, the intracellular domain of Notch (NICD) is released and translocated to the nucleus, where it activates target genes. In mammals, four receptors and five ligands have been described. Delta-1, Delta-3 and Delta-4 are homologues to Drosophila Delta and Jagged-1 and Jagged-2 to Drosophila Serrate." SIGNOR-209738 ERN1 protein O75460 UNIPROT JUN protein P05412 UNIPROT up-regulates 9606 BTO:0001976 18065414 f lperfetto "The induction of MTHFR was also observed after overexpression of inositol-requiring enzyme-1 (IRE1) and was inhibited by a dominant-negative mutant of IRE1. Because IRE1 triggers c-Jun signaling, we examined the possible involvement of c-Jun in up-regulation of MTHFR. Transfection of c-Jun and two activators of c-Jun (LiCl and sodium valproate) increased MTHFR expression" SIGNOR-253146 AURKB protein Q96GD4 UNIPROT GFAP protein P14136 UNIPROT "down-regulates activity" phosphorylation Ser38 LGPGTRLsLARMPPP -1 12686604 t lperfetto "We report here that aurora-b phosphorylates gfap and desmin in vitro, and this phosphorylation leads to a reduction in filament forming ability. The sites phosphorylated by aurora-b;thr-7/ser-13/ser-38 of gfap, and thr-16 of desmin are common with those related to rho-associated kinase (rho-kinase), which has been reported to phosphorylate gfap and desmin at cleavage furrow during cytokinesis. We identified ser-59 of desmin to be a specific site phosphorylated by aurora-b in vitro." SIGNOR-100169 "Cullin 1-RBX1-Skp1" complex SIGNOR-C529 SIGNOR CRY2 protein Q49AN0 UNIPROT "down-regulates quantity by destabilization" polyubiquitination 9606 BTO:0000007 17463251 t miannu " We found that both Cry1 and Cry2 proteins are ubiquitinated and degraded via the SCF(Fbxl3) ubiquitin ligase complex. This regulation by SCF(Fbxl3) is a prerequisite for the efficient and timely reactivation of Clock-Bmal1 and the consequent expression of Per1 and Per2, two regulators of the circadian clock that display tumor suppressor activity. HEK293T cells were transfected with Cry2, Skp1, Cul1, and Roc1 in the absence or presence of either FLAG-tagged Fbxl3 or a FLAG-tagged Fbxl3(ΔF-box) mutant. Fbxl3, but not an inactive Fbxl3(ΔF-box) mutant (4), induced the ubiquitination of Cry2 (Fig. 2D), which supports the notion that the effect of Fbxl3 on Cry2 is direct." SIGNOR-271650 Ub:E2 complex SIGNOR-C497 SIGNOR HECW1 protein Q76N89 UNIPROT "up-regulates activity" ubiquitination 9606 34199813 t miannu "The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t" SIGNOR-271302 CENPH protein Q9H3R5 UNIPROT "CCAN complex" complex SIGNOR-C365 SIGNOR "form complex" binding 9606 BTO:0000567 18007590 t lperfetto "CENP-A NAC/CAD components have been subdivided into either NAC proteins (nucleosome-associated complex; CENP-C, CENP-H, CENP-50CENP−U, CENP-M, CENP-T and Chl4RCENP−N) or CAD proteins (CENP-A Distal; CENP-I, Mcm21RCENP−O, Fta1RCENP−L, Sim4RCENP−K, CENP-P, CENP-Q, CENP-R and CENP-S)." SIGNOR-265198 STK11 protein Q15831 UNIPROT MARK2 protein Q7KZI7 UNIPROT up-regulates phosphorylation Thr208 TFGNKLDtFCGSPPY 9606 14976552 t lperfetto "Lkb1 is a master kinase that activates 13 kinases of the ampk subfamily, including mark/par-1we recently demonstrated that the lkb1 tumour suppressor kinase, in complex with the pseudokinase strad and the scaffolding protein mo25, phosphorylates and activates amp-activated protein kinase (ampk). A total of 12 human kinases (nuak1, nuak2, brsk1, brsk2, qik, qsk, sik, mark1, mark2, mark3, mark4 and melk) are related to ampk. Here we demonstrate that lkb1 can phosphorylate the t-loop of all the members of this subfamily, apart from melk, increasing their activity >50-fold" SIGNOR-122628 "Multiaminoacyl-tRNA synthetase" complex SIGNOR-C472 SIGNOR diphosphate(3-) smallmolecule CHEBI:33019 ChEBI "up-regulates quantity" "chemical modification" 9606 28271488 t miannu "Aminoacyl-tRNA synthetases (AARSs) are essential enzymes that specifically aminoacylate one tRNA molecule by the cognate amino acid. In mammals, nine synthetases, those specific for amino acids Arg, Asp, Gln, Glu, Ile, Leu, Lys, Met and Pro, associate into a multi-aminoacyl-tRNA synthetase complex, an association which is believed to play a key role in the cellular organization of translation, but also in the regulation of the translational and nontranslational functions of these enzymes." SIGNOR-270415 ADRA1B protein P35368 UNIPROT GNA14 protein O95837 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257190 "Nucleosome_H3.3 variant" complex SIGNOR-C339 SIGNOR Chromatine_condensation phenotype SIGNOR-PH21 SIGNOR up-regulates 9606 15776021 f miannu "Variant histone H3.3 is incorporated into nucleosomes by a mechanism that does not require DNA replication and has also been implicated as a potential mediator of epigenetic memory of active transcriptional states." SIGNOR-263878 WDR48 protein Q8TAF3 UNIPROT USP1 protein O94782 UNIPROT "up-regulates activity" binding 9606 BTO:0000567 18082604 t lperfetto "In vitro reconstitution of USP1 deubiquitinating enzyme activity, using either ubiquitin-7-amido-4-methylcoumarin (Ub-AMC) or purified monoubiquitinated FANCD2 protein as substrates, demonstrates that UAF1 functions as an activator of USP1. UAF1 binding increases the catalytic turnover (kcat) but does not increase the affinity of the USP1 enzyme for the substrate (KM)." SIGNOR-263274 FOXA1 protein P55317 UNIPROT HSPA1B protein P0DMV9 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000093 19486887 f miannu "The results showed overexpression of Foxa1 promoted the expression of HSP72, while Foxa1 depletion, induced by antisense oligonucleotides, decreased the expression of HSP72 in MCF-7 cells under normal and heat stress condition." SIGNOR-254165 PBRM1 protein Q86U86 UNIPROT S100A13 protein Q99584 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000562 15601824 f miannu "We found that baf180 deficiency leads to a decreased expression of select target genes, such as s100a13 and ra targets rar_2 and crabpii in heart tissues." SIGNOR-132431 lofepramine chemical CHEBI:47782 ChEBI SLC6A2 protein P23975 UNIPROT "down-regulates activity" "chemical inhibition" 9606 BTO:0000007 9537821 t miannu "At the human norepinephrine transporter, among the antidepressants desipramine was the most potent with a KD=0.83±0.05 nM. All the tetracyclic antidepressants, except mirtazapine, which is a structural analog of mianserin, were more potent at the norepinephrine transporter than at the serotonin transporter. Tomoxetine, considered from animal data to be very selective for the norepinephrine transporter, had high affinity for the human norepinephrine transporter (KD=2.03±0.06 nM). However, at the human serotonin transporter, tomoxetine was nearly as potent and close to that for dothiepin and venlafaxine. Venlafaxine, considered a serotonin and norepinephrine re-uptake inhibitor based on animal data, was very weak at the human norepinephrine transporter. Its KD value was 5× less that than for norepinephrine. All of the serotonin selective re-uptake inhibitors, with the exception of paroxetine, were also weak at the human norepinephrine transporter. " SIGNOR-258881 RLF protein Q13129 UNIPROT RIT1 protein Q92963 UNIPROT "up-regulates activity" binding 9606 10545207 t miannu "Rit and Rin were found to interact with the known Ras binding proteins RalGDS, Rlf, and AF-6/Canoe. These interactions were GTP and effector domain dependent and suggest that RalGDS, Rlf, and AF-6 are Rit and Rin effectors." SIGNOR-220799 INO80B protein Q9C086 UNIPROT "INO80 complex" complex SIGNOR-C498 SIGNOR "form complex" binding 9606 25016522 t miannu "Here, we have systematically investigated the involvement of the catalytic subunit of the human INO80 complex during unchallenged replication and under replication stress by following the effects of its depletion on cell survival, S-phase checkpoint activation, the fate of individual replication forks, and the consequences of fork collapse. We report that INO80 was specifically needed for efficient replication elongation, while it was not required for initiation of replication." SIGNOR-270846 ATM protein Q13315 UNIPROT RAD17 protein O75943 UNIPROT unknown phosphorylation Ser646 ETWSLPLsQNSASEL 9606 10608806 t lperfetto "We determined a general phosphorylation consensus sequence for atm and identified putative in vitro targets by using glutathione s-transferase peptides as substrates. Putative atm in vitro targets include p95/nibrin, mre11, brca1, rad17, pts, wrn, and atm (s440) itself." SIGNOR-73520 EGR1 protein P18146 UNIPROT COL10A1 protein Q03692 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 21931594 f Regulation miannu "Egr-1 induced a time-dependent ECM gene expression program, with the number of ECM genes increasing >2.5-fold (from 16 to 41) between 24 and 48 h. Genes in this group include those coding for multiple collagens (COL4A1, COL4A2, COL11A1, COL7A1, COL10A1)" SIGNOR-251921 GATA1 protein P15976 UNIPROT FLI1 protein Q01543 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 10523830 f irozzo "Our results suggest that Spi-1 and GATA-1 might play a key role in the regulation of Fli-1. Most notably, we observed that the GATA/EBS dual element near the Fli-1 CAP sites had an enhancer activity in HEL cells. Spi-1 and GATA-1 were both found to bind to this sequence and hence both factors could represent potential regulators of Fli-1 expression." SIGNOR-256053 TNK2 protein Q07912 UNIPROT SNX9 protein Q9Y5X1 UNIPROT up-regulates phosphorylation 9606 16316319 t gcesareni "We have previously shown that sh3px1, phosphorylated by ack2 (activated cdc42-associated tyrosine kinase 2), regulates the degradation of egf (epidermal growth factor) receptor." SIGNOR-142569 p38 proteinfamily SIGNOR-PF16 SIGNOR NFATC4 protein Q14934 UNIPROT down-regulates phosphorylation Ser168 QGGGAFFsPSPGSSS 9606 11997522 t lperfetto "Phosphorylation of nfatc4 by p38 mitogen-activated protein kinasesthe p38 map kinase phosphorylates multiple residues, including ser(168) and ser(170), in the nfat homology domain of nfatc4. Replacement of ser(168,170) with ala promotes nuclear localization of nfatc4 and increases nfat-mediated transcription activity." SIGNOR-87393 CPSF6 protein Q16630 UNIPROT "CFI complex" complex SIGNOR-C388 SIGNOR "form complex" binding 9606 BTO:0000567 8626397 t lperfetto "We report here the purification of CF Im from HeLa cell nuclear extracts. Three polypeptides of 68, 59, and 25 kDa copurified with CF Im activity." SIGNOR-266123 SRF protein P11831 UNIPROT SERPINE1 protein P05121 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0000161 15514113 f miannu "We previously demonstrated that serum response factor (SRF), a critical smooth muscle transcription factor, is highly expressed in LAM cells. Here we show that a high SRF level alters the plasminogen (Plg) system. Specifically, overexpression of SRF in human lung fibroblasts upregulated urokinase-type plasminogen activator (uPA) and its substrate Plg, whereas it downregulated plasminogen activator inhibitor (PAI)-1." SIGNOR-255228 URB597 chemical CID:1383884 PUBCHEM FAAH protein O00519 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-207615 glutaryl-CoA(5-) smallmolecule CHEBI:57378 ChEBI "coenzyme A(4-)" smallmolecule CHEBI:57287 ChEBI "up-regulates quantity" "precursor of" 33148467 t lperfetto "The acyl-CoA thioesterase (ACOT) family catalyses the hydrolysis of acyl-CoA thioesters to their corresponding non-esterified fatty acid and coenzyme A (CoA)." SIGNOR-271812 TBX2 protein Q13207 UNIPROT MYOG protein P15173 UNIPROT "down-regulates activity" binding 9606 24470334 t "We have found that TBX2 is highly up regulated in both ERMS and ARMS subtypes of RMS and demonstrate that TBX2 is a repressor of myogenesis by binding to MyoD and myogenin and inhibiting their activity." SIGNOR-251561 Ub:E2 complex SIGNOR-C497 SIGNOR DZIP3 protein Q86Y13 UNIPROT "up-regulates activity" ubiquitination 9606 34199813 t miannu "The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t" SIGNOR-271191 MRE11 protein P49959 UNIPROT PIH1D1 protein Q9NWS0 UNIPROT "up-regulates activity" binding 9606 phosphorylation:Ser688;Ser689;Ser561;Ser558 SKGVDFEsSEDDDDD;KGVDFESsEDDDDDP;MANDSDDsISAATNK;AEQMANDsDDSISAA 28436950 t miannu "Here we show that MRE11 directly interacts with PIH1D1, a subunit of heat-shock protein 90 cochaperone R2TP complex, which is required for the assembly of large protein complexes, such as RNA polymerase II, small nucleolar ribonucleoproteins and mammalian target of rapamycin complex 1. The MRE11-PIH1D1 interaction is dependent on casein kinase 2 (CK2) phosphorylation of two acidic sequences within the MRE11 C terminus containing serines 558/561 and 688/689." SIGNOR-265898 RALA protein P11233 UNIPROT FOXO4 protein P98177 UNIPROT "up-regulates activity" phosphorylation Thr455 ALGTPVLtPPTEAAS 10090 11689711 t gcesareni "We conclude that Ral-mediated phosphorylation of threonines 447 and 451 is required for proper activity of AFX-WT." SIGNOR-249665 RPS6KB1 protein P23443 UNIPROT IRS1 protein P35568 UNIPROT "down-regulates activity" phosphorylation Ser639 YMPMSPKsVSAPQQI 10090 15306821 t lperfetto "Nevertheless, s6k1-deficient mice remain sensitive to insulin owing to the apparent loss of a negative feedback loop from s6k1 to insulin receptor substrate 1 (irs1), which blunts s307 and s636/s639 phosphorylation; thus under conditions of nutrient satiation s6k1 negatively regulatesinsulin." SIGNOR-127203 NFATC2 protein Q13469 UNIPROT MYOG protein P15173 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 18676376 f gcesareni "€ provide a novel transcriptional paradigm for the first steps of myogenesis, where a calcineurin/NFATc3 pathway regulates myogenin induction in cooperation with MyoD during myogenesis." SIGNOR-235006 (R)-noradrenaline smallmolecule CHEBI:18357 ChEBI ADRA2A protein P08913 UNIPROT "up-regulates activity" "chemical activation" 9606 BTO:0002524 31160049 t "Ligand-GPCR dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257453 GSK3B protein P49841 UNIPROT MACF1 protein Q9UPN3 UNIPROT "down-regulates activity" phosphorylation Ser7310 ADPKKSAsRPGSRAG 9606 BTO:0004905 21295697 t lperfetto "We discovered that GSK3β, a kinase inhibited by Wnt signaling, directly phosphorylates ACF7, a > 500 kDa microtubule-actin crosslinking protein abundant in hair follicle stem cells (HF-SCs). We map ACF7's GSK3β sites to the microtubule-binding domain and show that phosphorylation uncouples ACF7 from microtubules." SIGNOR-264430 "1-[2-[(diphenylmethylene)amino]oxyethyl]-3,6-dihydro-2H-pyridine-5-carboxylic acid" chemical CHEBI:92744 ChEBI SLC6A1 protein P30531 UNIPROT "down-regulates activity" "chemical inhibition" -1 7851497 t miannu "Recently, a number of lipophilic GABA transport inhibitors have been designed and synthesized, which are capable of crossing the blood brain barrier, and which display anticonvulsive activity. We have now determined the potency of four of these compounds, SK&F 89976-A (N-(4,4-diphenyl-3-butenyl)-3-piperidinecarboxylic acid), tiagabine ((R)-1-[4,4-bis(3-methyl-2-thienyl)-3-butenyl]-3- piperidencarboxylic acid), CI-966 ([1-[2-[bis 4-(trifluoromethyl)phenyl]methoxy]ethyl]-1,2,5,6-tetrahydro-3- pyridinecarboxylic acid), and NNC-711 (1-(2-(((diphenylmethylene)amino)oxy)ethyl)-1,2,4,6-tetrahydro-3- pyridinecarboxylic acid hydrochloride), at each of the four cloned GABA transporters, and find them to be highly selective for GAT-1." SIGNOR-258479 "sorafenib tosylate" chemical CHEBI:50928 ChEBI RET protein P07949 UNIPROT "down-regulates activity" "chemical inhibition" -1 16757355 t miannu "Further characterization of sorafenib revealed that this molecule was a multikinase inhibitor that targeted the vascular endothelial growth factor receptor family (VEGFR-2 and VEGFR-3) and platelet-derived growth factor receptor family (PDGFR-beta and Kit), which play key roles in tumor progression and angiogenesis. The in vitro and cellular profile of sorafenib is summarized in Table I." SIGNOR-259229 SMURF2 protein Q9HAU4 UNIPROT BMPR1A protein P36894 UNIPROT down-regulates ubiquitination 9606 22298955 t gcesareni "Smurf1 and smurf2 are e3 ubiquitin ligases known to suppress tgf-beta signaling through degra-dation of smads and receptors for tgf-beta and bmps" SIGNOR-192898 L-glutamate(1-) smallmolecule CHEBI:29985 ChEBI 2-oxoglutarate(2-) smallmolecule CHEBI:16810 ChEBI "up-regulates quantity" "precursor of" 9606 11863375 t miannu "Alanine aminotransferase (ALT) catalyzes the reversible transamination between alanine and 2-oxoglutarate to form pyruvate and glutamate, and thereby has a key role in the intermediary metabolism of glucose and amino acids. Two ALT isoenzymes are known to exist, but only one ALT gene has been cloned, GPT. In this study, we cloned a homolog of GPT and named it GPT2, and the corresponding protein ALT2" SIGNOR-266924 AMPK complex SIGNOR-C15 SIGNOR CCNY protein Q8ND76 UNIPROT "up-regulates activity" phosphorylation Ser326 SARKRSAsADNLTLP 9606 32723157 t lperfetto "Our in vitro and cellular analyses supported the mass spectrometry data that implicated serine 326 (S326) as the phospho-acceptor site on CCNY by AMPK. |Mechanistically the S326 phosphorylation by AMPK promotes the interaction of CCNY with CDK16, which in turn autophosphorylates S336, which serves as a marker for active CCNY-CDK16" SIGNOR-273001 mifepristone chemical CHEBI:50692 ChEBI NR1I2 protein O75469 UNIPROT "up-regulates activity" "chemical activation" 9534 BTO:0000318 9727070 t miannu "As shown in Fig. 4 A, hPXR was activated by the synthetic steroids dexamethasone, dexamethasone-t-butylacetate, PCN, RU486, spironolactone, and cyproterone-acetate. Dexamethasone-t-butylacetate and RU486 were the most efficacious activators of hPXR among the synthetic steroids tested." SIGNOR-258829 CyclinE1/CDK3 complex SIGNOR-C546 SIGNOR LIN9 protein Q5TKA1 UNIPROT "up-regulates activity" phosphorylation Thr96 KFTATMStPDKKASQ 9606 BTO:0002181 24475316 t lperfetto "In this report, we demonstrate that cyclin e1/cdk3 phosphorylates lin-9 on thr-96. Mutating thr-96 to alanine inhibits activation of cyclins a2 and b1 promoters, whereas a phosphomimetic asp mutant strongly activates their promoters and triggers accelerated entry into g2/m phase in 293t cells." SIGNOR-273184 CHRM4 protein P08173 UNIPROT GNAI1 protein P63096 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-256686 DOCK7 protein Q96N67 UNIPROT CDC42 protein P60953 UNIPROT "up-regulates activity" "guanine nucleotide exchange factor" 10090 BTO:0000132 29187380 t lperfetto "As a GEF, Dock7 exchanges GDP for GTP on Cdc42 and Rac1, causing their activation, followed by activation of downstream effectors, including the dephosphorylation (activation) of cofilin, a key regulator of actin turnover." SIGNOR-261886 CAMK2A protein Q9UQM7 UNIPROT EGFR protein P00533 UNIPROT "down-regulates activity" phosphorylation Ser1120 QPLNPAPsRDPHYQD 9606 BTO:0000007 10347170 t llicata " We show that serines 1046/1047 are sites for CaM kinase II phosphorylation, although there is a preference for serine 1047, which resides within the consensus -R-X-X-S-. In addition, we have identified major phosphorylation sites at serine 1142 and serine 1057, which lie within a novel -S-X-D- consensus. Mutation of serines 1046/1047 in full-length EGFR enhanced both fibroblast transformation and tyrosine autokinase activity that was significantly potentiated by additional mutation of serines 1057 and 1142. A single CaM kinase II site was also identified at serine 744 within sub-kinase domain III, and autokinase activity was significantly affected by mutation of this serine to an aspartic acid making this site appear constitutively phosphorylated. We have addressed the mechanism by which CaM kinase II phosphorylation of the EGFR might regulate receptor autokinase activity and show that this modification can hinder association of the cytoplasmic tail with the kinase domain to prevent an enzyme-substrate interaction. " SIGNOR-250623 "AP-2/clathrin vescicle" complex SIGNOR-C249 SIGNOR Endocytosis phenotype SIGNOR-PH123 SIGNOR up-regulates 24130457 f lperfetto "AP-2 is the core-organizing element in clathrin-mediated endocytosis. During the formation of clathrin-coated vesicles, clathrin and endocytic accessory proteins interact with AP-2 in a temporally and spatially controlled manner" SIGNOR-260705 CHD4 protein Q14839 UNIPROT CD79A protein P11912 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 10090 BTO:0000776 23071088 f lperfetto "However, NuRD complexes greatly reduce activation of the B cell-specific mb-1 (Cd79a) gene by the transcription factors EBF1 and Pax5|We conclude that repressive functions of MBD2-containing NuRD complexes are dependent on cooperative interactions between the major domains of CHD4 with histones and DNA and on binding of methylated DNA by MBD2." SIGNOR-254090 tacedinaline chemical CHEBI:90195 ChEBI HDAC1 protein Q13547 UNIPROT "down-regulates activity" "chemical inhibition" -1 20139990 t Luana "Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1)." SIGNOR-258009 AKT proteinfamily SIGNOR-PF24 SIGNOR PFKFB2 protein O60825 UNIPROT unknown phosphorylation Ser483 IRRPRNYsVGSRPLK 9606 BTO:0000567 12853467 t "14-3-3s bind directly to cardiac PFK-2 phosphorylated by PKB. PFK-2 was phosphorylated on both Ser466 and Ser483 by PKB. the precise mechanism of fru-2,6-P2 regulation by 14-3-3s is still puzzling." SIGNOR-251485 REN protein P00797 UNIPROT ATP6AP2 protein O75787 UNIPROT up-regulates binding 9606 BTO:0000887;BTO:0000142;BTO:0000671;BTO:0001260 12045255 t gcesareni "We report the expression cloning of the human renin receptor complementary dna encoding a 350-amino acid protein with a single transmembrane domain and no homology with any known membrane protein. Transfected cells stably expressing the receptor showed renin- and prorenin-specific binding. The binding of renin induced a fourfold increase of the catalytic efficiency of angiotensinogen conversion to angiotensin i and induced an intracellular signal with phosphorylation of serine and tyrosine residues associated to an activation of map kinases erk1 and erk2" SIGNOR-88416 JUN protein P05412 UNIPROT CFI protein P05156 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 10630630 f miannu "The production of CFI by Hep G2 cells was enhanced in a dose- and time-dependent fashion by 12-O-tetradecanoyl-1,2-phorbol 13-acetate (TPA), a potent PKC activator. The enhancement of the activity of transfected chimeric CAT constructs by TPA was abrogated by calphostin C and by pyrrolidine dithiocarbamate (an inhibitor of NF-kappaB and AP-1 transactivation). These results indicate that TPA regulation of CFI gene requires PKC signalling and is mediated by via a TPA response element (TRE) in the CFI promoter region located at -136/-130 and involves the transactivation of AP-1 and NF-kappaB transcription factors" SIGNOR-254787 PPP1R8 protein Q12972 UNIPROT PP1 proteinfamily SIGNOR-PF54 SIGNOR "down-regulates activity" binding -1 1322907 t lperfetto "We have purified two of these nuclear inhibitors of PP-1 (NIPP-1a and NIPP-1b) until homogeneity." SIGNOR-264673 EP300 protein Q09472 UNIPROT SMAD1 protein Q15797 UNIPROT up-regulates binding 9606 SIGNOR-C6 12419246 t gcesareni "Thus, Ski/SnoN represses TGFβ signaling by multiple mechanisms. In addition to recruitment of a transcriptional repressor complex and dissociation of the transcriptional coactivator p300/CBP from the Smads" SIGNOR-95462 5-aza-2'-deoxycytidine chemical CHEBI:50131 ChEBI DNMT1 protein P26358 UNIPROT "down-regulates activity" "chemical inhibition" 9606 14585280 t miannu "Both Azacitidine and Decitabine may also exert antitumor activity through induction of DNA hypomethylation, by forming a covalent complex with the major DNA methyltransferase (now termed DNMT1).Azacitidine and Decitabine effectively deplete the cell of functional DNA methylating activity, which results in profound hypomethylation after several rounds of DNA replication (Fig. 2). DNMT1 is considered a bona fide anticancer target at different levels" SIGNOR-259294 MCU_MICU2_variant complex SIGNOR-C502 SIGNOR calcium(2+) smallmolecule CHEBI:29108 ChEBI "up-regulates quantity" relocalization 9606 32315830 t miannu "MCU is a Ca2+-selective channel that mediates mitochondrial Ca2+ influx. The human channel contains tetrameric pore-forming MCU, regulatory subunits MICU1/2, and EMRE that is required both for channel function and MICU1/2-mediated Ca2+ regulation." SIGNOR-270878 PTPN12 protein Q05209 UNIPROT SHC1 protein P29353 UNIPROT down-regulates dephosphorylation Tyr349 EEPPDHQyYNDFPGK 9606 8939605 t gcesareni "The shc adaptor protein is highly phosphorylated at conserved, twin tyrosine residues (y239/240) that mediate protein-protein interactions." SIGNOR-44361 PRKCZ protein Q05513 UNIPROT NCF1 protein P14598 UNIPROT up-regulates phosphorylation Ser328 QDAYRRNsVRFLQQR 9606 BTO:0000130 12056906 t lperfetto "Phosphopeptide mapping of p47(phox) showed that, as opposed to pkc zeta, pkc alpha, beta ii, and delta are able to phosphorylate all the major pkc sites. The use of p47(phox) mutants identified serines 303, 304, 315, 320, 328, 359, 370, and 379 as targets of pkc alpha, beta ii, and delta.Taken together, these results suggest that pkc alpha, beta ii, delta, and zeta expressed in human neutrophils can individually phosphorylate p47(phox) and induce both its translocation and nadph oxidase activation." SIGNOR-89272 LUBAC complex SIGNOR-C527 SIGNOR TRAF1 protein Q13077 UNIPROT "up-regulates activity" polyubiquitination 9606 BTO:0002748 25996949 t miannu "LUBAC attaches M1-pUb chains to LMP1/TRAF1 complexes, which recruits the IKK complex.we found that LMP1 TES1 domain signaling induced an association between TRAF1 and the linear ubiquitin chain assembly complex (LUBAC), and stimulated linear (M1)-linked polyubiquitin chain attachment to TRAF1 complexes." SIGNOR-272435 CDK9 protein P50750 UNIPROT TP53 protein P04637 UNIPROT "up-regulates quantity by stabilization" phosphorylation Ser392 FKTEGPDsD 9606 23603988 t gcesareni "We recently demonstrated that through their physical interaction, cdk9 phosphorylates p53 on ser-392, leading to p53 stability and accumulation" SIGNOR-201931 CALM3 protein P0DP25 UNIPROT GEM protein P55040 UNIPROT "up-regulates activity" binding 10116 BTO:0001009 14701738 t miannu "Inhibition of voltage-gated calcium channels by Gem requires GTP and calmodulin binding, but not phosphorylation of serine 261 or 289. Calmodulin binding in the C-terminal extension of Gem is required for maximal inhibition of HVA Ca2+ channels by ectopically expressed Gem, as determined by measurement of electrical activity in primary neurons and by Ca2+-evoked secretion in PC12 cells." SIGNOR-266341 GLI3 protein P10071 UNIPROT MED12 protein Q93074 UNIPROT down-regulates binding 9606 17000779 t gcesareni "We propose that activated gli3 physically targets med12 in mediator to reverse mediator-dependent suppression of shh target gene (i.e., Gli1 or cyclin d1) transcription." SIGNOR-149876 NOXO1 protein Q8NFA2 UNIPROT NOXA1 protein Q86UR1 UNIPROT "up-regulates activity" relocalization 9606 BTO:0000007 20943948 t lperfetto "Tks4 and Tks5 bind NoxA1 through their SH3 domains in a Rac-independent manner|NoxO1 is required for full Nox1 and Nox3 oxidase activity at least partially because of its role in the plasma membrane recruitment of the NoxA1 activator protein|Tks4 and Tks5 support Nox1- and Nox3-dependent ROS generation" SIGNOR-264709 N2,N4-Dibenzylquinazoline-2,4-diamine chemical CID:676352 PUBCHEM VCP protein P55072 UNIPROT "down-regulates activity" "chemical inhibition" -1 21383145 t Monia "DBeQ (1) is a reversible and selective inhibitor of p97" SIGNOR-261100 VRK1 protein Q99986 UNIPROT JUN protein P05412 UNIPROT up-regulates phosphorylation Ser73 VGLLKLAsPELERLI 9606 15378002 t flangone "Vrk1 phosphorylates c-jun in ser63 and ser73 in vitro...VRK1 Activates c-jun dependent transcription" SIGNOR-127073 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR JAK2 protein O60674 UNIPROT down-regulates phosphorylation Ser523 GVSDVPTsPTLQRPT 9534 BTO:0004055 16705159 t "16705160:the phosphorylation of Jak2 on Ser523 inhibits Jak2 activity and represents a novel mechanism for the regulation of Jak2-dependent cytokine signaling." lperfetto "We hypothesize that phosphorylation of ser523 in jak2 by erks 1 and/or 2 or other as-yet-unidentified kinases acts in a negative feedback manner" SIGNOR-244553 PPP3CA protein Q08209 UNIPROT NFATC3 protein Q12968 UNIPROT up-regulates dephosphorylation 9606 21880741 t gcesareni "Calcineurin directly dephosphorylates nfat resulting in the nuclear import of nfat." SIGNOR-176376 NR0B2 protein Q15466 UNIPROT ESRRG protein P62508 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 11705994 f gcesareni "The current study also demonstrates that shp inhibits err_ transactivation." SIGNOR-111620 CAMK1G protein Q96NX5 UNIPROT EIF4G3 protein O43432 UNIPROT up-regulates phosphorylation Ser1156 NTFMRGGsSKDLLDN 9606 22514323 t lperfetto "Here we report that activity-dependent translational initiation in cultured rat hippocampal neurons is enhanced by camki-mediated phosphorylation of ser1156 in eukaryotic initiation factor eif4gii (4gii)." SIGNOR-197149 KRT14 protein P02533 UNIPROT TRADD protein Q15628 UNIPROT "down-regulates activity" binding 9606 11684708 t "Regulation of binding" miannu "TRADD specifically bound K18 and K14, type I (acidic) keratins. it is possible that epidermal K14 may function as an inhibitor of TNF–TNFR1 signaling through an association with TRADD." SIGNOR-251907 ATM protein Q13315 UNIPROT ATM protein Q13315 UNIPROT "up-regulates activity" phosphorylation Ser1893 PANLDSEsEHFFRCC 9606 21149446 t gcesareni "In human cells, the activation process involves autophosphorylation on three sites (ser367, ser1893, and ser1981) and acetylation on lys3016. We now describe the identification of a new atm phosphorylation site, thr(p)1885 and an additional autophosphorylation site, ser(p)2996, that is highly dna damage-inducible." SIGNOR-170465 FOXO3 protein O43524 UNIPROT GALT protein P07902 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 BTO:0000975 17975019 f miannu "Our finding that FOXO3 regulates the expression of Galt and enhances its transcriptional activity indicates that it is the repression of FOXO3 by PRL acting through RS that prevents Galt expression in the ovary and causes follicular death." SIGNOR-254186 EGFR protein P00533 UNIPROT VAV2 protein P52735 UNIPROT up-regulates phosphorylation Tyr172 EDGGDDIyEDIIKVE 9606 12454019 t miannu "To understand the mechanism of egf-dependent vav2 activation, we examined first the egf-dependent phosphorylation sites on vav2 and the nature of interaction of vav2 with the activated egf receptor. Based on our in vitro and in vivo data all three tyrosine residues (142, 159, and 172) in the n-terminal domain of vav2 can be phosphorylated by the egf receptor." SIGNOR-95980 GXYLT2 protein A0PJZ3 UNIPROT NOTCH proteinfamily SIGNOR-PF30 SIGNOR up-regulates binding 9606 22117070 t "Xylosylation in ER membrane." gcesareni "Recently, we have shown (28) that two members of the human glycosyltransferase 8 family (gt8) (29), gxylt1 and gxylt2 (glucoside-xylosyltransferase 1/2), are able to transfer the first alfa1,3-linked xylose to o-glucosylated mammalian notch egf repeats." SIGNOR-254314 CSNK2A2 protein P19784 UNIPROT AQP4 protein P55087 UNIPROT "down-regulates activity" phosphorylation Ser276 AAQQTKGsYMEVEDN 9615 BTO:0000837 11742978 t llicata "We found that the stress-induced kinase casein kinase (CK)II phosphorylates the Ser276 immediately preceding the tyrosine motif, increasing AQP4-mu 3A interaction and enhancing AQP4-lysosomal targeting and degradation. | To determine whether Ser276 is an actual CKII substrate, we used GST–AQP4‐Cter proteins in which only one out of the three C‐terminal CKII consensus sites was sequentially conserved (Ser276, Ser285 and Ser315, respectively). Figure 7B (right panel) shows that the three serine residues, including Ser276, were indeed efficiently phosphorylated by CKII." SIGNOR-250974 KMT2A protein Q03164 UNIPROT RUNX1 protein Q01196 UNIPROT "up-regulates quantity by stabilization" binding 9606 23817177 t irozzo "RUNX1 wild-type protein first binds to the PU.1 URE region and recruits the MLL complex to open up part of the compact chromatin structure. The partially relaxed chromatin allows the binding of another RUNX1 at the PU.1 promoter region to further distort compact DNA structure. The relaxed form of chromatin facilitates the accumulation of transcription factors and cofactors to initiate transcriptional activity." SIGNOR-255708 JAK1 protein P23458 UNIPROT STAT1 protein P42224 UNIPROT up-regulates phosphorylation 9606 21576360 t "When IFN-γ binds to its receptor, the receptor-associated protein tyrosine kinases Janus kinase I (JAK1) and JAK2 are activated (37). This leads to the phosphorylation of STAT1, which then dimerizes, translocates to the nucleus, and activates its target promoters, including the pIV promoter of Ciita" SIGNOR-256247 CUL3 protein Q13618 UNIPROT LZTR1 protein Q8N653 UNIPROT "up-regulates activity" binding 9606 BTO:0000007 31337872 t Gianni "Leucine zipper-like transcriptional regulator 1 (LZTR1) encodes a member of the BTB-Kelch superfamily, which interacts with the Cullin3 (CUL3)-based E3 ubiquitin ligase complex." SIGNOR-269070 CTDNEP1 protein O95476 UNIPROT LPIN1 protein Q14693 UNIPROT "up-regulates activity" dephosphorylation Ser106 IPMHLATsPILSEGA 9606 BTO:0001131 17420445 t "Dullard significantly dephosphorylates mouse lipin 1b only in BHK cells (Fig. 5A). This is most clearly seen by using the antibody prepared against the phosphorylation site Ser-106.|Dephosphorylation of lipin results in its translocation to the nuclear envelope and endoplasmic reticulum membranes from the cytosol and generation of diacylglycerol" SIGNOR-248346 MYF6 protein P23409 UNIPROT Skeletal_muscle_differentiation phenotype SIGNOR-PH1 SIGNOR "up-regulates activity" BTO:0001103 7532173 f "Simone Vumbaca" "Finally, MRF4 may be responsible for the final myogenic events of the fully differentiated myofiber" SIGNOR-255645 NR1D1 protein P20393 UNIPROT Adipogenesis phenotype SIGNOR-PH26 SIGNOR up-regulates 10090 BTO:0000011 12821652 f miannu "Mutations of the 5' or 3' half-sites of the response element totally abrogated PPARgamma binding and transcriptional activation, identifying this site as a novel type of functional PPARgamma response element. Finally, ectopic expression of Rev-Erbalpha in 3T3-L1 preadipocytes potentiated adipocyte differentiation induced by the PPARgamma ligand rosiglitazone. These results identify Rev-Erbalpha as a target gene of PPARgamma in adipose tissue and demonstrate a role for this nuclear receptor as a promoter of adipocyte differentiation." SIGNOR-268023 ELANE protein P08246 UNIPROT F5 protein P12259 UNIPROT "up-regulates activity" cleavage Ile1512 KEFNPLViVGLSKDG -1 9242537 t lperfetto "Human neutrophil elastase activates human factor V but inactivates thrombin-activated human factor V|NH2-terminal sequence analysis of F.V treated with HNE indicated cleavage at Ile819 and Ile1484 under conditions during which the procofactor expressed enhanced cofactor activity in the prothrombinase complex." SIGNOR-263633 PTPRJ protein Q12913 UNIPROT INSR protein P06213 UNIPROT down-regulates dephosphorylation Tyr999 YASSNPEyLSASDVF 9606 1715686 t gcesareni "Dephosphorylation of autophosphorylated insulin and epidermal-growth-factor receptors by two major subtypes of protein-tyrosine-phosphatase from human placenta." SIGNOR-21307 HNRNPU protein Q00839 UNIPROT GADD45A protein P24522 UNIPROT "up-regulates quantity by stabilization" "post transcriptional regulation" 17174306 f lperfetto "In the present study, we show that hnRNP-U specifically enhances the expression of tumor necrosis factor alpha mRNA by increasing its stability, possibly through binding to the 3' untranslated region. We also show that hnRNP-U enhances the expression of several other genes as well, including GADD45A, HEXIM1, HOXA2, IER3, NHLH2, and ZFY, by binding to and stabilizing these mRNAs." SIGNOR-262282 C3 protein P01024 UNIPROT "C3 convertase complex (C3bBb)" complex SIGNOR-C314 SIGNOR "form complex" binding 9606 BTO:0000089 cleavage:Arg748 ASHLGLArSNLDEDI 26489954 t "complement C3b fragment: PRO_0000005911" lperfetto "Surface‐associated C3b recruits FB, which leads to FB activation and the formation of C3bBb, the AP C3 convertase, which cleaves more C3 and amplifies complement activation. In addition to the surface‐bound C3 convertase, a fluid‐phase convertase can be formed by association of water‐reacted C3, termed C3(H20), to FB thus constantly maintaining a low level of complement activation in solution (tick‐over)" SIGNOR-263485 GNG12 protein Q9UBI6 UNIPROT PRKACA protein P17612 UNIPROT down-regulates binding 9606 17251915 t gcesareni "As pka suppresses the activity of gli, smo might use the stimulation of pi3k by galfai and gbetagamma subu- nits to block pka in cells that have high levels of camp." SIGNOR-152615 FLT3 protein P36888 UNIPROT FZD4 protein Q9ULV1 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 BTO:0002882 15650056 f "AML-typical Flt3 mutations induce the expression of Frizzled-4 on the mRNA and protein level, mimicking the effects of IL-3." SIGNOR-261533 NPC complex SIGNOR-C263 SIGNOR Nuclear_pore_function phenotype SIGNOR-PH130 SIGNOR up-regulates 9606 BTO:0000007 9660920 f miannu "Exportin-t Is Predominantly Nuclear, Binds NPCs, and Shuttles Rapidly between Nucleus and Cytoplasm. RanGTP appears to have at least two functions in this complex. First, it stabilizes the tRNA/exportin-t interaction (see Figure 4B). Second, exportin-t apparently has to bind RanGTP for rapid exit from the nucleus . RanGTP causing a conformational change in exportin-t, which increases the affinity for export sites at the NPC. Exportin-t probably makes a direct contact to the NPC and accounts for the interactions that drive translocation of the tRNA/exportin-t/RanGTP complex out of the nucleus." SIGNOR-261395 PRKCD protein Q05655 UNIPROT CXCR4 protein P61073 UNIPROT "down-regulates activity" phosphorylation Ser324 LTSVSRGsSLKILSK 9606 10521508 t Manara "Therefore, internalization of CXCR4 in response to PMA appears to be mediated by activation of protein kinase C | However, mutation of the dileucine motif or the serines at positions 324, 325, 338, and 339 profoundly decreased internalization." SIGNOR-260898 RYBP protein Q8N488 UNIPROT ABL1 protein P00519 UNIPROT down-regulates binding 9606 8943360 t gcesareni "We identified a novel protein, aap1 (abl-associated protein 1), that associates with these c-abl domains and fails to bind to the sh3 domain in the activated oncoprotein bcrabl. we conclude that aap1 inhibits c-abl tyrosine kinase activity" SIGNOR-45325 MAPK1 protein P28482 UNIPROT MKNK2 protein Q9HBH9 UNIPROT up-regulates phosphorylation 9606 9155017 t gcesareni "We have identified a new subfamily of murine serine/threonine kinases, whose members, map kinase-interacting kinase 1 (mnk1) and mnk2, bind tightly to the growth factor-regulated map kinases, erk1 and erk2erk and p38 phosphorylate mnk1 and mnk2, which stimulates their in vitro kinase activity" SIGNOR-48338 EIF4EBP1 protein Q13541 UNIPROT EIF4E protein P06730 UNIPROT "down-regulates activity" binding 9606 23584478 t lperfetto "The rate-limiting factor for translation is eukaryotic translation initiation factor 4E (eIF4E), which is negatively regulated by eIF4E-binding protein 1 (4E-BP1)." SIGNOR-167176 CSF2RA/CSF2RB complex SIGNOR-C212 SIGNOR PI3K complex SIGNOR-C156 SIGNOR "up-regulates activity" phosphorylation 9606 BTO:0000876 BTO:0001103 19436055 t miannu "As a consequence of Jak2 activation and tyrosine phosphorylation of the cytoplasmic tail of Œ≤c, Src homology 2 and phosphotyrosine binding domain proteins are recruited to the active receptor and initiate the major tyrosine phosphorylation-dependent signaling pathways, including the Jak/signal transducer and activator of transcription, Ras/mitogen-activated protein kinase, and phosphatidylinositol 3 (PI-3) kinase pathways" SIGNOR-255585 UBE3A protein Q05086 UNIPROT PSMD7 protein P51665 UNIPROT "down-regulates quantity by destabilization" ubiquitination 9606 BTO:0000007 28559284 t lperfetto "Our experiments collectively suggest that UBE3A stimulates Wnt pathway activation by interacting with, ubiquitinating, and reducing the levels of multiple (PSMB1, PSMC2, PSMD2, and PSMD7) proteasome subunits." SIGNOR-265134 DDX3X protein O00571 UNIPROT PABPC1 protein P11940 UNIPROT "up-regulates activity" binding 9606 21883093 t miannu "In the present study, we indentified the SG marker PABP1 [poly(A)-binding protein 1] as another direct interaction partner of DDX3. Interestingly, down-regulation of DDX3 interfered with SG assembly, led to nuclear accumulation of PABP1 and reduced cell viability following stress. Conversely, supplementation with a shRNA (short hairpin RNA)-resistant DDX3 restored SG formation, the translocation of PABP1 into SGs and cell survival." SIGNOR-269194 PCDHA2 protein Q9Y5H9 UNIPROT PCDHGA8 protein Q9Y5G5 UNIPROT "up-regulates activity" binding 9606 BTO:0000227 16697637 t miannu "The clustered protocadherins comprise the largest subfamily of the cadherin superfamily and are predominantly expressed in the nervous system. Pcdh-alpha proteins interact with beta1-integrin to promote cell adhesion. They also form oligomers with Pcdh-gamma proteins at the same membrane sites." SIGNOR-265680 FGF18 protein O76093 UNIPROT FGFR2 protein P21802 UNIPROT up-regulates binding 9606 8663044 t tpavlidou "Fgfs bind and activate high-affinity receptor tyrosine kinases. The cloning of fgf receptors (fgfrs) has identified four distinct genes" SIGNOR-42368 PPP4C protein P60510 UNIPROT BANF1 protein O75531 UNIPROT up-regulates dephosphorylation Ser4 sQKHRDFV 9606 24265311 t lperfetto "Herein, we demonstrate we demonstrate that phosphorylation of ser4 and/or thr2/thr3 abrogates the interaction of baf with dna and reduces its interaction with the lem domain. We have identified the major phosphatase responsible for dephosphorylation of ser-4 to be protein phosphatase 4 catalytic subunit." SIGNOR-203281 AT9283 chemical CID:11696609 PUBCHEM JAK3 protein P52333 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-190020 PRKCZ protein Q05513 UNIPROT HABP4 protein Q5JVS0 UNIPROT "down-regulates activity" phosphorylation Thr375 GRGARGGtRGGRGRI 9606 BTO:0004974 14699138 t lperfetto "We found a strong phosphorylation of Ki-1/57 by PKCalphabeta, PKCdelta, PKClambda/zeta, and especially by PKCsigma, however not by PKCmi. These data show that Ki-1/57 can serve in principal as a substrate for a wide variety of different PKC isoforms but also that its phosphorylation is strongest with PKCsigma. | This suggests that the two threonine residues present in this fragment (Thr354 and Thr375) might be the main target residues for phosphorylation by PKC in vitro. | Ki-1/57 Exits the Nucleus upon PMA Activation" SIGNOR-249257 ARNT protein P27540 UNIPROT JUN protein P05412 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0000599 21544813 f lperfetto "Screening by quantitative reverse-transcription PCR and PCR arrays revealed that cyclin E1, CDK2, Fos and Jun were negatively regulated by ARNT, whereas CDKN1C, CNKN2A, CDKN2B, MAPK11 and MAPK14 were positively regulated in HCC" SIGNOR-253697 CDK5 protein Q00535 UNIPROT HTR6 protein P50406 UNIPROT "down-regulates activity" phosphorylation Ser350 ERQASLAsPSLRTSH 10090 BTO:0000942 32047117 t lperfetto "Cdk5 phosphorylates the 5-HT6R on serine 350 (Ser350)|This suggests that the 5-HT6R is unable to interact with GPRIN1 when it is phosphorylated by Cdk5." SIGNOR-264407 MLLT11 protein Q13015 UNIPROT Differentiation phenotype SIGNOR-PH37 SIGNOR up-regulates 10090 BTO:0003295 21715312 f irozzo "Our results indicate that AF1q cooperates with the Notch signaling pathway to foster the emergence of BM prothymocytes and drive subsequent intrathymic specification toward the T-cell lineage." SIGNOR-259201 ELOVL5 protein Q9NYP7 UNIPROT palmitoyl-CoA smallmolecule CHEBI:15525 ChEBI "down-regulates quantity" "chemical modification" 9606 31616255 t miannu "The ELOVL family of enzymes in mammals is comprised of seven members that all reside in the endoplasmic reticulum (ER) and are thought to form a multimeric complex. Together, the ELOVL family is responsible for the elongation of saturated and unsaturated fatty acids.Fatty acid elongation occurs by cycling through a four step process (condensation, reduction, dehydration, and reduction), with two carbon atoms added through each cycle." SIGNOR-267891 POMC protein P01189 UNIPROT OPRK1 protein P41145 UNIPROT "up-regulates activity" "chemical activation" 10029 BTO:0000246 9686407 t miannu "Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors." SIGNOR-258410 EGR1 protein P18146 UNIPROT Monocyte_differentiation phenotype SIGNOR-PH101 SIGNOR up-regulates 9606 BTO:0001412 1864967 f irozzo "Finally, we demonstrate that dexamethasone, an inhibitor of monocytic differentiation, blocks the associated increases in EGR-1 and EGR-2 expression. Taken together, the results indicate that the EGR-1 and EGR-2 early response genes are involved in the induction of myeloid leukemia cell differentiation along the monocytic lineage and in the activation of human monocytes." SIGNOR-256088 CDK1 protein P06493 UNIPROT KIF11 protein P52732 UNIPROT up-regulates phosphorylation Thr926 LDIPTGTtPQRKSYL 9606 9235942 t lperfetto "The kinesin-related motor hseg5 is essential for centrosome separation, and its association with centrosomes appears to be regulated by phosphorylation of tail residue threonine 927 by the p34(cdc2) protein kinase.Phosphorylation also enhanced the specific binding of p150(glued) to the tail domain of hseg5 in vitro" SIGNOR-50169 BMAL1/NPAS2 complex SIGNOR-C431 SIGNOR CRY1 protein Q16526 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 20817722 t miannu "The mammalian clock is regulated at the cellular level by a transcriptional/translational feedback loop. BMAL1/clock (or NPAS2) heterodimers activate the expression of the period (PER) and cryptochrome (CRY) genes acting as transcription factors directed to the PER and CRY promoters via E-box elements." SIGNOR-267967 TMLHE protein Q9NVH6 UNIPROT 2-oxoglutarate(2-) smallmolecule CHEBI:16810 ChEBI "down-regulates quantity" "chemical modification" 9606 11431483 t miannu "Epsilon-N-Trimethyllysine hydroxylase (EC ) is the first enzyme in the biosynthetic pathway of l-carnitine and catalyzes the formation of beta-hydroxy-N-epsilon-trimethyllysine from epsilon-N-trimethyllysine, a reaction dependent on alpha-ketoglutarate, Fe(2+), and oxygen." SIGNOR-269682 CTBP1 protein Q13363 UNIPROT CDKN2A protein P42771 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 23303449 f irozzo "Our findings suggest an important role of CtBP1 in the transcriptional control of p16INK4a and Brca1[.]. Additionally, the inhibitor of cyclin-dependent protein kinases (CDKs), p16INK4a, whose loss has been related to the pathogenesis of melanoma, was repressed by CtBP1 as well." SIGNOR-259195 Ub:E2 complex SIGNOR-C497 SIGNOR RNF44 protein Q7L0R7 UNIPROT "up-regulates activity" ubiquitination 9606 34199813 t miannu "The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t" SIGNOR-271180 TAOK2 protein Q9UL54 UNIPROT MAP2K6 protein P52564 UNIPROT "up-regulates activity" binding 9606 10497253 t lperfetto "Cotransfection experiments suggested that tao2 selectively activates mek3 and mek6 but not meks 1, 4, or 7." SIGNOR-70950 1-[2-chloro-4-[(6,7-dimethoxy-4-quinolinyl)oxy]phenyl]-3-(5-methyl-3-isoxazolyl)urea chemical CHEBI:91327 ChEBI FLT1 protein P17948 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-207296 ARHGAP22 protein Q7Z5H3 UNIPROT CDC42 protein P60953 UNIPROT "down-regulates activity" "gtpase-activating protein" 9606 BTO:0000007 32203420 t Luana "We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2)." SIGNOR-260478 GLI1 protein P08151 UNIPROT HHIP protein Q96QV1 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 BTO:0002572 16571352 f lperfetto "Primary mouse embryonic fibroblasts responded to Shh stimulation with the induction of Hh target genes Gli1, Ptc1, and Hip1.These observations support the previously advanced notion of a functional redundancy or cooperativity between Gli2 and Gli1 in activation of target genes [18] and [43] and indicate a functional cooperation between Gli3 and Gli1." SIGNOR-209623 DUSP3 protein P51452 UNIPROT ERBB2 protein P04626 UNIPROT "down-regulates activity" dephosphorylation Tyr877 LDIDETEyHADGGKV 9606 BTO:0002552 21262974 t "Expression of VHR inhibited the activation of phospholipase Cγ and protein kinase C, both downstream effectors of Tyr-992 phosphorylation of EGFR. | We found that VHR decreased ErbB2 phosphorylation in vitro and in a cellular context, and the dephosphorylation of ErbB2 was more evident at Tyr-877 and Tyr-1221 than those at Tyr-1139 and Tyr-1248 (supplemental Fig. S1). Our data indicated that VHR was a cellular PTP against EGFR and ErbB2." SIGNOR-248533 CDK8 protein P49336 UNIPROT SMAD3 protein P84022 UNIPROT "down-regulates activity" phosphorylation Ser208 DAGSPNLsPNPMSPA 9606 19914161 t lpetrilli "Similarly, tgf-?-Induced and cdk8/9-mediated phosphorylation of smad3 at threonine 179 (t179) is important for binding of the nedd4l e3 ubiquitin ligase, which accelerates smad3 turnover;cdk8 and cyclint-cdk9 showed a preference for s206 and s214 but also phosphorylated s186 and s195 in the case of smad1;and t179, s208 and s213 in the case of smad3." SIGNOR-161553 RPS6KA1 protein Q15418 UNIPROT H3-3A protein P84243 UNIPROT "down-regulates activity" phosphorylation Ser11 TKQTARKsTGGKAPR 9606 14625384 t "Ser 11 phosphorylation of H3 is either activatory and inhibitory as promotes DNA condensation (activatory) and induce transcription (inhibitory)." gcesareni "Phosphorylation at ser-11 (h3s10ph) by rps6ka4 and rps6ka5 is important during interphase because it enables the transcription of genes following external stimulation, like mitogens, stress, growth factors or uv irradiation and result in the activation of genes, such as c-fos and c-jun." SIGNOR-119221 AMPK complex SIGNOR-C15 SIGNOR SLC12A1 protein Q13621 UNIPROT "up-regulates activity" phosphorylation Ser122 YRNTGSIsGPKVNRP 10090 BTO:0003946 17341212 t miannu "In the present study, we demonstrate that the metabolic sensing kinase AMPK (AMP-activated protein kinase) phosphorylates NKCC2 on Ser126 in vitro. Activation of AMPK in the MMDD1 (mouse macula densa-derived 1) cell line resulted in an increase in Ser126 phosphorylation in situ, suggesting that AMPK may phosphorylate NKCC2 in vivo. The functional significance of Ser126 phosphorylation was examined by mutating the serine residue to an alanine residue resulting in a marked reduction in co-transporter activity when exogenously expressed in Xenopus laevis oocytes under isotonic conditions." SIGNOR-263103 MAPK1 protein P28482 UNIPROT FOXO3 protein O43524 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser425 TKGSGLGsPTSSFNS 9606 18204439 t lperfetto "Here, we show that erk downregulates forkhead box o 3a (foxo3a) by directly interacting with and phosphorylating foxo3a at ser 294, ser 344 and ser 425, which consequently promotes cell proliferation and tumorigenesisMDM2 is required for ERk-mediated FOXO3a degradation." SIGNOR-160415 PRKCA protein P17252 UNIPROT GMFB protein P60983 UNIPROT unknown phosphorylation Ser53 DEELEGIsPDELKDE -1 9030586 t lperfetto "Using synthetic peptide fragments containing putative phosphorylation sites of GMF, we demonstrate that PKA is capable of phosphorylating threonine 26 and serine 82, whereas PKC, p90 ribosomal S6 kinase, and casein kinase II, can phosphorylate serine 71, threonine 26, and serine 52, respectively." SIGNOR-248960 FGF2 protein P09038 UNIPROT ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR up-regulates 9606 20974802 f "inferred from 70% of family members" gcesareni "We show that several proline-directed mitogen-activated protein kinases (mapks), such as p38, erk1/2, and jnk1 are sufficient and required for the phosphorylation of ppps/tp motifs of lrp6. External stimuli, which control the activity of mapks, such as phorbol esters and fibroblast growth factor 2 (fgf2) control the choice of the lrp6-ppps/tp kinase and regulate the amplitude of lrp6 phosphorylation and wnt/beta-catenin-dependent transcription." SIGNOR-269929 SRC protein P12931 UNIPROT CDKN1B protein P46527 UNIPROT down-regulates phosphorylation Tyr88 KGSLPEFyYRPPRPP 9606 BTO:0000150 17254967 t lperfetto "Src regulates p27 stability through phosphorylation of p27 at tyrosine 74 and tyrosine 88. Our data indicate that phosphorylation by src impairs the cdk2 inhibitory action of p27" SIGNOR-152835 IRF7 protein Q92985 UNIPROT IFNA1 protein P01562 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 16612387 f gcesareni "Ikkalfa can also phosphorylate and activate interferon regulatory factor-7 (irf7), which is required for interferon-alfa (ifnalfa) production." SIGNOR-146119 PRKAA1 protein Q13131 UNIPROT CCNY protein Q8ND76 UNIPROT "up-regulates activity" phosphorylation Ser326 SARKRSAsADNLTLP 32723157 t lperfetto "Our in vitro and cellular analyses supported the mass spectrometry data that implicated serine 326 (S326) as the phospho-acceptor site on CCNY by AMPK. |Mechanistically the S326 phosphorylation by AMPK promotes the interaction of CCNY with CDK16, which in turn autophosphorylates S336, which serves as a marker for active CCNY-CDK16" SIGNOR-273011 OTUD5 protein Q96G74 UNIPROT TRAF3 protein Q13114 UNIPROT "down-regulates activity" deubiquitination 9606 BTO:0000007 17991829 t miannu "TRAF3 is an E3 ubiquitin ligase that preferentially assembled lysine-63-linked polyubiquitin chains. DUBA selectively cleaved the lysine-63-linked polyubiquitin chains on TRAF3, resulting in its dissociation from the downstream signaling complex containing TANK-binding kinase 1." SIGNOR-265873 PRKG1 protein Q13976 UNIPROT PLCB3 protein Q01970 UNIPROT "down-regulates activity" phosphorylation Ser26 VETLRRGsKFIKWDE 10116 BTO:0004576 11278298 t lperfetto "PKG can directly phosphorylate PLC-beta2 and PLC-beta3 in vitro with purified proteins and in vivo with metabolic labeling. Phosphorylation of PLC-beta leads to the inhibition of G-protein-activated PLC-beta3 activity by 50-70% in COS-7 cell transfection assays. By using phosphopeptide mapping and site-directed mutagenesis, we further identified two key phosphorylation sites for the regulation of PLC-beta3 by PKG (Ser(26) and Ser(1105)). Mutation at these two sites (S26A and S1105A) of PLC-beta3 completely blocked the phosphorylation of PLC-beta3 protein catalyzed by PKG." SIGNOR-249079 AKT proteinfamily SIGNOR-PF24 SIGNOR PIKFYVE protein Q9Y2I7 UNIPROT up-regulates phosphorylation Ser307 PARNRSAsITNLSLD 9606 BTO:0000887 15546921 t gcesareni "Here we report that serine318 on the fyve domain-containing ptdins3p 5-kinase (pikfyve) is a novel substrate for pkb, and show that phosphorylation stimulates the ptdins3p 5-kinase activity of the enzyme." SIGNOR-130920 CyclinY/CDK16 complex SIGNOR-C540 SIGNOR CDKN1B protein P46527 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser10 NVRVSNGsPSLERMD 9606 BTO:0000567 25205104 t lperfetto "In vitro kinase assays showed PCTAIRE1 phosphorylates p27 at Ser10. PCTAIRE1 silencing modulated Ser10 phosphorylation on p27 and led to its accumulation in cancer cells but not in nontransformed cells.|Together our findings reveal an unexpected role for PCTAIRE1 in regulating p27 stability, mitosis, and tumor growth, suggesting PCTAIRE1 as a candidate cancer therapeutic target." SIGNOR-273012 CyclinY/CDK16 complex SIGNOR-C540 SIGNOR PRC1 protein O43663 UNIPROT "up-regulates activity" phosphorylation Thr481 RRGLAPNtPGKARKL 9606 BTO:0000815 35449080 t lperfetto "Mechanistically, CDK16 exerts its function by phosphorylating protein regulator of cytokinesis 1 (PRC1) to regulate spindle formation during mitosis.|Indeed, immunoblot analysis showed that PRC1 phosphorylation at the T481 site (CDK-dependent major phosphorylation site) fluctuated with the abundance of CDK16 protein in the cell cycle process" SIGNOR-273013 serotonin(1+) smallmolecule CHEBI:350546 ChEBI HTR4 protein Q13639 UNIPROT "up-regulates activity" "chemical activation" 9606 BTO:0002524 31160049 t "Ligand-GPCR dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257524 ITGB7 protein P26010 UNIPROT "A4/b7 integrin" complex SIGNOR-C187 SIGNOR "form complex" binding 16988024 t lperfetto "Integrins are one of the major families of cell adhesion receptors (Humphries, 2000; Hynes, 2002). All integrins are non-covalently-linked, heterodimeric molecules containing an α and a β subunit. Both subunits are type I transmembrane proteins, containing large extracellular domains and mostly short cytoplasmic domains (Springer and Wang, 2004; Arnaout et al., 2005). Mammalian genomes contain 18 α subunit and 8 β subunit genes, and to date 24 different α,β combinations have been identified at the protein level. Although some subunits only appear in a single heterodimer, twelve integrins contain the β1 subunit, and five contain αV." SIGNOR-253294 phentolamine chemical CHEBI:8081 ChEBI ADRA1A protein P35348 UNIPROT "down-regulates activity" "chemical inhibition" 10029 BTO:0000246 7651358 t miannu "Membrane preparations from CHO cells stably transfected with the cloned human a1-AR genes showed saturable binding of [‘251]HEAT; Bm,,ı values were 1.3 ± 0.2, 5.5 ± 0.1, and 1.1 ± 0.1 pmol/mg of protein, with Kd values of 110 ± 21, 60 ± 1, and 300 ± 26 ıM (three experiments each), for the ala-, alb-, and ald-ARS, respectively. The potencies of a1-AR agonists and antagonists at the cloned human a1-ARs are shown in Table 1." SIGNOR-258445 AURKB protein Q96GD4 UNIPROT ZWINT protein O95229 UNIPROT "up-regulates activity" phosphorylation Ser250 PTRPQEQsTGDTMGR -1 21775627 t lperfetto "Zwint-1 is a novel Aurora B substrate required for the assembly of a dynein-binding platform on kinetochores|During prometaphase, AurB phosphorylation of zwint-1 is required for recruitment of ZW10-, pT89 dynein-, and RZZ-dependent proteins to kinetochores. This is defective after AurB inhibition or after expression of the triple-A zwint-1 mutant. Triple-E mutant zwint-1 mimics phospho–zwint-1 in RZZ recruitment, even after AurB inhibition" SIGNOR-265009 RXRB protein P28702 UNIPROT THRA protein P10827 UNIPROT up-regulates binding 9606 10976919 t gcesareni "Like many receptors belonging to the superfamily of steroid/thyroid nuclear receptors, thyroid hormone receptors (trs) bind to specific th-dna responsive elements (tre) upstream of target gene in heterodimeric complex with the 9-cis retinoid acid receptor (rxr" SIGNOR-81452 CDK2 protein P24941 UNIPROT PGR protein P06401 UNIPROT unknown phosphorylation Ser25 PPSPEVGsPLLCRPA 9606 11110801 t llicata "In vitro phosphorylation of pr with cdk2 has revealed five additional in vitro cdk2 phosphorylation sites: ser(25), ser(213), thr(430), ser(554), and ser(676)." SIGNOR-84988 AKT proteinfamily SIGNOR-PF24 SIGNOR ZFP36L1 protein Q07352 UNIPROT down-regulates phosphorylation Ser92 RFRDRSFsEGGERLL 9606 15538381 t lperfetto "Here we report that protein kinase b (pkb/akt) stabilizes are transcripts by phosphorylating brf1 at serine 92 (s92). Recombinant brf1 promoted in vitro decay of are-containing mrna (are-mrna), yet phosphorylation by pkb impaired this activity." SIGNOR-244385 TNF protein P01375 UNIPROT NOTCH1 protein P46531 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0004914 14586405 f "We found that TNF induced the expression of Notch-1, Notch-4, and Jagged-2 in RSF. The expression of these proteins was detected in the RA synovial tissues." SIGNOR-253606 AGRP protein O00253 UNIPROT MC1R protein Q01726 UNIPROT "down-regulates activity" binding 9606 BTO:0000142 20371771 t lperfetto "The melanocortin (MC) receptor family consists of five Gs-coupled receptors that control various physiological functions in response to four distinct agonists, adrenocorticotropic hormone (ACTH, also known as corticotrophin) and alpha, beta, and gamma melanocyte-stimulating hormone (MSH), which are derived from the proopiomelanocortin precursor protein, and two inverse agonists, agouti and agouti-related proteins" SIGNOR-268699 EN2 protein P19622 UNIPROT FGF8 protein P55075 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 10090 10026229 t miannu "Our results in ES cells suggest that Engrailed inhibits Fgf8 expression in the absence of Pbx1. We identified single Engrailed- and Pbx-binding sites in the Fgf8 intron that inhibit expression of Fgf8 in mouse ES cells, but that together can allow full Fgf8 expression." SIGNOR-265775 TRAF2 protein Q12933 UNIPROT RIPK1 protein Q13546 UNIPROT "up-regulates activity" ubiquitination Lys377 NEPSLQSkLQDEANY 9606 9712898 t lperfetto "Following binding to tradd, traf2 was thought to mediate non-degradative lys-63-linked polyubiquitination of rip1 via its ring e3 ligase domain. Rip1 is known to directly interact with traf2." SIGNOR-59689 CTNND1 protein O60716 UNIPROT CDH1 protein P12830 UNIPROT "up-regulates quantity by stabilization" binding 9606 BTO:0000414 14610055 t miannu "P120 regulates E-cadherin turnover at the cell membrane. Because direct binding of p120 to E-cadherin is required, it is possible that p120 binding blocks the interaction of an unknown binding partner (or event) that targets E-cadherin for degradation" SIGNOR-252123 MLH1 protein P40692 UNIPROT MLH1/PMS1 complex SIGNOR-C58 SIGNOR "form complex" binding 9606 10542278 t miannu "We now show that hpms1 is expressed in human cells and that it interacts with hmlh1 with high affinity to form the heterodimer hmutl_." SIGNOR-71768 AKT1 protein P31749 UNIPROT PDE3B protein Q13370 UNIPROT "up-regulates activity" phosphorylation Ser295 VIRPRRRsSCVSLGE 10090 BTO:0000944 10454575 t "PDE3B is a physiological substrate of Akt and that Akt-mediated phosphorylation of PDE3B on serine-273 is important for insulin-induced activation of PDE3B" SIGNOR-252573 STAT3 protein P40763 UNIPROT SOCS3 protein O14543 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 12565872 t "We also found that the wild type SOCS-3 promoter construct has significantly greater activity in non-small-cell lung cancer cell lines than in normal cells in accordance with STAT3 disregulation in these cells" SIGNOR-253583 PTPN6 protein P29350 UNIPROT NTRK1 protein P04629 UNIPROT "down-regulates activity" dephosphorylation Tyr680 RDIYSTDyYRVGGRT 10116 "phosphorylation: tyr496" HIIENPQyFSDACVH 14662744 t "Here, we identify SHP-1 as a phosphotyrosine phosphatase that negatively regulates TrkA. SHP-1 formed complexes with TrkA at Y490, and dephosphorylated it at Y674/675." SIGNOR-248468 ADAM17 protein P78536 UNIPROT NOTCH1 protein P46531 UNIPROT "up-regulates activity" cleavage 9606 10882063 t gcesareni "... here we show that an additional processing event occurs in the extracellular part of the receptor, preceding cleavage by the gamma-secretase-like activity. Purification of the activity accounting for this cleavage in vitro shows that it is due to tace (tnfalpha-converting enzyme), a member of the adam (a disintegrin and metalloprotease domain) family of metalloproteases." SIGNOR-78903 MAPK3 protein P27361 UNIPROT RPTOR protein Q8N122 UNIPROT "up-regulates activity" phosphorylation Ser863 LTQSAPAsPTNKGVH 9606 SIGNOR-C3 21071439 t lperfetto "We found three proline-directed residues within raptor, ser(8), ser(696), and ser(863), which are directly phosphorylated by erk1/2. Expression of phosphorylation-deficient alleles of raptor revealed that phosphorylation of these sites by erk1/2 normally promotes mtorc1 activity and signaling to downstream substrates, such as 4e-bp1." SIGNOR-169534 SOCS5 protein O75159 UNIPROT EGFR protein P00533 UNIPROT "down-regulates quantity" binding 9606 BTO:0000007 15590694 t miannu "SOCS5 Can Physically Associate with the EGFR. The complex recruited by SOCS proteins is composed of ElonginBC, Cullin, and Roc1 (15, 16). Together, this complex has E3 ubiquitin ligase activity. We suspect that the role of the SB domain is to mediate coupling of EGFR with the Elongin-Cullin-Roc E3 ubiquitin ligase complex, resulting in enhanced EGFR degradation." SIGNOR-271516 YAP1 protein P46937 UNIPROT FSTL3 protein O95633 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000222;BTO:0002314 BTO:0000887;BTO:0001103 23038772 f gcesareni "In our analysis bmp4 (bone morphogenetic protein 4) and fstl3 (follistatin-related protein 3) increased their expression in response to hyap1 s127a overexpression." SIGNOR-199072 PRKACA protein P17612 UNIPROT CREB1 protein P16220 UNIPROT "up-regulates activity" phosphorylation 9606 BTO:0001103 21902831 t gcesareni "Phosphorylation of CREB by PKA allows it to initiate the transcription of genes that contain a CRE element, two of which are PAX3 and MYF5." SIGNOR-176560 dacomitinib chemical CHEBI:132268 ChEBI ERBB2 protein P04626 UNIPROT down-regulates "chemical inhibition" 9606 23405260 t gcesareni "The goal of this study was to compare dacomitinib (pf-00299804), a next generation small molecule tyrosine kinase inhibitor that irreversibly blocks multiple her family receptors (her-1 (egfr), her-2 and her-4 tyrosine kinases), to cetuximab, the current fda approved anti-egfr medication for hnscc and erlotinib, an egfr specific small molecule tyrosine kinase inhibitor." SIGNOR-200905 PSMD11 protein O00231 UNIPROT "26S Proteasome" complex SIGNOR-C307 SIGNOR "form complex" binding 9606 BTO:0000007 29636472 t lperfetto "Here, we report near-atomic resolution cryo-EM structures of the activated human proteasome|The proteasome is composed of a 28-subunit barrel-shaped core particle (CP) and two 19- subunit regulatory particles (RP)5–8 capped at both sides of the CP|Human proteasomes were purified through affinity chromatography on a large scale from a stable HEK293 cell line" SIGNOR-263351 FASLG protein P48023 UNIPROT FAS protein P25445 UNIPROT "up-regulates activity" binding 9606 BTO:0000007 BTO:0000671 9228058 t lperfetto "The death-inducing receptor fas is activated when cross-linked by the type ii membrane protein faslg (fasl)" SIGNOR-49688 CKMT2 protein P17540 UNIPROT N-phosphocreatine smallmolecule CHEBI:17287 ChEBI "up-regulates quantity" "chemical modification" 9606 18502307 t miannu "Creatine kinase catalyses the reversible transphosphorylation of creatine by ATP. In the cell, creatine kinase isoenzymes are specifically localized at strategic sites of ATP consumption to efficiently regenerate ATP in situ via phosphocreatine or at sites of ATP generation to build-up a phosphocreatine pool." SIGNOR-265789 GSK3B protein P49841 UNIPROT GSK3B protein P49841 UNIPROT "up-regulates activity" phosphorylation Tyr216 RGEPNVSyICSRYYR 9606 BTO:0000007 14570592 t lperfetto "However, in the present study, we clearly demonstrate that GSK3_ is capable of catalysing the autophosphorylation of Tyr216 in vitro." SIGNOR-236564 CDK2 protein P24941 UNIPROT SF3B1 protein O75533 UNIPROT up-regulates phosphorylation Thr248 GSETPGAtPGSKIWD 9606 SIGNOR-C16 12105215 t gcesareni "To map the set of phosphorylation sites in sap155-(223-322) that determine its interaction with nipp1, we have identified phosphorylation sites of cyclin e-cdk2 by the sequencing of proteolytically derived phosphopeptides. Three phosphorylation sites were identified as thr244, thr248, and thr313" SIGNOR-90438 XAV939 chemical CHEBI:62878 ChEBI TNKS2 protein Q9H2K2 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-207833 "lysophosphatidic acid" smallmolecule CHEBI:132742 ChEBI LPAR1 protein Q92633 UNIPROT "up-regulates activity" "chemical activation" 9606 BTO:0002524 31160049 t "Ligand-GPCR dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257528 DUSP1 protein P28562 UNIPROT Gbeta proteinfamily SIGNOR-PF4 SIGNOR down-regulates dephosphorylation 9606 10617468 t "inferred from 70% of family members" gcesareni "The mitogen-activated protein (map) kinase cascade is inactivated at the level of map kinase by members of the map kinase phosphatase (mkp) family, including mkp-1." SIGNOR-269910 SIRT1 protein Q96EB6 UNIPROT XBP1 protein P17861-2 UNIPROT "down-regulates activity" deacetylation 9606 BTO:0000007 20955178 t miannu "P300 increases the acetylation and protein stability of XBP1s, and enhances its transcriptional activity, whereas SIRT1 deacetylates XBP1s and inhibits its transcriptional activity.. The mRNA encoding the active spliced form of XBP1 (XBP1s) is generated from the unspliced form by IRE1 (inositol-requiring enzyme 1) during the UPR." SIGNOR-260430 CSNK1E protein P49674 UNIPROT CSNK1E protein P49674 UNIPROT "down-regulates activity" phosphorylation Ser408 RIPASQTsVPFDHLG 9606 BTO:0000007 10542239 t llicata "Amino acids Ser-323, Thr-325, Thr-334, Thr-337, Ser-368, Ser-405, Thr-407, and Ser-408 in the carboxyl-terminal tail of CKIepsilon were identified as probable in vivo autophosphorylation sites. A recombinant CKIepsilon protein with serine and threonine to alanine mutations eliminating these autophosphorylation sites was 8-fold more active than wild-type CKIepsilon using IkappaBalpha as a substrate. T" SIGNOR-250810 CDK5 protein Q00535 UNIPROT CRMP1 protein Q14194 UNIPROT up-regulates phosphorylation Thr509 PVYEVPAtPKYATPA 9606 BTO:0000938 18003833 t lperfetto "These findings suggest that sema3a-induced spine development is regulated by phosphorylation of crmp1 by cdk5. Introduction of crmp1-wt, but not crmp1-t509a/s522a, a crmp1 mutant that cannot be phosphorylated by cdk5, rescued the defect in sema3a responsiveness." SIGNOR-159318 PRLHR protein P49683 UNIPROT GNA13 protein Q14344 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257280 CSNK1A1L protein Q8N752 UNIPROT GLI2 protein P10070 UNIPROT up-regulates phosphorylation 9606 18698484 t gcesareni "Gli2 is phosphorylated by gsk3 and ck1 for the fbxw11 (betatrcp2)-mediated degradation ci is phosphorylated by pka at multiple sites priming phosphorylation by both gsk3 and cki, leading to partial proteolysis. The pka, gsk3, and cki sites are conserved in gli2 and gli3, vertebrate homologs of ci that are similarly processed" SIGNOR-179972 CDK5 protein Q00535 UNIPROT AMPH protein P49418 UNIPROT unknown phosphorylation Ser276 PLPSPTAsPNHTLAP -1 11113134 t llicata "Amphiphysin is phosphorylated by cdk5 in a region including serines 272, 276, and 285. Amphiphysin 1 is also phosphorylated by the cdc2/cyclin B kinase complex in the same region and undergoes mitotic phosphorylation in dividing cells. " SIGNOR-250649 "N-[4-[(hydroxyamino)-oxomethyl]phenyl]carbamic acid [6-(diethylaminomethyl)-2-naphthalenyl]methyl ester" chemical CHEBI:94187 ChEBI HDAC1 protein Q13547 UNIPROT down-regulates "chemical inhibition" 9606 17891169 t fspada "Hydroxamate derivatives are the most powerful category of hdaci, active on class i and ii hdac,especially on hdac1 and hdac2. In the study reported here, we described the anti-leukaemic properties of itf2357, a recently synthesized, orally active hydroxamate derivative." SIGNOR-157857 PI3K complex SIGNOR-C156 SIGNOR AKT proteinfamily SIGNOR-PF24 SIGNOR "up-regulates activity" phosphorylation 9606 15526160 t miannu "C-Kit promotes survival via PI3-kinase-dependent activation of Akt and phosphorylation of Bad, a pro-apoptotic molecule, at S136 in vivo." SIGNOR-254950 TUBA3D protein P0DPH8 UNIPROT Neuron_migration phenotype SIGNOR-PH67 SIGNOR up-regulates 9606 BTO:0000007 19185337 f miannu "We show here that Elongator regulates corticogenesis because an acute disruption of its activity in dorsal progenitors results in radial migration delays and defective terminal branching of projection neurons that come with a reduction in α-tubulin acetylation. Importantly, this complex interacts with the microtubule cytoskeleton, where Elp3 may directly acetylate α-tubulin, a posttranslational modification known to regulate the intracellular trafficking that is critical for cell shape remodeling during migration and terminal branching." SIGNOR-269723 ODAD4 protein Q96NG3 UNIPROT Axonemal_Dynein proteinfamily SIGNOR-PF66 SIGNOR "up-regulates activity" binding 10090 BTO:0000379 33347437 t miannu "CFAP53 likely facilitates the transport of TTC25 and the dyneins into cilia. CFAP53 at the centriolar satellites may form a complex with TTC25 and ODAs, including DNAH5 and DNAH11, and regulate their trafficking into the cilium (Fig 10B). It also interacts with ODA proteins including dynein heavy chains such as DNAH11 and possibly DNAH5/9. CFAP53 likely facilitates the transport of TTC25 and the dyneins into cilia." SIGNOR-265546 SRC protein P12931 UNIPROT EPHA2 protein P29317 UNIPROT "up-regulates activity" phosphorylation Tyr594 TYVDPHTyEDPNQAV 9606 24457997 t gcesareni "SRC phosphorylates EPHA2 on Tyr594|. It is therefore likely that this phosphorylation site is included in the binding motif of an additional signalling molecule required for cell transformation." SIGNOR-246104 PPP1R1B protein Q9UD71 UNIPROT PKA proteinfamily SIGNOR-PF17 SIGNOR "down-regulates activity" binding 9606 BTO:0000938 10604473 t miannu "We find that DARPP-32 is converted into an inhibitor of PKA when phosphorylated at threonine 75 by cyclin-dependent kinase 5 (Cdk5). Cdk5 phosphorylates DARPP-32 in vitro and in intact brain cells. Phospho-Thr 75 DARPP-32 inhibits PKA in vitro by a competitive mechanism." SIGNOR-265087 RPS6KB1 protein P23443 UNIPROT DEPTOR protein Q8TB45 UNIPROT down-regulates phosphorylation Ser286 SSMSSCGsSGYFSSS 9606 22017876 t llicata "Deptor is phosphorylated by s6k1 and rsk1 on the degron serine residues upon serum stimulation s6k1/rsk1 and _trcp are required for ubiquitination and degradation of endogenous deptor upon mitogen stimulation." SIGNOR-176858 LMO3 protein Q8TAP4 UNIPROT NHLH2 protein Q02577 UNIPROT "up-regulates activity" binding 9606 21573214 t miannu "Here we found that LMO3 forms a complex with HEN2 and acts as an upstream mediator for transcription of Mash1 in neuroblastoma." SIGNOR-254827 NARS1 protein O43776 UNIPROT asparagine smallmolecule CHEBI:22653 ChEBI "down-regulates quantity" "chemical modification" 9606 32788587 t miannu "Asparaginyl-tRNA synthetase1 (NARS1) is a member of the ubiquitously expressed cytoplasmic Class IIa family of tRNA synthetases required for protein translation. Asparaginyl-tRNA synthetase1 (NARS1) belongs to the class IIa family, based upon a 7 beta-strand protein structure. There are two NARS genes: NARS1 functions in the cytoplasm while NARS2 functions in mitochondria, solely responsible for asparagine tRNA charging in these locations." SIGNOR-270454 STK38 protein Q15208 UNIPROT STK38 protein Q15208 UNIPROT up-regulates phosphorylation Ser281 NRRQLAFsTVGTPDY 9606 BTO:0000007 16314523 t lperfetto "Ndr1/ndr2 protein kinase is activated by phosphorylation on the activation loop phosphorylation site ser281/ser282 and the hydrophobic motif phosphorylation site thr444/thr442. Autophosphorylation of ndr is responsible for phosphorylation on ser281/ser282, whereas thr444/thr442 is targeted by an upstream kinase. Here we show that mst3, a mammalian ste20-like protein kinase, is able to phosphorylate ndr protein kinase at thr444/thr442. In vitro, mst3 selectively phosphorylated thr442 of ndr2, resulting in a 10-fold stimulation of ndr activity." SIGNOR-142514 TCF4 protein P15884 UNIPROT CNTNAP2 protein Q9UHC6 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 22777675 f miannu "we show that TCF4 can transactivate the NRXN1β and CNTNAP2 promoters in luciferase assays." SIGNOR-255390 "sphingosine 1-phosphate" smallmolecule CHEBI:37550 ChEBI S1PR3 protein Q99500 UNIPROT "up-regulates activity" "chemical activation" 10116 10617617 t "We observed that S1P treatment significantly increased proliferation of HTC4 hepatoma cells stably transfected with human S1P receptor Edg3 or Edg5, which was attributable to stimulation of cell growth and inhibition of apoptosis caused by serum starvation." SIGNOR-261142 RPS4Y1 protein P22090 UNIPROT "40S cytosolic small ribosomal subunit" complex SIGNOR-C286 SIGNOR "form complex" binding -1 25901680 t lperfetto "Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins." SIGNOR-262446 PRKACA protein P17612 UNIPROT ITPKA protein P23677 UNIPROT "up-regulates activity" phosphorylation Ser121 LQQPRRLsTSSVSST -1 9374536 t miannu "Two isoforms of the inositol 1,4,5-trisphosphate 3-kinase have been identified, the A form and the B form. phosphorylation of isoform A by the cyclic AMP-dependent protein kinase increased activity 1.5-fold, whereas phosphorylation of isoform B decreased activity by 45%. major phosphorylation sites in the protein are Ser119 for PKA. Ser119 in the A isoform is conserved in the B isoform as Ser328" SIGNOR-249994 ULK1 protein O75385 UNIPROT ULK1/Atg13/Fip200 complex SIGNOR-C100 SIGNOR "form complex" binding 9606 23863160 t lperfetto "In mammals, two protein complexes, namely the ULK1-Atg13-FIP200 (200kDa focal adhesion kinase family-interacting protein) complex and the Beclin–Vps34 complex, function jointly to produce the phagophore membrane, the initial phase of autophagosome formation." SIGNOR-209890 PRKG2 protein Q13237 UNIPROT PLCB3 protein Q01970 UNIPROT "down-regulates activity" phosphorylation Ser1105 LDRKRHNsISEAKMR 10116 11278298 t lperfetto "PKG can directly phosphorylate PLC-beta2 and PLC-beta3 in vitro with purified proteins and in vivo with metabolic labeling. Phosphorylation of PLC-beta leads to the inhibition of G-protein-activated PLC-beta3 activity by 50-70% in COS-7 cell transfection assays. By using phosphopeptide mapping and site-directed mutagenesis, we further identified two key phosphorylation sites for the regulation of PLC-beta3 by PKG (Ser(26) and Ser(1105)). Mutation at these two sites (S26A and S1105A) of PLC-beta3 completely blocked the phosphorylation of PLC-beta3 protein catalyzed by PKG." SIGNOR-249078 PLK1 protein P53350 UNIPROT BORA protein Q6PGQ7 UNIPROT down-regulates phosphorylation Ser497 SSNIQMDsGYNTQNC 9606 18521620 t gcesareni "Following cdk1-dependent recruitment, plk1 triggers hbora destruction by phosphorylating a recognition site for scf(beta-trcp)." SIGNOR-178803 "Ub:E1 (UBA6 substrate)" complex SIGNOR-C496 SIGNOR UBE2Q2 protein Q8WVN8 UNIPROT "up-regulates activity" ubiquitination 9606 34199813 t miannu "The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t" SIGNOR-271363 EIF2AK3 protein Q9NZJ5 UNIPROT EIF2S1 protein P05198 UNIPROT "down-regulates activity" phosphorylation Ser52 MILLSELsRRRIRSI 9606 25660019 t Manara "We now demonstrate a major role for Rheb in inhibiting protein synthesis by enhancing the phosphorylation of eIF2α by protein kinase-like ER kinase (PERK)." SIGNOR-260874 CASP8 protein Q14790 UNIPROT RNF31 protein Q96EP0 UNIPROT "down-regulates activity" cleavage Asp387 QPPSLVVdSRDAGIC 9606 BTO:0005111 32122970 t miannu "We show that LUBAC interacted with caspase-1 via HOIP and modified its CARD domain with linear polyubiquitin and that depletion of HOIP or Sharpin resulted in heightened caspase-1 activation and cell death in response to inflammasome activation, unlike what is observed in macrophages. Reciprocally, caspase-1, as well as caspase-8, regulated LUBAC activity by proteolytically processing HOIP at Asp-348 and Asp-387 during the execution of cell death." SIGNOR-272195 CDK5 protein Q00535 UNIPROT CDK5R1 protein Q15078 UNIPROT down-regulates phosphorylation Ser8 MGTVLSLsPSYRKAT 9606 18326489 t lperfetto "When overexpressed with cdk5, a large fraction of the double mutant p35(s8a/t138a) co-sedimented with microtubules (fig. 5b), further supporting the idea that the phosphorylation at these two residues by cdk5 is inhibitory to the microtubule association." SIGNOR-177963 CYP17A1 protein P05093 UNIPROT 17alpha-hydroxypregnenolone smallmolecule CHEBI:28750 ChEBI "up-regulates quantity" "chemical modification" 9606 BTO:0001363;BTO:0000048;BTO:0000050 17192295 t lperfetto "THE MICROSOMAL ENZYME P450c17 catalyzes two reactions: the 17α-hydroxylation of progesterone and pregnenolone and the subsequent cleavage of the C17–20 carbon bond to produce dehydroepiandrosterone (DHEA) and androstenedione. Whereas only 17α-hydroxylase activity is necessary for the production of corticosteroids, both activities of P450c17 are required to synthesize sex hormones." SIGNOR-268652 Ub:E2 complex SIGNOR-C497 SIGNOR TRIM23 protein P36406 UNIPROT "up-regulates activity" ubiquitination 9606 34199813 t miannu "The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t" SIGNOR-271002 DAPK3 protein O43293 UNIPROT MYL12B protein O14950 UNIPROT up-regulates phosphorylation Thr19 KKRPQRAtSNVFAMF 9606 12429016 t gcesareni "Hzipk phosphorylated the regulatory light chain of myosin ii (mrlc) at both ser19 and thr18 in vitro. Phosphorylation of mrlc is required to generate the driving force in the migration of the cells but not necessary for localization of myosin ii at the leading edge." SIGNOR-95524 BRCA1 protein P38398 UNIPROT ERCC6 protein Q03468 UNIPROT "down-regulates quantity by destabilization" polyubiquitination 9606 BTO:0000007 21756275 t miannu "BRCA1 polyubiquitinates CSB and this polyubiquitination and subsequent degradation of CSB occur following UV irradiation, even in the absence of Cockayne syndrome A (CSA) protein. " SIGNOR-272754 EDNRB protein P24530 UNIPROT GNAZ protein P19086 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257321 ROR1 protein Q01973 UNIPROT SRC protein P12931 UNIPROT up-regulates phosphorylation 9606 BTO:0000551 22439932 t miannu "Ror1 binds to and phosphorylates c-src / ror1 kinase-dependent c-src activation" SIGNOR-196751 EGFR protein P00533 UNIPROT SOX2 protein P48431 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 19882665 f miannu "We show that egfr-mediated signaling promotes sox2 expression, which in turn binds to the egfr promoter and directly upregulates egfr expression." SIGNOR-189033 TUBA1C protein Q9BQE3 UNIPROT Neuron_migration phenotype SIGNOR-PH67 SIGNOR up-regulates 9606 BTO:0000007 19185337 f miannu "We show here that Elongator regulates corticogenesis because an acute disruption of its activity in dorsal progenitors results in radial migration delays and defective terminal branching of projection neurons that come with a reduction in α-tubulin acetylation. Importantly, this complex interacts with the microtubule cytoskeleton, where Elp3 may directly acetylate α-tubulin, a posttranslational modification known to regulate the intracellular trafficking that is critical for cell shape remodeling during migration and terminal branching." SIGNOR-269728 HOXA9 protein P31269 UNIPROT MSI2 protein Q96DH6 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 20805843 f gcesareni "Nup98-hoxa9 oncogene binds the putative element at 5.7 kb upstream of transcription start site to trigger the upregulated expression of musashi2 gene (b). The elevated level of musashi2 leads to the downregulation of numb, by binding to the 3' utr of numb mrna to inhibit translation" SIGNOR-167725 BMPR1B protein O00238 UNIPROT SMAD5 protein Q99717 UNIPROT "up-regulates activity" phosphorylation 9606 19620713 t lperfetto "Two types of bmp-induced signaling pathways are known, the smad and p38 mapk pathways. In the former case, bmpr1 phosphorylates smad-1,-5,-8, which forms a complex with smad4 that translocates into the nucleus and regulates gene expression." SIGNOR-255260 PRKCA protein P17252 UNIPROT NCF1 protein P14598 UNIPROT up-regulates phosphorylation Ser359 EERQTQRsKPQPAVP 9606 BTO:0000130 12056906 t lperfetto "Phosphopeptide mapping of p47(phox) showed that, as opposed to pkc zeta, pkc alpha, beta ii, and delta are able to phosphorylate all the major pkc sites. The use of p47(phox) mutants identified serines 303, 304, 315, 320, 328, 359, 370, and 379 as targets of pkc alpha, beta ii, and delta.Taken together, these results suggest that pkc alpha, beta ii, delta, and zeta expressed in human neutrophils can individually phosphorylate p47(phox) and induce both its translocation and nadph oxidase activation." SIGNOR-89170 CDK4 protein P11802 UNIPROT PELP1 protein Q8IZL8 UNIPROT up-regulates phosphorylation Ser477 ADALKLRsPRGSPDG 9606 BTO:0000150 20807815 t llicata "Using site-directed mutagenesis and in vitro kinase assays, we identified ser(477) and ser(991) of pelp1 as cdk phosphorylation sites. we identified pelp1 as a novel substrate of cdks and found that cdk phosphorylation is important for the proper function of pelp1 in modulating hormone-driven cell cycle progression and also for optimal e2f transactivation function." SIGNOR-167770 "Cullin 3-RBX1-Skp1" complex SIGNOR-C526 SIGNOR DEK protein P35659 UNIPROT "down-regulates quantity by destabilization" ubiquitination Lys57 KSLIVEGkREKKKVE 9606 BTO:0000007 25278611 t miannu "Here, we analyzed changes in the ubiquitin landscape induced by prostate cancer-associated mutations of SPOP, an E3 ubiquitin ligase substrate-binding protein. SPOP mutants impaired ubiquitylation of a subset of proteins in a dominant-negative fashion. Of these, DEK and TRIM24 emerged as effector substrates consistently up-regulated by SPOP mutants. Up-regulation of DEK, TRIM24 and NCOA3 is a feature of prostate cancer SPOP mutations. This result aligns well with the observation that multiple ubiquitylated DEK lysine residues were detected in the initial proteome analysis (fig. S2E)." SIGNOR-272828 MAPK1 protein P28482 UNIPROT ELK1 protein P19419 UNIPROT up-regulates phosphorylation Thr336 GGPGPERtPGSGSGS 10090 BTO:0000944 7889942 t lperfetto "We demonstrate that elk-1, a protein closely related to p62tcf in function, is a nuclear target of two members of the map kinase family, erk1 and erk2, erki phosphorylates five c-terminal sites in elk-i (s324,t336, s383, s389 and s422) with varying degrees of efficiency." SIGNOR-235467 EPAS1 protein Q99814 UNIPROT KDM5B protein Q9UGL1 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 32938217 t SaraGualdi "To this end, we confirm that KDM3A, KDM4B, KDM4C, KDM5B, KDM5C, and KDM62 are direct targets of HIF-1a while extent the list of known targets to KDM2A, KDM2B, KDM4D, KDM5A, and KDM6A. The results demonstrated that majority of the KDMs were similarly induced (KDM2A, KDM2B, KDM3A, KDM4B, KDM4C, KDM4D, KDM5A, KDM5B, KDM5C, KDM6B, and KDM7A) or repressed (KDM NO66 and KDM1A) by both HIF-1a and HIF-2a." SIGNOR-271578 PSMB7 protein Q99436 UNIPROT "26S Proteasome" complex SIGNOR-C307 SIGNOR "form complex" binding 9606 BTO:0000007 29636472 t lperfetto "Here, we report near-atomic resolution cryo-EM structures of the activated human proteasome|The proteasome is composed of a 28-subunit barrel-shaped core particle (CP) and two 19- subunit regulatory particles (RP)5–8 capped at both sides of the CP|Human proteasomes were purified through affinity chromatography on a large scale from a stable HEK293 cell line" SIGNOR-263360 STAT3 protein P40763 UNIPROT RORC protein P51449 UNIPROT up-regulates 9606 18454151 f "The inflammatory cytokines IL-6, IL-21 and IL-23 share signaling pathways by activating both STAT1 and STAT3, while IL-1beta is thought to activate the kinases IRAK1 and IRAK2 through recruitment of the adaptor MyD88. Thus, STAT3 is likely to be a common denominator in the induction of RORgammaT and IL-17 expression" SIGNOR-254303 GDP smallmolecule CHEBI:17552 ChEBI GNAI1 protein P63096 UNIPROT down-regulates "chemical inhibition" 9606 12040175 t gcesareni "Galfa subunits cycle between inactive (gdp-bound) and active (gtp-bound) states, and the lifetime of the active state is limited by gtp hydrolysis." SIGNOR-88226 MAPK8 protein P45983 UNIPROT IRS1 protein P35568 UNIPROT down-regulates phosphorylation Ser312 TESITATsPASMVGG 9606 18728222 t gcesareni "Insulin also activates jnk, erk, pkc and mtor, which induce the phosphorylation of irs1 on serine residues 307, 612 and 632 and inhibit its functions. Our results indicate that the insulin-stimulated degradation of irs-1 via the phosphatidylinositol 3-kinase pathway is in part dependent upon the ser(312) phosphorylation of irs-1." SIGNOR-180532 CEBPB protein P17676 UNIPROT STAR protein P49675 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0003697 18583320 t "Electrophoretic mobility shift assay demonstrated that this region of the StAR promoter was bound by C/EBPalpha, C/EBPbeta, and CREB. Forced expression of either C/EBPalpha or C/EBPbeta alone was sufficient to up-regulate StAR promoter activity whereas PGE(2) was needed to induce StAR promoter activity in CREB-overexpressed cells." SIGNOR-254046 WNT5A protein P41221 UNIPROT FZD3 protein Q9NPG1 UNIPROT "up-regulates activity" binding 9606 BTO:0000393 21903638 t gcesareni "It has been shown that wnt5a activates the calcium signaling pathway in the presence of receptor fz2, 3, 4, 6 and receptor fz 5." SIGNOR-176579 CDK1 protein P06493 UNIPROT KRT18 protein P05783 UNIPROT up-regulates phosphorylation Ser34 RPVSSAAsVYAGAGG 9606 9524113 t lperfetto "We identified k18 ser33 as an interphase phosphorylation site, which increases its phosphorylation during mitosis in cultured cells and regenerating liver, and as an in vitro cdc2 kinase phosphorylation site. K18 ser33 phosphorylation dictates binding to 14_3_3 proteins" SIGNOR-55994 NRAS protein P01111 UNIPROT GLI1 protein P08151 UNIPROT up-regulates 9606 17845852 f gcesareni "Ras and akt signaling enhances the nuclear localization of gli1, counteracting its suppression by other modifiers that retain it in the cytoplasm, such as suppressor of fused (sufu)" SIGNOR-157773 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR ALOX5 protein P09917 UNIPROT "up-regulates activity" phosphorylation Ser272 CSLERQLsLEQEVQQ 9606 BTO:0000567 12670876 t lperfetto "Intriguingly, a significant difference in the potency of nonredox-type inhibitors (but not of BWA4C) was determined between wild-type 5-LO and the mutant S271A/S663A-5-LO (lacking phosphorylation sites for ERK1/2 and MAPKAPK-2) in HeLa cells. Collectively, our data suggest that compared with Ca2+-mediated 5-LO product formation, enzyme activation involving 5-LO phosphorylation events specifically and strongly alters the susceptibility of 5-LO toward nonredox-type inhibitors in intact cells." SIGNOR-264443 MRE11/RAD50/NBS1 complex SIGNOR-C147 SIGNOR DNA_repair phenotype SIGNOR-PH57 SIGNOR up-regulates 17713585 f lperfetto "The mre11_rad50_nbs1 (mrn) complex is among the earliest respondents to dna double-strand breaks (dsbs).|Current emerging structural and biological evidence suggests that MRN has 3 coupled critical roles in DSB sensing, stabilization, signaling, and effector scaffolding: (1) expeditious establishment of protein--nucleic acid tethering scaffolds for the recognition and stabilization of DSBs; (2) initiation of DSB sensing, cell-cycle checkpoint signaling cascades, and establishment of epigenetic marks via the ATM kinase; and (3) functional regulation of chromatin remodeling in the vicinity of a DSB." SIGNOR-251502 FLT3 protein P36888 UNIPROT SIRT1 protein Q96EB6 UNIPROT "up-regulates quantity by stabilization" "post transcriptional regulation" 9606 26049753 f "SIRT1 protein but not mRNA expression is increased in CD34+ cells from FLT3-ITD positive AML patients compared to FLT3 wild-type AML patients" SIGNOR-261555 MECOM protein Q03112 UNIPROT TEK protein Q02763 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 BTO:0000669 15889140 t Luana "We finally observed that the forced expression of Evi1 induced GATA-2 expression in a hematopoietic cell line, EML C1, along with GATA-1, Ang-1, Ang-2 and Tie2 " SIGNOR-266063 RPAP2 protein Q8IXW5 UNIPROT POLR2A protein P24928 UNIPROT "up-regulates activity" dephosphorylation Ser1717 SPSYSPTsPSYSPTS 9606 BTO:0000567 22137580 t "In addition, we show that RPAP2 is a CTD Ser5 phosphatase. Taken together, our results indicate that during transcription of snRNA genes, Ser7 phosphorylation facilitates recruitment of RPAP2, which in turn both recruits Integrator and dephosphorylates Ser5.|The Pol II CTD is first phosphorylated on Ser5 and then on Ser7 by CDK7. RPAP2 associates with the Pol II CTD after Ser7 phosphorylation and tethers a subcomplex of Integrator to snRNA genes. RPAP2 dephosphorylates Ser5P of the CTD, facilitating transcription and the subsequent recruitment of the Int11 catalytic subunit of Integrator" SIGNOR-248742 BDNF protein P23560 UNIPROT NTRK2 protein Q16620 UNIPROT up-regulates binding 9606 7679912 t gcesareni "Its interactions with trkb can be distinguished from those of brain-derived neurotrophic factor (bdnf) with trkb" SIGNOR-31597 AURKB protein Q96GD4 UNIPROT H3C1 protein P68431 UNIPROT "up-regulates activity" phosphorylation Ser11 TKQTARKsTGGKAPR 9606 14583461 t "Ser 11 phosphorylation of H3 is either activatory and inhibitory as promotes DNA condensation (activatory) and induce transcription (inhibitory)." gcesareni "Phosphorylation at ser-11 (h3s10ph) by aurkb is crucial for chromosome condensation and cell-cycle progression during mitosis and meiosis. Phosphorylation at ser-11 (h3s10ph) by aurkb is crucial for chromosome condensation and cell-cycle progression during mitosis and meiosis." SIGNOR-118894 BIRC2 protein Q13490 UNIPROT CSE1L protein P55060 UNIPROT "down-regulates quantity by destabilization" polyubiquitination 9606 BTO:0000007 26668314 t miannu "We find that TRAIL induces up-regulation of CAS in a posttranscriptional, caspase-8-dependent manner through degradation of cIAP1, an E3 ligase that targets CAS for ubiquitin-dependent proteasomal degradation. " SIGNOR-272812 PRKAA2 protein P54646 UNIPROT ULK1 protein O75385 UNIPROT up-regulates phosphorylation Ser317 SHLASPPsLGEMQQL 9606 SIGNOR-C15 19584320 t gcesareni "In a screen for conserved substrates of ampk, we identified ulk1 and ulk2, mammalian orthologs of the yeast protein kinase atg1, which is required for autophagy." SIGNOR-186633 ACAT1 protein P24752 UNIPROT IDH2 protein P48735 UNIPROT "down-regulates activity" acetylation Lys413 VESGAMTkDLAGCIH 9606 BTO:0001545 34289383 t lperfetto "Mitochondrial acetyltransferase ACAT1 and deacetylase SIRT3 are responsible for acetylation and deacetylation, respectively, at K413 of mIDH2|K413 acetylation inhibits mIDH2 by simultaneously attenuating dimer formation from monomers and destabilizing dimers for conversion to monomers" SIGNOR-267627 JAK2 protein O60674 UNIPROT ITGB2 protein P05107 UNIPROT "up-regulates activity" phosphorylation 9606 25624455 t miannu "PTKs of the JAK and SRC families have a regulatory role in LFA-1 affinity triggering, with JAKs showing a positive role (3), whereas SRCs possibly have a negative role." SIGNOR-254738 NCS1 protein P62166 UNIPROT DRD2 protein P14416 UNIPROT "down-regulates activity" binding 9606 BTO:0000007;BTO:0000938 12351722 t miannu "Here we show that the neuronal calcium sensor-1 (NCS-1) can mediate desensitization of D2 dopamine receptors. Analysis of D2 receptors expressed in human embryonic kidney 293 cells indicates that NCS-1 attenuates agonist-induced receptor internalization via a mechanism that involves a reduction in D2 receptor phosphorylation. Coimmunoprecipitation experiments from striatal neurons reveal that NCS-1 is found in association with both the D2 receptor and G-protein-coupled receptor kinase 2, a regulator of D2 receptor desensitization." SIGNOR-263964 FLT3 protein P36888 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR "up-regulates activity" phosphorylation 10090 BTO:0001516 14981546 t "These data confirm previous findings that FLT3 receptors with ITD mutations efficiently trigger the activation of ERK, STAT5 and Akt in the absence of FL stimulation." SIGNOR-261522 TP63 protein Q9H3D4 UNIPROT SUN1 protein O94901 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 BTO:0005098 28595999 t lperfetto "Here we show that in the developing skin, epidermal progenitor cells of mice lacking p63 transcription factor display alterations in the nuclear shape accompanied by a marked decrease in expression of several nuclear envelope-associated components (Lamin B1, Lamin A/C, Sun1, Nesprin-3, Plectin) compared with controls. Furthermore, chromatin immunoprecipitation-quantitative PCR assay showed enrichment of p63 on Sun1, Syne3, and Plec promoters, suggesting them as p63 targets." SIGNOR-263278 NDN protein Q99608 UNIPROT BMI1 protein P35226 UNIPROT down-regulates 9606 BTO:0000007 24392140 f lperfetto "In HEK293A cells transfected with luciferase reporter constructs, necdin relieves Bmi1-dependent repression of p16 promoter activity," SIGNOR-253384 SOSTDC1 protein Q6X4U4 UNIPROT WNT1 protein P04628 UNIPROT "down-regulates activity" 10090 22829579 f lperfetto "Our laboratory identified an almost twofold upregulation of sclerostin domain-containing 1 (Sostdc1; also referred to as WISE, USAG-1, ectodin), a dual Bmp/Wnt inhibitor, in postnatal day (P)1 pancreata from transgenic mice misexpressing hepatocyte nuclear factor (Hnf)6 in islet endocrine cells." SIGNOR-242704 PPP2CA protein P67775 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR "down-regulates activity" dephosphorylation 9606 18160256 t "Overexpression of BTBD10 increased phosphorylation levels of Akts at both Thr(308) and Ser(473) while the reduction of the endogenous BTBD10 level resulted in a decrease in the phosphorylation levels of Akts. In vitro analysis indicated that BTBD10 bound to protein phosphatase 2A (PP2A) and inhibited dephosphorylation of Akts by PP2A." SIGNOR-248655 CH5132799 chemical CID:49784945 PUBCHEM PIK3CB protein P42338 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-190946 APC-c complex SIGNOR-C150 SIGNOR PHF8 protein Q9UPP1 UNIPROT "down-regulates quantity by destabilization" polyubiquitination 9606 BTO:0000007 23979597 t miannu " We showed that PHF8 interacts with the CDC20-containing APC (APC(cdc20)) primarily during mitosis. we demonstrate that mutations of the LXPKXLF motif abrogate polyubiquitylation of PHF8 by the APC. APC substrates are typically cell cycle regulators, and consistent with this, the loss of PHF8 leads to prolonged G2 phase and defective mitosis." SIGNOR-272881 NKX2-5 protein P52952 UNIPROT CTNNB1 protein P35222 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0003265 19479054 f "Using antisense inhibition we disrupted the expression of NKX2-5 and studied changes in expression of cardiac-associated genes. Down-regulation of NKX2-5 resulted in increased beta-catenin while GATA4 was decreased. We demonstrated that this regulation was conferred by binding of NKX2-5 to specific elements (NKEs) in the promoter region of the beta-catenin and GATA4 genes. Using promoter-luciferase reporter assay combined with mutational analysis of the NKEs we demonstrated that the identified NKX2-5 binding sites were essential for the suppression of beta-catenin, and upregulation of GATA4 by NKX2-5." SIGNOR-253653 SKP2 protein Q13309 UNIPROT SMAD4 protein Q13485 UNIPROT down-regulates ubiquitination 9606 15314162 t gcesareni "We found that skp2, the f-box component of scfskp2, physically interacted with smad4 at the physiological levels. Several cancer-derived unstable mutants exhibited significantly increased binding to skp2, which led to their increased ubiquitination and accelerated proteolysis. These results suggest an important role for the scfskp2 complex in switching cancer mutants of smad4 to undergo polyubiquitination-dependent degradation." SIGNOR-127964 "Ub:E1 (UBA1 substrate)" complex SIGNOR-C495 SIGNOR UBE2A protein P49459 UNIPROT "up-regulates activity" ubiquitination 9606 34199813 t miannu "The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t" SIGNOR-271327 IFNG protein P01579 UNIPROT Inflammation phenotype SIGNOR-PH12 SIGNOR up-regulates 9606 18231581 f lperfetto "Induction and over-production of proinflammatory cytokines and chemokines, such as IL-6, IL-8, TNF-a and INF-c, were considered to be main mediators in the pathogenesis of SARS" SIGNOR-260259 PKI-402 chemical CID:44187953 PUBCHEM PIK3CD protein O00329 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-206256 PIK3C3 protein Q8NEB9 UNIPROT AKT1 protein P31749 UNIPROT up-regulates relocalization 9606 10698680 t lperfetto "One of the best characterized targets of pi3k lipid products is the protein kinase akt or protein kinase b (pkb). In quiescent cells, pkb resides in the cytosol in a low-activity conformation. Upon cellular stimulation, pkb is activated through recruitment to cellular membranes by pi3k lipid products and phosphorylation by 3h-phosphoinositide-dependent kinase-1 (pdk1)." SIGNOR-252632 GGCX protein P38435 UNIPROT F10 protein P00742 UNIPROT "up-regulates activity" carboxylation Glu47 RANSFLEeMKKGHLE -1 9538022 t lperfetto "This report describes the expression, purification, and characterization of a series of recombinant factor Xa variants bearing aspartate substitutions for each of the glutamate residues which normally undergo gamma-carboxylation. |We have produced fully active recombinant human factor Xa and demonstrated that gla residues 16, 26, and 29 are critical for normal activity of factor Xa.|This observation suggests that, for wild-type r-fX expressed in HEK cells, carboxylation by the gamma-glutamyl carboxylase proceeds to completion once initiated; | 11 amino terminal glutamic acid residues of fX which normally undergo gamma-carboxylation (glas 6, 7, 14, 16, 19, 20, 25, 26, 29, 32, 39)." SIGNOR-263665 LCK protein P06239 UNIPROT VAV1 protein P15498 UNIPROT unknown phosphorylation Tyr160 VEEDEDLyDCVENEE -1 10669745 t "Lck recognizes preferentially the tyrosine residue of Vav located at position 174 and, with significantly less affinity, those present at positions 142 and 160. It is now clear that this posttranslational modification will be involved in the activation of Vav, in the regulation of the strength of the signals emanating from this molecule, and also in the negative regulation of its function." SIGNOR-251390 GSK3B protein P49841 UNIPROT PSEN1 protein P49768 UNIPROT "down-regulates activity" phosphorylation Ser357 PHRSTPEsRAAVQEL 9606 BTO:0000007 SIGNOR-C110 17360711 t gcesareni "We demonstrate that phosphorylation of serines 353 and 357 by glycogen synthase kinase-3beta (gsk3beta) induces a structural change of the hydrophilic loop of ps1the structural change of ps1 reduces the interaction with beta-catenin leading to decreased phosphorylation and ubiquitination of beta-catenin." SIGNOR-153631 PTPN1 protein P18031 UNIPROT PDGFRB protein P09619 UNIPROT down-regulates dephosphorylation Tyr1009 LDTSSVLyTAVQPNE 9606 18567737 t gcesareni "Ptp1b blocked pdgf-induced tyr716 and tyr751 phosphorylation of the pdgfr." SIGNOR-179064 5-[(Z)-(5-Fluoro-2-oxo-1H-indol-3-ylidene)methyl]-N-[(2S)-2-hydroxy-3-morpholin-4-ylpropyl]-2,4-dimethyl-3H-pyrrole-3-carboxamide chemical CID:73755145 PUBCHEM KDR protein P35968 UNIPROT "down-regulates activity" "chemical inhibition" -1 22037378 t llicata "Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here." SIGNOR-258289 MAP2K3 protein P46734 UNIPROT MAPK14 protein Q16539 UNIPROT "up-regulates activity" phosphorylation Tyr182 TDDEMTGyVATRWYR 9606 8622669 t lperfetto "Mkk3 is a protein kinase that phosphorylates and activates p38 map kinase but does not phosphorylate the related jnk or erk map kinases." SIGNOR-40353 NfKb-p65/p50 complex SIGNOR-C13 SIGNOR SLC25A27 protein O95847 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 20385226 t lperfetto "We present the first direct evidence that UCP4 is regulated by NF-kappaB, mediated via a functional NF-kappaB site in its promoter region, and that UCP4 has a significant role in NF-kappaB prosurvival signaling, mediating its protection against MPP(+) toxicity.|NF-kappaB inhibition significantly suppressed the MPP(+)-induced increase in UCP4 expression." SIGNOR-268984 ZSTK-474 chemical CHEBI:90545 ChEBI PIK3CA protein P42336 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-207935 CDO1 protein Q16878 UNIPROT SHH protein Q15465 UNIPROT up-regulates binding 9606 BTO:0000887 16647304 t gcesareni "Cdo and boc bind shh through a high-affinity interaction with a specific fibronectin repeat that is essential for activity. We propose a model where cdo and boc enhance shh signaling within its target field." SIGNOR-146461 "long-chain fatty acid anion" smallmolecule CHEBI:57560 ChEBI "long-chain fatty acyl-CoA(4-)" smallmolecule CHEBI:83139 ChEBI "up-regulates quantity" "precursor of" 9606 24269233 t "ACSs catalyze the conversion of FAs to their active form acyl-CoAs. The human genome codes for 26 ACS isozymes, which are classified into six subfamilies based on their substrate specificities toward the chain length of FAs and on sequence similarity" SIGNOR-267711 DERA protein Q9Y315 UNIPROT "2-deoxy-D-ribofuranose 5-phosphate(2-)" smallmolecule CHEBI:62877 ChEBI "down-regulates quantity" "chemical modification" 9606 25229427 t miannu "Deoxyribose-phosphate aldolase (EC 4.1.2.4), which converts 2-deoxy-d-ribose-5-phosphate into glyceraldehyde-3-phosphate and acetaldehyde, belongs to the core metabolism of living organisms. his study provides the first experimental evidence that DERA, which is mainly expressed in lung, liver and colon, is the human deoxyribose phosphate aldolase." SIGNOR-267097 UNC5A protein Q6ZN44 UNIPROT Chemorepulsion_of_axon phenotype SIGNOR-PH198 SIGNOR up-regulates 9606 30108487 f miannu "Netrin binding to the receptor deleted in colorectal cancer (DCC) results in attractive responses, viahomodimerization of DCC (covered in detail in later sections), whereas heterodimerization between DCC and receptor uncoordinated locomotion 5 (UNC5) converts this attractive response into repulsion" SIGNOR-268182 PRKACA protein P17612 UNIPROT LRP1 protein Q07954 UNIPROT "up-regulates activity" phosphorylation Ser4520 GGHGSRHsLASTDEK 10029 11158305 t miannu "LRP phosphorylation is mediated by PKA at residue serine 76 of its cytoplasmic tail and that this phosphorylation contributes to receptor-mediated endocytosis." SIGNOR-250000 ZC3H11A protein O75152 UNIPROT "TREX complex" complex SIGNOR-C444 SIGNOR "up-regulates activity" binding 9606 BTO:0000567 22928037 t miannu "PDIP3 and ZC11A Function in mRNA Export. PDIP3 and ZC11A associate with UAP56 and the TREX complex in an ATP-dependent manner." SIGNOR-268516 MAPK1 protein P28482 UNIPROT RPS6KA5 protein O75582 UNIPROT "up-regulates activity" phosphorylation Ser376 EKLFQGYsFVAPSIL 15568999 t lperfetto "In the present study, we show that, in addition to being phosphorylated on Thr-581 and Ser-360 by ERK1/2 or p38, MSK1 can autophosphorylate on at least six sites: Ser-212, Ser-376, Ser-381, Ser-750, Ser-752 and Ser-758. Of these sites, the N-terminal T-loop residue Ser-212 and the 'hydrophobic motif' Ser-376 are phosphorylated by the C-terminal kinase domain of MSK1, and their phosphorylation is essential for the catalytic activity of the N-terminal kinase domain of MSK1" SIGNOR-249445 PPM1D protein O15297 UNIPROT MDM2 protein Q00987 UNIPROT "down-regulates quantity by destabilization" dephosphorylation Ser395 SQESEDYsQPSTSSS 9606 17936559 t "Here we show that the wild-type p53-induced phosphatase 1 (Wip1), or PPM1D, downregulates p53 protein levels by stabilizing Mdm2 and facilitating its access to p53. Wip1 interacts with and dephosphorylates Mdm2 at serine 395, a site phosphorylated by the ATM kinase." SIGNOR-248324 AKT2 protein P31751 UNIPROT HSPB1 protein P04792 UNIPROT down-regulates phosphorylation Ser82 RALSRQLsSGVSEIR 9606 19593530 t "10383393: We demonstrate that both phosphorylated sHsps and the triple mutant Hsp27-S15D,S78D,S82D show significantly decreased abilities to act as molecular chaperones suppressing thermal denaturation and facilitating refolding of citrate synthase in vitro." lperfetto "First, the akt1, akt2, and akt3 isoforms can bind directly to hsp27 and can be found in a complex with p38 mapk, mk2, and hsp27 [98_100]. Second, rane and colleagues showed that akt could phosphorylate hsp27 at ser-82, but not ser-15 or ser-78, in vitro, while co-expression of an active akt mutant and hsp27 in hek cells resulted in hsp27 phosphorylation at the same residue." SIGNOR-186776 "Complement C1 complex" complex SIGNOR-C309 SIGNOR C4A protein P0C0L4 UNIPROT "up-regulates activity" cleavage Arg679 EKTTRKKrNVNFQKA -1 9087411 t lperfetto "The classical complement activation pathway, like the MELinitiated pathway, involves the generation of a C3-converting complex, C4b2b, through enzymatic activation of C4 and C2. In the C1 complex (C1qr2s2), this specific protease activity is exhibited by C1s after activation of this enzyme by C1r. When C4 is activated, its reactive thiol ester is exposed and C4b binds covalently to nearby amino or hydroxyl groups. The C4-activating abilities of MASP-1 and MASP-2 were compared.|Activation of C4 by Ct sand MASP-2 on western blots." SIGNOR-263433 NMUR2 protein Q9GZQ4 UNIPROT GNA15 protein P30679 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257352 PRKAA1 protein Q13131 UNIPROT RB1 protein P06400 UNIPROT down-regulates phosphorylation Ser811 IYISPLKsPYKISEG 9606 SIGNOR-C15 19217427 t gcesareni "Amp-activated protein kinase phosphorylates retinoblastoma protein. Rb phosphorylation sites, ser804 (ser811 in human), resembled the ampk consensus phosphorylation site." SIGNOR-184052 "AIIB/b3 integrin" complex SIGNOR-C173 SIGNOR PTK2 protein Q05397 UNIPROT "up-regulates activity" 9606 15688067 f miannu "Focal adhesion kinase (FAK) is activated by growth factors and integrins during migration, and functions as a receptor-proximal regulator of cell motility. At contacts between cells and the extracellular matrix, FAK functions as an adaptor protein to recruit other focal contact proteins or their regulators, which affects the assembly or disassembly of focal contacts. Whereas it was first hypothesized that FAK might bind directly to the cytoplasmic tails of integrins, accumulated evidence supports an indirect association of FAK with integrins through binding to integrin-associated proteins such as paxillin and talin." SIGNOR-257717 PTPN11 protein Q06124 UNIPROT HOXA10 protein P31260 UNIPROT up-regulates dephosphorylation 9606 19022774 t fspada "We also identified hoxa10 as a substrate for shp2 in undifferentiated myeloid cells, an effect that diminished during myelopoiesis. However, a constitutively active form of shp2 dephosphorylated hoxa10 throughout ex vivo myelopoiesis and sustained repression of hoxa10 target genes involved in phagocyte effector functions." SIGNOR-182475 TLR4 protein O00206 UNIPROT MAPK14 protein Q16539 UNIPROT "up-regulates activity" phosphorylation 9606 28137827 t miannu "Binding of S100A9 to TLR4 stimulates the phosphorylation of JNK, ERK1/2, and p38 MAPK, which leads to the activation of c-Jun, CREB, and NF-κB. Activation of neutrophils by S100A9 also proceeds via p38 MAPK, JNK, and ERK1/2 phosphorylation." SIGNOR-263652 ATF6 protein P18850 UNIPROT ATF6 protein P18850 UNIPROT "up-regulates activity" binding -1 12805554 t miannu "E4BP4, ATF-6, OASIS, and XBP-1 all formed strong homodimeric associations on the array Transcription factor dimerization can increase the selectivity of protein-DNA interactions and generate a large amount of DNA binding diversity from a relatively small number of proteins" SIGNOR-224202 Ub:E2 complex SIGNOR-C497 SIGNOR RNF135 protein Q8IUD6 UNIPROT "up-regulates activity" ubiquitination 9606 34199813 t miannu "The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t" SIGNOR-271092 BMI1 protein P35226 UNIPROT CDKN2A protein P42771 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 24392140 t lperfetto "In HEK293A cells transfected with luciferase reporter constructs, necdin relieves Bmi1-dependent repression of p16 promoter activity," SIGNOR-253385 E2F1 protein Q01094 UNIPROT MCPH1 protein Q8NEM0 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 22136275 f miannu "Overexpression of E2F1 led to the upregulation of MCPH1 transcription, and knocking down the endogenous E2F1 resulted in the inhibition of the MCPH1 promoter activity." SIGNOR-253848 DYRK1A protein Q13627 UNIPROT NOTCH1 protein P46531 UNIPROT down-regulates phosphorylation 9606 BTO:0000142 19383720 t gcesareni "Dyrk1a physically interacts with the nicd inducing its phosphorylation in the ankyrin domain, thereby attenuating notch ." SIGNOR-185494 PRLHR protein P49683 UNIPROT GNA14 protein O95837 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257198 EFNA5 protein P52803 UNIPROT EPHA8 protein P29322 UNIPROT up-regulates binding 9606 9330863 t gcesareni "Efna5 are able to activate epha8" SIGNOR-52479 RPS6KA1 protein Q15418 UNIPROT RPTOR protein Q8N122 UNIPROT up-regulates phosphorylation Ser722 PRLRSVSsYGNIRAV 9606 SIGNOR-C3 18722121 t llicata "Ser719, ser721, and ser722 are the predominant rsk-dependent phosphorylation sites in raptor raptor phosphorylation regulates mtorc1 activity" SIGNOR-180466 TP53 protein P04637 UNIPROT Glycolysis phenotype SIGNOR-PH34 SIGNOR down-regulates 9606 27692180 f miannu "P53 regulates basal expression of AIF and SCO2 and facilitates oxidative phosphorylation. The expression of GLUT1, GLUT4, and HK2 is negatively regulated by p53, whereas TIGAR expression is induced by p53. The net result of p53-mediated regulation of these glycolytic enzymes is the suppression of glycolysis. In addition, p53 directly binds and inhibits G6PD activity and downregulates the pentose phosphate pathway." SIGNOR-267467 FOXO proteinfamily SIGNOR-PF27 SIGNOR G6P proteinfamily SIGNOR-PF81 SIGNOR "up-regulates quantity by expression" "transcriptional regulation" 9606 16308421 f "inferred from family member" gcesareni "In the gk gene regulation, foxo1 represses hnf-4-potentiated transcription of the gene, whereas it synergizes with hnf-4 in activating the g6pase gene transcription." SIGNOR-270252 PDGFRB protein P09619 UNIPROT RASA1 protein P20936 UNIPROT up-regulates binding 9606 11896619 t miannu "The gtpase activating protein (gap) of ras binds only to beta-receptors / we have previously shown that the binding site for gtpase activating protein of ras (rasgap) in the pdgf beta-receptor, tyr771, is phosphorylated to a much lower extent in the heterodimeric configuration of pdgf alpha- and beta-receptors, compared to the pdgf beta-receptor homodimer. / the decreased recruitment of the rasgap to the receptor leads to prolonged activation of the ras/map kinase pathway" SIGNOR-115843 CSNK2B protein P67870 UNIPROT IRS1 protein P35568 UNIPROT unknown phosphorylation Thr88 KHLVALYtRDEHFAI -1 8349691 t llicata "These data suggest that casein kinase II mediates a portion of the insulin-stimulated serine/threonine phosphorylation of overexpressed IRS-1 in vivo. | Thr-502 was identified as the major casein kinase II-catalyzed phosphorylation site in rat IRS-1." SIGNOR-251076 EP300 protein Q09472 UNIPROT RUNX2 protein Q13950 UNIPROT "up-regulates quantity" acetylation 9606 20851880 t gcesareni "These results indicate that Erk signaling increases Runx2 stability and transcriptional activity, partly via increasing p300 protein levels and histone acetyltransferase activity and subsequently increasing Runx2 acetylation by p300" SIGNOR-167966 SP1 protein P08047 UNIPROT SLC19A3 protein Q9BZV2 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 7227 BTO:0001677 15217784 f miannu "In transiently transfected Drosophila SL2 cells, both SP1 and SP3 transactivated the SLC19A3 minimal promoter in a dose-dependent manner and in combination demonstrated an additive stimulatory effect." SIGNOR-255215 NELFA protein Q9H3P2 UNIPROT NELF complex SIGNOR-C521 SIGNOR "form complex" binding 9606 18628398 t miannu "The Negative Elongation Factor (NELF) is a transcription regulatory complex that induces stalling of RNA polymerase II (Pol II) during early transcription elongation and represses expression of several genes studied to date, including Drosophila Hsp70, mammalian proto-oncogene junB, and HIV RNA. It is composed of four subunits, NELF-A, NELF-B, NELF-C/D, and NELF-E." SIGNOR-271401 "4-[[9-chloro-7-(2,6-difluorophenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-yl]amino]benzoic acid" chemical CHEBI:91366 ChEBI AURKA protein O14965 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-194518 PTPRG protein P23470 UNIPROT ITGAL protein P20701 UNIPROT "down-regulates activity" 9606 25624455 f miannu "PTPRG activation inhibits chemoattractantinduced LFA-1 affinity triggering and mediated adhesion in human primary monocytes. we show that PTPRG is a novel negative regulator of LFA-1 high-affinity-state triggering and mediated arrest by chemoattractants in human primary monocytes. Notably, PTKs of the JAK and SRC families have a regulatory role in LFA-1 affinity triggering, with JAKs showing a positive role (3), whereas SRCs possibly have a negative role (37). In our context, SRC appears inhibited by PTPRG activation (Table I), thus making it unlikely that the antiadhesive effect of PTPRG is mediated by SRC activation." SIGNOR-254736 CDK1 protein P06493 UNIPROT GOLGA2 protein Q08379 UNIPROT down-regulates phosphorylation Ser37 REYQQRNsPGVPTGA 9606 9753325 t lperfetto "Cdc2 kinase directly phosphorylates the cis-golgi matrix protein gm130 and is required for golgi fragmentation in mitosis. Mitotic fragmentation of the golgi apparatus can be largely explained by disruption of the interaction between gm130 and the vesicle-docking protein p115. Here we identify a single serine (ser-25) in gm130 as the key phosphorylated target and cdc2 as the responsible kinase" SIGNOR-60281 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR RAF1 protein P04049 UNIPROT "down-regulates activity" phosphorylation Ser289 RSHSESAsPSALSSS 10090 15664191 t lperfetto "Here, we identify six residues of Raf-1 (S29, S43, S289, S296, S301, and S642) that become hyperphosphorylated in a manner coincident with Raf-1 inactivation. | Five of the identified sites are proline-directed targets of activated ERK, and phosphorylation of all six sites requires MEK signaling, indicating a negative feedback mechanism. Hyperphosphorylation of these six sites inhibits the Ras/Raf-1 interaction and desensitizes Raf-1 to additional stimuli.|FLAG-Raf-1 phosphorylated by activated ERK2" SIGNOR-244677 PYHIN1 protein Q6K0P9 UNIPROT HDAC1 protein Q13547 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0001570 18247378 f miannu "We found that maspin is selectively upregulated in IFIXα-expressing cells and involved in anti-invasive activity of IFIXα. We also present evidence indicating that IFIXα downregulates histone deacetylase 1 (HDAC1), which is possibly involved in the silencing of the maspin gene in human breast cancer cells. To confirm these results, we performed a luciferase assay using a maspin-promoter-luciferase plasmid. The results showed that HDAC1 overexpression suppressed the activity of the maspin promoter (Figure 3C). Therefore, our results suggest that IFIXα enhances maspin expression through the downregulation of HDAC1." SIGNOR-268495 SIRT1 protein Q96EB6 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR up-regulates deacetylation 9606 15126506 t gcesareni "Deacetylation of foxos involves binding of the nad-dependent deacetylase hsir2(sirt1). Accordingly, hsir2(sirt1)-mediated deacetylation precludes foxo inhibition through acetylation and thereby prolongs foxo-dependent transcription of stress-regulating genes." SIGNOR-252993 PRKDC protein P78527 UNIPROT RPA2 protein P15927 UNIPROT unknown phosphorylation Ser33 GFGSPAPsQAEKKSR -1 9139719 t lperfetto "In this study, we show that efficient phosphorylation of HSSB-p34 by DNA-PK requires Ku as well as DNA. The DNA-PK phosphorylation sites in HSSB-p34 have been mapped at Thr-21 and Ser-33. Kinetic studies demonstrated that a phosphate residue is first incorporated at Thr-21 followed by the incorporation of a second phosphate residue at Ser-33." SIGNOR-248971 NFKBIA protein P25963 UNIPROT NfKb-p65/p50 complex SIGNOR-C13 SIGNOR "down-regulates activity" binding 9606 1340770 t lperfetto "Nf-kappa b is an inducible transcription factor comprised of a 50-kd (p50) and a 65-kd (p65) subunit. Induction of nf-kappa b activity, which is a critical event in many signal transduction pathways, involves release from a cytoplasmic inhibitory protein, i kappa b, followed by translocation of the active transcription factor complex into the nucleus. we demonstrate by in vitro and in vivo methods that the recently cloned i kappa b/mad-3 interacts with both the p50 and p65 subunits of nf-kappa b" SIGNOR-217394 SGK1 protein O00141 UNIPROT CDKN1B protein P46527 UNIPROT down-regulates phosphorylation Thr157 GIRKRPAtDDSSTQN 9606 18570873 t gcesareni "Activated sgk1 and p27 phosphorylation at t157, and both were inhibited by short-term rapamycin treatment and by sgk1 shrna." SIGNOR-179117 SLC18A2 protein Q05940 UNIPROT dopamine smallmolecule CHEBI:18243 ChEBI "up-regulates quantity" relocalization 9606 BTO:0000938 30465801 t miannu "Key regulators of transmitter release and the signaling dynamics of dopamine are the plasma membrane reuptake transporter (DAT) and the vesicular monoamine transporter (VMAT2). These proteins serve to remove dopamine molecules from the extracellular and cytosolic space, respectively and both determine the amount of transmitter released from synaptic vesicles." SIGNOR-269190 doxorubicin chemical CHEBI:28748 ChEBI TOP2A protein P11388 UNIPROT "down-regulates activity" "chemical inhibition" 9606 19377506 t "An important reason why Top2 has held the interest of researchers studying cancer was the discovery that active anti-cancer drugs, notably etoposide and doxorubicin target Top2" SIGNOR-261911 PHF12 protein Q96QT6 UNIPROT TLE6 protein Q9H808 UNIPROT "up-regulates activity" binding 9606 BTO:0000007 11390640 t miannu "We have cloned and characterized a new member of the PHD zinc finger family called Pf1 that interacts with two global transcription corepressors: mSin3A and TLE. Pf1 interacts with TLE. The Groucho/TLE proteins are members of an abundant corepressor family, and we hypothesized that Pf1 might interact with TLE family members. Together, these data suggest that in the absence of interactions with mSin3A, Gal4-Pf1 (102–273 L212P/A216P)-dependent repression can be attributed to interaction with endogenous TLE." SIGNOR-266991 STOML2 protein Q9UJZ1 UNIPROT ATP smallmolecule CHEBI:15422 ChEBI "up-regulates quantity" 9606 20359165 f Giorgia "In addition, mitochondrial and whole-cell ATP levels in resting SLP-2hi T cells were significantly higher than those in SLP-2lo T cells (P < 0.05) (Fig. 7d). Such an increase in ATP levels in SLP-2hi T cells correlated with increased resistance to depletion of mitochondrial ATP with oligomycin" SIGNOR-260384 ADRB2 protein P07550 UNIPROT GNAL protein P38405 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-256952 "MLL3 complex" complex SIGNOR-C446 SIGNOR H3-4 protein Q16695 UNIPROT "down-regulates activity" methylation Lys5 kQTARKST 9606 34156443 t miannu "MLL3/KMT2C and MLL4/KMT2D are two paralogous histone modifiers that belong to the SET1/MLL (also named COMPASS) family of lysine methyltransferases and play critical roles in enhancer-regulated gene activation. MLL3 and MLL4 form identical multi-protein complexes for modifying mono-methylation of histone H3 lysine 4 (H3K4) at enhancers, which together with the p300/CBP-mediated H3K27 acetylation can generate an active enhancer landscape for long-range target gene activation." SIGNOR-268812 CDK4 protein P11802 UNIPROT MEF2C protein Q06413 UNIPROT down-regulates binding 9606 SIGNOR-C18 21902831 t gcesareni "In contrast to cdk2, cyclin d/cdk4 blocks myod activity through an as yet unclear mechanism that may involve direct binding. Cyclin d/cdk4 can also block the activity of myogenin and all mef2 isoforms." SIGNOR-176518 PAK1 protein Q13153 UNIPROT PGAM proteinfamily SIGNOR-PF78 SIGNOR down-regulates phosphorylation 9606 BTO:0000130 12189148 t "Activated pak1|inferred from family member" gcesareni "Activated pak1 inhibits glycolysis by association of its catalytic domain with pgam-b and subsequent phosphorylation of the enzyme on serine residues 23 and 118, thereby abolishing pgam activity." SIGNOR-270283 STK3 protein Q13188 UNIPROT NEK2 protein P51955 UNIPROT up-regulates phosphorylation Ser438 EKNYQLKsRQILGMR 9606 21076410 t lperfetto "Our data suggest that mst2 phosphorylates nek2a thereby recruiting nek2a to centrosomes and promoting phosphorylation and displacement of centrosomal linker proteins" SIGNOR-169539 "CKM complex" complex SIGNOR-C406 SIGNOR NOTCH1 protein P46531 UNIPROT "down-regulates quantity by destabilization" phosphorylation -1 25344755 t lperfetto "Mapping of cyclin C-dependent phosphosites on ICN1, using mass spectrometry revealed that several of them are located within the PEST-domain of Notch1, which controls ICN1 degradation38,39 (Fig. 5g and Supplementary Table 1). Three of them (T2512, S2514 and S2517) are localized within the consensus motif, “Cdc4 phosphodegron”, which is shared by most substrates of Fbw7 (Cdc4) ubiquitin ligase38. Two of these residues (S2514 and S2517) were previously shown by Fryer et al.20 to be phosphorylated by cyclin C-CDK8 in vitro, and all three were shown to play a role in controlling ICN1 stability via Fbw740. We verified that cyclin C-CDK8, C-CDK19 and C-CDK3 phosphorylate ICN1 on these three residues" SIGNOR-273160 UBE2I protein P63279 UNIPROT SOX6 protein P35712 UNIPROT "down-regulates activity" sumoylation Lys417 TSPVTQkVkDEAAAQP 9606 16442531 t "We show that SOX6 is modified in vitro and in vivo by small ubiquitin‐related modifier (SUMO) on two distinct sites. Mutation of both sites abolished SOX6 sumoylation and increased SOX6 transcriptional activity. SUMO dependent repression of SOX6 transcription was promoted by UBC9 whereas siRNA to UBC9, cotransfection of inactive UBC9 or a SUMO protease increased SOX6 transcriptional activity." SIGNOR-256130 DLGAP5 protein Q15398 UNIPROT SHANK3 protein Q9BYB0 UNIPROT "up-regulates activity" relocalization 9606 BTO:0000938 28179641 t miannu "SHANK proteins are ‘master’ scaffolding proteins that tether and organize intermediate scaffolding proteins. They are located at excitatory synapses, where they are crucial for proper synaptic development and function. SAPAP proteins subsequently bind to the PDZ domain of members of the SHANK protein family. SHANK proteins then bind to the actin cytoskeleton and to Homer protein, which in turn interacts with mGluRs. Through these extended links, PSD95, SAPAP, SHANK and Homer proteins form a quaternary complex that brings together mGluR and NMDAR complexes in the PSD (FIG. 3)." SIGNOR-264600 PGM2 protein Q96G03 UNIPROT "D-ribofuranose 5-phosphate(2-)" smallmolecule CHEBI:78346 ChEBI "up-regulates quantity" "chemical modification" 9606 17804405 t miannu "Phosphopentomutase catalyzes the conversion of the nucleoside breakdown products ribose 1-phosphate and deoxyribose 1-phosphate to the corresponding 5-phosphopentoses. The role of phosphopentomutase is to utilize ribose 1-phosphate and deoxyribose 1-phosphate, which are formed by purine nucleoside phosphorylase and uridine phosphorylase. Using catalytic efficiency as a criterion, PGM2 acted more than 10-fold better as a phosphopentomutase (both on deoxyribose 1-phosphate and on ribose 1-phosphate) than as a phosphoglucomutase." SIGNOR-267076 CHD8 protein Q9HCK8 UNIPROT NEUROG1 protein Q92886 UNIPROT "down-regulates quantity" "transcriptional regulation" 10090 32839322 t Gianni "Many of the most significantly up-regulated genes in Chd8+/− and Chd8−/− NPCs are involved in later stages of neuronal development, including Ascl1 [a central driver of neural reprogramming (29)], Dcx, Map2, Nefm, Neurod4, and Neurog1 (Fig. 2 E and F). Additionally, we found that Sox3 is derepressed in both Chd8+/− and Chd8−/− NPCs, and several other Sox TF members (Sox2, Sox7, and Sox11) became derepressed in the Chd8−/− cells" SIGNOR-268919 (4R,4aS,7aR,12bS)-3-(cyclopropylmethyl)-4a,9-dihydroxy-6-(phenylmethylene)-1,2,4,5,7a,13-hexahydro-4,12-methanobenzofuro[3,2-e]isoquinoline-7-one chemical CHEBI:125500 ChEBI OPRM1 protein P35372 UNIPROT "down-regulates activity" "chemical inhibition" 10029 9686407 t miannu "Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors." SIGNOR-258774 ID2 protein Q02363 UNIPROT MYOD/E2-2 complex SIGNOR-C129 SIGNOR "down-regulates activity" binding 10090 BTO:0004058 9242638 t 2 miannu "All three Ids bound with high affinity to E proteins .Each Id was able to disrupt the ability of E protein-MyoD complexes to transactivate from a muscle creatine kinase reporter construct in vivo." SIGNOR-241146 CDK9 protein P50750 UNIPROT SMAD3 protein P84022 UNIPROT "down-regulates activity" phosphorylation Thr179 PQSNIPEtPPPGYLS 9606 19914161 t lpetrilli "Similarly, tgf-?-Induced and cdk8/9-mediated phosphorylation of smad3 at threonine 179 (t179) is important for binding of the nedd4l e3 ubiquitin ligase, which accelerates smad3 turnover;cdk8 and cyclint-cdk9 showed a preference for s206 and s214 but also phosphorylated s186 and s195 in the case of smad1;and t179, s208 and s213 in the case of smad3." SIGNOR-161589 SRC protein P12931 UNIPROT TNS3 protein Q68CZ2 UNIPROT up-regulates phosphorylation 9606 BTO:0000150;BTO:0000551;BTO:0000848 19732724 t gcesareni "Although sh2 domains have not been reported previously to be phosphorylated, the tensin-3 sh2 domain is a physiologic substrate for src. Tyrosines in the sh2 domain contribute to the biological activity of tensin-3, and phosphorylation of these tyrosines can regulate ligand binding." SIGNOR-187854 SSU72 protein Q9NP77 UNIPROT POLR2A protein P24928 UNIPROT "up-regulates activity" dephosphorylation Ser1647 SPSYSPTsPSYSPTS -1 15125841 t "Phosphorylation of serine-2 (S2) and serine-5 (S5) of the C-terminal domain (CTD) of RNA polymerase II (RNAP II) is a dynamic process that regulates the transcription cycle and coordinates recruitment of RNA processing factors. The Fcp1 CTD phosphatase catalyzes dephosphorylation of S2-P.| Depletion of Ssu72 impairs transcription in vitro" SIGNOR-248806 RPAP2 protein Q8IXW5 UNIPROT POLR2A protein P24928 UNIPROT "up-regulates activity" dephosphorylation Ser1763 TPTSPSYsPTSPSYS 9606 BTO:0000567 22137580 t "In addition, we show that RPAP2 is a CTD Ser5 phosphatase. Taken together, our results indicate that during transcription of snRNA genes, Ser7 phosphorylation facilitates recruitment of RPAP2, which in turn both recruits Integrator and dephosphorylates Ser5.|The Pol II CTD is first phosphorylated on Ser5 and then on Ser7 by CDK7. RPAP2 associates with the Pol II CTD after Ser7 phosphorylation and tethers a subcomplex of Integrator to snRNA genes. RPAP2 dephosphorylates Ser5P of the CTD, facilitating transcription and the subsequent recruitment of the Int11 catalytic subunit of Integrator" SIGNOR-248756 HCK protein P08631 UNIPROT PLCG2 protein P16885 UNIPROT "up-regulates activity" phosphorylation Tyr753 ERDINSLyDVSRMYV -1 7682059 t lperfetto "The phosphorylation of purified phospholipase C-gamma 1 (PLC-gamma 1) and PLC-gamma 2 by src-family-protein tyrosine kinases (PTKs) P56lck, p53/56lyn, p59hck, p59fyn, and p60src was studied in vitro. All five PTKs phosphorylated PLC-gamma 1 and PLC-gamma 2, suggesting that both PLC-gamma isozymes can be phosphorylated in cells by any of the src-family PTKs in response to the activation of cell surface receptors." SIGNOR-249363 N-(2-aminophenyl)-4-[[[4-(3-pyridinyl)-2-pyrimidinyl]amino]methyl]benzamide chemical CHEBI:94525 ChEBI HDAC2 protein Q92769 UNIPROT "down-regulates activity" "chemical inhibition" -1 20139990 t Luana "Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1)." SIGNOR-257973 BTC protein P35070 UNIPROT EGFR protein P00533 UNIPROT up-regulates binding 9606 10209155 t gcesareni "Betacellulin is synthesized primarily as a transmembrane precursor, which is then processed to mature molecule by proteolytic events;ten growth factors and their erbb specificities are depicted: egf, amphiregulin((ar), and tgfalfa bind erbb-1, betacellulin, heparin binding egf-like growth factor, and epiregulin bing both erbb-1 and erbb-4." SIGNOR-67003 CBFA2T3 protein O75081 UNIPROT CBFA2T3/ZNF651 complex SIGNOR-C197 SIGNOR "form complex" binding 9606 BTO:0000007 20116376 t "Previously we reported that a classical C2H2 zinc finger DNA binding protein ZNF652 functionally interacts with CBFA2T3 to repress transcription of genes containing ZNF652 consensus DNA binding sequence within the promoters of these target genes. Here we show that ZNF651 is a ZNF652 paralogue that shares a common DNA binding sequence with ZNF652 and represses target gene expression through the formation of a CBFA2T3-ZNF651 corepressor complex." SIGNOR-253956 CAMK2A protein Q9UQM7 UNIPROT SMAD2 protein Q15796 UNIPROT down-regulates phosphorylation Ser260 TLSPVNHsLDLQPVT 9606 SIGNOR-C8 11027280 t gcesareni "Smad2 is a target substrate for cam kinase ii in vitro at serine-110, -240, and -260. furthermore, cam kinase ii blocked nuclear accumulation of a smad2 and induced smad2-smad4 hetero-oligomerization independently of tgfbeta receptor activation, while preventing tgfbeta-dependent smad2-smad3 interactions." SIGNOR-82974 PDGFRA protein P16234 UNIPROT PDGFRA protein P16234 UNIPROT "up-regulates activity" phosphorylation Tyr1018 RLSADSGyIIPLPDI 9823 BTO:0004007 7535778 t miannu "We have identified two autophosphorylation sites, Tyr-988 and Tyr-1018, in the platelet-derived growth factor (PDGF) alpha-receptor carboxyl-terminal tail, which are involved in binding of phospholipase C-gamma (PLC-gamma). We conclude that phosphorylated Tyr-988 and Tyr-1018 in the PDGF α-receptor carboxyl-terminal tail bind PLC-γ, but this association leads to only a relatively low level of tyrosine phosphorylation and activation of PLC-γ." SIGNOR-250250 MECP2 protein P51608 UNIPROT FKBP5 protein Q13451 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 10090 16002417 t Luana "These results are compatible with the hypothesis that MeCP2 associates with the Sgk and Fkbp5 promoters and has a repressive effect that is over-ridden by elevated glucocorticoids in response to stress." SIGNOR-264542 DLGAP2 protein Q9P1A6 UNIPROT SHANK3 protein Q9BYB0 UNIPROT "up-regulates activity" relocalization 9606 BTO:0000938 28179641 t miannu "SHANK proteins are ‘master’ scaffolding proteins that tether and organize intermediate scaffolding proteins. They are located at excitatory synapses, where they are crucial for proper synaptic development and function. SAPAP proteins subsequently bind to the PDZ domain of members of the SHANK protein family. SHANK proteins then bind to the actin cytoskeleton and to Homer protein, which in turn interacts with mGluRs. Through these extended links, PSD95, SAPAP, SHANK and Homer proteins form a quaternary complex that brings together mGluR and NMDAR complexes in the PSD (FIG. 3)." SIGNOR-264591 IL1RAPL1 protein Q9NZN1 UNIPROT NCS1 protein P62166 UNIPROT "up-regulates activity" binding 10116 BTO:0001009 12783849 t miannu "IL1 receptor accessory protein like, a protein involved in X-linked mental retardation, interacts with Neuronal Calcium Sensor-1 and regulates exocytosis. our data show that IL1RAPL interacts only with NCS-1 through its specific C-terminal domain. The functional relevance of IL1RAPL activity was further supported by the inhibitory effect on exocytosis in PC12 cells overexpressing IL1RAPL. Taken together, our data suggest that IL1RAPL may regulate calcium-dependent exocytosis and provide insight into the understanding of physiopathological mechanisms underlying cognitive impairment resulting from IL1RAPL dysfunction." SIGNOR-263962 IFNG protein P01579 UNIPROT NfKb-p65/p50 complex SIGNOR-C13 SIGNOR "down-regulates activity" 10090 23667107 f "Early inhibition of IL-1β expression by IFN-γ is mediated by impaired binding of NF-κB to the IL-1β promoter but is independent of nitric oxide." SIGNOR-255937 Motilin smallmolecule CHEBI:80269 ChEBI MLNR protein O43193 UNIPROT "up-regulates activity" "chemical activation" 9606 31160049 t "Ligand-GPCR dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257542 MAPK1 protein P28482 UNIPROT SMAD1 protein Q15797 UNIPROT down-regulates phosphorylation Ser187 NSHPFPHsPNSSYPN 9606 9335504 t llicata "In contrast to the bmp-stimulated phosphorylation of smad1, which affects carboxy-terminal serines and induces nuclear accumulation of smad1, erk-mediated phosphorylation specifically inhibits the nuclear accumulation of smad1. phosphorylation occurs at specific serines within the region linking the inhibitory and effector domains of smad1" SIGNOR-52674 MYOD1 protein P15172 UNIPROT SMARCA4 protein P51532 UNIPROT up-regulates binding 9606 SIGNOR-C92 17194702 t miannu "Myod targets brg1 to the myogenin promoter during the initiation of myogenesis in tissue culture models for skeletal muscle differentiation /initiation of myogenin transcription is dependent upon myod, the pbx homeodomain factor, and swi/snf chromatin-remodeling enzymes" SIGNOR-151685 NFX1 protein Q12986 UNIPROT HLA-DRA protein P01903 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 7964459 t Luana "A novel cysteine-rich sequence-specific DNA-binding protein interacts with the conserved X-box motif of the human major histocompatibility complex class II genes via a repeated Cys-His domain and functions as a transcriptional repressor" SIGNOR-266224 "Factor Va-Xa" complex SIGNOR-C318 SIGNOR F2 protein P00734 UNIPROT "up-regulates activity" cleavage 11983337 t lperfetto "This activation is accomplished at a physiologically relevant rate by the prothrombinase complex, a macromolecular association of the serine protease factor Xa (fXa) with its cognate cofactor, factor Va (fVa), and substrate, prothrombin|Factor Va Increases the Affinity of Factor Xa for Prothrombin" SIGNOR-263546 calcium(2+) smallmolecule CHEBI:29108 ChEBI Synaptic_vesicle_exocytosis phenotype SIGNOR-PH160 SIGNOR up-regulates 9606 BTO:0000938 29953871 f miannu "Ca2+ is arguably the most important second messenger in the brain because of its pivotal roles in presynaptic neurotransmitter release, postsynaptic responses, and plasticity induction." SIGNOR-264954 "Elongin E3-Cul-5" complex SIGNOR-C531 SIGNOR FLNB protein O75369 UNIPROT "down-regulates quantity by destabilization" polyubiquitination 10090 BTO:0000165 19300455 t miannu "Here, we provide the first evidence that a novel ASB2 isoform, ASB2beta, is important for muscle differentiation. ASB2beta is expressed in muscle cells during embryogenesis and in adult tissues. ASB2beta is part of an active E3 ubiquitin ligase complex and targets the actin-binding protein filamin B (FLNb) for proteasomal degradation.  Altogether, our results indicated that ASB2β can assemble with elongin B, elongin C, Cullin 5 and Rbx2 to reconstitute an active E3 ubiquitin ligase complex.ASB2β induces polyubiquitylation of FLNb." SIGNOR-271801 PIP3 smallmolecule CHEBI:16618 ChEBI ZFYVE26 protein Q68DK2 UNIPROT "up-regulates quantity" relocalization 9606 BTO:0000567 20208530 t miannu "We show that PtdIns(3)P localizes to the midbody during cytokinesis and recruits a centrosomal protein, FYVE-CENT (ZFYVE26), and its binding partner TTC19, which in turn interacts with CHMP4B, an endosomal sorting complex required for transport (ESCRT)-III subunit implicated in the abscission step of cytokinesis." SIGNOR-265537 EML4-ALK "fusion protein" SIGNOR-FP8 SIGNOR STAT3 protein P40763 UNIPROT "up-regulates activity" phosphorylation 10090 BTO:0000944 21415216 t irozzo "We also found that phosphorylation of both the mitogen-activated proteinkinase (MAPK) ERK and STAT3 was markedly increased inthe cells expressing either variant of EML4-ALK[.]. Oncogenic EML4-ALK tyrosine kinase activates ERKand STAT3 signaling pathways" SIGNOR-259203 TNKS2 protein Q9H2K2 UNIPROT TERF1 protein P54274 UNIPROT "down-regulates activity" ADP-ribosylation -1 11739745 t lperfetto "Tankyrase 2 poly(ADP-ribosyl)ated itself and TRF1. Overexpression of tankyrase 2 in the nucleus released endogenous TRF1 from telomeres." SIGNOR-263376 dopamine smallmolecule CHEBI:18243 ChEBI noradrenaline smallmolecule CHEBI:33569 ChEBI "up-regulates quantity" "precursor of" 10090 7961964 t brain lperfetto "Dopamine beta-hydroxylase (DBH; EC 1.14.17.1) catalyzes the production of the neurotransmitter and hormone norepinephrine in the third step of the catecholamine biosynthesis pathway." SIGNOR-264182 CSNK2A1 protein P68400 UNIPROT TTI1 protein O43156 UNIPROT down-regulates phosphorylation Ser828 DVADGNVsDFDNEEE 9606 23263282 t lperfetto "Here we report that tel2 and tti1 are targeted for degradation within mtorc1 by the scffbxo9 ubiquitin ligase to adjust mtor signalling to growth factor availability. This process is primed by ck2, which translocates to the cytoplasm to mediate mtorc1-specific phosphorylation of tel2/tti1" SIGNOR-200240 SP3 protein Q02447 UNIPROT SOX18 protein P35713 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0000567 18496767 f miannu "co-transfection experiments revealed that over-expression of Sp3 and ZBP-89 down-regulate, while over-expression of NF-Y up-regulates SOX18 promoter activity in HeLa cells" SIGNOR-254820 NLGN4X protein Q8N0W4 UNIPROT NRXN3 protein Q9Y4C0 UNIPROT "up-regulates activity" binding 9606 BTO:0000938 18923512 t brain lperfetto "Pre- and postsynaptic plasma membranes are always precisely aligned, and are separated by a synaptic cleft of ~20 nm. The cleft contains an undefined proteinaceous material in the middle, and is presumably bridged by synaptic cell-adhesion molecules such as Nrxns and Nlgns that align the pre- and postsynaptic elements and mediate trans-synaptic signaling.|Nlgns bind to both alpha- and beta-Nrxns with nanomolar affinities; binding involves the sixth LNS-domain of alpha-Nrxns which corresponds to the only LNS-domain of beta-Nrxns52. The binding affinities differ characteristically between various pairs of Nlgns and Nrxns, and are controlled by alternative splicing of both Nrxns and Nlgns (Figure 1c)" SIGNOR-264165 "glycerone phosphate(2-)" smallmolecule CHEBI:57642 ChEBI "D-glyceraldehyde 3-phosphate(2-)" smallmolecule CHEBI:59776 ChEBI "up-regulates quantity" "precursor of" 9606 16051738 t miannu "Triosephosphate isomerase (TPI) is the glycolytic enzyme with the highest activity in vitro. TPI catalyzes the interconversion of glyceraldehyde-3-phosphate and DHAP (Figure 1). It consists of a dimer with 2 identical subunits of 248 amino acids (27 kDa)." SIGNOR-268136 Gbeta proteinfamily SIGNOR-PF4 SIGNOR SCNN1G protein P51170 UNIPROT "down-regulates quantity by destabilization" phosphorylation -1 11805112 t "inferred from 70% family members" lperfetto "Using a number of different approaches it was demonstrated that the protein kinase acting on betaThr-613 and gammaThr-623 is the extracellular regulated kinase (ERK). It is suggested that an ERK-mediated phosphorylation of betaThr-613 and gammaThr-623 down-regulates the channel by facilitating its interaction with Nedd4." SIGNOR-270061 GRIN1 protein Q05586 UNIPROT "NMDA receptor_2A" complex SIGNOR-C347 SIGNOR "form complex" binding 9606 BTO:0000938 12871085 t miannu "The NMDA receptor, a ligand-gated ion channel composed of the NR1 and NR2 subunits, is located mainly at synapses of CNS neurons. The NMDA receptor subtypes are encoded by three gene families that process mRNA transcripts to yield six distinct subunits (NR1, NR2A-2D, NR3A). Receptors are thought to be tetrameric complexes of two NR1 and two NR2 subunits" SIGNOR-264120 CSF1R protein P07333 UNIPROT CSF1R protein P07333 UNIPROT up-regulates phosphorylation Tyr699 DPEGGVDyKNIHLEK 9606 15297464 t lperfetto "Csf-1r homodimerizes and autophosphorylates on six tyrosines in the cytoplasmic portion of the receptor. Tyr807 is located in the activation loop of the kinase domain (9) and its phosphorylation is important for kinase activity (10). The remaining tyrosines serve as binding sites for proteins containing src homology 2 (sh2) binding domains. Three sites are found in the ki: grb2/mona (tyr697) (11, 12), p85 subunit of phosphatidylinositol 3-kinase (tyr721) (13), and stat1 (tyr706) (14), the c-cbl binding site is in the cooh terminus (tyr974) (15, 16), and the src family kinase (sfk) binding site is in the jmd (y559) (17). These molecules further propagate the csf-1 signal through activation of ras/erk, phosphatidylinositol 3-kinase/akt, and stat proteins." SIGNOR-127536 BTRC protein Q9Y297 UNIPROT "Cullin 1-RBX1-Skp1" complex SIGNOR-C529 SIGNOR "up-regulates activity" binding 9534 BTO:0004055 10514424 t miannu "Interaction with beta-TrCP is also necessary for ubiquitination of IkappaBbeta upon stimulation of cells, and deletion of the F-box in beta-TrCP abolishes its ability to ubiquitinate IkappaBbeta. Therefore, these results indicate that beta-TrCP plays a critical role in the activation of NF-kappaB by assembling the ubiquitin ligase complex for both phosphorylated IkappaBalpha and IkappaBbeta.β-TrCP recognizes IκBα phosphorylated at Ser-32 and Ser-36 through its WD40 domain, whereas the F-box motif recruits additional proteins including Skp1 and Cullin to form the Skp1-cullin-F-box (SCF) ubiquitin ligase complex" SIGNOR-272555 IRAK1 protein P51617 UNIPROT PELI1 protein Q96FA3 UNIPROT "up-regulates activity" phosphorylation Thr86 YTLSRAQtVVVEYTH 9606 12496252 t lperfetto "In this article we demonstrate that pellino 1 is phosphorylated at multiple sites by irak1 or irak4 in vitro. The key residues involved in activation are located between residues 76 and 86 (ser-76, ser-78, thr-80, ser-82, and thr-86) and at thr-288 and ser-293, just n-terminal to the ring-like domain that carries the e3 ligase activity. Unusually, we found that the phosphorylation of ser-76 or thr-288 or ser-293 alone was sufficient for maximal activation" SIGNOR-96759 PTEN protein P60484 UNIPROT AKT1 protein P31749 UNIPROT "down-regulates activity" 9606 BTO:0001271 20596030 f lperfetto "Exposure of eol-1r cells to imatinib failed to dephosphorylate akt, erk and stat5, although pdgfralpha was effectively inactivated. The forced expression of pten negatively regulated these signal pathways and sensitized eol-1r cells to imatinib." SIGNOR-252638 SIRT5 protein Q9NXA8 UNIPROT ACOX1 protein Q15067 UNIPROT "down-regulates activity" "catalytic activity" 9606 BTO:0000007 29491006 t Monia "SIRT5‐mediated desuccinylation inhibits ACOX1 activity by suppressing its active dimer formation." SIGNOR-261210 SHPK protein Q9UHJ6 UNIPROT "sedoheptulose 7-phosphate" smallmolecule CHEBI:15721 ChEBI "up-regulates quantity" phosphorylation 9606 22682222 t miannu "The sedoheptulose kinase CARKL directs macrophage polarization through control of glucose metabolism. CARKL bridges glycolysis and PPP by catalyzing the formation of S7P from sedoheptulose" SIGNOR-267084 CNTFR protein P26992 UNIPROT STAT1 protein P42224 UNIPROT up-regulates 9606 10582086 f gcesareni "Signal transduction by cntf requires that it bind first to cntfr alpha, permitting the recruitment of gp130 and lifr beta, forming a tripartite receptor complex. Cntf-induced heterodimerization of the beta receptor subunits leads to tyrosine phosphorylation (through constitutively associated jaks), and the activated receptor provides docking sites for sh2-containing signaling molecules, such as stat proteins." SIGNOR-72771 INS protein P01308 UNIPROT CEBPA protein P49715 UNIPROT up-regulates 9606 11279134 f fspada "The differentiation of 3t3-l1 preadipocytes is regulated in part by a cascade of transcriptional events involving activation of the ccaat/enhancer-binding proteins (c/ebps) and peroxisome proliferator-activated receptor gamma (ppargamma) by dexamethasone (dex), 3-isobutyl-1-methylxanthine (mix), and insulin" SIGNOR-250570 CSNK1A1 protein P48729 UNIPROT LRP6 protein O75581 UNIPROT up-regulates phosphorylation Thr1493 NPPPSPAtERSHYTM 9606 16341017 t lperfetto "We show that wnt induces sequential phosphorylation of lrp6 by gsk3 and casein kinase 1, and this dual phosphorylation promotes the engagement of lrp6 with the scaffolding protein axin.Site ii, like site i, was phosphorylated, as detected by means of a phospho-specific antibody (ab1493, for phosphorylated t1493 in lrp6)" SIGNOR-143034 PRKACA protein P17612 UNIPROT PLCG1 protein P19174 UNIPROT down-regulates phosphorylation Ser1248 HGRAREGsFESRYQQ 9606 BTO:0000782;BTO:0000661 1370476 t llicata "The observation that pka also phosphorylates plc-yl on serine 1248 suggests that phosphorylation of this residue may be a common mechanism by which pkc and pka inhibit plc-yl." SIGNOR-17901 SRGAP3 protein O43295 UNIPROT WASF1 protein Q92558 UNIPROT up-regulates binding 9606 12447388 t miannu "Wrp binds directly to wave-1 through its src homology domain 3 and specifically inhibits rac function in vivo." SIGNOR-95967 NR5A2 protein O00482 UNIPROT CYP19A1 protein P11511 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0001555 19022561 f miannu "We found that both SF1 and LRH1 can transcriptionally cooperate with the AP-1 family members c-JUN and c-FOS, known to be associated with enhanced proliferation of endometrial carcinoma cells, to further enhance activation of the STAR, HSD3B2, and CYP19A1 PII promoters." SIGNOR-254872 SMDT1 protein Q9H4I9 UNIPROT MCU_MICUB_variant complex SIGNOR-C499 SIGNOR "form complex" binding 9606 32315830 t miannu "MCU is a Ca2+-selective channel that mediates mitochondrial Ca2+ influx. The human channel contains tetrameric pore-forming MCU, regulatory subunits MICU1/2, and EMRE that is required both for channel function and MICU1/2-mediated Ca2+ regulation." SIGNOR-270861 Norbinaltorphimine chemical CHEBI:81529 ChEBI OPRM1 protein P35372 UNIPROT "down-regulates activity" "chemical inhibition" 10029 BTO:0000246 9686407 t miannu "Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors." SIGNOR-258821 RPS17 protein P08708 UNIPROT "40S cytosolic small ribosomal subunit" complex SIGNOR-C286 SIGNOR "form complex" binding -1 25901680 t lperfetto "Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins." SIGNOR-262434 PCDHA2 protein Q9Y5H9 UNIPROT PCDHGB6 protein Q9Y5F9 UNIPROT "up-regulates activity" binding 9606 BTO:0000227 16697637 t miannu "The clustered protocadherins comprise the largest subfamily of the cadherin superfamily and are predominantly expressed in the nervous system. Pcdh-alpha proteins interact with beta1-integrin to promote cell adhesion. They also form oligomers with Pcdh-gamma proteins at the same membrane sites." SIGNOR-265684 FBXW11 protein Q9UKB1 UNIPROT SUFU protein Q9UMX1 UNIPROT up-regulates binding 9606 BTO:0001130;BTO:0000848;BTO:0000527 10564661 t tpavlidou "We found that in vitro-translated 35s- labeled slimb indeed specifically bound to su(fu) in the gst pull-down assay. In our functional gli reporter assay, slimb alone did not alter gli-induced reporter expression;however, when cotransfected with hsu(fu), slimb significantly potentiated the inhibitory effect of su(fu) on gli activity." SIGNOR-72240 GATA4 protein P43694 UNIPROT CTNNA3 protein Q9UI47 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0002320 21598020 t miannu "GATA-4 and MEF2C are known to bind to the GATA box 2 in the major promoter of CTNNA3 and this element is essential in directly regulating expression of CTNNA3 in cardiac muscle cells. The co-transfection of GATA-4 with MEF2C leads to a synergistic activation of the CTNNA3 promoter" SIGNOR-265490 CAMKK2 protein Q96RR4 UNIPROT PRKAA2 protein P54646 UNIPROT up-regulates phosphorylation Thr172 SDGEFLRtSCGSPNY 9606 BTO:0000567 SIGNOR-C15 15980064 t gcesareni "These data indicate that the camkks function in intact cells as ampkks, predicting wider roles for these kinases in regulating ampk activity in vivo." SIGNOR-138364 AARS1 protein P49588 UNIPROT ATP(4-) smallmolecule CHEBI:30616 ChEBI "down-regulates quantity" "chemical modification" 9606 32314272 t miannu "Alanyl-tRNA synthetase 1 (AARS1) gene encodes a ubiquitously expressed class II enzyme that catalyzes the attachment of alanine to the cognate tRNA. AARS1 mutations are frequently responsible for autosomal dominant Charcot-Marie-Tooth disease type 2N (CMT2N)." SIGNOR-270448 KIF13A protein Q9H1H9 UNIPROT "Early Endosome" complex SIGNOR-C246 SIGNOR up-regulates relocalization 9606 30404817 t lperfetto "Recycling endosomes (REs) are transient endosomal tubular intermediates of early/sorting endosomes (E/SEs) that function in cargo recycling to the cell surface and deliver the cell type-specific cargo to lysosome-related organelles such as melanosomes in melanocytes.|Taken together, these findings suggest that Rab22A promotes the assembly of a BLOC-1-BLOC-2-KIF13A complex on E/SEs to generate REs that maintain cellular and organelle homeostasis." SIGNOR-260703 EIF2AK2 protein P19525 UNIPROT EIF2S1 protein P05198 UNIPROT down-regulates phosphorylation Ser52 MILLSELsRRRIRSI 9606 16179259 t lperfetto "The antiviral protein kinase pkr inhibits protein synthesis by phosphorylating the translation initiation factor eif2alpha on ser51the protein kinases pkr, hri, perk, and gcn2 specifically phosphorylate ser51 on the _ subunit of the translation initiation factor eif2, a gtp binding protein that delivers the initiator methionyl-trna to the small ribosomal subunit in the first step of translation initiation. Phosphorylation of eif2_ converts eif2 from a substrate to an inhibitor of its gdp-gtp exchange factor eif2b, thereby blocking protein synthesis" SIGNOR-140656 cabazitaxel chemical CHEBI:63584 ChEBI TUBA4A protein P68366 UNIPROT "down-regulates activity" "chemical inhibition" 9606 21770474 t miannu "Among these, larotaxel (XRP9881, formerly RPR109881A)[3,4] and cabazitaxel (XRP6258, TXD258, RPR116258A)[5] share a mechanism of action unique to taxanes, promoting tubulin assembly and stabilizing microtubules against cold-induced depolymerization" SIGNOR-259340 MELK protein Q14680 UNIPROT MELK protein Q14680 UNIPROT up-regulates phosphorylation Ser407 SNGVESKsLTPALCR 9606 16216881 t lperfetto "We have mapped no less than 16 autophosphorylation sites including serines, threonines, and a tyrosine residue and show that the phosphorylation of thr167 and ser171 is required for the activation of melk.We have not yet explored the role of autophosphorylation of nine residues in the c-terminal, autoinhibitory domain (fig. 4c). An enticing hypothesis is that these autophosphorylations decrease the inhibitory potency of this domain and thereby contribute to the activation of the kinase." SIGNOR-141006 TNF protein P01375 UNIPROT Inflammation phenotype SIGNOR-PH12 SIGNOR up-regulates 9606 18231581 f lperfetto "Induction and over-production of proinflammatory cytokines and chemokines, such as IL-6, IL-8, TNF-a and INF-c, were considered to be main mediators in the pathogenesis of SARS" SIGNOR-260258 NFATC2 protein Q13469 UNIPROT MYOF protein Q9NZM1 UNIPROT up-regulates "transcriptional regulation" 9606 23612709 f "Activated NFATc2 stimulates myoblast fusion through the increased production of IL-4 and myoferlin" SIGNOR-255461 ITGB1 protein P05556 UNIPROT "A9/b1 integrin" complex SIGNOR-C166 SIGNOR "form complex" binding 16988024 t lperfetto "Integrins are one of the major families of cell adhesion receptors (Humphries, 2000; Hynes, 2002). All integrins are non-covalently-linked, heterodimeric molecules containing an α and a β subunit. Both subunits are type I transmembrane proteins, containing large extracellular domains and mostly short cytoplasmic domains (Springer and Wang, 2004; Arnaout et al., 2005). Mammalian genomes contain 18 α subunit and 8 β subunit genes, and to date 24 different α,β combinations have been identified at the protein level. Although some subunits only appear in a single heterodimer, twelve integrins contain the β1 subunit, and five contain αV." SIGNOR-253184 dopamine smallmolecule CHEBI:18243 ChEBI DRD3 protein P35462 UNIPROT "up-regulates activity" "chemical activation" 9606 BTO:0002524 31160049 t "Ligand-GPCR dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257479 RPL21 protein P46778 UNIPROT "60S cytosolic large ribosomal subunit" complex SIGNOR-C287 SIGNOR "form complex" binding -1 25901680 t lperfetto "Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins." SIGNOR-262478 CHEK2 protein O96017 UNIPROT E2F1 protein Q01094 UNIPROT "up-regulates quantity by stabilization" phosphorylation Ser364 PLLSRMGsLRAPVDE 9606 12717439 t lperfetto "We report that checkpoint kinase 2 (chk2) regulates e2f-1 activity in response to the dna-damaging agent etoposide. A chk2 consensus phosphorylation site in e2f-1 is phosphorylated in response to dna damage" SIGNOR-100898 UCHL5 protein Q9Y5K5 UNIPROT TGFBR1 protein P36897 UNIPROT "up-regulates quantity by stabilization" binding 9606 17052192 t gcesareni "Smad7 can act as an adaptor able to recruit uch37 to the type i tgf-beta receptor. Consequently, uch37 dramatically up-regulates tgf-beta-dependent gene expression by de-ubiquitinating and stabilizing the type i tgf-beta receptor." SIGNOR-150135 PTPRG protein P23470 UNIPROT LIMK1 protein P53667 UNIPROT "down-regulates activity" dephosphorylation Tyr507 KPDRKKRyTVVGNPY -1 25624455 t miannu "PTPRG activation by the P1-WD peptide affected the tyrosine phosphorylation of several signaling molecules. Data analysis identified 31 molecules whose phosphorylation was modified in a statistically significant manner (Table I). inhibition of ABL1, BMX, BTK, DAB1, ITGB1, JAK2, KDR, KIT, LIMK1, MET, PDGFRB, SHC1, and VCL correlates with tyrosine dephosphorylation. In contrast, SRC inhibition correlates with hyperphosphorylation of the inhibitory Tyr530 residue and with dephosphorylation of the activatory Tyr419. Moreover, CDK2 and CTTN inhibition correlates with a hyperphosphorylation of the inhibitory Tyr15 and Tyr470, respectively. In contrast, a subgroup of 13 proteins, including BLNK, DOK2, ERBB2, GRIN2B, INSR, PDGFRA, PRKCD, PXN, STAT1, STAT2, STAT3, STAT5A, and ZAP70, appears to be activated by PTPRG activity." SIGNOR-254711 SRC protein P12931 UNIPROT AFAP1 protein Q8N556 UNIPROT unknown phosphorylation Tyr93 TSSLPEGyYEEAVPL 9534 9655255 t lperfetto "In this report, site-directed mutagenesis and a transient expression system that permits co-expression of activated pp60c-src (Src527F) and AFAP-110 in Cos-1 cells were used to identify the SH2-binding motif in AFAP-110. Four tyrosine residues, two in the amino terminus (Y93 and Y94) and two in the carboxy terminus (Y451 and Y453), were mutated to phenylalanine, significantly reducing overall steady-state levels of tyrosine phosphorylation and preventing Src527F from forming a stable complex with AFAP-110." SIGNOR-246359 BMPR1B protein O00238 UNIPROT SMAD1 protein Q15797 UNIPROT up-regulates phosphorylation Ser463 SPHNPISsVS 9606 9335504 t llicata "The c terminus of smad1, which is phosphorylated directly by the bmp type i receptor at the ssvs sequence in contrast to the bmp-stimulated phosphorylation of smad1, which affects carboxy-terminal serines and induces nuclear accumulation of smad1, erk-mediated phosphorylation specifically inhibits the nuclear accumulation of smad1." SIGNOR-52666 SLC24A1 protein O60721 UNIPROT sodium(1+) chemical CHEBI:29101 ChEBI "up-regulates quantity" relocalization 9606 BTO:0000938 30173760 t miannu "K+-dependent Na+-Ca2+ Exchangers (NCKX) are bi-directional plasma membrane Ca2+ transporters which belong to the Solute Carrier Family 24 A (SLC24 A) of membrane transporters. NCKXs operate via the alternating access model and mediate the extrusion of one Ca2+ ion coupled with one K+ ion in exchange for four Na+ ions (4Na+↔ 1Ca2+ + 1 K+)" SIGNOR-264400 MAP3K3 protein Q99759 UNIPROT RCAN1 protein P53805 UNIPROT up-regulates phosphorylation Ser167 FLISPPAsPPVGWKQ 9606 BTO:0000782 16126726 t gcesareni "Essential role of mekk3 signaling in angiotensin ii-induced calcineurin/nuclear factor of activated t-cells activation" SIGNOR-138945 LCMT1 protein Q9UIC8 UNIPROT PPP2CB protein P62714 UNIPROT "up-regulates activity" methylation Leu309 RRTPDYFl -1 18394995 t lperfetto "Methylation of the carboxy-terminal Leu309 in a conserved TPDYFL309 motif of the C subunit has been shown to enhance the affinity of the PP2A core enzyme for some, but not all, regulatory subunits |The PP2A core enzyme was methylated by a PP2A-specific leucine carboxyl methyltransferase (LCMT1)" SIGNOR-265751 GHSR protein Q92847 UNIPROT GNAZ protein P19086 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257322 P300/PCAF complex SIGNOR-C7 SIGNOR SMAD2 protein Q15796 UNIPROT "up-regulates activity" acetylation Lys19 VKRLLGWkKSAGGSG 9606 17074756 t lperfetto "Acetylation of the short isoform of Smad2 improves its DNA binding activity in vitro and enhances its association with target promoters in vivo, thereby augmenting its transcriptional activity. Smad2(FL) and Smad2(_E3) were also acetylated by P/CAF in vivo and the acetylation of both proteins was lost following mutation of Lys19 (Fig. 2D), suggesting that Lys19 in Smad2 is also targeted by P/CAF." SIGNOR-217607 ARNT protein P27540 UNIPROT TH protein P07101 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 10090 BTO:0003945 17457889 f lperfetto "Overexpression and siRNA experiments revealed that NPAS1, in concert with ARNT, negatively regulates the expression of TH and that this regulation is mediated by a direct binding of NPAS1 on the TH promoter." SIGNOR-253701 NUMB protein P49757 UNIPROT NOTCH proteinfamily SIGNOR-PF30 SIGNOR down-regulates BTO:0001103 12361602 t apalma "Therefore, these genetic data further support the hypothesis that activation of Notch-1 promotes a less committed myogenic phenotype and that the attenuation of Notch-1 activity by Numb promotes progression along the myogenic lineage toward a myoblast cell fate." SIGNOR-255375 SRC protein P12931 UNIPROT KCNA3 protein P22001 UNIPROT up-regulates phosphorylation Tyr499 EGEEQSQyMHVGSCQ 9606 11812778 t gcesareni "The shaker family k+ channel protein, kv1.3, is tyrosine phosphorylated by v-src kinase at tyr137 and tyr449 to modulate current magnitude and kinetic properties." SIGNOR-114645 CSNK2A1 protein P68400 UNIPROT GPI protein P06744 UNIPROT "down-regulates activity" phosphorylation Ser185 GPRVWYVsNIDGTHI 9606 BTO:0000459 15637053 t llicata "It is known that human PGI/AMF is phosphorylated at Ser(185) by protein kinase CK2 (CK2) | These results demonstrate that phosphorylation affects the allosteric kinetic properties of the enzyme, resulting in a less active form of PGI, whereas non-phosphorylated protein species retain cytokine activity. " SIGNOR-250869 MAPK3 protein P27361 UNIPROT MKNK1 protein Q9BUB5 UNIPROT up-regulates phosphorylation 9606 9155017 t gcesareni "We have identified a new subfamily of murine serine/threonine kinases, whose members, map kinase-interacting kinase 1 (mnk1) and mnk2, bind tightly to the growth factor-regulated map kinases, erk1 and erk2." SIGNOR-48352 G3BP1 protein Q13283 UNIPROT EIF2AK2 protein P19525 UNIPROT "up-regulates activity" binding 9606 BTO:0001938;BTO:0000567 25784705 t SARA "PKR directly interacts with G3BP1 through the NTF2-like and PXXP domains of G3BP1. The recruitment of inactive PKR to SGs through this interaction correlates with its activation" SIGNOR-260981 MLL-ENL "fusion protein" SIGNOR-FP7 SIGNOR HOXA9 protein P31269 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 14701735 f irozzo "Here we demonstrate that MLL-ENL immortalizes cells mainly through inducing a reversible block on myeloid differentiation that is dependent on upregulation of Hoxa9 and Meis1 and that enforced expression of these two genes is sufficient to substitute for MLL-ENL function." SIGNOR-255863 POLR3A protein O14802 UNIPROT "RNA Polymerase III" complex SIGNOR-C389 SIGNOR "form complex" binding 9606 BTO:0000567 12391170 t lperfetto "In this article, we use this proposed nomenclature for the S. cerevisiae subunits as the guide to refer to the human RNA polymerase III subunits, as indicated in Table ​Table1,1, and consequently the numbering of the human subunits does not always correspond to their decreasing apparent molecular weights." SIGNOR-266133 TEK protein Q02763 UNIPROT TEK protein Q02763 UNIPROT "up-regulates activity" phosphorylation Tyr992 LSRGQEVyVKKTMGR -1 11513602 t lperfetto "Isoelectric focusing electrophoresis and mass spectrometric analysis of a tie2 autophosphorylation time course showed that tyr992 on the putative activation loop was phosphorylated first followed by tyr1108 in the c-terminal tail autophosphorylation of tie2 to produce ptie2 resulted in a 100-fold increase in kcat and a 460-fold increase in kcat/km." SIGNOR-109790 MLXIPL protein Q9NP71 UNIPROT ELOVL6 protein Q9H5J4 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000599 27524233 t Luana "In this study, we clearly show that mouse and human Elovl6 are direct targets of ChREBP. " SIGNOR-267945 dabrafenib chemical CHEBI:75045 ChEBI RAF1 protein P04049 UNIPROT "down-regulates activity" "chemical inhibition" -1 24720932 t miannu "Dabrafenib is known to inhibit V600E, V600K and V600D BRAF enzymes with in vitro IC50 values of 0.65, 0.5 and 1.84 nM, respectively. Dabrafenib can inhibit wild-type BRAF and CRAF kinases with IC50 values of 3.2 and 5.0 nM. Other kinases (SIK1, NEK111 and LIMK1) can be inhibited by dabrafenib when administered in high concentrations" SIGNOR-259218 WNK3 protein Q9BYP7 UNIPROT SLC12A3 protein P55017 UNIPROT "up-regulates activity" phosphorylation 21613606 t lperfetto "We have shown that with-no-lysine kinase 3 (WNK3) possesses several properties that suggest it could be the Cl−/volume-sensitive regulatory kinase that, in association with protein phosphatases, reciprocally modifies the phosphorylation/dephosphorylation states of the SLC12 proteins and thus their activities|WNK3 activates NKCC1/2 and NCC and inhibits the KCCs" SIGNOR-264624 HRAS protein P01112 UNIPROT RAF1 protein P04049 UNIPROT up-regulates binding 9606 21779497 t lperfetto "The first RAS effector pathway to be identified was the RAF-MEK-ERK pathway. This pathway is an essential, shared element of mitogenic signaling involving tyrosine kinase receptors, leading to a wide range of cellular responses, including growth, differentiation, inflammation, and apoptosis.23 The RAF family of proteins (Raf-1, A-Raf, and B-Raf) is serine/threonine kinases that bind to the effector region of RAS-GTP, thus inducing translocation of the protein to the plasma membrane." SIGNOR-236656 D-glucitol smallmolecule CHEBI:17924 ChEBI FUS protein P35637 UNIPROT "down-regulates activity" relocalization 9606 BTO:0000312 33172210 f "We found that osmotic stress robustly induced nuclear loss of TDP-43, SPFQ, FUS, hnRNPA1 and hnRNPK, with characteristic changes in nucleocytoplasmic localisation in an RBP-dependent manne" SIGNOR-262813 ITGB1BP1 protein O14713 UNIPROT "A3/b1 integrin" complex SIGNOR-C161 SIGNOR "down-regulates activity" binding 9606 19118207 t miannu "Integrins also bind to many PTBdomain-containing proteins (Calderwood et al., 2003) – including Dok1 and integrincytoplasmic-domain-associated protein 1 (ICAP1) – and these can compete with talin for binding to integrin and so can impair activation" SIGNOR-257641 ACACA protein Q13085 UNIPROT malonyl-CoA smallmolecule CHEBI:15531 ChEBI "up-regulates quantity" "chemical modification" 9606 20952656 t miannu "ACC catalyzes the carboxylation of acetyl-CoA to malonyl-CoA, the rate-limiting and first committed step in de novo fatty acid biosynthesis. Two isoforms of ACC exist in mammals, ACC1 and ACC2, and both enzymes function to carboxylate acetyl-CoA to form malonyl-CoA" SIGNOR-267109 "Caspase 3 complex" complex SIGNOR-C221 SIGNOR ROCK1 protein Q13464 UNIPROT up-regulates cleavage 9606 11283607 t gcesareni "Rock i is cleaved by casp3 at a conserved detd1113/g sequence and its carboxy-terminal inhibitory domain is removed, resulting in deregulated and constitutive kinase activity." SIGNOR-256460 TRIM38 protein O00635 UNIPROT TRAF6 protein Q9Y4K3 UNIPROT "down-regulates quantity by destabilization" polyubiquitination 9606 BTO:0000007 22323536 t miannu "As an E3 ligase, TRIM38 bound to TRAF6 and promoted K48-linked polyubiquitination, which led to the proteasomal degradation of TRAF6. " SIGNOR-272009 GSK3A protein P49840 UNIPROT MAFA protein Q8NHW3 UNIPROT "down-regulates quantity by destabilization" phosphorylation Thr57 LSSTPLStPCSSVPS 9606 18042454 t miannu "We also demonstrate that gsk-3 triggers mafa sequential phosphorylation on residues s61, t57, t53, and s49 /we demonstrated that phosphorylation by gsk-3 is conserved among the large maf proteins. It couples ubiquitination/degradation and transcriptional activation and modulates maf biological activity./ Taken together, these results suggest that, in contrast to what can be expected from ubiquitination/degradation, gsk-3-mediated mafa phosphorylation increases its transactivating ability, thereby controlling its biological activity." SIGNOR-159398 GSK690693 chemical CHEBI:90677 ChEBI AKT1 protein P31749 UNIPROT "down-regulates activity" "chemical inhibition" -1 22037378 t Luana "Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here." SIGNOR-258118 KDM5D protein Q9BY66 UNIPROT "Histone H3" proteinfamily SIGNOR-PF69 SIGNOR "up-regulates activity" demethylation 9606 30246379 t miannu "KDM5 subfamily is capable of removing tri‚Äê and di‚Äê methyl marks from lysine 4 on histone H3 (H3K4). Depending on the methylation site, its effect on transcription can be either activating or repressing." SIGNOR-265336 MAPK1 protein P28482 UNIPROT RPS6KA5 protein O75582 UNIPROT up-regulates phosphorylation Thr581 PDNQPLKtPCFTLHY 9606 18267068 t gcesareni "Together, our in vivo and in vitro studies indicate that the pkc/c-raf/mek/erk pathway plays a major role in the s6k1 activation in hypertrophic cardiac growth." SIGNOR-160787 BABAM2 protein Q9NXR7 UNIPROT "BRCC ubiquitin ligase complex" complex SIGNOR-C295 SIGNOR "form complex" binding 9606 BTO:0000007 14636569 t lperfetto "These findings identify BRCC as a ubiquitin E3 ligase complex that enhances cellular survival following DNA damage.|Reconstitution of a recombinant four-subunit complex containing BRCA1/BARD1/BRCC45/BRCC36 revealed an enhanced E3 ligase activity compared to that of BRCA1/BARD1 heterodimer" SIGNOR-263209 MASP2 protein O00187 UNIPROT C4A protein P0C0L4 UNIPROT "up-regulates activity" cleavage Gly1446 TPLQLFEgRRNRRRR -1 17204478 t lperfetto "MASP-2 cleaves C4 releasing C4a and generating C4b, which attaches covalently to the pathogen surface upon exposure of its reactive thioester. C2 binds to C4b and is also cleaved by MASP-2 to form the C3 convertase (C4b2a)." SIGNOR-263437 NADP(3-) smallmolecule CHEBI:58349 ChEBI NADPH(4-) smallmolecule CHEBI:57783 ChEBI "up-regulates quantity" "precursor of" 9606 34775382 t miannu "6 PG undergoes oxidative decarboxylation by 6-phosphogluconate dehydrogenase (6PGD) producing Ru5P and the second NADPH molecule." SIGNOR-268111 ACVR1 protein Q04771 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR "down-regulates activity" 9606 18801898 f gcesareni "Akt/mTOR signaling is a key target that accounts for myostatin function during muscle atrophy, uncovering a novel role for myostatin in protein metabolism and more specifically in the regulation of translation in skeletal muscle." SIGNOR-243185 "Caspase 1 complex" complex SIGNOR-C220 SIGNOR IL1B protein P01584 UNIPROT "up-regulates activity" cleavage Asp116 DNEAYVHdAPVRSLN -1 1919001 t lperfetto "IL-1 converting enzyme (ICE) specifically cleaves the human IL-1 beta precursor at two sequence-related sites: Asp27-Gly28 (site 1) and Asp116-Ala117 (site 2). Cleavage at Asp116-Ala117 results in the generation of mature, biologically active IL-1 beta. " SIGNOR-256376 "perfluorodecanoic acid" chemical CHEBI:35546 ChEBI PPARD protein Q03181 UNIPROT "up-regulates activity" "chemical activation" -1 31332417 t miannu "In the present study, we demonstrated PFASs bound to and activated human PPARb/d-LBD directly. The PPARb/d binding potency and transcriptional activity of PFASs were all related to the carbon chain length and the terminal functional group." SIGNOR-268758 BMPR1A protein P36894 UNIPROT FAM83G protein A6ND36 UNIPROT "up-regulates activity" phosphorylation Ser610 GPGPRRPsVASSVSE 9606 24554596 t lperfetto "These results indicate that ALK3 phosphorylates PAWS1 predominantly at Ser610 but can also phosphorylate at Ser614 and Ser616 in vitro. |Here, we report the discovery and characterization of PAWS1/FAM83G as a novel SMAD1 interactor. PAWS1 forms a complex with SMAD1 in a SMAD4-independent manner, and BMP signalling induces the phosphorylation of PAWS1 through BMPR1A. The phosphorylation of PAWS1 in response to BMP is essential for activation of the SMAD4-independent BMP target genes NEDD9 and ASNS. Our findings identify PAWS1 as the first non-SMAD substrate for type I BMP receptor kinases and as a novel player in the BMP pathway." SIGNOR-264765 PRKCA protein P17252 UNIPROT PRKCA protein P17252 UNIPROT up-regulates phosphorylation Ser657 QSDFEGFsYVNPQFV 9606 15277524 t lperfetto "Pkc is frequently autophosphorylated on two c-terminal sites, the turn motif (thr- 638 in human pkc) and the hydrophobic site (ser-657 in human pkc). Thus, it is becoming clear that autophosphorylation of pkc can be a regulated event and that it has significant impact on pkc function" SIGNOR-127253 RELA protein Q04206 UNIPROT SNAIL/RELA/PARP1 complex SIGNOR-C198 SIGNOR "form complex" binding 9606 BTO:0000452;BTO:0002625 22223884 t alessandro "Therefore, we conclude that the endogenous proteins PARP1, p65NF-κB and Snail1 form a ternary complex in the nuclei of cells that are actively expressing fibronectin" SIGNOR-254527 ARNTL protein O00327 UNIPROT VWF protein P04275 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 10090 BTO:0000394 20658528 t lperfetto "We also show that major circadian transcriptional regulators CLOCK and Bmal1 directly regulate the activity of vWF promoter and that lack of Bmal1 results in upregulation of vWF both at mRNA and protein level. Here we report a direct regulation of vWF expression in endothelial cells by biological clock gene Bmal1. This study establishes a mechanistic connection between Bmal1 and cardiovascular phenotype." SIGNOR-253704 1,2-diacyl-sn-glycerol smallmolecule CHEBI:17815 ChEBI PRKCZ protein Q05513 UNIPROT "up-regulates activity" binding 9606 14967450 t "PKCs (PRKCA, PRKCB and PRKCG) are activated by calcium and diacylglycerol (DAG) in the presence of phosphatidylserine." lperfetto "The molecular requirements for diacylglycerol (dag) and calcium (ca2+) to promote pkc membrane translocation, the hallmark of pkc activation, have been clarified." SIGNOR-242599 DZIP3 protein Q86Y13 UNIPROT ATXN1 protein P54253 UNIPROT "down-regulates quantity by destabilization" polyubiquitination 9606 BTO:0000567 24326307 t miannu "HOTAIR associates with E3 ubiquitin ligases bearing RNA-binding domains, Dzip3 and Mex3b, as well as with their respective ubiquitination substrates, Ataxin-1 and Snurportin-1. In this manner, HOTAIR facilitates the ubiquitination of Ataxin-1 by Dzip3 and Snurportin-1 by Mex3b in cells and in vitro, and accelerates their degradation." SIGNOR-272078 BTG2 protein P78543 UNIPROT KLK3 protein P07288 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 21172304 f "Androgen-induced promoter activation and expression of prostate-specific antigen (PSA) are significantly attenuated by BTG2." SIGNOR-253658 KANK1 protein Q14678 UNIPROT BAIAP2 protein Q9UQB8 UNIPROT "down-regulates activity" binding 10090 BTO:0000944 19171758 t miannu "In this study, we report that Kank disrupts the function of active Rac1 through IRSp53. The binding between IRSp53 and Kank inhibits the association of active Rac1 with IRSp53 rather than the association of active cdc42 with IRSp53. Kank inhibits the formation of lamellipodia and membrane ruffles induced by active Rac1 in NIH3T3 cells. Kank interacts with IRSp53 through their coiled-coil domains. Kank affected the interaction between IRSp53 and Rac1 and partially affected that between IRSp53 and cdc42 (Fig. 3)." SIGNOR-265553 acetyl-CoA smallmolecule CHEBI:15351 ChEBI "hexadecanoic acid" smallmolecule CHEBI:15756 ChEBI "up-regulates quantity" "precursor of" 9606 15507492 t miannu "Human fatty acid synthase (FAS) is a complex homodimeric (552-kDa) enzyme that regulates the¬†de novo¬†biosynthesis of long-chain fatty acids. This cytosolic enzyme catalyzes the formation of 16 carbon (C16) palmitate, from acetyl-coenzyme A (acetyl-CoA) and malonyl-coenzyme A (malonyl-CoA) in the presence of NADPH.¬†" SIGNOR-268089 ABI1 protein Q8IZP0 UNIPROT "WAVE complex" complex SIGNOR-C271 SIGNOR "form complex" binding 9606 BTO:0000567 15070726 t lperfetto "Here we purify Wave-2 from HeLa cells. Five proteins, Sra, Nap, Wave-2, Abi, and Hspc, are copurified, indicating that they form a tight complex. " SIGNOR-261872 VHL protein P40337 UNIPROT DAB2 protein P98082 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000037 15824735 f miannu "three of the nine targets had been identified previously as candidate TSGs (DOC-2/DAB2, CDKN1C and SPARC) and all were upregulated by wild-type pVHL." SIGNOR-255602 S100A4 protein P26447 UNIPROT MYH9 protein P35579 UNIPROT "down-regulates activity" binding 10090 BTO:0005138 16707441 t miannu "Our results show that S100A4 regulates cell polarization during directed motility by affecting the localization of protrusions through interactions with myosin-IIA, with S100A4 expressing cells displaying few side protrusions and extensive forward protrusions during chemotaxis compared with control cells. The mechanisms by which these antibodies and S100A4 increase protrusive activity and promote cellular motility are not well understood, but the observation that S100A4 can inhibit the actin-activated ATPase of myosin-IIA (34) suggests that S100A4 could function as a myosin-IIA inhibitor in vivo." SIGNOR-269282 DYRK4 protein Q9NR20 UNIPROT DYRK4 protein Q9NR20 UNIPROT "up-regulates activity" phosphorylation Tyr264 SSCYEHQkVYTYIQS 9606 21127067 t Manara "Autophosphorylation of DYRK4 in the Activation Loop Is Required for Kinase Activity" SIGNOR-260827 WNT6 protein Q9Y6F9 UNIPROT FZD3 protein Q9NPG1 UNIPROT up-regulates binding 9606 15578921 t gcesareni "Wnt proteins bind to the frizzled receptors and lrp5/6 co-receptors, and through stabilizing the critical mediator betBeta-catenin, initiate a complex signaling cascade that plays an important role in regulating cell proliferation and differentiation." SIGNOR-131891 romidepsin chemical CHEBI:61080 ChEBI HDAC7 protein Q8WUI4 UNIPROT "down-regulates activity" "chemical inhibition" -1 20139990 t Luana "Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1)." SIGNOR-257992 RAB8A protein P61006 UNIPROT Cilium_assembly phenotype SIGNOR-PH64 SIGNOR up-regulates 9606 18694559 f miannu "CEP290 cooperates with Rab8a to promote ciliogenesis and this function is antagonized by CP110" SIGNOR-252148 "bisphenol A" chemical CHEBI:33216 ChEBI ESR1 protein P03372 UNIPROT "up-regulates activity" "chemical activation" -1 9751507 t miannu "Bisphenol A is an equally strong agonist for ERα as for ERβ, and the same is true for 4,4′-biphenol, which differs from bisphenol A in that it lacks the propane group between the phenolic rings." SIGNOR-268738 14-3-3 proteinfamily SIGNOR-PF7 SIGNOR HDAC5 protein Q9UQL6 UNIPROT down-regulates binding 9606 BTO:0000887;BTO:0001103 12058061 t gcesareni "In the cytoplasm, 14-3-3 proteins bind the phosphorylated hdac5 and retain it in the cytosol." SIGNOR-89444 BCR-ABL "fusion protein" SIGNOR-FP6 SIGNOR CRKL protein P46109 UNIPROT up-regulates phosphorylation Tyr207 IPEPAHAyAQPQTTT 9606 BTO:0001271 9053848 t lperfetto "Tyrosine 207 in crkl is the bcr/abl phosphorylation sitephosphorylation of y207 provides a binding site for the crkl sh2 domain and potentially for other sh2-containing proteins." SIGNOR-46893 GSK3B/Axin/APC complex SIGNOR-C110 SIGNOR CTNNB1 protein P35222 UNIPROT "down-regulates activity" phosphorylation Ser37 YLDSGIHsGATTTAP 9606 BTO:0000586 16293724 t lperfetto "This leads to the inactivation and release of glycogen synthase kinase 3beta from its complex with axin, thereby relieving the inhibitory phosphorylation of beta-catenin and activating its signaling pathway." SIGNOR-227889 CyclinE/CDK2 complex SIGNOR-C16 SIGNOR MYOD1 protein P15172 UNIPROT down-regulates phosphorylation Ser200 YSGDSDAsSPRSNCS 9606 21902831 t lperfetto "Cyclin e/cdk2 can phosphorylate myod at serine 200, which causes ubiquitination and degradation of this transcription factor during g1, preventing its accumulation and a commitment to differentiation." SIGNOR-216706 CASP8 protein Q14790 UNIPROT Cell_death phenotype SIGNOR-PH109 SIGNOR up-regulates 9606 14585074 f amattioni "Downstream of caspase-8 activation, apoptosis induction takes place" SIGNOR-256639 RABGEF1 protein Q9UJ41 UNIPROT RAB5A protein P20339 UNIPROT up-regulates binding 9606 11452015 t miannu "We have previously shown that rab5, which regulates various steps of transport along the early endocytic pathway, is activated by a complex consisting of rabex-5, a rab5 nucleotide exchange factor, and the effector rabaptin-5." SIGNOR-109398 JUN protein P05412 UNIPROT Cell_migration phenotype SIGNOR-PH38 SIGNOR up-regulates 9606 23151663 f amattioni "Planar cell polarity (PCP) signalling is prominently involved in the regulation of cell polarity, cell motility and morphogenetic movements, throught the activation of JUN transcription factor." SIGNOR-229760 TAB1 protein Q15750 UNIPROT JNK proteinfamily SIGNOR-PF15 SIGNOR up-regulates binding 9606 25290089 t lperfetto "The irak1/traf6 complex can also activate jnk and p38 signalling through assembly of a catalytically active tab2-tab3-tak1 complex." SIGNOR-205437 AKT1 protein P31749 UNIPROT NUAK1 protein O60285 UNIPROT up-regulates phosphorylation Ser600 PARQRIRsCVSAENF 9606 12409306 t esanto "Ser(600) in ark5 was found to be phosphorylated by active akt resulting in the activation of kinase activity." SIGNOR-252591 PRPS2 protein P11908 UNIPROT "D-ribofuranose 5-phosphate(2-)" smallmolecule CHEBI:78346 ChEBI "down-regulates quantity" "chemical modification" 9606 16939420 t miannu "PRPP (phosphoribosylpyrophosphate) is an important metabolite essential for nucleotide synthesis and PRS (PRPP synthetase) catalyses synthesis of PRPP from R5P (ribose 5-phosphate) and ATP." SIGNOR-267081 PDE1C protein Q14123 UNIPROT "3',5'-cyclic AMP" smallmolecule CHEBI:17489 ChEBI "down-regulates quantity" "chemical modification" 9606 22014080 t "PDE1A and PDE1B preferentially hydrolyse cGMP, whereas PDE1C hydrolyses cAMP and cGMP with similar Km values" SIGNOR-253399 SGK1 protein O00141 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR "down-regulates activity" phosphorylation Ser315 DFRSRTNsNASTVSG 9606 BTO:0000007 11154281 t lperfetto "We show here that sgk1, like akt, promotes cell survival and that it does so in part by phosphorylating and inactivating fkhrl1. However, sgk and akt display differences with respect to the efficacy with which they phosphorylate the three regulatory sites on fkhrl1. While both kinases can phosphorylate thr-32, sgk displays a marked preference for ser-315 whereas akt favors ser-253." SIGNOR-252989 EIF3J protein O75822 UNIPROT EIF3_complex complex SIGNOR-C401 SIGNOR "form complex" binding -1 16920360 t miannu "Consistent with its diverse functions, eIF3 is the largest and most complex initiation factor: the mammalian version, for example, contains 13 nonidentical subunits that are designated eIF3a to eIF3m 8, 9, 10, 11, 12, 13 (Table 1)." SIGNOR-266391 PBX1 protein P40424 UNIPROT FGF8 protein P55075 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 10090 BTO:0003560 10026229 t miannu "Our results in ES cells suggest that Engrailed inhibits Fgf8 expression in the absence of Pbx1. We identified single Engrailed- and Pbx-binding sites in the Fgf8 intron that inhibit expression of Fgf8 in mouse ES cells, but that together can allow full Fgf8 expression. Our data support the model that Engrailed heterodimerized with Pbx might activate transcription, while Engrailed or Pbx proteins alone might repress transcription" SIGNOR-265803 PPP4C protein P60510 UNIPROT RELA protein Q04206 UNIPROT "up-regulates activity" dephosphorylation Thr435 PTQAGEGtLSEALLQ 9606 15073167 t "Suppression of MEK/ERK signaling pathway enhances cisplatin-induced NF-kappaB activation by protein phosphatase 4-mediated NF-kappaB p65 Thr dephosphorylation" SIGNOR-248549 KLF6 protein Q99612 UNIPROT ATF3 protein P18847 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 BTO:0001321 18755691 t Luana "KLF6 binds directly to and activates the ATF3 promoter." SIGNOR-266051 CDC73 protein Q6P1J9 UNIPROT PAF1C complex SIGNOR-C471 SIGNOR "form complex" binding 9606 BTO:0000567 20178742 t miannu "Human PAF1C was affinity purified from a FLAG-hPAF1 HeLa cell line and found to contain homologues (hCTR9, hLEO1, hPAF1, hCDC73 and hRTF1) of the five yeast PAF1C subunits, as well as the SKI8 subunit unique to hPAF1C (Figure 1A). " SIGNOR-269836 betrixaban chemical CHEBI:140421 ChEBI F10 protein P00742 UNIPROT "down-regulates activity" "chemical inhibition" -1 19297154 t Luana "Discovery of betrixaban (PRT054021), N-(5-chloropyridin-2-yl)-2-(4-(N,N-dimethylcarbamimidoyl)benzamido)-5-methoxybenzamide, a highly potent, selective, and orally efficacious factor Xa inhibitor." SIGNOR-257817 CHEK1 protein O14757 UNIPROT SNCB protein Q16143 UNIPROT unknown phosphorylation Tyr127 EDPPQEEyQEYEPEA 9606 21699177 t llicata "Chk preferentially phosphorylates recombinant _-synuclein at tyrosine-127" SIGNOR-174590 NOXA1 protein Q86UR1 UNIPROT NOX3 protein Q9HBY0 UNIPROT "up-regulates activity" binding 9606 BTO:0000007 20943948 t lperfetto "Tks4 and Tks5 bind NoxA1 through their SH3 domains in a Rac-independent manner|NoxO1 is required for full Nox1 and Nox3 oxidase activity at least partially because of its role in the plasma membrane recruitment of the NoxA1 activator protein|Tks4 and Tks5 support Nox1- and Nox3-dependent ROS generation" SIGNOR-264711 CSNK2A1 protein P68400 UNIPROT RELA protein Q04206 UNIPROT "up-regulates activity" phosphorylation Ser529 GLPNGLLsGDEDFSS 9606 10938077 t gcesareni "Tumor necrosis factor alpha-induced phosphorylation of RelA/p65 on Ser529 is controlled by casein kinase II.|Furthermore, our results indicate that the association between IkappaBalpha and p65 inhibits p65 phosphorylation by CKII and that degradation of IkappaBalpha allows CKII to phosphorylate p65 to increase NF-kappaB transactivation potential." SIGNOR-149635 Calcineurin complex SIGNOR-C155 SIGNOR NFATC2 protein Q13469 UNIPROT "up-regulates activity" dephosphorylation Ser172 LCLSPASsGSSASFI 9606 BTO:0000567 11030334 t "NFAT1 is phosphorylated on fourteen conserved phosphoserine residues in its regulatory domain, thirteen of which are dephosphorylated upon stimulation. Dephosphorylation of all thirteen residues is required to mask a nuclear export signal (NES), cause full exposure of a nuclear localization signal (NLS), and promote transcriptional activity" SIGNOR-252316 DPP10 protein Q8N608 UNIPROT KCND2 protein Q9NZV8 UNIPROT "up-regulates activity" relocalization 9534 BTO:0000298 15454437 t Luisa "Coexpression of DPP10 changes the subcellular localization of Kv4.2 expressed in COS-7 cells by promoting surface trafficking.DPP10 accelerates Kv4.2 inactivation at high and low voltages" SIGNOR-269006 ATM protein Q13315 UNIPROT WRN protein Q14191 UNIPROT unknown phosphorylation Ser1141 PEKAYSSsQPVISAQ -1 10608806 t llicata "We determined a general phosphorylation consensus sequence for ATM and identified putative in vitro targets by using glutathione S-transferase peptides as substrates. Putative ATM in vitro targets include p95/nibrin, Mre11, Brca1, Rad17, PTS, WRN, and ATM (S440) itself." SIGNOR-250577 CHEK2 protein O96017 UNIPROT CHEK2 protein O96017 UNIPROT "up-regulates activity" phosphorylation Thr383 GETSLMRtLCGTPTY 9606 BTO:0000007 11901158 t gcesareni "Phosphorylation of thr-68 by the ataxia telangiectasia-mutated is necessary for efficient activation of chk2 when cells are exposed to ionizing radiation. By an unknown mechanism, this initial event promotes additional autophosphorylation events including modifications of thr-383 and thr-387" SIGNOR-116127 HNRNPH1 protein P31943 UNIPROT SRC protein P12931 UNIPROT "up-regulates quantity by expression" "post transcriptional regulation" 9606 BTO:0000938 9858532 t lperfetto "HnRNP H is a component of a splicing enhancer complex that activates a c-src alternative exon in neuronal cells." SIGNOR-261273 RSPO2 protein Q6UXX9 UNIPROT LGR4 protein Q9BXB1 UNIPROT up-regulates binding 9606 21693646 t gcesareni "Here we demonstrate that lgr4 and lgr5 bind the r-spondins with high affinity and mediate the potentiation of wnt/betBeta-catenin signaling by enhancing wnt-induced lrp6 phosphorylation." SIGNOR-174486 "Caspase 8 complex" complex SIGNOR-C231 SIGNOR Apoptosis phenotype SIGNOR-PH2 SIGNOR up-regulates 9606 14585074 f amattioni "Downstream of caspase-8 activation, apoptosis induction takes place" SIGNOR-256549 GCC2 protein Q8IWJ2 UNIPROT M6PR protein P20645 UNIPROT "up-regulates activity" relocalization 18195106 t lperfetto "Rab9-dependent transport from late endosomes to the Golgi requires the Rab9 effectors p40 (Diaz et al., 1997) and TIP47 (Diaz and Pfeffer, 1998), a protein that recognizes the cytoplasmic domains of the two types of MPRs and packages them into nascent transport vesicles (Carroll et al., 2001). MPR recycling also utilizes a TGN-localized coiled-coil protein named GCC185 that is also a Rab9 effector" SIGNOR-253086 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR GAB2 protein Q9UQC2 UNIPROT up-regulates phosphorylation 9606 15356145 t "inferred from 70% family members" lperfetto "Phosphorylation of grb2-associated binder 2 on serine 623 by erk mapk regulates its association with the phosphatase shp-2 and decreases stat5 activation.We and others have demonstrated that il-2-induced tyrosine phosphorylation of gab2 and its interaction with its sh2 domain-containing partners, shp-2, p85 pi3k, and crkl (5, 26, 27). we report that pretreatment of kit 225 cells with the mek inhibitor u0126, strongly decreased the characteristic shift of gab2 in response to il-2 and increased gab2/shp-2 association, an effect that could be ascribed to erk phosphorylation of serine 623." SIGNOR-270133 PTPRG protein P23470 UNIPROT PDGFRA protein P16234 UNIPROT "up-regulates activity" dephosphorylation Tyr742 KQADTTQyVPMLERK -1 25624455 t miannu "PTPRG activation by the P1-WD peptide affected the tyrosine phosphorylation of several signaling molecules. Data analysis identified 31 molecules whose phosphorylation was modified in a statistically significant manner (Table I). inhibition of ABL1, BMX, BTK, DAB1, ITGB1, JAK2, KDR, KIT, LIMK1, MET, PDGFRB, SHC1, and VCL correlates with tyrosine dephosphorylation. In contrast, SRC inhibition correlates with hyperphosphorylation of the inhibitory Tyr530 residue and with dephosphorylation of the activatory Tyr419. Moreover, CDK2 and CTTN inhibition correlates with a hyperphosphorylation of the inhibitory Tyr15 and Tyr470, respectively. In contrast, a subgroup of 13 proteins, including BLNK, DOK2, ERBB2, GRIN2B, INSR, PDGFRA, PRKCD, PXN, STAT1, STAT2, STAT3, STAT5A, and ZAP70, appears to be activated by PTPRG activity." SIGNOR-254713 NUPR1 protein O60356 UNIPROT ATF4 protein P18848 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000567 19946894 f lperfetto "Nuclear protein 1 induced by ATF4 in response to various stressors acts as a positive regulator on the transcriptional activation of ATF4." SIGNOR-253731 SRC protein P12931 UNIPROT LATS1/2 proteinfamily SIGNOR-PF43 SIGNOR "down-regulates activity" phosphorylation 9606 30889378 t miannu "SRC can directly phosphorylate and inhibit LATS" SIGNOR-259056 ID2 protein Q02363 UNIPROT TCF12 protein Q99081 UNIPROT "down-regulates activity" binding 10090 BTO:0004058 SIGNOR-C128 9242638 t 2 miannu "All three Ids bound with high affinity to E proteins .Each Id was able to disrupt the ability of E protein-MyoD complexes to transactivate from a muscle creatine kinase reporter construct in vivo." SIGNOR-241131 LAT protein O43561 UNIPROT PIK3R1 protein P27986 UNIPROT "up-regulates activity" binding 9606 phosphorylation:Tyr161;Tyr200 DDYHNPGyLVVLPDS;SMESIDDyVNVPESG 11368773 t lperfetto "By substituting these tyrosine residues in LAT with phenylalanine and by utilizing phosphorylated peptides derived from these sites, we mapped the tyrosine residues in LAT required for the direct interaction and activation of Vav, p85/p110alpha and phospholipase Cgamma1 (PLCgamma1). Our results indicate that Tyr(226) and Tyr(191) are required for Vav binding, whereas Tyr(171) and Tyr(132) are necessary for association and activation of phosphoinositide 3-kinase activity and PLCgamma1 respectively." SIGNOR-246050 TALDO1 protein P37837 UNIPROT "D-erythrose 4-phosphate(2-)" smallmolecule CHEBI:16897 ChEBI "up-regulates quantity" "chemical modification" 9606 19401148 t miannu "Transaldolase (TAL, sedoheptulose 7-phosphate: d-glyceraldehyde 3-phosphate dihydroxyacetone transferase; EC number 2.2.1.2) is a cofactor-less enzyme of the pentose phosphate pathway (PPP) (Fig. 1A and B). It catalyzes the reversible transfer of a three carbon unit (‚Äúdihydroxyacetone‚Äù) between various sugar phosphates (from 3 to 8 carbon atoms in length). Physiological donor compounds are ketose sugar phosphates as fructose 6-phosphate or sedoheptulose 7-phosphate. Acceptor compounds are aldose sugar phosphates as glyceraldehyde 3-phosphate and erythrose 4-phosphate." SIGNOR-267092 AKT1 protein P31749 UNIPROT FOXO1 protein Q12778 UNIPROT down-regulates relocalization 10090 BTO:0002572 18423396 t lperfetto "Akt1/PKBalpha was found to be the major regulator of phosphorylation and nuclear export of FoxO1, whose presence in the nucleus strongly attenuates adipocyte differentiation." SIGNOR-236209 RCOR1 protein Q9UKL0 UNIPROT "CoREST-HDAC complex" complex SIGNOR-C105 SIGNOR "form complex" binding 9606 BTO:0000567 11171972 t miannu "Here we describe the components of a histone deacetylase (HDAC) complex that we term the CoREST-HDAC complex. CoREST Is a Component of an HDAC1/2 Complex. p40 is a Sox-like protein, p110b contains homology to polyamine oxidases, p110a is ZNF217, an eight-zinc finger protein, and p80 is a hypothetical protein of unknown function." SIGNOR-222115 PRKACA protein P17612 UNIPROT CFTR protein P13569 UNIPROT "down-regulates activity" phosphorylation Ser768 EPLERRLsLVPDSEQ 9606 19095655 t Luana "AMPK phosphorylates CFTR in vitro at two essential serines (Ser737and Ser768) in the R domain, formerly identified as ""inhibitory"" PKA sites." SIGNOR-18141 PPP1CA protein P62136 UNIPROT TP53 protein P04637 UNIPROT "down-regulates activity" dephosphorylation Ser15 PSVEPPLsQETFSDL 9606 16501611 t "Protein serine/threonine phosphatase-1 dephosphorylates p53 at Ser-15 and Ser-37 to modulate its transcriptional and apoptotic activities|In addition, our results reveal that one of the molecular mechanisms by which PP-1 promotes cell survival is to dephosphorylate p53, and thus negatively regulate p53-dependent death pathway." SIGNOR-248556 POLR2K protein P53803 UNIPROT "RNA Polymerase II" complex SIGNOR-C391 SIGNOR "form complex" binding 9606 BTO:0000567 9852112 t lperfetto "Pol II is composed of 10–12 polypeptides ranging in size from 220 to 7 kDa, depending on the source of purification (11, 12, 13). The subunits of human pol II (or RNA polymerase B) have been defined as RPB1 (220 kDa), RPB2 (140 kDa), RPB3 (33 kDa), RPB4 (18 kDa), RPB5 (28 kDa), RPB6 (19 kDa), RPB7 (27 kDa), RPB8 (17 kDa), RPB9 (14.5 kDa), RPB10alpha (or RPB12, 7.0 kDa), RPB10beta (or RPB10, 7.6 kDa), and RPB11 (14 kDa) (3,11, 12, 13). RPB5, RPB6, RPB8, RPB10alpha, and RPB10beta are shared by all three eukaryotic RNA polymerases, whereas the rest of the RPB components are unique to pol II" SIGNOR-266168 4-aminopyridine smallmolecule CHEBI:34385 ChEBI KCNJ13 protein O60928 UNIPROT "down-regulates activity" "chemical inhibition" 9606 BTO:0000007 9620703 t miannu "Figure 4 shows the response of Kir7.1 to increasing [Ba2+]o. The EC50 for Ba2+ block was 1 mM (Figure 4C), independent of the type of cell in which the channel was expressed. Other known inward rectifier K+ channels are sensitive to inhibition at much lower concentrations" SIGNOR-258924 GRIA3 protein P42263 UNIPROT calcium(2+) smallmolecule CHEBI:29108 ChEBI "up-regulates quantity" relocalization 9606 29953871 t miannu "Ca2+ is arguably the most important second messenger in the brain because of its pivotal roles in presynaptic neurotransmitter release, postsynaptic responses, and plasticity induction. iGluRs and mGluRs can generate intracellular Ca2+ signals, albeit by different mechanisms, whose crosstalk has not been thoroughly explored (Figure 2C). iGluRs allow the influx of extracellular Ca2+ upon pore opening. This is widely acknowledged for NMDARs, which have a high Ca2+ conductance, but Ca2+ flux through AMPARs and KARs can still be substantial." SIGNOR-264949 BIRC3 protein Q13489 UNIPROT RIPK1 protein Q13546 UNIPROT "down-regulates quantity by destabilization" polyubiquitination 9606 BTO:0000815 18570872 t miannu " In this report, we show that cIAP1 and cIAP2 promote cancer cell survival by functioning as E3 ubiquitin ligases that maintain constitutive ubiquitination of the RIP1 adaptor protein. We demonstrate that AEG40730, a compound modeled on BIR-binding tetrapeptides, binds to cIAP1 and cIAP2, facilitates their autoubiquitination and proteosomal degradation, and causes a dramatic reduction in RIP1 ubiquitination. We show that cIAP1 and cIAP2 directly ubiquitinate RIP1 and induce constitutive RIP1 ubiquitination in cancer cells and demonstrate that constitutively ubiquitinated RIP1 associates with the prosurvival kinase TAK1." SIGNOR-272637 PTPN2 protein P17706 UNIPROT EGFR protein P00533 UNIPROT down-regulates dephosphorylation 9606 15592458 t gcesareni "Here, we report that the 45-kda variant of the protein tyrosine phosphatase tcptp (tc45) can recognize delta egfr as a cellular substrate" SIGNOR-132316 BAD protein Q92934 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR down-regulates 9606 "BTO:0002418;BTO:0002552;BTO:0000018; BTO:0002207;BTO:0002203" 23725574 f irozzo "Our data suggested that increased expression of BAD enhance apoptosis and has negative influence on cell proliferation and tumor growth in NSCLC. Bad is a new potential target for tumor interventions." SIGNOR-256260 ZNF304 protein Q9HCX3 UNIPROT CDKN2B protein P42772 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0000391 24623306 t Luana "Finally, we show that ZNF304 also directs transcriptional silencing of INK4-ARF in human embryonic stem cells." SIGNOR-266099 UBE2I protein P63279 UNIPROT JUN protein P05412 UNIPROT "down-regulates activity" sumoylation Lys226 HPRLQALkEEPQTVP 9606 SIGNOR-C154 16055711 t lperfetto "We report here that lysine 265 of c-Fos is conjugated by the peptidic posttranslational modifiers SUMO-1, SUMO-2, and SUMO-3 and that c-Jun can be sumoylated on lysine 257 as well as on the previously described lysine 229. Sumoylation of c-Fos preferentially occurs in the context of c-Jun/c-Fos heterodimers.|Inhibition of c-Fos and c-Jun sumoylation stimulates AP-1-dependent transcription activity." SIGNOR-263002 PRKAA1 protein Q13131 UNIPROT EEF2K protein O00418 UNIPROT "up-regulates activity" phosphorylation Ser398 DSLPSSPsSATPHSQ -1 14709557 t miannu "Stimulation of the AMP-activated Protein Kinase Leads to Activation of Eukaryotic Elongation Factor 2 Kinase and to Its Phosphorylation at a Novel Site, Serine 398. phosphorylation of eEF2 kinase at Ser-398 leads to an increase in its activity." SIGNOR-250157 "Multiaminoacyl-tRNA synthetase" complex SIGNOR-C472 SIGNOR Gln-tRNA(Gln) smallmolecule CHEBI:29166 ChEBI "up-regulates quantity" "chemical modification" 9606 28271488 t miannu "Aminoacyl-tRNA synthetases (AARSs) are essential enzymes that specifically aminoacylate one tRNA molecule by the cognate amino acid. In mammals, nine synthetases, those specific for amino acids Arg, Asp, Gln, Glu, Ile, Leu, Lys, Met and Pro, associate into a multi-aminoacyl-tRNA synthetase complex, an association which is believed to play a key role in the cellular organization of translation, but also in the regulation of the translational and nontranslational functions of these enzymes." SIGNOR-270390 "Class I MHC" complex SIGNOR-C425 SIGNOR "Class I MHC:Antigen" complex SIGNOR-C426 SIGNOR "form complex" binding 9606 33374673 t scontino "The major histocompatibility complex (MHC) molecules, or human leukocyte antigens (HLA) in humans, bind these peptides to present them to T cells that recognise them with their surface T cell receptors (TCR)." SIGNOR-267774 PRKCD protein Q05655 UNIPROT ADD2 protein P35612 UNIPROT unknown phosphorylation Ser726 KKKEKVEs -1 8810272 t lperfetto "Ser-726 and Ser-713 in the C-terminal MARCKS-related domains of alpha- and beta-adducin, respectively, were identified as the major phosphorylation sites for PKC." SIGNOR-248953 14-3-3 proteinfamily SIGNOR-PF7 SIGNOR BAD protein Q92934 UNIPROT down-regulates binding 9606 10949026 t gcesareni "14-3-3 blocks bad activity by promoting ser-155 phosphorylation, which induces the dissociation of bad and bcl-xl. in the presence of survival factor il-3, cells phosphorylated bad on two serine residues embedded in 14-3-3 consensus binding sites. Only the nonphosphorylated bad heterodimerized with bcl-x(l) at membrane sites to promote cell death." SIGNOR-81106 SMURF1 protein Q9HCE7 UNIPROT CALCOCO1 protein Q9P1Z2 UNIPROT unknown ubiquitination -1 20804422 t miannu "Recombinant proteins were used to profile substrate ubiquitination by the Smurf1 ubiquitin ligase on a global scale using protein microarrays. T Proteins ubiquitinated on the protein microarray were confirmed as potential substrates of the Smurf1 activity using an off chip in vitro ubiquitination assay." SIGNOR-272688 SRC protein P12931 UNIPROT DGKA protein P23743 UNIPROT up-regulates phosphorylation Tyr335 ILPPSSIyPSVLASG 9606 17700527 t llicata "Diacylglycerol kinase-alpha phosphorylation by src on y335 is required for activation, membrane recruitment and hgf-induced cell motility." SIGNOR-157365 NFE2L3 protein Q9Y4A8 UNIPROT NQO1 protein P15559 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 15385560 t lperfetto "Deletion mutation analysis revealed that Nrf3 repression of NQO1 gene expression required heterodimerization and DNA binding domains but not transcriptional activation domain of Nrf3." SIGNOR-268976 CAMK2A protein Q9UQM7 UNIPROT GFAP protein P14136 UNIPROT "down-regulates activity" phosphorylation Ser17 ARRSYVSsGEMMVGG -1 7822264 t llicata "On the other hand, GFAP was phosphorylated to approximately 1.9 mol of phosphate/mol of GFAP by Ca(2+)-CaM-dependent protein kinase II, and this phosphorylation did induce disassembly of the filament. Sequential analysis of the purified phosphopeptides revealed that only Ser8 on GFAP was phosphorylated by cdc2 kinase, whereas Ser13, Ser17, Ser34, and Ser389 on GFAP were phosphorylated by Ca(2+)-CaM-dependent protein kinase II." SIGNOR-250627 SPRY4 protein Q9C004 UNIPROT RAF1 protein P04049 UNIPROT "down-regulates activity" binding 9606 12717443 t miannu "Here we show that mammalian Sprouty4 suppresses vascular epithelial growth factor (VEGF)-induced, Ras-independent activation of Raf1 but does not affect epidermal growth factor (EGF)-induced, Ras-dependent activation of Raf1. Sprouty4 binds to Raf1 through its carboxy-terminal cysteine-rich domain, and this binding is necessary for the inhibitory activity of Sprouty4." SIGNOR-253033 TGFBR1 protein P36897 UNIPROT SHC1 protein P29353 UNIPROT up-regulates phosphorylation 10090 BTO:0005065 17673906 t lperfetto "We now report that upon TGF-_ stimulation, T_RI phosphorylates ShcA on serine and, to a lesser degree, on tyrosine to activate Erk MAP kinases." SIGNOR-227503 INO80E protein Q8NBZ0 UNIPROT "INO80 complex" complex SIGNOR-C498 SIGNOR "form complex" binding 9606 25016522 t miannu "Here, we have systematically investigated the involvement of the catalytic subunit of the human INO80 complex during unchallenged replication and under replication stress by following the effects of its depletion on cell survival, S-phase checkpoint activation, the fate of individual replication forks, and the consequences of fork collapse. We report that INO80 was specifically needed for efficient replication elongation, while it was not required for initiation of replication." SIGNOR-270845 PLG protein P00747 UNIPROT Fibrinolysis phenotype SIGNOR-PH6 SIGNOR up-regulates 9606 1447176 f lperfetto "The conversion of plasminogen to plasmin can occur by several different mechanisms, but it appears that the most important in uiuo activator is tPA (2). tPA, M, = 70,000, is present in plasma as a single-chain serine protease, but proteolytic cleavage of the Agr275-Ile276 bond in tPA by plasmin yields a disulfide-linked two-chain enzyme" SIGNOR-263535 DUSP5 protein Q16690 UNIPROT ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR down-regulates dephosphorylation 9606 10224087 t "inferred from 70% of family members" gcesareni "Extracellular regulated kinases (erk) 1 and erk2 are authentic substrates for the dual-specificity protein-tyrosine phosphatase vhr. A novel role in down-regulating the erk pathway" SIGNOR-269932 ABL1 protein P00519 UNIPROT MDM2 protein Q00987 UNIPROT down-regulates phosphorylation Tyr276 SDEDDEVyQVTVYQA 9606 21081495 t lperfetto "Mdm2 has three known c-abl phosphorylation sites (tyr276, tyr394, and tyr405)these data show that c-abl is important for reducing mdm2 and mdmx protein levels after genotoxic stress and suggest another cellular mechanism for the stabilization and activation of p53." SIGNOR-169699 SP1 protein P08047 UNIPROT UGCG protein Q16739 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000738 15342415 f miannu "the results suggest that transcriptional up-regulation of GCS through DOX-induced activation of Sp1 is one potential mechanism to regulate ceramide increase and apoptosis in HL-60/ADR cells." SIGNOR-255205 STXBP1 protein P61764 UNIPROT NRXN1 protein Q9ULB1 UNIPROT "up-regulates activity" binding 9534 11036064 t miannu "We propose that all these neurexin complexes can interact with Munc18. Both Mint1 and Mint2 could function as direct adaptors of Munc18 to neurexins, whereas Mint1 in addition could recruit Munc18 to CASK-neurexin (Fig. 5 B)." SIGNOR-264040 BIRC3 protein Q13489 UNIPROT RIPK3 protein Q9Y572 UNIPROT "up-regulates activity" polyubiquitination 9606 BTO:0000007 21931591 t miannu "CIAP1/2 are direct E3 ligases conjugating diverse types of ubiquitin chains to receptor interacting proteins kinases 1 to 4 (RIP1-4).Together, our results demonstrate that depleting cIAP1/2 inhibits RIP1-4 mediated NF-kB activation without affecting RIP auto-phosphorylation." SIGNOR-272714 ZFPM1 protein Q8IX07 UNIPROT Megakaryocyte_differentiation phenotype SIGNOR-PH103 SIGNOR "up-regulates activity" 10090 BTO:0000725 22068055 f "We here use conditional removal of the GATA-1 and FOG-1 transcription factors to identify FOG-1 as required for the formation of all committed Mk- and E-lineage progenitors, whereas GATA-1 was observed to be specifically required for E-lineage commitment." SIGNOR-259963 (4R,4aS,7aR,12bS)-3-(cyclopropylmethyl)-4a,9-dihydroxy-6-(phenylmethylene)-1,2,4,5,7a,13-hexahydro-4,12-methanobenzofuro[3,2-e]isoquinoline-7-one chemical CHEBI:125500 ChEBI OPRK1 protein P41145 UNIPROT "down-regulates activity" "chemical inhibition" 10029 9686407 t miannu "Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors." SIGNOR-258776 SMOC1 protein Q9H4F8 UNIPROT COL1A2 protein P08123 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 20359165 f lperfetto "The expression of several osteoblast differentiation markers (ALP, COL1, OPN, ON, BSP and OC) was higher in SMOC1-overexpressing cells than in emptyvector-expressing cells" SIGNOR-260404 GSK3B protein P49841 UNIPROT NFATC2 protein Q13469 UNIPROT down-regulates phosphorylation 9606 15276472 t lperfetto "Gsk3 was previously shown to directly phosphorylate the n-terminal regulatory domain of nfatc1, thus antagonizing the action of calcineurin and inhibiting nuclear shuttling of nfat." SIGNOR-179784 AKT1 protein P31749 UNIPROT TERT protein O14746 UNIPROT up-regulates phosphorylation Ser824 AVRIRGKsYVQCQGI 9606 10224060 t gcesareni "Akt kinase enhances human telomerase activity through phosphorylation of htert subunit as one of its substrate proteins." SIGNOR-67317 CCNC protein P24863 UNIPROT CyclinC/CDK19 complex SIGNOR-C544 SIGNOR "form complex" binding 9606 BTO:0004173 25344755 t lperfetto "We found that in MOLT-16 cells cyclin C physically interacts with CDK19 (Fig. 5a) and activates its kinase activity (Fig. 5e and Supplementary Fig. 4f,g)." SIGNOR-273154 RPS6KA3 protein P51812 UNIPROT EIF2AK2 protein P19525 UNIPROT up-regulates phosphorylation Thr451 KRTRSKGtLRYMSPE 9606 BTO:0001286 17404396 t gcesareni "Our data indicated that phosphorylation of pkr at thr(451) is mediated through erk2 and rsk2, but not through p38 kinase." SIGNOR-154183 PTPN1 protein P18031 UNIPROT SRC protein P12931 UNIPROT up-regulates dephosphorylation Tyr530 FTSTEPQyQPGENL 9606 12857726 t gcesareni "The tyrosine kinase pp60c-src has also been identified as a good substrate of ptp1b leading to an activation of this kinase (27)." SIGNOR-103607 MRAP protein Q8TCY5 UNIPROT MC1R protein Q01726 UNIPROT "down-regulates activity" binding 10029 BTO:0000246 19329486 t miannu "We report that MRAP and MRAP2 can interact with all 5 MCRs. This interaction results in MC2R surface expression and signaling. In contrast, MRAP and MRAP2 can reduce MC1R, MC3R, MC4R, and MC5R responsiveness to [Nle4,D-Phe7]alpha-melanocyte-stimulating hormone (NDP-MSH). MRAP and MRAP2 can reduce the surface expression of MC4R and also the signaling of this receptor. we observed a significant decrease in the cell-surface expression of MC4R and MC5R in the presence of MRAP and MRAP2. It is interesting that MRAP and MRAP2 have opposite effects in the modulation of different MCR family members." SIGNOR-252364 ACAN protein P16112 UNIPROT ECM_synthesis phenotype SIGNOR-PH8 SIGNOR up-regulates 9606 16051604 t lperfetto "Cartilage oligomeric matrix protein/thrombospondin 5 (COMP/TSP5) is a major component of the extracellular matrix of the musculoskeletal system. " SIGNOR-266983 "Ub:E1 (UBA1 substrate)" complex SIGNOR-C495 SIGNOR UBE2E2 protein Q96LR5 UNIPROT "up-regulates activity" ubiquitination 9606 34199813 t miannu "The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t" SIGNOR-271317 SYK protein P43405 UNIPROT IL15RA protein Q13261 UNIPROT "up-regulates activity" phosphorylation Tyr227 AVSLLACyLKSRQTP 9606 BTO:0001154 11714793 t lperfetto "Mutation of a defined region of the intracellular signaling portion of IL-15Ralpha (Tyr227) abrogates both the IL-15Ralpha/Syk association and IL-15Ralpha phosphorylation. Taken together, this suggests that Syk kinase physically and functionally associates with the IL-15Ralpha chain in B cells and that Syk plays a key role in mediating IL-15-induced signal transduction, thus accounting for the distinct functional consequences of IL-15 vs IL-2 binding to B cells" SIGNOR-246556 HTRA2 protein O43464 UNIPROT PEA15 protein Q15121 UNIPROT down-regulates binding 9606 15328349 t gcesareni "Htra2 promotes cell death by binding and degrading the anti-apoptotic protein pea15" SIGNOR-126966 VCB-Cul2 complex SIGNOR-C524 SIGNOR USP33 protein Q8TEY7 UNIPROT "down-regulates quantity by destabilization" polyubiquitination 9534 BTO:0000298 11739384 t miannu " Finally, we demonstrate that VDU1 is able to be ubiquitinated via a pVHL-dependent pathway for proteasomal degradation, and VHL mutations that disrupt the interaction between VDU1 and pVHL abrogate the ubiquitination of VDU1. Our findings indicate that VDU1, a novel ubiquitin-specific processing protease, is a downstream target for ubiquitination and degradation by pVHL E3 ligase. Targeted degradation of VDU1 by pVHL could be crucial for regulating the ubiquitin-proteasome degradation pathway." SIGNOR-272623 AKT1 protein P31749 UNIPROT CASP9 protein P55211 UNIPROT "down-regulates activity" phosphorylation Ser196 KLRRRFSsLHFMVEV 9606 BTO:0000938 10529400 t lperfetto "Akt phosphorylation site found in human caspase-9 is absent in mouse caspase-9BAD phosphorylation by Akt is an essential step for growth factor-mediated inhibition of caspase activation" SIGNOR-252585 ULK3 protein Q6PHR2 UNIPROT GLI3 protein P10071 UNIPROT "up-regulates activity" phosphorylation 9606 BTO:0000007 19878745 t Manara "We show that ULK3 is able to phosphorylate three mammalian GLI proteins in vitro" SIGNOR-260799 BAZ1B protein Q9UIG0 UNIPROT MDC1 protein Q14676 UNIPROT down-regulates 9606 20965415 f gcesareni "H2ax tyr142 is constitutively phosphorylated by the kinase wstf, a member of the baz/wal family of chromatin remodelling enzymes, and blocks mdc1 recruitment" SIGNOR-168831 MCRIP1 protein C9JLW8 UNIPROT CTBP1 protein Q13363 UNIPROT "down-regulates activity" binding 9606 BTO:0000007 25728771 t lperfetto "CtBP is recruited to promoter elements of target genes by interacting with the DNA-binding transcriptional repressor ZEB1. We found that MCRIP1 binds to CtBP, thereby competitively inhibiting CtBP-ZEB1 interaction. When phosphorylated by ERK, MCRIP1 dissociates from CtBP, allowing CtBP to interact with ZEB1. In this manner, the CtBP co-repressor complex is recruited to, and silences, the E-cadherin promoter by inducing chromatin modifications." SIGNOR-264776 PIGG protein Q5H8A4 UNIPROT PIGO protein Q8TEQ8 UNIPROT "up-regulates quantity by stabilization" binding 10029 BTO:0000246 15632136 t miannu "We show that the human homolog of Gpi7p, termed hGPI7, binds to and is stabilized by PIG-F and that hGPI7 competes with PIG-O for binding to PIG-F. PIG-F Binds to and Stabilizes hGPI7 and PIG-O Independently. These results are consistent with the hypothesis that overexpression of hGPI7 decreases the biosynthetic activity of PIG-O by decreasing the available PIG-F, thereby destabilizing PIG-O." SIGNOR-261359 CDK7 protein P50613 UNIPROT ESR1 protein P03372 UNIPROT up-regulates phosphorylation Ser118 LHPPPQLsPFLQPHG 9606 10949034 t lperfetto "Activation of estrogen receptor alpha by s118 phosphorylation involves a ligand-dependent interaction with tfiih and participation of cdk7." SIGNOR-81170 CHEK1 protein O14757 UNIPROT RB1 protein P06400 UNIPROT "up-regulates activity" phosphorylation Ser612 MYLSPVRsPKKKGST 9606 17380128 t llicata "These results suggest that ser612 is phosphorylated by chk1/2 after dna damage, leading to the formation of prb-e2f-1. phosphorylation of prb at ser612 enhanced the formation of a complex between prb and e2f-1" SIGNOR-153904 CAD protein P27708 UNIPROT glutamine smallmolecule CHEBI:28300 ChEBI "down-regulates quantity" "chemical modification" 9606 24332717 t "In animals, the first three reactions of the pathway are catalyzed by CAD, an 240 kDa multifunctional protein that combines glutamine-dependent carbamyl phosphate synthetase (GLNCPSase), aspartate transcarbamylase (ATCase), and dihydroorotase (DHOase) activities" SIGNOR-267199 MAP3K6 protein O95382 UNIPROT MAP3K5 protein Q99683 UNIPROT "up-regulates activity" phosphorylation Thr838 GINPCTEtFTGTLQY 9606 17210579 t Manara "These results suggested that ASK2 activates ASK1 by direct phosphorylation of Thr838 of ASK1." SIGNOR-260773 FNTB protein P49356 UNIPROT HRAS protein P01112 UNIPROT "up-regulates activity" 9606 24294527 t lperfetto "Major investments have been made to target Ras through indirect routes. Inhibition of farnesyl transferase to block Ras maturation has failed in large clinical trials." SIGNOR-242565 LCK protein P06239 UNIPROT PTEN protein P60484 UNIPROT up-regulates phosphorylation Tyr315 RADNDKEyLVLTLTK 9606 11948419 t gcesareni "Thus, y240a and y315a are involved in the ability of mmac/pten to dephosphorylate ptdins and regulate tumor cell growth in vitro and in vivo." SIGNOR-116499 TWIST1 protein Q15672 UNIPROT GDF15 protein Q99988 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0004828 19051271 f miannu "we performed microarray analysis to compare the gene expression profiles in HGC-27 cells, with or without small interfering RNA (siRNA)-mediated depletion of TWIST. Our results showed that NF1, RAP1A, SRPX, RBL2, PFDN4, ILK, F2R, ERBB3, and MYB were up-regulated, whereas AKR1C2, FOS, GDF15, NR2F1, ATM, and CTPS were down-regulated after TWIST depletion" SIGNOR-255527 PPM1A protein P35813 UNIPROT PIK3R1 protein P27986 UNIPROT "up-regulates activity" dephosphorylation Ser608 ENTEDQYsLVEDDED 10090 BTO:0000944 15016818 t "Protein phosphatase-2C alpha as a positive regulator of insulin sensitivity through direct activation of phosphatidylinositol 3-kinase in 3T3-L1 adipocytes|PP2Cα dephosphorylates the p85 subunit of PI3K, and dephosphorylation of the p85 subunit of PI3K at Ser608 increases its activity" SIGNOR-248489 JAK2 protein O60674 UNIPROT STAP2 protein Q9UGK3 UNIPROT "up-regulates activity" phosphorylation Tyr310 LPNQEENyVTPIGDG BTO:0000007 12540842 t lperfetto "To examine this possibility, STAP-2 was co-transfected with constitutively active tyrosine kinases in HEK-293 cells. STAP-2 was strongly phosphorylated by various tyrosine kinases, including v-Src (Fig.2 A-a), a JAK2 tyrosine kinase |On the other hand, the phosphorylation levels of Y22F, Y310F, and Y322F by GST-JH1 were reduced to 80€“60% of the levels of wild-type STAP-2, which suggests that these three are potential phosphorylation sites by activated JAK2." SIGNOR-249372 GDNF protein P39905 UNIPROT Neural_tissue_regeneration phenotype SIGNOR-PH68 SIGNOR up-regulates 10116 15212950 f miannu "The glial cell line-derived neurotrophic factor (GDNF) is involved in the development and maintenance of neural tissues. In normal development, GDNF promotes survival of sympathetic, parasympathetic, and spinal motorneurons. It even promotes regeneration of spinal motor neurons after spinal cord injury." SIGNOR-252170 DLK1 protein P80370 UNIPROT Adipogenesis phenotype SIGNOR-PH26 SIGNOR down-regulates 10090 8500166 f "This indicates that pref-1 functions as a negative regulator of adipocyte differentiation, possibly in a manner analogous to EGF-like proteins that govern cell fate decisions in invertebrates." SIGNOR-254980 KAT2B protein Q92831 UNIPROT H3Y2 protein P0DPK5 UNIPROT "down-regulates activity" acetylation Lys10 RTKQTARkATAWQAP 9606 SIGNOR-C465 34811519 t "Acetlyation of H3 causes transcriptional activation, thus has an inhibitory role on H3" lperfetto "The HAT module within the SAGA and ADA complexes acetylates histone H3, mainly on residues K9 and K14." SIGNOR-269615 PAK1 protein Q13153 UNIPROT BAD protein Q92934 UNIPROT down-regulates phosphorylation Ser99 PFRGRSRsAPPNLWA 9606 10611223 t lperfetto "Pak phosphorylates bad in vitro and in vivo on ser112 and ser136, resulting in a markedly reduced interaction between bad and bcl-2 or bcl-x(l) and the increased association of bad with 14-3-3tau." SIGNOR-73533 MARK2 protein Q7KZI7 UNIPROT KIF13B protein Q9NQT8 UNIPROT "down-regulates activity" phosphorylation Ser1410 SNKGRWEsQQDVSQT 9534 BTO:0000298 20194617 t miannu "We report here the identification of GAKIN/KIF13B as a novel in vivo substrate for Par1b and present evidence that GAKIN/KIF13B plays a critical role in axon formation in neurons, which is negatively regulated by Par1b-mediated phosphorylation. Par1b phosphorylates GAKIN/KIF13B at both Ser1381 and Ser1410." SIGNOR-262956 PHLPP2 protein Q6ZVD8 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR down-regulates dephosphorylation Ser473 RPHFPQFsYSASGTA 9606 BTO:0000527 15808505 t gcesareni "Here, we identify a protein phosphatase, ph domain leucine-rich repeat protein phosphatase (phlpp), that specifically dephosphorylates the hydrophobic motif of akt (ser473 in akt1), triggering apoptosis and suppressing tumor growth.[...] These data are consistent with phlpp terminating akt signaling by directly dephosphorylating and inactivating akt." SIGNOR-135046 Ub:E2 complex SIGNOR-C497 SIGNOR RLIM protein Q9NVW2 UNIPROT "up-regulates activity" ubiquitination 9606 34199813 t miannu "The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t" SIGNOR-271054 PHKG1 protein Q16816 UNIPROT PYGL protein P06737 UNIPROT "up-regulates activity" phosphorylation Ser15 QEKRRQIsIRGIVGV 9606 BTO:0002049 22225877 t "It is well-characterized that GP is activated by PhK-mediated serine phosphorylation at Ser-15" SIGNOR-267399 AHCYL1 protein O43865 UNIPROT PP1 proteinfamily SIGNOR-PF54 SIGNOR "up-regulates activity" relocalization 10090 BTO:0000988 21317537 t lperfetto "WNK kinases acted as scaffolds to recruit SPAK, which phosphorylated CFTR and NBCe1-B, reducing their cell surface expression. IRBIT opposed the effects of WNKs and SPAK by recruiting PP1 to the complex to dephosphorylate CFTR and NBCe1-B, restoring their cell surface expression," SIGNOR-264645 TAK-875 chemical CID:24857286 PUBCHEM FFAR1 protein O14842 UNIPROT up-regulates "chemical activation" 9606 Other t Selleck gcesareni SIGNOR-207182 TALDO1 protein P37837 UNIPROT "D-glyceraldehyde 3-phosphate(2-)" smallmolecule CHEBI:59776 ChEBI "down-regulates quantity" "chemical modification" 9606 19401148 t miannu "Transaldolase (TAL, sedoheptulose 7-phosphate: d-glyceraldehyde 3-phosphate dihydroxyacetone transferase; EC number 2.2.1.2) is a cofactor-less enzyme of the pentose phosphate pathway (PPP) (Fig. 1A and B). It catalyzes the reversible transfer of a three carbon unit (“dihydroxyacetone”) between various sugar phosphates (from 3 to 8 carbon atoms in length). Physiological donor compounds are ketose sugar phosphates as fructose 6-phosphate or sedoheptulose 7-phosphate. Acceptor compounds are aldose sugar phosphates as glyceraldehyde 3-phosphate and erythrose 4-phosphate." SIGNOR-267090 QRICH1 protein Q2TAL8 UNIPROT FARSB protein Q9NSD9 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 33384352 t miannu "QRICH1 promotes the expression of translation-related genes. our combined ChIP-seq and RNA-seq analyses identified that QRICH1 and ATF4 were enriched at the promoters of these specific tRNA synthetases, and that ER stress positively regulated their transcription (Fig. 4I). Together, these findings suggest that QRICH1 and ATF4 modulate tRNA metabolic processes to promote secreted protein synthesis during ER stress." SIGNOR-269404 LPAR3 protein Q9UBY5 UNIPROT GNAI3 protein P08754 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257025 TNC protein P24821 UNIPROT "A8/b1 integrin" complex SIGNOR-C165 SIGNOR "up-regulates activity" binding 9606 BTO:0000007 7559467 t lperfetto "The human integrin alpha 8 beta 1 functions as a receptor for tenascin, fibronectin, and vitronectin." SIGNOR-253306 CENPI protein Q92674 UNIPROT "CCAN complex" complex SIGNOR-C365 SIGNOR "form complex" binding 9606 BTO:0000567 18007590 t lperfetto "CENP-A NAC/CAD components have been subdivided into either NAC proteins (nucleosome-associated complex; CENP-C, CENP-H, CENP-50CENP−U, CENP-M, CENP-T and Chl4RCENP−N) or CAD proteins (CENP-A Distal; CENP-I, Mcm21RCENP−O, Fta1RCENP−L, Sim4RCENP−K, CENP-P, CENP-Q, CENP-R and CENP-S)." SIGNOR-265213 IL6 protein P05231 UNIPROT AMPK complex SIGNOR-C15 SIGNOR up-regulates 10090 23531613 f "AMPK phosphorylation was increased nearly fourfold (Fig. 2C) with the high dose of IL-6" SIGNOR-255338 PRKCB protein P05771 UNIPROT IBTK protein Q9P2D0 UNIPROT down-regulates phosphorylation Ser1203 LHSVSSKsFRDFLLE 9606 BTO:0000776 21482705 t llicata "We found that ibtk_ is phosphorylated at serines 87 and 90 by pkc on bcr engagement;this phosphorylation causes the dissociation of the btk:ibtk_ complex and allows btk to translocate to the plasma membrane." SIGNOR-173387 2-(2,6-dioxopiperidin-3-yl)-1H-isoindole-1,3(2H)-dione chemical CHEBI:74947 ChEBI CRBN protein Q96SW2 UNIPROT "up-regulates activity" "chemical activation" 9606 20223979 t gcesareni "We identified cereblon (CRBN) as a thalidomide-binding protein. CRBN forms an E3 ubiquitin ligase complex with damaged DNA binding protein 1 (DDB1) and Cul4A that is important for limb outgrowth and expression of the fibroblast growth factor Fgf8 in zebrafish and chicks" SIGNOR-234786 MYOD1 protein P15172 UNIPROT MYOD/E12E47 complex SIGNOR-C127 SIGNOR "form complex" binding 10090 BTO:0001103 18094043 t lperfetto "MyoD omodimers or heterodimers of MyoD plus E12 or E47 serve as transcription factor complexes that bind to CANNTG consensus sites in the promoter regions of genes, performing major functions in specification and differentiation of skeletl muscle precursor cells." SIGNOR-241548 maraviroc chemical CHEBI:63608 ChEBI CCL3 protein P10147 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-193928 COL18A1 protein P39060 UNIPROT "A5/b1 integrin" complex SIGNOR-C163 SIGNOR up-regulates binding 9606 12682293 t gcesareni "The activity of human endostatin is mediated by alpha 5 beta 1 integrin." SIGNOR-99871 SLC2A3 protein P11169 UNIPROT α-D-glucose smallmolecule CHEBI:17925 ChEBI "up-regulates quantity" relocalization 9606 23506862 t miannu "The SLC2A3 gene encoding GLUT3 was first cloned from a human fetal skeletal muscle cell line (Kayano et al., 1988). It shares ~64% sequence identity with SLC2A1. GLUT3 has a higher apparent affinity (lower Km) and a higher maximum turnover number for glucose than the other Class 1 GLUT proteins, and its principal physiological substrate is clearly D-glucose" SIGNOR-267459 RPS6KA3 protein P51812 UNIPROT MAD1L1 protein Q9Y6D9 UNIPROT "up-regulates activity" 9606 20383198 f lperfetto "We also show that this kinase might also participate in the maintenance of the SAC in mammalian cells as Rsk2 knockdown in these cells prevents the kinetochore localization of Mad1, Mad2 and CENP-E under checkpoint conditions." SIGNOR-252038 ERG protein P11308 UNIPROT CDH5 protein P33151 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 18195090 t Luana "Erg overexpression resulted in an approximate 1.8-fold transactivation of VE-cadherin promoter activity. Thus, our data indicate that Erg drives constitutive VE-cadherin expression in human ECs " SIGNOR-261595 "phosphatidic acid" smallmolecule CHEBI:16337 ChEBI PRKCZ protein Q05513 UNIPROT up-regulates "chemical activation" 9606 12401205 t gcesareni "The pkc isoform pkc-zeta appear to be activated by direct interactions with pa" SIGNOR-94867 UBE3A protein Q05086 UNIPROT SOX9 protein P48436 UNIPROT "down-regulates quantity by destabilization" ubiquitination 9606 BTO:0000007 24155239 t miannu "We show that E6-AP ubiquitinates SOX9 in vitro and in vivo and that SOX9 levels are enhanced after addition of the proteasome inhibitor bortezomib. Similar, siRNA knockdown of E6-AP and the E2 ligase Ubc9 increased cellular SOX9 amounts, supporting the notion that SOX9 may be ubiquitinated in hypertrophic chondrocytes by E6-AP and degraded by proteasomes." SIGNOR-272134 PP1 proteinfamily SIGNOR-PF54 SIGNOR CDC25C protein P30307 UNIPROT up-regulates binding 9606 14592972 t lperfetto "Pp1 recognizes cdc25 directly by interacting with a pp1-binding motif in the cdc25 n-terminus." SIGNOR-264654 C5AR1 protein P21730 UNIPROT superoxide smallmolecule CHEBI:18421 ChEBI "up-regulates quantity by expression" 1847994 f lperfetto "The C5a receptor mediates the pro-inflammatory and chemotactic actions of the complement anaphylatoxin C5a. In addition to stimulating chemotaxis, granule enzyme release and superoxide anion production, this receptor stimulates upregulation of expression and activity of the adhesion molecule MAC-1, and of CR1, and a decrease in cell-surface glycoprotein 100MEL-14 on neutrophils." SIGNOR-263469 NLK protein Q9UBE8 UNIPROT TCF7L2 protein Q9NQB0 UNIPROT "down-regulates quantity" phosphorylation 9606 BTO:0000007 16714285 t miannu "NLK Augments the Ubiquitylation Activity of NARF against TCF/LEF. ctivation of NLK induced by unknown ligands leads to the phosphorylation of TCF/LEF. NARF then acts on TCF/LEF as an E3 ubiquitin-ligase and, together with E1 and E2 ubiquitylation enzymes, catalyze the ubiquitylation of TCF/LEF. Finally, ubiquitylated TCF/LEF is degraded by the 26 S proteasome." SIGNOR-271597 MC4R protein P32245 UNIPROT GNAQ protein P50148 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257336 HNF1B protein P35680 UNIPROT AFP protein P02771 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000599 7549116 f miannu "HNF-1 beta was found to be more potent than HNF-1 alpha in activating the AFP promoter in the HepG2 cells." SIGNOR-254638 F7 protein P08709 UNIPROT "Factor FVIIa:TF" complex SIGNOR-C319 SIGNOR "form complex" binding 9606 BTO:0000131 32665005 t lperfetto "During vascular injury, TF is exposed to the blood, where it functions as a cofactor for the circulating zymogen factor VII (FVII). This TF:FVIIa complex can then bind and activate either factor IX (FIX) or factor X (FX), triggering a cascade that generates fibrin and activates platelets, resulting in a hemostatic plug at the site of injury." SIGNOR-263555 PTK2 protein Q05397 UNIPROT ACTN4 protein O43707 UNIPROT down-regulates phosphorylation Tyr4 yHAANQSY 9606 23454549 t lperfetto "Phosphorylation at y12 by fak reduces _-actinin1's affinity for actin [25] and [27]. _-actinin4 is phosphorylated at y4, y31, and y265. Phosphorylation at y4 or y31 decreases its binding to actin [28] while phosphorylation of y265 increases its affinity for actin" SIGNOR-192199 ENO2 protein P09104 UNIPROT phosphonatoenolpyruvate smallmolecule CHEBI:58702 ChEBI "up-regulates quantity" "chemical modification" 9606 29767008 t miannu "Alpha-enolase (ENO1), also known as 2-phospho-D-glycerate hydrolase, is a metalloenzyme that catalyzes the conversion of 2-phosphoglyceric acid to phosphoenolpyruvic acid in the glycolytic pathway. Subsequent studies have shown that three types of enolase isoenzymes exist in mammals: Œ±-enolase (ENO1) is present in almost all mature tissues; Œ≤-enolase (ENO3) exists primarily in muscle tissues; and Œ≥-enolase (ENO2) occurs mainly in nervous and neuroendocrine tissues. All enolases are composed of two identical subunits." SIGNOR-266525 "glutamic acid" smallmolecule CHEBI:18237 ChEBI "NMDA receptor_2B" complex SIGNOR-C348 SIGNOR "up-regulates activity" "chemical activation" 9606 12871085 t miannu "The NMDA receptor, a ligand-gated ion channel composed of the NR1 and NR2 subunits, is located mainly at synapses of CNS neurons. Each receptor has two binding sites for glycine and two binding sites for glutamate" SIGNOR-264129 Ub:E2 complex SIGNOR-C497 SIGNOR MUL1 protein Q969V5 UNIPROT "up-regulates activity" ubiquitination 9606 34199813 t miannu "The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t" SIGNOR-270999 TICAM1 protein Q8IUC6 UNIPROT TBK1 protein Q9UHD2 UNIPROT "up-regulates activity" binding 9606 BTO:0000007 14530355 t lperfetto "Toll/il-1 receptor domain-containing adaptor inducing ifn-beta (trif) associates with tnf receptor-associated factor 6 and tank-binding kinase 1, and activates two distinct transcription factors, nf-kappa b and ifn-regulatory factor-3, in the toll-like receptor signaling" SIGNOR-118458 AKT proteinfamily SIGNOR-PF24 SIGNOR FANCA protein O15360 UNIPROT unknown phosphorylation Ser1149 CLRSRDPsLMVDFIL -1 11855836 t "FANCA is phosphorylated at Ser1149 by Akt. The biological significance of FANCA phosphorylation and its regulation by Akt remains unclear at this time." SIGNOR-251476 G3BP1 protein Q13283 UNIPROT DDX58 protein O95786 UNIPROT "down-regulates activity" binding 9606 BTO:0002181 30804210 t SARA "G3BP1 binds RIG-I and that this interaction involves the C-terminal RGG domain of G3BP1, G3BP1 significantly enhances RIG-I-induced ifn-b mRNA synthesis." SIGNOR-260980 RPS6KA5 protein O75582 UNIPROT RPS6KA5 protein O75582 UNIPROT unknown phosphorylation Ser758 TSTETRSsSSESSHS 9606 15568999 t lperfetto "Msk1 can autophosphorylate on at least six sites: ser-212, ser-376, ser-381, ser-750, ser-752 and ser-758. ser-750, ser-752 and ser-758 are phosphorylated by the n-terminal kinase domain;however, their function is not known." SIGNOR-131407 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR MITF protein O75030 UNIPROT down-regulates phosphorylation Ser180 PGSSAPNsPMAMLTL 9606 10673502 t "The effect has been demonstrated using O75030-9" gcesareni "The current study reveals that c-kit signaling triggers two phosphorylation events on mi, which up-regulate transactivation potential yet simultaneously target mi for ubiquitin-dependent proteolysis. The specific activation/degradation signals derive from mapk/erk targeting of serine 73the results suggested that s1p reduced melanin synthesis via s1p(3) receptor-mediated erk and rsk-1 activation, and subsequent mitf dual phosphorylation and degradation." SIGNOR-249575 "Caspase 8 complex" complex SIGNOR-C231 SIGNOR CASP7 protein P55210 UNIPROT up-regulates cleavage 9606 18073771 t amattioni "Active caspase-8 then proteolytically processes and activates caspase-7" SIGNOR-256454 TNF protein P01375 UNIPROT PIK3CB protein P42338 UNIPROT up-regulates 9606 10485710 f gcesareni "Tnf activates phosphatidylinositol-3-oh kinase (pi(3)k)." SIGNOR-70619 MAPK8 protein P45983 UNIPROT MAPK8IP1 protein Q9UQF2 UNIPROT unknown phosphorylation Ser29 FLGLHIAsPPNFRLT 9534 BTO:0000298 12756254 t miannu "After mapping JNK-dependent JIP1 phosphorylation sites and testing their functional significance, it was observed that phosphorylation by JNK of JIP1 on Thr-103 and not other phosphorylated JIP1 residues is necessary for the regulation of DLK association with JIP1, DLK activation, and subsequent module activation. The data presented corroborates our previous observations using endogenous proteins, demonstrates that JNK binding to JIP1 is necessary for module activation, and shows that activation of JIP1-JNK module dynamics requires phosphorylation of JIP1 on Thr-103 by JNK. and Thr-205 are phosphorylated directly by JNK after JNK binds to JIP1." SIGNOR-250125 AMP smallmolecule CHEBI:456215 ChEBI adenosine smallmolecule CHEBI:16335 ChEBI "up-regulates quantity" "precursor of" -1 31461341 t Luana "Ecto-5'-nucleotidase [cluster of differentiation 73 (CD73)] is a ubiquitously expressed glycosylphosphatidylinositol-anchored glycoprotein that converts extracellular adenosine 5'-monophosphate to adenosine." SIGNOR-269741 KLHL3 protein Q9UH77 UNIPROT WNK1 protein Q9H4A3 UNIPROT "down-regulates quantity by destabilization" binding 9606 BTO:0000567 23387299 t miannu "CUL3 assembles with BTB proteins to form Cullin-RING E3 ubiquitin ligase complexes. To explore how a CUL3-KLHL3 complex might operate, we immunoprecipitated KLHL3 and found that it associated strongly with WNK isoforms and CUL3. These results suggest that the CUL3-KLHL3 E3 ligase complex regulates blood pressure via its ability to interact with and ubiquitylate WNK isoforms." SIGNOR-272099 MAP3K1 protein Q13233 UNIPROT CRTC1 protein Q6UUV9 UNIPROT up-regulates phosphorylation 9606 18784253 t miannu "We report on the activation oftorc1through mekk1-mediated phosphorylation." SIGNOR-180816 GXYLT1 protein Q4G148 UNIPROT NOTCH2 protein Q04721 UNIPROT up-regulates binding 9606 22117070 t gcesareni "We have previously identified two human genes, gxylt1 and gxylt2, encoding glucoside xylosyltransferases responsible for the transfer of xylose to o-linked glucose. The identity of the enzyme further elongating the glycan to generate the final trisaccharide xylose-xylose-glucose, however, remained unknown. Here, we describe that the human gene c3orf21 encodes a udp-xylose:alfa-xyloside alfa1,3-xylosyltransferase, acting on xylose-alfa1,3-glucosebeta1-containing acceptor structures. We have, therefore, renamed it xxylt1 (xyloside xylosyltransferase 1). Xxylt1 cannot act on a synthetic acceptor containing an alfa-linked xylose alone, but requires the presence of the underlying glucose. Activity on notch egf repeats was proven by in vitro xylosylation of a mouse notch1 fragment recombinantly produced in sf9 insect cells, a bacterially expressed egf repeat from mouse notch2 modified in vitro by rumi and gxylt2 and in vivo by co-expression of the enzyme with the notch1 fragment. The enzyme was shown to be a typical type ii membrane-bound glycosyltransferase localized in the endoplasmic reticulum." SIGNOR-177694 IFIH1 protein Q9BYX4 UNIPROT MAVS protein Q7Z434 UNIPROT "up-regulates activity" binding 9606 19052324 t miannu "Initially, RIG-I and MDA5 sense dsRNA in the cytoplasm, produced as a by-product of RNA virus replication.Once one or both of these sensors are activated, they interact with a mitochondrial membrane protein called MAVS (mitochondrial antiviral) (also called IPS1, Cardif, and VISA). They signal to the mitochondrial membrane protein MAVS, which in turn activates the kinases TBK1 and IKKɛ." SIGNOR-260140 PRKD1 protein Q15139 UNIPROT PRKD1 protein Q15139 UNIPROT unknown phosphorylation Ser738 ARIIGEKsFRRSVVG -1 10867018 t lperfetto "The last two autophosphorylation sites (Ser(744) and Ser(748)) are located in the activation loop but are only phosphorylated in the isolated PKD-catalytic domain and not in the full-length PKD; they may affect enzyme catalysis but are not involved in the activation of wild-type PKD by phorbol ester. | These results indicate that neither of the activation loop serines is involved in PDBu-induced activation but that they may be involved in catalysis or in maintaining the conformation of the enzyme prot" SIGNOR-249046 MAPKAPK2 protein P49137 UNIPROT AGO2 protein Q9UKV8 UNIPROT up-regulates phosphorylation Ser387 SKLMRSAsFNTDPYV 9606 20626350 t gcesareni "Mk2 was found to phopsphorylate in vitro the ago2 protein in ser387, which was identified as the major ago2 phosphorylation site in cells.and mutation of ser387 to alanineimpairsago2 localization to therna-containing granules termedprocessing bodies" SIGNOR-166615 RAC1 protein P63000 UNIPROT MAPK8 protein P45983 UNIPROT "up-regulates activity" 9606 23151663 f gcesareni "Planar cell polarity (pcp) signalling triggers activation of the small gtpases rhoa and rac1, which in turn activate rho kinase (rock) and jun-n-terminal kinase (jnk), respectively, leading to actin polymerization and microtubule stabilization." SIGNOR-199539 EID2 protein Q8N6I1 UNIPROT SMAD3 protein P84022 UNIPROT down-regulates binding 9606 14612439 t gcesareni "In this study, we examined the effect of eid-2 on smad-mediated tgf- signaling. Here, we show that eid-2 inhibits tgf- /smad transcriptional responses. Eid-2 interacts constitutively with smad proteins, and most strongly with smad3." SIGNOR-119171 FOS protein P01100 UNIPROT AP1 complex SIGNOR-C154 SIGNOR "form complex" binding 9606 1904542 t irozzo "The proteins encoded by the proto-oncogenes c-fos and c-jun (Fos and Jun, respectively) form a heterodimeric complex that regulates transcription by interacting with the DNA-regulatory element known as the activator protein 1 (AP-1) binding site." SIGNOR-256364 TFIIH complex SIGNOR-C457 SIGNOR POLR2A protein P24928 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser1899 SPTYSPTsPVYTPTS 9606 14662762 t lperfetto "Although there is some inconsistency in the literature, it is generally thought that cdk7, a component of the transcription factor (tf) iih, is a major ser-5 kinase, whereas cdk9, a component of positive transcription elongation factor (p-tef) b, is a major ser-2 kinase within cells. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination." SIGNOR-269347 FLT3 protein P36888 UNIPROT IDH1 protein O75874 UNIPROT "up-regulates activity" phosphorylation Tyr42 VELDLHSyDLGIENR -1 34289383 t lperfetto "Moreover, in an in vitro kinase assay, purified recombinant FLT3 (rFLT3) phosphorylated recombinant IDH2 R140Q mutant but did not alter its catalytic activity (Figure 1C), whereas rFLT3 phosphorylated mIDH1 protein and enhanced its catalytic activity" SIGNOR-267629 AKT1 protein P31749 UNIPROT YBX1 protein P67809 UNIPROT up-regulates phosphorylation Ser102 NPRKYLRsVGDGETV 9606 BTO:0000150 19036157 t lperfetto "Phosphorylation of yb-1 at the serine 102 residue is required for transcriptional activation of growth-enhancing genes, such as egfr. Herein, we illustrate that activated akt binds to and phosphorylates the yb-1 cold shock domain at ser102" SIGNOR-252521 MAP2K1 protein Q02750 UNIPROT ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR "up-regulates activity" phosphorylation 10090 BTO:0000011 12270934 t lperfetto "MEK1 as indicated by extensive phosphorylation of ERK1 and ERK2 during the initial 2 h of adipogenesis." SIGNOR-235352 dothiepin chemical CHEBI:36798 ChEBI CHRM3 protein P20309 UNIPROT "down-regulates activity" "chemical inhibition" 10029 BTO:0000246 8100134 t miannu "Antagonism of the five cloned human muscarinic cholinergic receptors expressed in CHO-K1 cells by antidepressants and antihistaminics. Competition between [‘H]QNB and the antidepressant compounds (Table 1) showed that at the ml subtype the most potent drugs were amitriptyline > dothiepin > doxepin = nortriptyline; at the m2 receptor, amitriptyline > imipramine > nortriptyline = dothiepin; at the m3 recep- tor, amitriptyline > dothiepin > nortriptyline; at the m4 receptor, amitriptyline > dothiepin > doxepin = nortrip- tyline; and at the m5 receptor, amitriptyline > doxepin > imipramine." SIGNOR-258696 CALM2 protein P0DP24 UNIPROT CAMKK2 protein Q96RR4 UNIPROT up-regulates binding 9606 BTO:0000782 BTO:0000142 9822657 t miannu "The ca2+-calmodulin-dependent protein kinase (cam kinase) cascade includes three kinases: cam-kinase kinase (camkk);and the cam kinases camki and camkiv, which are phosphorylated and activated by camkk." SIGNOR-266329 PRKAA2 protein P54646 UNIPROT TSC1 protein Q92574 UNIPROT up-regulates phosphorylation 9606 SIGNOR-C15 14651849 t gcesareni "Under energy starvation conditions, the amp-activated protein kinase (ampk) phosphorylates tsc2 and enhances its activity." SIGNOR-119541 CCNY protein Q8ND76 UNIPROT CDK14 protein O94921 UNIPROT up-regulates binding 9606 20059949 t gcesareni "L63 and its vertebrate homolog pftk are regulated by the membrane tethered g2/m cyclin, cyclin y, which mediates binding to and phosphorylation of lrp6." SIGNOR-162920 "Factor FVIIa:TF" complex SIGNOR-C319 SIGNOR F5 protein P12259 UNIPROT "down-regulates activity" cleavage Arg1220 LSPELIQrNLSPALG -1 10026263 t lperfetto "Thrombin is considered the physiological activator of factor V and is the most potent activator, catalyzing the cleavage of three peptide bonds at Arg709, Arg1018, and Arg1545" SIGNOR-263648 PLK1 protein P53350 UNIPROT PKMYT1 protein Q99640 UNIPROT unknown phosphorylation Ser426 CSLLLDSsLSSNWDD 9606 BTO:0000567 12738781 t lperfetto "These results suggest that Ser-426 is a major phosphorylation site by Plk1, and Thr-495 is a second major site. " SIGNOR-249207 "Cullin 1-RBX1-Skp1" complex SIGNOR-C529 SIGNOR IKBKB protein O14920 UNIPROT "down-regulates quantity by destabilization" polyubiquitination 9606 BTO:0000007 10321728 t miannu "We identified a human F-box/WD40 repeats protein (HOS), which is homologous to Slimb/h betaTrCP. Being a part of SCF complex with Skp1 and Cullin1, HOS specifically interacted with the phosphorylated IkappaB and beta-catenin, targeting these proteins for proteasome-dependent degradation in vivo. " SIGNOR-272547 WARS1 protein P23381 UNIPROT Trp-tRNA(Trp) smallmolecule CHEBI:29159 ChEBI "up-regulates quantity" "chemical modification" 9606 14660560 t miannu "Aminoacyl-tRNA synthetases (aaRSs)1 are a family of ancient enzymes that catalyze amino acid activation by ATP and the subsequent aminoacylation to its cognate tRNA. Alternative splicing produces two forms of hTrpRS in human cells: full-length hTrpRS (residues 1-471) and mini-hTrpRS (residues 48-471)" SIGNOR-270514 IFNG protein P01579 UNIPROT IFNGR1 protein P15260 UNIPROT up-regulates binding 9606 12438563 t gcesareni "Ifn-g Binds to the ifn-g Receptor binding subunit (ifn-gR1;receptor chain 1), a species-specific cell surface transmembrane receptor chain (41, 42). A second transmembrane protein (ifn-gR2) (4345) is required for signal transduction" SIGNOR-95626 MAPK8 protein P45983 UNIPROT HNRNPK protein P61978 UNIPROT "up-regulates activity" phosphorylation Ser216 ILDLISEsPIKGRAQ 9606 11259409 t lperfetto "The current studies demonstrate the identification of hnrnp-k as a jnk and erk substrate. The phosphoacceptor sites for jnk and erk on the k protein are different, and indeed, erk phosphorylation results in biological consequences different from those of phosphorylation by jnk (49). Whereas erk phosphorylation on aa 284 and 353 contributes to k protein nuclear export and concomitant inhibition of rna translation (49), phosphorylation by k protein on aa 216 and 353 increases the transcriptional effects of the k protein." SIGNOR-105247 FBXL17 protein Q9UF56 UNIPROT SUFU protein Q9UMX1 UNIPROT "down-regulates quantity by destabilization" ubiquitination 27234298 t "Here, we show that Fbxl17 (F-box and leucine-rich repeat protein 17) targets Sufu for proteolysis in the nucleus. The ubiquitylation of Sufu, mediated by Fbxl17, allows the release of Gli1 from Sufu for proper Hh signal transduction" SIGNOR-253545 UBE3A protein Q05086 UNIPROT RAD23B protein P54727 UNIPROT "down-regulates quantity by destabilization" polyubiquitination 9534 BTO:0000298 10373495 t miannu " Here we report the identification of HHR23A, one of the human homologues of the yeast DNA repair protein Rad23, as an E6-independent target of E6AP.  E6AP-mediated ubiquitination and degradation of HHR23A and HHR23B." SIGNOR-272551 NF90-NF45 complex SIGNOR-C443 SIGNOR DNA-PK complex SIGNOR-C107 SIGNOR "up-regulates activity" binding -1 9442054 t miannu "These proteins are NF90 and NF45, which are the 90- and 45-kDa subunits of a protein known to bind specifically to the antigen receptor response element of the interleukin 2 promoter, and the alpha, beta, and gamma subunits of eukaryotic translation initiation factor eIF-2. We also show that NF90, NF45, and eIF-2 beta are substrates for DNA-PK in vitro. In addition, recombinant NF90 promotes formation of a complex between DNA-PKcs, Ku, and DNA, and antibodies to recombinant NF90 or recombinant NF45 immunoprecipitate DNA-PKcs in vitro. Together, our data suggest that NF90, in complex with NF45, interacts with DNA-PKcs and Ku on DNA and that NF90 and NF45 may be important for the function of DNA-PK." SIGNOR-268489 MAP3K7 protein O43318 UNIPROT HDAC7 protein Q8WUI4 UNIPROT down-regulates phosphorylation Ser155 FPLRKTVsEPNLKLR 9606 16980613 t lperfetto "We further show that emk and c-tak1 phosphorylate class iia hdacs on one of their multiple 14-3-3 binding sites and alter their subcellular localization and repressive function" SIGNOR-149579 NXF1 protein Q9UBU9 UNIPROT mRNA-nucleus_export phenotype SIGNOR-PH127 SIGNOR up-regulates 9606 28831067 f lperfetto "SUN1, a component of the LINC (Linker of Nucleoskeleton and Cytoskeleton) complex, functions in mammalian mRNA export through the NXF1-dependent pathway. It associates with mRNP complexes by direct interaction with NXF1." SIGNOR-263298 CDK11B protein P21127 UNIPROT EIF3F protein O00303 UNIPROT unknown phosphorylation Thr119 GAARVIGtLLGTVDK 9606 19245811 t lperfetto "Here, we identified a second eif3f phosphorylation site (thr119) by cdk11p46 during apoptosis.Thr119 is located in the mov34 domain of eif3f which is important for both the translational inhibitory function of eif3ffurther studies of how eif3f phosphorylation regulates its function will refine insights into the mechanism and regulation of translation initiation, apoptotic signaling, and tumorigenesis." SIGNOR-184185 MAP4K3 protein Q8IVH8 UNIPROT MAP4K3 protein Q8IVH8 UNIPROT up-regulates phosphorylation Ser170 ATIAKRKsFIGTPYW 9606 20227368 t gcesareni "We identify a transautophosphorylation site in the map4k3 kinase activation segment (ser170) that is required for map4k3 activity and its activation of mtorc1 signaling." SIGNOR-164103 erlotinib chemical CHEBI:114785 ChEBI EGFR protein P00533 UNIPROT "down-regulates activity" "chemical inhibition" -1 22037378 t Luana "Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here." SIGNOR-258212 MAPK3 protein P27361 UNIPROT SPHK1 protein Q9NYA1 UNIPROT up-regulates phosphorylation Ser225 VGSKTPAsPVVVQQG 9606 14532121 t gcesareni "Activation of sphingosine kinase 1 by erk1/2-mediated phosphorylation." SIGNOR-118550 RCHY1 protein Q96PM5 UNIPROT COPE protein O14579 UNIPROT "down-regulates quantity by destabilization" polyubiquitination 9606 BTO:0000007 17721809 t miannu "PIRH2 promotes the ubiquitylation of epsilon-COP in vitro and in vivo and consequently promotes the degradation of epsilon-COP. " SIGNOR-272630 IRF2BPL protein Q9H1B7 UNIPROT CTNNB1 protein P35222 UNIPROT "down-regulates quantity by destabilization" ubiquitination 9606 BTO:0000498 29374064 t miannu "FOXF2 directly bound the promoter of E3 ligase interferon regulatory factor 2-binding protein-like (IRF2BPL) and induced its transcriptional expression. IRF2BPL in turn interacted with β-catenin, increasing its ubiquitination and degradation." SIGNOR-267153 DNMT3B protein Q9UBC3 UNIPROT DPP6 protein P42658 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 10090 BTO:0000596 23409053 t lperfetto "In the absence of Dnmt3b, Dnmt3a was associated with Dpp6 gene promoter and regulated its expression and methylation in P19 cells." SIGNOR-268964 PFN1 protein P07737 UNIPROT Actin_cytoskeleton_reorganization phenotype SIGNOR-PH84 SIGNOR up-regulates 9606 18667433 f areggio " Additionally, the association of Ror2 with the actin-binding protein filamin A is required for Wnt5a-induced JNK activation and polarized cell migration." SIGNOR-258977 SLC16A3 protein O15427 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR down-regulates 9606 26384349 f lperfetto "Treatment with _-cyano-4-hydroxy cinnamate (CHC), a known inhibitor of MCT1, MCT2 and MCT4, dose-dependently induced cell death in MM cell lines and primary MM cells (Figure 1C). Thus, monocarboxylate transportation across membranes appears crucial for MM cell survival." SIGNOR-256581 CASP3 protein P42574 UNIPROT NFKBIA protein P25963 UNIPROT "up-regulates quantity by stabilization" cleavage -1 9367996 t lperfetto "The cell-death protease cpp32 (caspase-3) in vitro specifically cleaved chicken and human ikappab-alpha at a conserved asp-ser sequence.Therefore, cleavage of I_B-_ by a CPP32-like protease could create what is sometimes called a super-repressor form of I_B-_ (20). That is, cleavage by CPP32 would block the ability of I_B-_ to undergo signal-induced degradation by removing the sites of signal-induced ubiquitination and by likely disrupting the ability of I_B-_ to become phosphorylated at critical Ser residues." SIGNOR-51936 PRKAA1 protein Q13131 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR "up-regulates activity" phosphorylation Ser626 SLECDMEsIIRSELM 9606 BTO:0000007 17711846 t gcesareni "Phosphorylation by AMPK leads to the activtion of FOXO3 transcriptional activity without affecting FOXO3 subcellular localization." SIGNOR-252979 PDK3 protein Q15120 UNIPROT PDHA1 protein P08559 UNIPROT "down-regulates activity" phosphorylation Ser232 NRYGMGTsVERAAAS -1 11485553 t lperfetto "Here we report that the four isoenzymes of protein kinase responsible for the phosphorylation and inactivation of pyruvate dehydrogenase (pdk1, pdk2, pdk3 and pdk4) differ in their abilities to phosphorylate the enzyme. Pdk1 can phosphorylate all three sites (s232, s293, s300), whereas pdk2, pdk3 and pdk4 each phosphorylate only s232 and s293." SIGNOR-109613 3-[1-[[4-(7-phenyl-3H-imidazo[4,5-g]quinoxalin-6-yl)phenyl]methyl]-4-piperidinyl]-1H-benzimidazol-2-one chemical CHEBI:91346 ChEBI AKT1 protein P31749 UNIPROT "down-regulates activity" "chemical inhibition" 25309440 t lperfetto "Different agents were used to inhibit either the PI3K/Akt or MEK/ERK pathways. The PI3K inhibitor, LY294002, and the Akt inhibitor, Akt inhibitor VIII, were used to inhibit the PI3K/Akt pathway." SIGNOR-262010 PTGS2 protein P35354 UNIPROT MYOD1 protein P15172 UNIPROT up-regulates 9606 BTO:0001103 20219869 t apalma "Furthermore, COX-2 inhibition reduced MyoD expression in regenerating muscle, suggesting a role for COX-2 in modulating muscle differentiation, as well as growth" SIGNOR-256214 MAGEC2 protein Q9UBF1 UNIPROT TRIM28 protein Q13263 UNIPROT "up-regulates activity" binding 9606 BTO:0000594 28394358 t lperfetto "In this study, we demonstrated that the tripartite motif-containing protein 28 (TRIM28) binds directly to and promotes FBP1 for ubiquitination and degradation. MAGE-A3 and MAGE-C2, which are known to be overexpressed in HCC, can enhance TRIM28-dependent degradation of FBP1 by forming ubiquitin ligase complexes with TRIM28." SIGNOR-267593 GRIA1 protein P42261 UNIPROT Excitatory_synaptic_transmission phenotype SIGNOR-PH133 SIGNOR up-regulates 9606 BTO:0000938 30825796 f miannu "In the mammalian brain the majority of fast excitatory neurotransmission is carried out by α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA)-sensitive ionotropic glutamate receptors located within the post-synaptic density of glutamatergic synapses" SIGNOR-264615 TEK protein Q02763 UNIPROT MYOD1 protein P15172 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 BTO:0000222 26042050 f lperfetto "the effects of the angiopoietins are not specific for vascular endothelial cells, as their receptors (Tie1, Tie2) are known to be expressed in hematopoietic cells and they have also recently been shown to be expressed in skeletal muscle cellsExogenous Ang-1 enhanced myogenic (MyoD and Myogenin) mRNA in differentiating myoblasts and increased myosin heavy chain protein." SIGNOR-241532 STK4 protein Q13043 UNIPROT TNNI3 protein P19429 UNIPROT unknown phosphorylation Thr143 RGKFKRPtLRRVRIS 9606 BTO:0000671 18986304 t llicata "Ms analysis indicated that mst1 phosphorylates ctni at thr(31), thr(51), thr(129) and thr(143)." SIGNOR-182053 PTPRF protein P10586 UNIPROT FYN protein P06241 UNIPROT up-regulates dephosphorylation Tyr531 FTATEPQyQPGENL 9606 12496362 t gcesareni "Regulation of lck and fyn tyrosine kinase activities by transmembrane protein tyrosine phosphatase leukocyte common antigen-related molecule." SIGNOR-96764 SARS1 protein P49591 UNIPROT AMP smallmolecule CHEBI:456215 ChEBI "up-regulates quantity" "chemical modification" 9606 24095058 t miannu "As a member of the aminoacyl-tRNA synthetase family, seryl-tRNA synthetase (SerRS) catalyzes the aminoacylation reaction that charges serine onto its cognate tRNA for protein synthesis" SIGNOR-270497 "Cy3-bifunctional dye zwitterion" chemical CHEBI:37990 ChEBI ADRB2 protein P07550 UNIPROT "up-regulates activity" "chemical activation" 10030 BTO:0000457 20590599 t Luana "Denopamine is the most selective ligand for β1-receptors, with regard to intrinsic activity and efficacy, and clenbuterol, procaterol, zinterol, AZ 40140d and salbutamol are more selective for the β2-adrenoceptor than the β1-adrenoceptor based on intrinsic activity and efficacy. " SIGNOR-257858 PLK1 protein P53350 UNIPROT SRI protein P30626 UNIPROT unknown phosphorylation Thr155 YSTNGKItFDDYIAC 9606 24427308 t lperfetto "Sorcin interacts physically with plk1, is phosphorylated by plk1 and induces plk1 autophosphorylation, thereby regulating kinase activity." SIGNOR-203732 TNFRSF10D protein Q9UBN6 UNIPROT TNFSF10 protein P50591 UNIPROT down-regulates binding 9606 9382840 t amattioni "One function of trail-r4 may be inhibition of trail cytotoxicy. Dcr2 functions as an inhibitory apo2l receptor." SIGNOR-53447 WNT16 protein Q9UBV4 UNIPROT LRP6 protein O75581 UNIPROT up-regulates binding 9606 15578921 t gcesareni "Wnt proteins bind to the frizzled receptors and lrp5/6 co-receptors, and through stabilizing the critical mediator betBeta-catenin, initiate a complex signaling cascade that plays an important role in regulating cell proliferation and differentiation." SIGNOR-131677 pipamperone chemical CHEBI:78549 ChEBI HTR1A protein P08908 UNIPROT "down-regulates activity" "chemical inhibition" 10116 BTO:0000601 8935801 t miannu "Risperidone and its active metabolite 9-OH-risperidone were compared to reference antipsychotic drugs (haloperidol, pipamperone, fluspirilene, clozapine, zotepine) and compounds under development (olanzapine, seroquel, sertindole, ORG-5222, ziprasidone) for in vitro binding to neurotransmitter receptors in brain tissue and on membranes of recombinant cells expressing cloned human receptors and for in vivo occupancy of neurotransmitter receptors in rat and guinea-pig brain following acute treatment (2 h., s.c.). The binding affinities of the compounds for various neurotransmitter receptors were measured using membrane preparations of animal brain regions and of recombinant cells expressing cloned, mostly human receptors. Receptors, tissues and cells are indicated in Table I; results are shown in Table 4A-B." SIGNOR-258575 metformin chemical CHEBI:6801 ChEBI G6P proteinfamily SIGNOR-PF81 SIGNOR "up-regulates quantity by expression" "transcriptional regulation" 9606 17909097 f "inferred from family member" gcesareni "In this study, we found that metformin increased shp gene expression via ampk activation and inhibited the expression of the hepatic gluconeogenic genes pepck and g6pase via upregulation of shp." SIGNOR-270254 DSCAML1 protein Q8TD84 UNIPROT Neurite_outgrowth phenotype SIGNOR-PH134 SIGNOR down-regulates 9606 BTO:0000938 30745319 f miannu "Nuclear DSCAM and DSCAML1 impair neurite outgrowth. this demonstrates that enhanced nuclear translocation of the DSCAM and DSCAML1 ICDs profoundly impairs neurite outgrowth and development of primary cortical neurons" SIGNOR-264275 SETBP1 protein Q9Y6X0 UNIPROT HOXA9 protein P31269 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0001271 22566606 f miannu "Setbp1 activates hoxa9 and hoxa10 expression in myeloid progenitors" SIGNOR-197321 TBP protein P20226 UNIPROT TFIIIB complex SIGNOR-C393 SIGNOR "form complex" binding 29378333 t lperfetto "Both in yeast and mammalian cells, TFIIIB consists of three subunits: TFIIB-related Brf1, TATA-box binding protein (TBP), common also for the other two RNA polymerases, and Pol III-specific subunit, Bdp1 (Table 1)." SIGNOR-266192 KDM5A protein P29375 UNIPROT H3-4 protein Q16695 UNIPROT "up-regulates activity" demethylation Lys5 kQTARKST 9606 30246379 t miannu "KDM5 subfamily is capable of removing tri‐ and di‐ methyl marks from lysine 4 on histone H3 (H3K4). Depending on the methylation site, its effect on transcription can be either activating or repressing." SIGNOR-264300 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR UBTF protein P17480 UNIPROT down-regulates phosphorylation 9606 11741541 t "inferred from 70% family members" lperfetto "Erk1/2 was found to phosphorylate the architectural transcription factor ubf at amino acids 117 and 201 within hmg boxes 1 and 2, preventing their interaction with dna" SIGNOR-270181 M2_polarization phenotype SIGNOR-PH55 SIGNOR IL10 protein P22301 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" BTO:0000801 BTO:0001103 22933625 f apalma "P38 activation contributes to the macrophage phenotype switch in injured muscle, which could elevate production of IL-10 (63), creating positive feedback for the phenotype switch" SIGNOR-255448 STK38 protein Q15208 UNIPROT YAP1 protein P46937 UNIPROT "down-regulates activity" phosphorylation Ser127 PQHVRAHsSPASLQL 9606 25601544 t Luana "We show that mammalian NDR1/2 kinases phosphorylate YAP1 on S127 and thereby negatively regulate YAP1 activity in tissue-cultured cells." SIGNOR-259855 PDP1 protein Q9P0J1 UNIPROT PDHA1 protein P08559 UNIPROT "up-regulates activity" dephosphorylation Ser300 SMSDPGVsYRTREEI -1 7782287 t "Sites 1, 2, and 3 were dephosphorylated either individually or in the presence of the other sites by the phospho-E1-phosphatase resulting in complete reactivation of the E1. The rates of dephosphorylation and reactivation were similar for sites 1, 2, and 3, indicating a random dephosphorylation mechanism" SIGNOR-252056 risperidone chemical CHEBI:8871 ChEBI HTR2A protein P28223 UNIPROT "down-regulates activity" "chemical inhibition" 10090 8935801 t miannu "Risperidone and its active metabolite 9-OH-risperidone were compared to reference antipsychotic drugs (haloperidol, pipamperone, fluspirilene, clozapine, zotepine) and compounds under development (olanzapine, seroquel, sertindole, ORG-5222, ziprasidone) for in vitro binding to neurotransmitter receptors in brain tissue and on membranes of recombinant cells expressing cloned human receptors and for in vivo occupancy of neurotransmitter receptors in rat and guinea-pig brain following acute treatment (2 h., s.c.). The binding affinities of the compounds for various neurotransmitter receptors were measured using membrane preparations of animal brain regions and of recombinant cells expressing cloned, mostly human receptors. Receptors, tissues and cells are indicated in Table I; results are shown in Table 4A-B." SIGNOR-258529 NF1 protein P21359 UNIPROT HRAS protein P01112 UNIPROT "down-regulates activity" 9606 19777070 t "NF1 negatively regulates Ras as an exchangefactor converting Ras-GTP to Ras-GDP by its GTPase-activating (Ras-GAP) domain." SIGNOR-256067 GSK3B protein P49841 UNIPROT ESR1 protein P03372 UNIPROT up-regulates phosphorylation Ser104 FPPLNSVsPSPLMLL 9606 16076840 t gcesareni "The gsk-3 inhibitor lithium chloride was used to determine the role of gsk-3 in phosphorylation of ser-102, -104, and -106 and ser-118 in vivo and to explore the role of these serines in the regulation of eralpha function. Treatment of cells with lithium chloride resulted in dephosphorylation of ser-104 and -106 and ser-118, which suggests these serine residues as targets for gsk-3 in vivo. Our results further suggest that eralpha phosphorylation by gsk-3 stabilizes eralpha under resting conditions and modulates eralpha transcriptional activity upon ligand binding. Estradiol and phorbol ester cause phosphorylation of serine 118 in the human estrogen receptor. Potentiation of human estrogen receptor alpha transcriptional activation through phosphorylation of serines 104 and 106 by the cyclin a-cdk2 complex." SIGNOR-139316 TERF2 protein Q15554 UNIPROT ATM protein Q13315 UNIPROT "down-regulates activity" binding SIGNOR-C306 18680434 t lperfetto "It is not yet clear how the presence of TRF2 at telomeres averts the activation of the ATM kinase.> In this regard, overexpression of TRF2can dampen the activation of the ATM kinase, even at nontelomeric sites of DNA damage (95). Furthermore, TRF2 can interact with the ATM kinase as well as with the Mre11 complex" SIGNOR-263323 FHL2 protein Q14192 UNIPROT AR protein P10275 UNIPROT up-regulates binding 9606 BTO:0001129 10654935 t gcesareni "Fhl2 contains a strong, autonomous transactivation function and binds specifically to the ar in vitro and in vivo." SIGNOR-74703 ABL1 protein P00519 UNIPROT NCK1 protein P16333 UNIPROT up-regulates phosphorylation Tyr105 VDPGERLyDLNMPAY 9606 22327338 t lperfetto "Activated c-abl reduces the amplitude of mitogen-activated protein kinases (erk1/2, jnks and p38) activation in a dose-dependent manner by a negative feedback mechanism. By analysis of the adaptor proteins nck1 and grb2 mutants we further show that the negative loop on p38 is mediated by c-abl phosphorylation at tyrosine 105 of the adaptor protein nck1" SIGNOR-196043 ATP6V1H protein Q9UI12 UNIPROT "AP-2 complex" complex SIGNOR-C245 SIGNOR "up-regulates activity" binding 10090 BTO:0004122 29782852 t miannu "ATP6V1H interacts with TGF-β receptor I and AP-2 complex to regulate the proliferation and differentiation of BMSCs. Lack of ATP6V1H function decreases bone formation in vivo" SIGNOR-266887 NOTCH1 protein P46531 UNIPROT LFNG protein Q8NES3 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 22298955 f gcesareni "Notch signal transduction pathway genes, lfng, hey1, and hes1, are differen-tially regulated by bmp-2 and tgf-beta." SIGNOR-195621 GSK3B protein P49841 UNIPROT MAPT protein P10636 UNIPROT down-regulates phosphorylation Thr522 SSPGSPGtPGSRSRT 9606 BTO:0000142 20308788 t "The effect has been demonstrated using P10636-8" lperfetto "Abnormal hyperphosphorylation of tau appears to be crucial in neurofibrillary degeneration in alzheimer's disease (ad). Gsk-3beta phosphorylated tau at many sites, with ser199, thr205, and ser396 being the most favorable sites in cells." SIGNOR-164655 WEE1 protein P30291 UNIPROT CDK2 protein P24941 UNIPROT down-regulates phosphorylation Tyr15 EKIGEGTyGVVYKAR 9606 BTO:0000567 11029659 t gcesareni "Identification and characterization of human wee1b, a new member of the wee1 family of cdk-inhibitory kinases." SIGNOR-83139 NUCKS1 protein Q9H1E3 UNIPROT DNA_repair phenotype SIGNOR-PH57 SIGNOR up-regulates 9606 26323318 f miannu "From these results, we can conclude that NUCKS1 plays a role in HR DNA repair, as does its paralog RAD51AP1. we have tested and uncovered a role for NUCKS1 in HR and in maintaining DNA replication integrity and genome stability." SIGNOR-261960 "Nucleosome_H3.1 variant" complex SIGNOR-C324 SIGNOR Chromatine_condensation phenotype SIGNOR-PH21 SIGNOR up-regulates 9606 21812398 f miannu "The elemental repeating unit of chromatin is the nucleosome core particle (NCP), which consists of 146 base pairs of DNA wrapped in 1.65 left-handed superhelical turns around the histone octamer. The histone octamer comprises two each of the core histones, H2A, H2B, H3 and H4, which form two H2A/H2B dimers and an H3/H4 tetramer, respectively, in the NCP." SIGNOR-263723 MED13L protein Q71F56 UNIPROT "CKM complex" complex SIGNOR-C406 SIGNOR "form complex" binding 9606 23563140 t miannu "The CDK8 kinase module (CKM) is a conserved, dissociable Mediator subcomplex whose component subunits were genetically linked to the RNA polymerase II (RNAPII) C-terminal domain (CTD) and individually recognized as transcriptional repressors before Mediator was identified as a pre-eminent complex in eukaryotic transcription regulation." SIGNOR-266702 MAPK3 protein P27361 UNIPROT JUND protein P17535 UNIPROT up-regulates phosphorylation Ser100 LGLLKLAsPELERLI 9606 22327296 t gcesareni "Menin binds the jun family transcription factor jund and inhibits its transcriptional activity. The menin-jund interaction blocks jun n-terminal kinase (jnk)-mediated jund phosphorylation and suppresses jund-induced transcription. We found a role for phosphorylation of the ser100 residue of jund;jund phosphorylation were prevented by inhibitors of calcium, calmodulin, or erk1/2 kinase." SIGNOR-196034 mTORC2 complex SIGNOR-C2 SIGNOR mTORC2 complex SIGNOR-C2 SIGNOR "up-regulates activity" phosphorylation 9606 BTO:0000782 10702316 t lperfetto "We report here the identification of a FRAP autophosphorylation site. This site, Ser-2481, is located in a hydrophobic region near the conserved carboxyl-terminal FRAP tail. We demonstrate that the COOH-terminal tail is required for FRAP kinase activity and for signaling to the translational regulator p70(s6k) (ribosomal subunit S6 kinase)." SIGNOR-217000 EP300 protein Q09472 UNIPROT CDX2/PAX6/P300 complex SIGNOR-C33 SIGNOR "form complex" binding 9606 10506141 t lperfetto "In the present study, we investigated the interaction of cdx-2 and pax-6 with p300, a co-activator coupled to the basal transcription machinery. In transient transfection-expression experiments, we found that the transactivating effects of cdx-2 and pax-6 on the glucagon gene were greatly enhanced by the additional expression of p300." SIGNOR-70960 pembrolizumab antibody DB09037 DRUGBANK PDCD1 protein Q15116 UNIPROT "down-regulates activity" binding 9606 "BTO:0000848; BTO:0002058" 25685857 t miannu "Preclinical studies described PD-1 blockade resulting in tumor growth suppression and even decreased metastasis. This has led to the development of pembrolizumab (MK-3475), a highly selective, humanized monoclonal IgG4-kappa isotype antibody against PD-1. Early clinical trials have shown high tumor response rates and long duration of effect in previously treated advanced melanoma resulting in accelerated FDA approval for the drug in this situation. Pembrolizumab has also had success in non-small cell lung cancer and is being tested in multiple other tumor types." SIGNOR-259899 TBP protein P20226 UNIPROT TFIID complex SIGNOR-C343 SIGNOR "form complex" binding 9606 27096372 t miannu "The general transcription factor IID (TFIID) plays a central role in the initiation of RNA polymerase II (Pol II)-dependent transcription by nucleating pre-initiation complex (PIC) assembly at the core promoter. TFIID comprises the TATA-binding protein (TBP) and 13 TBP-associated factors (TAF1-13), which specifically interact with a variety of core promoter DNA sequences." SIGNOR-263933 ATG13 protein O75143 UNIPROT RB1CC1 protein Q8TDY2 UNIPROT up-regulates binding 9606 19225151 t gcesareni "Atg13 directly binds fip200." SIGNOR-184120 MAP2K2 protein P36507 UNIPROT ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR up-regulates phosphorylation 9606 11971971 t lperfetto "Mapk1 is phosphorylated by map2k1/mek1 and map2k2/mek2 on thr-185 and tyr-187 in response to external stimuli like insulin or ngf. Both phosphorylations are required for activity." SIGNOR-244637 PKA proteinfamily SIGNOR-PF17 SIGNOR BAD protein Q92934 UNIPROT down-regulates phosphorylation 9606 10230396 t "inferred from 70% family members" gcesareni "Ser-155 is the major phosphoacceptor site for pka on bad, but that pka also phosphorylates ser-112 and ser-136. Phosphorylated bad appears to be the inactive moiety. These results implicate pkac as the candidate kinase for s112 phosphorylation in vivo." SIGNOR-270129 TYSND1 protein Q2T9J0 UNIPROT TYSND1 protein Q2T9J0 UNIPROT "down-regulates activity" cleavage 9606 BTO:0000567 22002062 t miannu "Self-cleavage of Tysnd1 in the active oligomer most likely inactivates its protease activity. Subsequently, the cleaved products are degraded by PsLon and removed from the Tysnd1 oligomer." SIGNOR-261053 NUP98-HOXA9 "fusion protein" SIGNOR-FP15 SIGNOR CEBPA protein P49715 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 17442773 f miannu "Over 102 cytoplasmic mRNAs were significantly altered in K562 myeloid leukemic cells transduced with NUP98‐HOXA9, 92 being increased and only 10 decreased. The transcription factor CCAAT enhancer binding protein‐α (C/EBPα), a tumor suppressor gene and a crucial regulator of granulopoiesis through inhibition of c‐JUN, was downmodulated by NUP98‐HOXA9" SIGNOR-261501 FGF2 protein P09038 UNIPROT FGFR3 protein P22607 UNIPROT up-regulates binding 9606 15780951 t gcesareni "Fgf-2 and fgf-9 increased expression of other osteogenic factors bmp-2 and tgf-beta1, and endogenous fgf/fgfr signaling is a positive upstream regulator of the bmp-2 gene in calvarial osteoblasts." SIGNOR-134788 IGF1R protein P08069 UNIPROT IRS1 protein P35568 UNIPROT up-regulates phosphorylation Tyr896 EPKSPGEyVNIEFGS 9606 17827393 t gcesareni "Furthermore, IGF-1 stimulates tyrosine phosphorylation of insulin receptor substrate-1 (IRS-1) and IRS-2 and their association with the p85 subunit of phosphoinositide-3 kinase (PI3K)." SIGNOR-157750 TWIST1 protein Q15672 UNIPROT MYB protein P10242 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0004828 19051271 f miannu "we performed microarray analysis to compare the gene expression profiles in HGC-27 cells, with or without small interfering RNA (siRNA)-mediated depletion of TWIST. Our results showed that NF1, RAP1A, SRPX, RBL2, PFDN4, ILK, F2R, ERBB3, and MYB were up-regulated, whereas AKR1C2, FOS, GDF15, NR2F1, ATM, and CTPS were down-regulated after TWIST depletion" SIGNOR-255529 SARS1 protein P49591 UNIPROT serine smallmolecule CHEBI:17822 ChEBI "down-regulates quantity" "chemical modification" 9606 24095058 t miannu "As a member of the aminoacyl-tRNA synthetase family, seryl-tRNA synthetase (SerRS) catalyzes the aminoacylation reaction that charges serine onto its cognate tRNA for protein synthesis" SIGNOR-270494 RAB6C protein Q9H0N0 UNIPROT Neurite_outgrowth phenotype SIGNOR-PH134 SIGNOR up-regulates 10116 25492866 f miannu "Cohen syndrome-associated protein COH1 physically and functionally interacts with the small GTPase RAB6 at the Golgi complex and directs neurite outgrowth. COH1 and RAB6 regulate neurite outgrowth in primary neurons" SIGNOR-266875 sapitinib chemical CHEBI:132986 ChEBI SHC3 protein Q92529 UNIPROT down-regulates "chemical inhibition" 9606 BTO:0000551 20145185 t gcesareni "In vivo, azd8931 inhibited xenograft growth in a range of models while significantly affecting egfr, erbb2, and erbb3 phosphorylation and downstream signaling pathways, apoptosis, and proliferation." SIGNOR-163733 MRPS22 protein P82650 UNIPROT "28S mitochondrial small ribosomal subunit" complex SIGNOR-C266 SIGNOR "form complex" binding 9606 25838379 t miannu "The mammalian mitochondrial ribosome (mitoribosome) has a highly protein-rich composition with a small sedimentation coefficient of 55 S, consisting of 39 S large and 28 S small subunits. . We report here the identification of 28 S small subunit proteins." SIGNOR-261434 MBOAT7 protein Q96N66 UNIPROT acyl-CoA smallmolecule CHEBI:17984 ChEBI "down-regulates quantity" "chemical modification" -1 18772128 t miannu "The cycle of deacylation and reacylation of phospholipids plays a critical role in regulating availability of arachidonic acid for eicosanoid production. The major yeast lysophospholipid acyltransferase, Ale1p, is related to mammalian membrane-bound O-acyltransferase (MBOAT) proteins. MBOAT7 is a lysophosphatidylinositol acyltransferase with remarkable specificity for arachidonoyl-CoA. MBOAT5 and MBOAT7 are particularly susceptible to inhibition by thimerosal. Human neutrophils express mRNA for these four enzymes, and neutrophil microsomes incorporate arachidonoyl chains into phosphatidylinositol, phosphatidylcholine, PS, and phosphatidylethanolamine in a thimerosal-sensitive manner. These results strongly implicate MBOAT5 and MBOAT7 in arachidonate recycling, thus regulating free arachidonic acid levels and leukotriene synthesis in neutrophils." SIGNOR-267244 EP300 protein Q09472 UNIPROT PCK1 protein P35558 UNIPROT "down-regulates quantity by destabilization" acetylation Lys594 KEVEDIEkYLEDQVN 9606 BTO:0000007 21726808 t lperfetto "Acetylation Regulates Gluconeogenesis by Promoting PEPCK1 Degradation via Recruiting the UBR5 Ubiquitin Ligase|P300 Acetylates and Destabilizes PEPCK1|Furthermore, coexpression of P300 increased acetylation levels of wild-type PEPCK1, but not PEPCK13K/R, indicating that P300 acts on these lysine residues of PEPCK1" SIGNOR-267604 CAV1 protein Q03135 UNIPROT SLC1A1 protein P43005 UNIPROT "down-regulates activity" binding 9606 BTO:0000938 26690923 t miannu "EAAT3 has previously been shown to form complexes with caveolin-1, a major component of caveolae, which participate in the regulation of transport proteins. The present study explored the impact of caveolin-1 on electrogenic transport by excitatory amino acid transporter isoforms EAAT1-4. caveolin-1 is a powerful negative regulator of the excitatory glutamate transporters EAAT1, EAAT2, EAAT3, and EAAT4. Caveolin-1 has been shown to form complexes with the excitatory amino acid transporter EAAT3 (EAAC1) (Gonzalez et al. 2007) and may thus modify the EAAT isoforms by direct interaction with the carriers." SIGNOR-264807 MRPL52 protein Q86TS9 UNIPROT "39S mitochondrial large ribosomal subunit" complex SIGNOR-C285 SIGNOR "form complex" binding -1 25838379 t lperfetto "We have determined the structure of the intact mitoribosome to 3.5 angstrom resolution by single-particle electron cryo-microscopy. It reveals 80 extensively interconnected proteins, 36 of which are specific to mitochondria, and three rRNA molecules" SIGNOR-262346 MC2R protein Q01718 UNIPROT GNAS protein Q5JWF2 UNIPROT "up-regulates activity" binding 9606 20371771 t lperfetto "The melanocortin (MC) receptor family consists of five Gs-coupled receptors that control various physiological functions in response to four distinct agonists, adrenocorticotropic hormone (ACTH, also known as corticotrophin) and alpha, beta, and gamma melanocyte-stimulating hormone (MSH), which are derived from the proopiomelanocortin precursor protein, and two inverse agonists, agouti and agouti-related proteins" SIGNOR-268694 WNK1 protein Q9H4A3 UNIPROT OXSR1 protein O95747 UNIPROT up-regulates phosphorylation Ser325 VRRVPGSsGRLHKTE 9606 17190791 t gcesareni "Activation of wnk1 coincides with the phosphorylation and activation of two wnk1 substrates, namely, the protein kinases ste20/sps1-related proline alanine-rich kinase (spak) and oxidative stress response kinase-1 (osr1)" SIGNOR-151659 ACE2 protein Q9BYF1 UNIPROT APLN protein Q9ULZ1 UNIPROT "up-regulates activity" cleavage -1 11815627 t miannu "ACE2 hydrolyzes the hormone apelin-13 with high catalytic efficiency and cleaves apelin-36, whose C-terminal 13 amino acids are identical to those of apelin-13." SIGNOR-256316 AURKB protein Q96GD4 UNIPROT BIRC5 protein O15392 UNIPROT down-regulates phosphorylation Thr117 KNKIAKEtNNKKKEF 9606 17457057 t lperfetto "Phosphorylation by aurora-b negatively regulates survivin function . hat survivin is phosphorylated at t117 during mitosis, and once phosphorylated, dephosphorylation is crucial for chromosome congression and progression into anaphaseduring mitosis" SIGNOR-154569 ASPG protein Q86U10 UNIPROT "L-asparagine zwitterion" smallmolecule CHEBI:58048 ChEBI "down-regulates quantity" "chemical modification" 9606 24657844 t miannu "Recently, we structurally and biochemically characterized the enzyme human L-asparaginase 3 (hASNase3), which possesses L-asparaginase activity and belongs to the N-terminal nucleophile superfamily of enzymes. l-Asparaginases (EC 3.5.1.1; l-asparagine amidohydrolase; l-ASNase2) are enzymes that primarily catalyze the conversion of l-asparagine (l-Asn) to l-aspartic acid (l-Asp) and ammonia, although some of them are able to also hydrolyze l-glutamine (l-Gln) to l-glutamic acid (l-Glu) and ammonia." SIGNOR-267537 9-(1-Methyl-4-pyrazolyl)-1-[1-(1-oxoprop-2-enyl)-2,3-dihydroindol-6-yl]-2-benzo[h][1,6]naphthyridinone chemical CID:71748056 PUBCHEM BMX protein P51813 UNIPROT "down-regulates activity" "chemical inhibition" -1 24556163 t miannu "This analysis revealed that QL47 also potently inhibits BMX with an IC50 of 6.7 nM but impressively displays more than 100-fold selectivity against EGFR, HER2, JAK3, BLK, TEC, and ITK that possess an equivalently placed cysteine" SIGNOR-262232 MSL2 protein Q9HCI7 UNIPROT "MSL acetyltransferase" complex SIGNOR-C344 SIGNOR "form complex" binding 9606 BTO:0000567 16227571 t miannu "We describe a stable, multisubunit human histone acetyltransferase complex (hMSL) that contains homologs of the Drosophila dosage compensation proteins MOF, MSL1, MSL2, and MSL3. This complex shows strong specificity for histone H4 lysine 16 in chromatin in vitro, and RNA interference-mediated knockdown experiments reveal that it is responsible for the majority of H4 acetylation at lysine 16 in the cell." SIGNOR-263941 TYK2 protein P29597 UNIPROT IFNAR1 protein P17181 UNIPROT "up-regulates activity" phosphorylation Tyr481 PSSSIDEyFSEQPLK 9606 7526154 t lperfetto "In this report, we demonstrate that the alpha subunit of the type I IFN receptor (IFN-R) corresponds to the product of a previously cloned receptor subunit cDNA and, further, that the p135tyk2 tyrosine kinase directly binds and tyrosine phosphorylates this receptor subunit.These data support the hypothesis that the Tyk2 protein functions as part of a receptor complex to initiate intracellular signaling in response to type I IFNs" SIGNOR-246939 SCF-FBW7 complex SIGNOR-C135 SIGNOR MED13 protein Q9UHV7 UNIPROT "down-regulates quantity by destabilization" ubiquitination 9606 BTO:0000007 SIGNOR-C406 23322298 t miannu "The SCF-Fbw7 ubiquitin ligase degrades MED13 and MED13L and regulates CDK8 module association with Mediator. We show that Fbw7, a tumor suppressor and ubiquitin ligase, binds to CDK8-Mediator and targets MED13/13L for degradation. MED13/13L physically link the CDK8 module to Mediator, and Fbw7 loss increases CDK8 module-Mediator association." SIGNOR-266691 FYN protein P06241 UNIPROT CNN1 protein P51911 UNIPROT "down-regulates activity" phosphorylation Tyr261 SQRGMTVyGLPRQVY 9534 BTO:0000298 15206927 t "We identify, for the first time, tyrosine-phosphorylated calponin h3 within COS 7 cells, before and after their transfection with the pSV vector containing cDNA encoding the cytoplasmic, Src-related, tyrosine kinase, Fyn. we have localized the tyrosines phosphorylated without actin to Tyr261 in calponin h3 and to Tyr261 and Tyr182 in calponin h1. Tyrosine phosphorylation of calponins inhibits their binding to F-actin" SIGNOR-251158 MYC protein P01106 UNIPROT CDKN1A protein P38936 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 12835716 t gcesareni "C-myc also directly represses transcription of cdk kinase inhibitors including p27kip1, p21cip1, p15ink4b and p16ink4a" SIGNOR-102740 STK3 protein Q13188 UNIPROT MOB1A protein Q9H8S9 UNIPROT up-regulates phosphorylation Thr12 FSSRSSKtFKPKKNI 9606 23431053 t milica "Mob1, when phosphorylated by MST1/2, binds to the autoinhibitory motif in Lats1/2, which in turn leads to the phosphorylation of the Lats activation loop (Lats1 S909 and Lats2 S872) and thereby an increase of their kinase activity" SIGNOR-201282 MAPK14 protein Q16539 UNIPROT PPARGC1A protein Q9UBK2 UNIPROT up-regulates phosphorylation Ser266 SLPLTPEsPNDPKGS 9606 BTO:0000887 11741533 t gcesareni "Cytokine stimulation of energy expenditure through p38 map kinase activation of ppargamma coactivator-1we show here that many cytokines activate the transcriptional ppar gamma coactivator-1 (pgc-1) through phosphorylation by p38 kinase, resulting in stabilization and activation of pgc-1 proteinp38 mapk directly phosphorylates pgc-1 on residues threonine 262, serine 265, and threonine 298" SIGNOR-112766 AKT3 protein Q9Y243 UNIPROT POU5F1 protein Q01860 UNIPROT "up-regulates quantity by stabilization" phosphorylation Thr235 QARKRKRtSIENRVR 9606 BTO:0004180 23041284 t flangone "Here we show that in ECCs, Akt phosphorylated the master pluripotency factor Oct4 at threonine 235, and that the levels of phosphorylated Oct4 in ECCs correlated with resistance to apoptosis and tumorigenic potential. Phosphorylation of Oct4 increased its stability and facilitated its nuclear localization and its interaction with Sox2, which promoted the transcription of the core stemness genes POU5F1 and NANOG." SIGNOR-242107 Corticotropin protein P01189-PRO_0000024969 UNIPROT MC3R protein P41968 UNIPROT "up-regulates activity" binding 9606 BTO:0000142 20371771 t lperfetto "The melanocortin (MC) receptor family consists of five Gs-coupled receptors that control various physiological functions in response to four distinct agonists, adrenocorticotropic hormone (ACTH, also known as corticotrophin) and alpha, beta, and gamma melanocyte-stimulating hormone (MSH), which are derived from the proopiomelanocortin precursor protein, and two inverse agonists, agouti and agouti-related proteins" SIGNOR-268706 PRKAB1 protein Q9Y478 UNIPROT NOS3 protein P29474 UNIPROT up-regulates phosphorylation Ser1177 TSRIRTQsFSLQERQ 9606 SIGNOR-C15 11729179 t gcesareni "Recently many investigators have shown that protein phosphorylation of enos by several serine/threonine kinases is a critical control step for no production by endothelial cells. Phosphorylation by amp kinase, akt (or protein kinase b), or protein kinase a on serine 1179 (bovine) or serine 1177 (human) of enos leads to enhanced activity of the enzyme and, thus, augmented production of no." SIGNOR-112367 EGLN3 protein Q9H6Z9 UNIPROT PKM protein P14618 UNIPROT "up-regulates activity" hydroxylation Pro403 EELRRLApITSDPTE 9606 BTO:0000567 21620138 t "Interaction of PKM2 with prolyl hydroxylase 3 (PHD3) enhances PKM2 binding to HIF-1α and PKM2 coactivator function. Mass spectrometry and anti-hydroxyproline antibody assays demonstrate PKM2 hydroxylation on proline-403/408. PHD3 knockdown inhibits PKM2 coactivator function, reduces glucose uptake and lactate production, and increases O(2) consumption in cancer cells." SIGNOR-267476 CSNK2A2 protein P19784 UNIPROT HDAC1 protein Q13547 UNIPROT "up-regulates activity" phosphorylation Ser423 CEEEFSDsEEEGEGG 9606 BTO:0000661 11602581 t llicata "Human HDAC1 protein was analyzed by ion trap mass spectrometry, and two phosphorylated serine residues, Ser(421) and Ser(423), were unambiguously identified. Loss of phosphorylation at Ser(421) and Ser(423) due to mutation to alanine or disruption of the casein kinase 2 consensus sequence directing phosphorylation reduced the enzymatic activity and complex formation of HDAC1." SIGNOR-251000 AKT proteinfamily SIGNOR-PF24 SIGNOR CTNNB1 protein P35222 UNIPROT up-regulates phosphorylation Ser552 QDTQRRTsMGGTQQQ 9606 17287208 t lperfetto "Phosphorylation of beta-catenin by akt promotes beta-catenin transcriptional activity|we have demonstrated that akt phosphorylates beta-catenin at ser552 in vitro and in vivo." SIGNOR-244222 mTORC2 complex SIGNOR-C2 SIGNOR SGK1 protein O00141 UNIPROT up-regulates phosphorylation Ser422 AEAFLGFsYAPPTDS 9606 18925875 t lperfetto "Mtorc2 immunoprecipitated from wild-type, but not from mlst8- or rictor-knockout cells, phosphorylated sgk1 at ser(422)" SIGNOR-217016 PDGFRB protein P09619 UNIPROT PTK2 protein Q05397 UNIPROT up-regulates phosphorylation Tyr5 yLDPNLNH 9606 20802513 t llicata "In this study, we demonstrate that growth factor receptors including hepatocyte growth factor receptor met, epidermal growth factor receptor, and platelet-derived growth factor receptor directly phosphorylate fak on tyr194 in the ferm domain collectively, this study provides the first example to explain how fak is activated by receptor tyrosine kinases." SIGNOR-167662 CEBPB protein P17676 UNIPROT C3 protein P01024 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 25617152 t Gianni "CCAAT/enhancer binding protein β directly regulates the expression of the complement component 3 gene in neural cells: implications for the pro-inflammatory effects of this transcription factor" SIGNOR-261927 EPAS1 protein Q99814 UNIPROT KDM4C protein Q9H3R0 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 32938217 t SaraGualdi "To this end, we confirm that KDM3A, KDM4B, KDM4C, KDM5B, KDM5C, and KDM62 are direct targets of HIF-1a while extent the list of known targets to KDM2A, KDM2B, KDM4D, KDM5A, and KDM6A. The results demonstrated that majority of the KDMs were similarly induced (KDM2A, KDM2B, KDM3A, KDM4B, KDM4C, KDM4D, KDM5A, KDM5B, KDM5C, KDM6B, and KDM7A) or repressed (KDM NO66 and KDM1A) by both HIF-1a and HIF-2a." SIGNOR-271585 Ub:E2 complex SIGNOR-C497 SIGNOR MIB1 protein Q86YT6 UNIPROT "up-regulates activity" ubiquitination 9606 34199813 t miannu "The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t" SIGNOR-271133 L-thyroxine smallmolecule CHEBI:18332 ChEBI iodide smallmolecule CHEBI:16382 ChEBI "up-regulates quantity" "precursor of" 9606 34674502 t scontino "Thyroid hormone (TH) deiodinases play a pivotal role in the functional diversification of TH signaling. They are involved in development, growth, and metabolic processes, and act in a cell-specific manner in the fine regulation of TH homeostasis. TH deiodinases catalyze activation and inactivation of THs through the removal of one iodine atom in the outer or inner ring of the TH molecule.¬†" SIGNOR-268126 IGF1 protein P05019 UNIPROT Calcineurin complex SIGNOR-C155 SIGNOR up-regulates 10090 10448861 f lperfetto "Treatment with igf-1 or insulin and dexamethasone mobilizes intracellular calcium, activates the ca2+/calmodulin-dependent phosphatase calcineurin, and induces the nuclear translocation of the transcription factor nf-atc1." SIGNOR-252306 POU4F3 protein Q15319 UNIPROT LHX3 protein Q9UBR4 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 BTO:0000630 17331196 t lperfetto "Using oligonucleotide microarrays to generate expression profiles of inner ears of Pou4f3(ddl/ddl) mutant and wild-type mice, we have identified and validated Lhx3, a LIM domain transcription factor, as an in vivo target gene regulated by Pou4f3. Lhx3 is a hair cell-specific gene expressed in all hair cells of the auditory and vestibular system as early as embryonic day 16. The level of Lhx3 mRNA is greatly reduced in the inner ears of embryonic Pou4f3 mutant mice. Our data also show that the expression of Lhx3 is regulated differently in auditory and vestibular hair cells." SIGNOR-262586 RET protein P07949 UNIPROT ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR up-regulates phosphorylation 9606 16153436 t lperfetto "We hypothesized that ret could directly phosphorylate fak and erk. erk 2 could be phosphorylated at y187 (y204 in erk1)." SIGNOR-244643 ROCK1 protein Q13464 UNIPROT Satellite_cells_self-renewal phenotype SIGNOR-PH100 SIGNOR up-regulates "transcriptional regulation" BTO:0001103 23290138 f apalma "FN in the satellite cell niche is required for the maintenance of the overall satellite cell pool during muscle regeneration. Moreover, FN is necessary to potentiate Wnt7a signaling through the Fzd7/Scd4 receptor complex, which controls the regulation of satellite stem cell numbers" SIGNOR-255850 PGAM5 protein Q96HS1 UNIPROT FUNDC1 protein Q8IVP5 UNIPROT "up-regulates activity" dephosphorylation 9606 BTO:0000567 24746696 t miannu "Here, we identify that the mitochondrially localized PGAM5 phosphatase interacts with and dephosphorylates FUNDC1 at serine 13 (Ser-13) upon hypoxia or carbonylcyanide p-trifluoromethoxyphenylhydrazone (FCCP) treatment. Dephosphorylation of FUNDC1 catalyzed by PGAM5 enhances its interaction with LC3, which is abrogated following knockdown of PGAM5 or the introduction of a cell-permeable unphosphorylated peptide encompassing the Ser-13 and LIR of FUNDC1. We further observed that CK2 phosphorylates FUNDC1 to reverse the effect of PGAM5 in mitophagy activation." SIGNOR-273654 ASIP protein P42127 UNIPROT MC4R protein P32245 UNIPROT "down-regulates activity" binding 9606 BTO:0000142 20371771 t lperfetto "The melanocortin (MC) receptor family consists of five Gs-coupled receptors that control various physiological functions in response to four distinct agonists, adrenocorticotropic hormone (ACTH, also known as corticotrophin) and alpha, beta, and gamma melanocyte-stimulating hormone (MSH), which are derived from the proopiomelanocortin precursor protein, and two inverse agonists, agouti and agouti-related proteins" SIGNOR-268708 GNA13 protein Q14344 UNIPROT ARHGEF11 protein O15085 UNIPROT "up-regulates activity" binding 9606 11799111 t "This RGS-like (RGL) domain provides a structural motif by which heterotrimeric G protein alpha subunits of the Galpha(12) family can bind and regulate the activity of RhoGEFs. Hence, these newly discovered RGL domain-containing RhoGEFs provide a direct link from Galpha(12) and Galpha(13) to Rho" SIGNOR-256517 "tacrolimus (anhydrous)" chemical CHEBI:61049 ChEBI PPP3CA protein Q08209 UNIPROT down-regulates "chemical inhibition" 9606 15276472 t gcesareni "Calcineurin catalytic activity is inhibited by the immunosuppressive drugs cyclosporine and fk506 through complexes with immunophilin proteins." SIGNOR-127239 TJP2 protein Q9UDY2 UNIPROT YAP1 protein P46937 UNIPROT down-regulates binding 9606 23829894 t milica "The Crumbs complex component AMOT co-localizes with MST1_ 2, LATS1_ 2 and YAP in a complex at the tight junction to control cell growth. Zona occludens-2 (ZO-2) in the tight junction, and a-catenin, b-catenin, or PTPN14 in the adherence junction, also bind to YAP_TAZ." SIGNOR-230754 VAV1 protein P15498 UNIPROT SYK protein P43405 UNIPROT up-regulates binding 9606 11331248 t lperfetto "Vav interacts with the tyrosine kinase syk" SIGNOR-107049 PICALM protein Q13492 UNIPROT CLTC protein Q00610 UNIPROT up-regulates binding 9606 16491119 t miannu "Calm interacts with the clathrin heavy chain through its c-terminal third and with phophoinositides through its ap180 n-terminal homology (anth) domain, promoting assembly of clathrin triskelia into clathrin cagesin vitro" SIGNOR-144683 lurasidone chemical CHEBI:70735 ChEBI HTR1A protein P08908 UNIPROT "up-regulates activity" "chemical activation" 10030 20404009 t Luana "In vitro functional assays demonstrated that lurasidone acts as an antagonist at D2 and 5-HT7 receptors and as a partial agonist at the 5-HT1A receptor subtype." SIGNOR-259463 SMARCB1 protein Q12824 UNIPROT CDC6 protein Q99741 UNIPROT down-regulates 9606 12226744 f miannu "We show that the ectopic expression of wild-type hsnf5/ini1, but not that of truncated versions, leads to a cell cycle arrest by inhibiting the entry into s phase of mrt cells. This g1 arrest is associated with down-regulation of a subset of e2f targets including cyclin a, e2f1 and cdc6." SIGNOR-92785 FGFR2 protein P21802 UNIPROT MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR up-regulates 10090 BTO:0000011 12270934 f lperfetto "Fibroblast growth factor-2 (FGF-2), in the presence of dexamethasone, isobutylmethylxanthine, and insulin, induces a prolonged activation of the MEK/ERK signaling pathway, which lasts for at least 12 h post-induction, and this activity is less sensitive to the MEK inhibitors" SIGNOR-244868 TGFB2 protein P61812 UNIPROT TGFBR2 protein P37173 UNIPROT up-regulates binding 9606 1310899 t gcesareni "A cdna encoding the tgf-beta type ii receptor protein has been isolated by an expression cloning strategy. The cloned cdna, when transfected into cos cells, leads to overexpression of an approximately 80 kd protein that specifically binds radioiodinated tgf-beta 1. Excess tgf-beta 1 competes for binding of radioiodinated tgf-beta 1 in a dose-dependent manner and is more effective than tgf-beta 2." SIGNOR-16690 GPC3 protein P51654 UNIPROT DPP4 protein P27487 UNIPROT down-regulates binding 9606 17549790 t miannu "The interaction occurred with both the glycosylated and unglycosylated forms of gpc3 and led to the inhibition of cd26 peptidase activity." SIGNOR-155527 SKP2 protein Q13309 UNIPROT IDH2 protein P48735 UNIPROT "down-regulates quantity by destabilization" ubiquitination phosphorylation:Thr197 GTFKMVFtPKDGSGV 34929314 t lperfetto "During the cell cycle S phase, Cyclin A-CDK2 phosphorylates IDH1 on its Threonine 157 residue (Threonine 197 in IDH2) to facilitate its recognition and ubiquitination by Skp2 E3 ubiquitin, followed by degradation through 26S proteasome" SIGNOR-267626 UBE2G2 protein P60604 UNIPROT DIO proteinfamily SIGNOR-PF83 SIGNOR "down-regulates quantity by destabilization" ubiquitination 9606 BTO:0001379 29892818 t "inferred from family member" scontino "ER residency places D2 physically close to an array of proteins that interact and modify the D2 molecule via ubiquitination and targeting to the proteasomal system, explaining its relatively short half-life. Both ubiquitin conjugases UBC6 and or UBC7 interact with D2 and support D2 ubiquitination. Two Lys residues in D2 are involved in this process, K237 and K244." SIGNOR-270244 MED16 protein Q9Y2X0 UNIPROT "Core mediator complex" complex SIGNOR-C405 SIGNOR "form complex" binding 9606 28467824 t miannu "Mediator is a multiprotein co-activator that binds the transcription pre-initiation complex (PIC) and regulates RNA polymerase (Pol) II. The Mediator head and middle modules form the essential core Mediator (cMed), whereas the tail and kinase modules play regulatory roles." SIGNOR-266671 TSC22D1 protein Q15714 UNIPROT NPPC protein P23582 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10116 9022669 t Luana "TSC-22 significantly enhanced CNP promoter activity in GH3 cells." SIGNOR-266226 TP53 protein P04637 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR down-regulates 9606 BTO:0000452 7667317 f "P53 controls both the G2/M and the G1 cell cycle checkpoints and mediates reversible growth arrest in human fibroblasts" SIGNOR-255669 MYLIP protein Q8WY64 UNIPROT LDLR protein P01130 UNIPROT "down-regulates quantity by destabilization" ubiquitination 9606 30896554 t miannu "The RING E3 ubiquitin ligase inducible degrader of the LDL receptor (IDOL, also known as MYLIP) promotes ubiquitylation and subsequent lysosomal degradation of the LDL receptor (LDLR), thus acting to limit uptake of lipoprotein-derived cholesterol into cells. " SIGNOR-271485 PDPK1 protein O15530 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates phosphorylation 9606 21798082 t lperfetto "Positive feedback involves mtorc2, which phosphorylates akt at serine 473, a phosphorylation required for maximum activation of akt in addition to phosphorylation at threonine 308 by pdk1." SIGNOR-244396 SLC1A5 protein Q15758 UNIPROT "L-glutamine zwitterion" smallmolecule CHEBI:58359 ChEBI "up-regulates quantity" relocalization 9606 26724577 t "Fourteen of them [[SLC transporters] , capable of transporting glutamine across the plasma membrane, are found in four families: SLC1, SLC6, SLC7, and SLC38. However, it is generally thought that the members of the SLC38 family are the principal transporters for glutamine." SIGNOR-266914 SPAG1 protein Q07617 UNIPROT "R2SP co-chaperone" complex SIGNOR-C517 SIGNOR "form complex" binding 9606 29844425 t miannu "Systematic interaction analyses show that one RPAP3-like protein, SPAG1, binds PIH1D2 and RUVBL1/2 to form an R2TP-like complex termed R2SP.  This co-chaperone is enriched in testis and among 68 of the potential clients identified, some are expressed in testis and others are ubiquitous. One substrate is liprin-α2, which organizes large signaling complexes." SIGNOR-270938 ITGAL protein P20701 UNIPROT ICAM1 protein P05362 UNIPROT up-regulates binding 9606 BTO:0000130 23994464 t apalma "This leads to further neutrophil-endothelial cell interactions through the binding of LFA-1 to its endothelial counterreceptor ICAM-1 during the slow rolling phase" SIGNOR-255040 DPYSL5 protein Q9BPU6 UNIPROT MAP2 protein P11137 UNIPROT "down-regulates activity" binding 9606 BTO:0000938 25040932 t lperfetto "The studies on CRMP5 function show that, by interacting with tubulin and MAP2, this protein inhibits neurite growth especially at the dendritic level and restricts the promotional effect of CRMP2 on axon and dendrite growth" SIGNOR-264836 ADNP protein Q9H2P0 UNIPROT "SWI/SNF complex" complex SIGNOR-C92 SIGNOR "up-regulates quantity" binding 9606 BTO:0000007 17878164 t miannu "ADNP Co-precipitates with the SWI/SNF Complex through ADNP C-terminal Interaction. Down-regulation of ADNP by shRNA resulted in morphological changes that are in line with the fact that ADNP contains a homeodomain profile (2) and with the SWI/SNF complex function that is associated with cellular differentiation. Our results suggest that ADNP functionality plays a role in these changes." SIGNOR-266757 FBXW7 protein Q969H0 UNIPROT ZNF322 protein Q6U7Q0 UNIPROT "down-regulates quantity by destabilization" ubiquitination 9606 BTO:0002552 phosphorylation:Ser391;Ser396 SEKGLELsPPHASEA;ELSPPHAsEASQMS 28581525 t lperfetto "CK1delta and GSK3beta kinases sequentially phosphorylate ZNF322A at serine-396 and then serine-391. Moreover, the doubly phosphorylated ZNF322A protein creates a destruction motif for the ubiquitin ligase FBXW7alpha leading to ZNF322A protein destruction." SIGNOR-264898 PTPN6 protein P29350 UNIPROT KIT protein P10721 UNIPROT down-regulates binding 9606 9528781 t miannu "Shp-1 binds and negatively modulates the c-kit receptor by interaction with tyrosine 569 in the c-kit juxtamembrane domain." SIGNOR-56104 aliskiren chemical CHEBI:601027 ChEBI REN protein P00797 UNIPROT "down-regulates activity" "chemical inhibition" 9606 18307734 t Luana "Aliskiren has a low bioavailality (between 2.6 and 5.0%) compensated by its high potency to inhibit renin (IC50: 0.6 nmol/L) and a long plasma half-life (23–36 h)" SIGNOR-257771 CDK16 protein Q00536 UNIPROT CyclinY/CDK16 complex SIGNOR-C540 SIGNOR "form complex" binding 30992425 t lperfetto "CDK16 (also known as PCTAIRE1 or PCTK1) is an atypical member of the cyclin-dependent kinase (CDK) family that forms an active complex with cyclin Y (CCNY)." SIGNOR-273003 HNF4A protein P41235 UNIPROT PCSK9 protein Q8NBP7 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000398 21123766 f miannu "Recent studies have demonstrated that PCSK9 mRNA expression was upregulated to a greater extent than that of the LDL receptor in human hepatocytes in primary culture. Our findings also support the role of SREBP-2 as a transcriptional regulator of both the LDL receptor and PCSK9 in human enterocytes." SIGNOR-254451 CTNNB1 protein P35222 UNIPROT NOTCH1 protein P46531 UNIPROT up-regulates binding 10090 BTO:0000165 19000719 t "Through Armadillo repeat domain" gcesareni "Beta-catenin can regulate the level and transcriptional activity of the notch1 and notch1 intracellular domain (nicd). The in vivo and in vitro results demonstrate that beta-catenin binds with notch1 and nicd, for which its armadillo repeat domain is essential." SIGNOR-236858 vorinostat chemical CHEBI:45716 ChEBI HDAC3 protein O15379 UNIPROT "down-regulates activity" "chemical inhibition" -1 20139990 t Luana "Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1)." SIGNOR-257948 PDPK1 protein O15530 UNIPROT RPS6KB2 protein Q9UBS0 UNIPROT up-regulates phosphorylation Thr228 HEGAVTHtFCGTIEY 9606 9445476 t gcesareni "A regulatory link between p70s6k and pkb was demonstrated, as pdk1 was found to selectively phosphorylate p70s6k at thr229. More importantly, pdk1 activated p70s6k in vitro and in vivo, whereas the catalytically inactive pdk1 blocked insulin-induced activation of p70s6k. one of the most studied signalling events controlled by ptdins(3,4,5)p3, comprises the activation of a group of agc family protein kinases, including isoforms of protein kinase b (pkb)/akt, p70 ribosomal s6 kinase (s6k), serum- and glucocorticoid-induced protein kinase (sgk) and protein kinase c (pkc), which play crucial roles in regulating physiological processes relevant to metabolism, growth, proliferation and survival. Here, we review recent biochemical, genetic and structural studies on the 3-phosphoinositide-dependent protein kinase-1 (pdk1), which phosphorylates and activates the agc kinase members regulated by pi 3-kinase. We also discuss whether inhibitors of pdk1 might have chemotherapeutic potential in the treatment of cancers in which the pdk1-regulated agc kinases are constitutively activated." SIGNOR-55371 "perfluorohexanesulfonic acid" chemical CHEBI:132448 ChEBI ESR2 protein Q92731 UNIPROT "up-regulates activity" "chemical activation" -1 23764977 t miannu "Seven PFCs [perfluorohexane sulfonate (PFHxS), perfluorooctane sulfonate (PFOS), perfluorooctanoate (PFOA), perfluorononanoate (PFNA), perfluorodecanoate (PFDA), perfluoroundecanoate (PFUnA), and perfluorododecanoate (PFDoA)] were analyzed in vitro for their potential to affect estrogen receptor (ER) and androgen receptor (AR) transactivity as well as aromatase enzyme activity. The PFCs were assessed as single compounds and in an equimolar mixture. PFHxS, PFOS and PFOA significantly induced the ER transactivity, whereas PFHxS, PFOS, PFOA, PFNA and PFDA significantly antagonized the AR activity in a concentration-dependent manner. " SIGNOR-268764 "1-methyl-3,6-dihydro-2H-pyridine-5-carboxylic acid prop-2-ynyl ester" chemical CHEBI:92418 ChEBI CHRM3 protein P20309 UNIPROT "up-regulates activity" "chemical activation" 10029 BTO:0000246 9224827 t miannu "We investigated whether the allosteric modulators can also increase the affinity of receptors for their agonists. Twelve agonists and five allosteric modulators were tested in experiments on membranes of CHO cells that had been stably transfected with genes for the M1-M4 receptor subtypes. Affinities of agonists for the M1–M4 receptor subtypes were determined according to the ability of the agonist to inhibit [3H]NMS binding in the presence of 0.5 mM GTP; in this way, the low affinity binding of agonists was measured.The computed pKi and nH values are summarized in Table 2." SIGNOR-258637 SPART protein Q8N0X7 UNIPROT WWP1 protein Q9H0M0 UNIPROT "up-regulates activity" binding 9606 19580544 t miannu "Cytosolic endogenous spartin is mono-ubiquitinated and we demonstrate that it interacts via a PPXY motif with the ubiquitin E3 ligases AIP4 [atrophin-interacting protein 4; ITCH (itchy E3 ubiquitin protein ligase homologue] [corrected] and AIP5 (WWP1). Surprisingly, the PPXY motif, AIP4 and AIP5 are not required for spartin's ubiquitination, and so we propose that spartin acts as an adaptor for these proteins." SIGNOR-261307 MAPK9 protein P45984 UNIPROT STMN1 protein P16949 UNIPROT down-regulates phosphorylation Ser38 SVPEFPLsPPKKKDL 9606 20630875 t gcesareni "Involved in the regulation of the microtubule (mt) filament system by destabilizing microtubules. Prevents assembly and promotes disassembly of microtubules. Here we show that in response to hyperosmotic stress, jnk phosphorylates a key cytoplasmic microtubule regulatory protein, stathmin (stmn), on conserved ser-25 and ser-38 residues. In in vitro biochemical studies, we identified stmn ser-38 as the critical residue required for efficient phosphorylation by jnk and identified a novel kinase interaction domain in stmn required for recognition by jnk. We revealed that jnk was required for microtubule stabilization in response to hyperosmotic stress." SIGNOR-166698 AKT2 protein P31751 UNIPROT KHSRP protein Q92945 UNIPROT down-regulates phosphorylation Ser193 GLPERSVsLTGAPES 10116 17177604 t lperfetto "AKT phosphorylates the mRNA decay-promoting factor KSRP at a unique serine residue, induces its association with the multifunctional protein 14-3-3, and prevents KSRP interaction with the exoribonucleolytic complex exosome. This impairs KSRP’s ability to promote rapid mRNA decay." SIGNOR-151220 AGRP protein O00253 UNIPROT MC4R protein P32245 UNIPROT down-regulates binding 9606 9311920 t gcesareni "Recombinant agouti-related protein was a potent, selective antagonist of mc3r and mc4r,." SIGNOR-51104 NUP188 protein Q5SRE5 UNIPROT NPC complex SIGNOR-C263 SIGNOR "form complex" binding 27016207 t lperfetto "The protein inventory of the NPC has been studied for a very diverse set of eukaryotes, including trypanosomes, fungi, plants, animals, and humans [4], [5], [6], [7], [8], [9]. In all cases, about 30 different Nups were found (Fig. 2)." SIGNOR-262084 FBN1 protein P35555 UNIPROT FBLN5 protein Q9UBX5 UNIPROT "down-regulates activity" binding 9606 19570982 t miannu "Fibulin-4 and -5 are extracellular glycoproteins with essential non-compensatory roles in elastic fiber assembly. We have determined how they interact with tropoelastin, lysyl oxidase, and fibrillin-1, thereby revealing how they differentially regulate assembly. Both fibulins differentially bound N-terminal fibrillin-1, which strongly inhibited their binding to lysyl oxidase and tropoelastin." SIGNOR-252138 RPS3 protein P23396 UNIPROT "40S cytosolic small ribosomal subunit" complex SIGNOR-C286 SIGNOR "form complex" binding -1 25901680 t lperfetto "Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins." SIGNOR-262421 RNF111 protein Q6ZNA4 UNIPROT SMAD2 protein Q15796 UNIPROT "down-regulates quantity by destabilization" ubiquitination 10090 BTO:0000165;BTO:0000222 17341133 t lperfetto "Arkadia represses the expression of myoblast differentiation markers through degradation of ski and the ski-bound smad complex in c2c12 myoblastsarkadia bound smad2/3 via ski to induce the ubiquitination of smad2/3. These results suggest that arkadia targets ski-bound, inactive phospho-smad2/3 to regulate positively myostatin/tgf-beta signaling." SIGNOR-236873 PLK1 protein P53350 UNIPROT WEE1 protein P30291 UNIPROT down-regulates phosphorylation Ser53 GHSTGEDsAFQEPDS 9606 15350223 t gcesareni "Phosphorylation of serines 53 and 123 (s53 and s123) of wee1a by polo-like kinase 1 (plk1) and cdk, respectively, are required for binding to beta-trcp." SIGNOR-128643 metformin chemical CHEBI:6801 ChEBI PRKAA1 protein Q13131 UNIPROT "up-regulates activity" 10116 11602624 f gcesareni "Using a novel AMPK inhibitor, we find that AMPK activation is required for metformin€™s inhibitory effect on glucose production by hepatocytes. In isolated rat skeletal muscles, metformin stimulates glucose uptake coincident with AMPK activation" SIGNOR-241952 codeine chemical CHEBI:16714 ChEBI OPRM1 protein P35372 UNIPROT "up-regulates activity" "chemical activation" 10029 BTO:0000246 9686407 t miannu "Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors." SIGNOR-258933 RBPJ/NOTCH complex SIGNOR-C97 SIGNOR CCND1 protein P24385 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 11486031 t lperfetto "Using this inducible system, we show that Notchic activates transcription of the cyclin D1 gene with rapid kinetics." SIGNOR-209753 PDX1 protein P52945 UNIPROT INS protein P01308 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 11309388 t "In conclusion, Pdx1 confers the expression of pancreatic β-cell-specific genes, such as genes encoding insulin, islet amyloid polypeptide, Glut2, and Nkx6.1." SIGNOR-255541 "MSL acetyltransferase" complex SIGNOR-C344 SIGNOR H2BC4 protein P62807 UNIPROT "down-regulates activity" monoubiquitination Lys35 KKRKRSRkESYSVYV 9606 21726816 t miannu "MSL1/2 ubiquitylates histone H2B on K 34. Importantly, only mono-ubiquitylation of H2B by MSL1/2 was detected in cells (data not shown), suggesting that MSL1/2, like RNF20/RNF40, was mainly a mono-ubiquitylase under physiological conditions.the MOF-MSL complex functions to promote both H4 K16ac and H2B K34ub. H2B K34ub, in turn, promotes H2B K120ub, H3 K4me3 and K79me2 to facilitate transcription elongation." SIGNOR-271986 "MSL acetyltransferase" complex SIGNOR-C344 SIGNOR H2BC18 protein Q5QNW6 UNIPROT "down-regulates activity" monoubiquitination Lys35 KKRKRSRkESYSVYV 9606 21726816 t miannu "MSL1/2 ubiquitylates histone H2B on K 34. Importantly, only mono-ubiquitylation of H2B by MSL1/2 was detected in cells (data not shown), suggesting that MSL1/2, like RNF20/RNF40, was mainly a mono-ubiquitylase under physiological conditions.the MOF-MSL complex functions to promote both H4 K16ac and H2B K34ub. H2B K34ub, in turn, promotes H2B K120ub, H3 K4me3 and K79me2 to facilitate transcription elongation." SIGNOR-271987 UBN1 protein Q9NPG3 UNIPROT "HIRA complex 1" complex SIGNOR-C461 SIGNOR "form complex" binding 9606 30285846 t miannu "H3.3 is an ancient and conserved H3 variant and plays essential roles in transcriptional regulation. HIRA complex, which is composed of HIRA, UBN1 or UBN2, and Cabin1, is a H3.3 specific chaperone complex. In this study, we demonstrate that the UBN1 or UBN2 subunit is mainly responsible for specific recognition and direct binding of H3.3 by the HIRA complex." SIGNOR-269433 AURKA protein O14965 UNIPROT MBD3 protein O95983 UNIPROT up-regulates phosphorylation Ser85 RQRVRYDsSNQVKGK 9606 BTO:0000567 12354758 t llicata "These results suggest that the biochemical changes of mbd3 may be intimately related to the targeting of mbd3 to centrosomes. aurora-a phosphorylates mbd3" SIGNOR-93697 SMARCD1 protein Q96GM5 UNIPROT "Embryonic stem cell-specific SWI/SNF" complex SIGNOR-C484 SIGNOR "form complex" binding 10090 BTO:0001086 19279220 t miannu "An embryonic stem cell chromatin remodeling complex, esBAF, is essential for embryonic stem cell self-renewal and pluripotency" SIGNOR-270722 BMS-754807 chemical CHEBI:88339 ChEBI IGF1R protein P08069 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-190497 ZSTK-474 chemical CHEBI:90545 ChEBI PIK3CG protein P48736 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-207944 PTPN1 protein P18031 UNIPROT SRC protein P12931 UNIPROT "up-regulates activity" dephosphorylation Tyr530 FTSTEPQyQPGENL 9606 17974954 t "Overexpression of PTP1B increased Src specific activity in colon cancer cells by reducing phosphorylation at Y530 of Src." SIGNOR-248422 AURKB protein Q96GD4 UNIPROT YY1 protein P25490 UNIPROT up-regulates phosphorylation Ser184 GKKSGKKsYLSGGAG 9606 23226345 t lperfetto "Aurora b kinase phosphorylates yy1 on serine 184 and to a lesser extent serine 180 at the g2/m stage of the cell cycle (fig. 7). We show that yy1 is rapidly dephosphorylated as the cells exit mitosis, likely by pp1. Also, our data indicates that phosphorylation at serine 180 and serine 184 can affect the dna binding activity of yy1" SIGNOR-200079 PSENEN protein Q9NZ42 UNIPROT RYK protein P34925 UNIPROT up-regulates cleavage 9606 19000841 t gcesareni "Ryk activity is modulated through cleavage of its icd by gamma-secretase" SIGNOR-182145 wortmannin chemical CHEBI:52289 ChEBI MYLK protein Q15746 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-207791 RHOBTB3 protein O94955 UNIPROT "Cullin 3-RBX1-Skp1" complex SIGNOR-C526 SIGNOR "up-regulates activity" binding 9606 BTO:0000007 24145166 t miannu "Here we show that RhoBTB3, a Golgi-associated, Rho-related ATPase, regulates the S/G2 transition of the cell cycle by targeting cyclin E for ubiquitylation. Depletion of RhoBTB3 arrested cells in S phase, triggered Golgi fragmentation, and elevated cyclin E levels. On the Golgi, RhoBTB3 bound cyclin E as part of a Cullin3 (CUL3)-dependent RING-E3 ubiquitin ligase complex comprised of RhoBTB3, CUL3, and RBX1." SIGNOR-272132 IC-87114 chemical CHEBI:90686 ChEBI PIK3CD protein O00329 UNIPROT down-regulates "chemical inhibition" 9606 BTO:0000848 21048785 t gcesareni "Ic87114 is a selective pi3kinhibitor." SIGNOR-169213 IRX5 protein P78411 UNIPROT KCND2 protein Q9NZV8 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 10090 BTO:0000387 16239150 t Luana "Irx5 Directly Represses the Kcnd2 Promoter" SIGNOR-266045 MC3R protein P41968 UNIPROT GNA12 protein Q03113 UNIPROT "up-regulates activity" binding 9606 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257407 EGFL7 protein Q9UHF1 UNIPROT NOTCH proteinfamily SIGNOR-PF30 SIGNOR "down-regulates activity" binding 10090 BTO:0002881 19503073 t miannu "Here we have identified transmembrane receptors of the Notch family as EGFL7-binding molecules. Secreted EGFL7 binds to a region in Notch involved in ligand-mediated receptor activation, thus acting as an antagonist of Notch signalling. Expression of EGFL7 in neural stem cells (NSCs) in vitro decreased Notch-specific signalling and consequently, reduced proliferation and self-renewal of NSCs." SIGNOR-266860 CTNNA2 protein P26232 UNIPROT YAP1 protein P46937 UNIPROT down-regulates binding 9606 23431053 t "In keratinocytes, YAP strongly interacts with a-catenin, and this interaction is mediated by 14-3-3." gcesareni "The trimeric complex of alfa-catenin, 14-3-3, and yap sequesters yap at ajs and prevents yap dephosphorylation/activation." SIGNOR-201245 WARS1 protein P23381 UNIPROT ATP(4-) smallmolecule CHEBI:30616 ChEBI "down-regulates quantity" "chemical modification" 9606 14660560 t miannu "Aminoacyl-tRNA synthetases (aaRSs)1 are a family of ancient enzymes that catalyze amino acid activation by ATP and the subsequent aminoacylation to its cognate tRNA. Alternative splicing produces two forms of hTrpRS in human cells: full-length hTrpRS (residues 1-471) and mini-hTrpRS (residues 48-471)" SIGNOR-270511 CSNK1A1 protein P48729 UNIPROT AXIN1 protein O15169 UNIPROT "up-regulates activity" phosphorylation Ser77 YEPEGSAsPTPPYLK -1 17318175 t lperfetto "Four sites, S80, S82, S222, and S473, were identified to be PP1 regulated (Supplementary Figure 3). Three of them (S80, S82, and S473) were also phosphorylated in vitro by CKI and are conserved between axin1 and axin2/conductin.|This suggests that cumulative phosphorylation of axin is required for it to fully downregulate Wnt/beta_catenin signaling." SIGNOR-249191 CSNK1E protein P49674 UNIPROT YAP1 protein P46937 UNIPROT down-regulates phosphorylation Ser403 ESTDSGLsMSSYSVP 9606 phosphorylation:Ser127 PQHVRAHsSPASLQL 23431053 t milica "Phosphorylation of YAP (S381) and TAZ (S311) by Lats1/2 primes subsequent phosphorylation events by Casein Kinase 1 (CK1d/e); this sequential phosphorylation results in recruitment of b-transducin repeat-containing proteins (b-TRCP; a subunit of the SCF ubiquitin E3 ligase) and consequently leads to degradation of YAP/TAZ" SIGNOR-201170 RPS6KA5 protein O75582 UNIPROT RPS6KA5 protein O75582 UNIPROT unknown phosphorylation Ser752 KMKKTSTsTETRSSS 9606 15568999 t lperfetto "Msk1 can autophosphorylate on at least six sites: ser-212, ser-376, ser-381, ser-750, ser-752 and ser-758. ser-750, ser-752 and ser-758 are phosphorylated by the n-terminal kinase domain;however, their function is not known." SIGNOR-131403 TBK1 protein Q9UHD2 UNIPROT IRF3 protein Q14653 UNIPROT "up-regulates activity" phosphorylation Ser396 NTVDLHIsNSHPLSL -1 18440553 t lperfetto "Virus-induced phosphoactivation of irf-3, thought to be mediated directly or indirectly by ikk? And/or tbk1 occurs in the c-terminal region of irf-3 at seven ser/thr residues, 385sslentvdlhisnshplslts405 (fig. 1a).Within This region, irf-3 has two phosphorylation sites: site 1 includes ser385 and ser386, whereas site 2 includes ser396, ser398, ser402, ser405, and thr404." SIGNOR-178399 PPM1D protein O15297 UNIPROT MAPK14 protein Q16539 UNIPROT "down-regulates activity" dephosphorylation 9606 19713933 t lperfetto "In addition, wip1 can dephosphorylate atm, as well as other components of the dna damage checkpoint, such as p38." SIGNOR-187770 CSNK1D protein P48730 UNIPROT GSK3B/Axin/APC complex SIGNOR-C110 SIGNOR up-regulates phosphorylation 9606 12000790 t lperfetto "We conclude that a major role of axin in the wnt is to provide the kinase activity that initiates the betBeta-catenin phosphorylation cascade at s45 . This process is mediated by cki, the alfa, delta, or ? Isoform, all detected in association with axin by lc/mscomplex of axin and casein kinase i (cki) induces betBeta-catenin phosphorylation at a single site: serine 45 (s45)" SIGNOR-227970 ARNT protein P27540 UNIPROT AHR-ARNT complex SIGNOR-C125 SIGNOR "form complex" binding -1 9020169 t 2 miannu "SIM1 and SIM2, and the mammalian aryl hydrocarbon receptor (AHR) and aryl hydrocarbon receptor nuclear translocator (ARNT) proteins are members of the basic-helix-loop-helix·PAS family of transcription factors. In the yeast two-hybrid system, we demonstrate strong constitutive interaction of ARNT with SIM1 and SIM2 and fully ligand-dependent interaction of ARNT with AHR. SIM1 inhibits binding of the AHR·ARNT dimer to the xenobiotic response element in vitro Introduction of SIM1 into hepatoma cells inhibits transcriptional transactivation by the endogenous AHR·ARNT dimer." SIGNOR-240814 UBE2D2 protein P62837 UNIPROT PDZRN3 protein Q9UPQ7 UNIPROT "up-regulates activity" binding 9534 BTO:0000298 17576800 t miannu "Our initial tests of various E2s showed that the RING domain of PDZRN3 exhibits ubiquitin ligase activity in the presence of E1 and the UbcH5 family of E2 enzymes (Fig. 3 A). Consistent with this finding, GST pull-down assays showed that PDZRN3 directly interacts with the UbcH5B ubiquitin conjugating enzyme (Fig. 3 B). " SIGNOR-271663 HIF1A protein Q16665 UNIPROT IL1B protein P01584 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 25750431 t svumbaca "The results of this study show that the absence of HIFs in MPs has no impact on the resolution of inflammation in two sterile models of skeletal muscle regeneration" SIGNOR-256236 CUL1 protein Q13616 UNIPROT CTNNB1 protein P35222 UNIPROT "down-regulates quantity by destabilization" ubiquitination 9606 SIGNOR-C5 10023660 t lperfetto "These results indicate that the cul1/skp1/beta-trcp complex forms a ubiquitin ligase that mediates the degradation of beta-catenin." SIGNOR-64499 "1-phosphatidyl-1D-myo-inositol 5-phosphate(3-)" smallmolecule CHEBI:57795 ChEBI "1-phosphatidyl-1D-myo-inositol 4,5-bisphosphate(5-)" smallmolecule CHEBI:58456 ChEBI "up-regulates quantity" "precursor of" 9606 9367159 t Gianni "The enzymes that produce PtdIns-4,5-P2 in vitro fall into two related subfamilies (type I and type II PtdInsP-5-OH kinases, or PIP(5)Ks) based on their enzymatic properties and sequence similarities'. Here we have reinvestigated the substrate specificities of these enzymes. As expected, the type I enzyme phosphorylates PtdIns-4-P at the D-5 position of the inositol ring. Surprisingly, the type II enzyme, which is abundant in some tissues, phosphorylates PtdIns-5-P at the D-4 position, and thus should be considered as a 4-OH kinase, or PIP(4)K" SIGNOR-268865 ITGB4 protein P16144 UNIPROT PIK3CA protein P42336 UNIPROT up-regulates binding 9606 9428518 t gcesareni "Stable expression of alpha6beta4 increased carcinoma invasion in a pi3k-dependent manner, and transient expression of a constitutively active pi3k increased invasion in the absence of alpha6beta4. Ligation of alpha6beta4 stimulated significantly more pi3k activity than ligation of beta1 integrins, establishing specificity among integrins for pi3k activation." SIGNOR-54530 CDK3 protein Q00526 UNIPROT CABLES1 protein Q8TDN4 UNIPROT unknown phosphorylation Ser273 PGQGGSTsAFEQLQR -1 11733001 t llicata "Here, we report that Ser274 of p70ik3-1 is phosphorylated by cdk2 or cdk3 bound to cyclin A and to cyclin E in vitro. We also found that in COS7 cells in which cyclin E and cdk3 were ectopically overexpressed, the phosphorylation level of Ser274 in coexpressed p70ik3-1 is upregulated. We therefore conclude that p70ik3-1 is a substrate for cdk3-mediated phosphorylation." SIGNOR-250679 ATM protein Q13315 UNIPROT TP53BP1 protein Q12888 UNIPROT unknown phosphorylation Ser25 PCLIIEDsQPESQVL 9606 12697768 t llicata "To examine whether the respective sq sites become phosphorylated in vivo, we raised polyclonal antibodies against phosphorylated ser-6 (anti-s6p), phosphorylated ser-25 and ser-29 (anti-s25p/29p), and phosphorylated ser-784 (anti-s784p). All affinity-purified antisera recognized 53bp1" SIGNOR-100641 HNF4A protein P41235 UNIPROT PCK1 protein P35558 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 20577053 f gcesareni "Pgc1alfa is thought to mediate transcription downstream of the nuclear receptor hepatocyte nuclear factor 4alfa (hnf4alfa) and the transcription factor foxo1 in the promoters of key gluconeogenic enzymes, including glucose-6-phosphatase (g6pase) and phosphoenolpyruvate carboxylase (pepck)" SIGNOR-166358 CNOT9 protein Q92600 UNIPROT GIGYF2 protein Q6Y7W6 UNIPROT "up-regulates activity" binding 9606 BTO:0000007 20878056 t miannu "Through interaction analysis of RQCD1 with full-length or partial proteins of GIGYF1 and GIGYF2, segments corresponding to 620-665th and 667-712th amino acids were identified as potential interacting regions on GIGYF1 and GIGYF2, respectively, with RQCD1. we found that RQCD1 was required for enhancement of the interaction of Grb10 with GIGYF1 and GIGYF2" SIGNOR-260058 trimetrexate chemical CHEBI:9737 ChEBI DHFR protein P00374 UNIPROT "down-regulates activity" "chemical inhibition" 9606 7981057 t miannu "We examined the cytotoxicity and biochemical effects of the lipophilic antifol trimetrexate (TMQ) in two human colon carcinoma cell lines, SNU-C4 and NCI-H630, with different inherent sensitivity to TMQ. Dihydrofolate reductase (DHFR) and thymidylate synthase were quantitatively and qualitatively similar in both lines. During drug exposure, DHFR catalytic activity was inhibited by > or = 85% in both cell lines" SIGNOR-258482 TDGF1 protein P13385 UNIPROT ACVR2A protein P27037 UNIPROT down-regulates binding 9606 BTO:0000007 12682303 t acerquone "Here we show that cripto can form a complex with activin and actrii/iib cripto inhibited crosslinking of activin to alk4 and the association of alk4 with actrii/iib." SIGNOR-100052 Naltrindole chemical CHEBI:81528 ChEBI OPRK1 protein P41145 UNIPROT "down-regulates activity" "chemical inhibition" 10029 BTO:0000246 9686407 t miannu "Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors." SIGNOR-258816 Laminin-5 complex SIGNOR-C184 SIGNOR "A6/b4 integrin" complex SIGNOR-C174 SIGNOR "up-regulates activity" binding 9790905 t lperfetto "We propose that these alpha6 beta4/Ln-5 complexes may provide links between plasma membrane and basement membrane that resist mechanical stress and support epithelial integrity." SIGNOR-253238 ELF4 protein Q99607 UNIPROT LYZ protein P61626 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0001271 14976184 f miannu "Myeloid elf-1-like factor (mef) or elf4, which is a member of the ets transcription factor family, up-regulates the basal expression of lysozyme gene in epithelial cells and is constitutively localized in the nucleus" SIGNOR-122236 TWIST1 protein Q15672 UNIPROT FN1 protein P02751 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0003879 20646316 f miannu "Individual genes upregulated by TWIST1 known to promote EMT and/or GBM invasion included SNAI2, MMP2, HGF, FAP and FN1." SIGNOR-255521 NME1 protein P15531 UNIPROT NME1 protein P15531 UNIPROT unknown phosphorylation Ser125 HGSDSVEsAEKEIGL -1 8810265 t miannu "For autophosphorylated rNm23-H1, phosphorylation was observed at serine 44 and on a fragment containing serines 120, 122, and 125.The biochemical function of Nm23 serine phosphorylation is unknown." SIGNOR-250198 SIAH2 protein O43255 UNIPROT SNCAIP protein Q9Y6H5 UNIPROT down-regulates ubiquitination 9606 16174773 t lperfetto "Siah proteins ubiquitylate synphilin-1 and promote its degradation through the ubiquitin proteasome system" SIGNOR-140651 CUDC-907 chemical CID:54575456 PUBCHEM PIK3CA protein P42336 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-191212 Ub:E2 complex SIGNOR-C497 SIGNOR RNF8 protein O76064 UNIPROT "up-regulates activity" ubiquitination 9606 34199813 t miannu "The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t" SIGNOR-270987 Ub:E2 complex SIGNOR-C497 SIGNOR PJA2 protein O43164 UNIPROT "up-regulates activity" ubiquitination 9606 34199813 t miannu "The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t" SIGNOR-271143 ABL1 protein P00519 UNIPROT DDX5 protein P17844 UNIPROT up-regulates phosphorylation Tyr593 NGMNQQAyAYPATAA 9606 17018282 t llicata "These results suggested that p68 was phosphorylated by c-abl in ht-29 cells under stimulation of pdgf. we demonstrated that tyrosine phosphorylation of p68 at y593 mediated pdgf-stimulated epithelial-mesenchymal transition (emt). We showed that pdgf treatment led to phosphorylation of p68 at y593 in the cell nucleus. The y593-phosphorylated p68 (referred to as phosphor-p68) promotes beta-catenin nuclear translocation via a wnt-independent pathway." SIGNOR-149988 NFIB protein O00712 UNIPROT ID3 protein Q02535 UNIPROT "down-regulates quantity" "transcriptional regulation" 10090 31838646 t Gianni "By integrating transcriptomic profiling (RNA-seq) of Nfia- and Nfix-deficient GNPs with epigenomic profiling (ChIP-seq against NFIA, NFIB and NFIX, and DNase I hypersensitivity assays), we reveal that these transcription factors share a large set of potential transcriptional targets, suggestive of complementary roles for these NFI family members in promoting neural development" SIGNOR-268879 BRSK2 protein Q8IWQ3 UNIPROT PRKAA1 protein Q13131 UNIPROT up-regulates phosphorylation Thr183 SDGEFLRtSCGSPNY 9606 21918180 t gcesareni "Ampka1 activators increased phosphorylation level and cytoplasmic localization (reduced nuclear/cytoplasmic ratio). Ampka1 activators reduced rna synthesis in the nucleoli." SIGNOR-176594 SMARCA1 protein P28370 UNIPROT ST7 protein Q9NRC1 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 15485929 t lperfetto "Human SWI/SNF-associated PRMT5 methylates histone H3 arginine 8 and negatively regulates expression of ST7 and NM23 tumor suppressor genes." SIGNOR-268991 Frizzled proteinfamily SIGNOR-PF11 SIGNOR GNAS protein P63092 UNIPROT "up-regulates activity" binding 9606 BTO:0000887;BTO:0001103 22944199 t gcesareni "Wnt7a binding to fzd7 activates pi3k through a g protein alpha s- dependent mechanism." SIGNOR-253125 ABI1 protein Q8IZP0 UNIPROT "WRC complex" complex SIGNOR-C191 SIGNOR "form complex" binding 9606 21107423 t miannu "WAVE proteins are constitutively associated with four additional proteins in cells: Sra1/Cyfip1, Nap1/Hem-2, Abi and HSPC300. The components of this ~400 kDa pentamer, termed the WAVE regulatory complex (WRC) have all been implicated in control of Arp2/3 complex-mediated actin assembly in a wide range of systems" SIGNOR-253571 UMPS protein P11172 UNIPROT orotate smallmolecule CHEBI:30839 ChEBI "down-regulates quantity" "chemical modification" 9606 2912371 t miannu "Uridine 5'-phosphate (UMP) synthase contains two sequential catalytic activities for the synthesis of orotidine 5'-phosphate (OMP) from orotate (EC 2.4.2.10, orotate phosphoribosyltransferase) and the decarboxylation of OMP to form UMP (EC 4.1.1.23, OMP decarboxylase)." SIGNOR-267436 KLHL20 protein Q9Y2M5 UNIPROT "Cullin 3-RBX1-Skp1" complex SIGNOR-C526 SIGNOR "up-regulates activity" binding 9606 BTO:0000007 26687681 t miannu "Cul3-KLHL20 Ubiquitin Ligase Governs the Turnover of ULK1 and VPS34 Complexes to Control Autophagy Termination. KLHL20 promotes ubiquitination of phagophore-residing VPS34 and Beclin-1" SIGNOR-272416 PIK3CA protein P42336 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR "up-regulates activity" 9606 BTO:0000150 19573809 f lperfetto "However, here we show through phosphoprotein profiling and functional genomic studies that many PIK3CA mutant cancer cell lines and human breast tumors exhibit only minimal AKT activation and a diminished reliance on AKT for anchorage-independent growth" SIGNOR-236436 ARHGAP15 protein Q53QZ3 UNIPROT RAC1 protein P63000 UNIPROT "down-regulates activity" "gtpase-activating protein" 9606 BTO:0000007 32203420 t Luana "We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2)." SIGNOR-260470 BTF3 protein P20290 UNIPROT IRAG1 protein Q9Y6F6 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0000584 17312387 f "In contrast, BTF3 silencing resulted in down-regulation of several cancer-associated genes, including EPHB2, ABL2, HPSE2 and ATM, and up-regulation of KRAG, RRAS2, NFkappa-B, MRVI1, MADCAM1 and others. In conclusion, BTF3 is overexpressed in PDAC, where it acts as a transcriptional regulator rather than a direct modulator of apoptosis." SIGNOR-253946 "Caspase 3 complex" complex SIGNOR-C221 SIGNOR GSN protein P06396 UNIPROT down-regulates cleavage 9606 BTO:0000130 9323209 t amattioni "Caspase-3 mediates cleavage of gelsolin, generating a fragment that severs actin filaments in an unregulated fashion. The cleavage of gelsolin causes cells to round up, detach and undergo nuclear fragmentation." SIGNOR-256461 AKT1 protein P31749 UNIPROT FOXO6 protein A8MYZ6 UNIPROT down-regulates phosphorylation 9606 18394876 t lperfetto "The phosphorylation of the two remaining akt-dependent sites inhibits foxo6 transcriptional activity" SIGNOR-252582 Ub:E2 complex SIGNOR-C497 SIGNOR RNF167 protein Q9H6Y7 UNIPROT "up-regulates activity" ubiquitination 9606 34199813 t miannu "The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t" SIGNOR-271224 HLF protein Q16534 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR down-regulates 9606 23415677 f miannu "Ectopic hlf expression inhibits apoptosis in murine and human cells, suggesting that hlf is regulating a conserved transcriptional program that inhibits cell death." SIGNOR-201034 IGFBP3 protein P17936 UNIPROT Neuron_maturation phenotype SIGNOR-PH169 SIGNOR down-regulates 10090 BTO:0000142 17278996 f Luana "IGFBP3 overexpression due to lack of MeCP2 may lead to delayed brain maturation." SIGNOR-265774 "NRZ complex" complex SIGNOR-C358 SIGNOR Vesicle_transport phenotype SIGNOR-PH172 SIGNOR up-regulates 25364732 f lperfetto "NRZ complex, which comprises NAG, RINT1, and ZW10, is also involved in Golgi-to-ER retrograde transport, but each component of the complex has diverse cellular functions including endosome-to-Golgi transport, cytokinesis, cell cycle checkpoint, autophagy, and mRNA decay." SIGNOR-265026 CNR1 protein P21554 UNIPROT GNAO1 protein P09471 UNIPROT "up-regulates activity" 9606 BTO:0002036 25012566 f lperfetto "We subsequently analyzed whether Gαo modulates the cellular activities of Necdin. Notably, expression of Gαo significantly augmented Necdin-mediated cellular responses, such as proliferation and differentiation. Moreover, activation of type 1 cannabinoid receptor (CB1R), a Gi/oα-coupled receptor, augmented cell growth suppression, which was mediated by Gαo and Necdin in U87MG cells containing CB1R, Gαo, and Necdin as normal components." SIGNOR-253389 PLK4 protein O00444 UNIPROT TUBGCP6 protein Q96RT7 UNIPROT "up-regulates activity" phosphorylation Ser1168 HGHVSDAsISLGESV -1 22302995 t miannu "Plk4 interacts with and phosphorylates GCP6. we show that GCP6 is an integral component of the centriole and required for centriole duplication. Moreover, we find that GCP6 interacts in vitro and in vivo with Plk4. We show that phosphorylation of GCP6 by Plk4 is required for Plk4-induced centriole overduplication." SIGNOR-262903 VAV1 protein P15498 UNIPROT MAPK1 protein P28482 UNIPROT up-regulates 9606 9013873 f gcesareni "Vav may link gp130 activation to downstream mapk activation in hematopoietic cells." SIGNOR-46064 CSNK1A1 protein P48729 UNIPROT FOXO3 protein O43524 UNIPROT down-regulates phosphorylation 9606 BTO:0000150;BTO:0001130;BTO:0001271;BTO:0000527 19188143 t gcesareni "Additionally, ck1, dyrk1a, and cdk2 also phosphorylate foxos at various sites to inhibit foxos activity." SIGNOR-183661 FUS protein P35637 UNIPROT SMN1 protein Q16637 UNIPROT "up-regulates activity" relocalization 9606 BTO:0000567 23022481 t lperfetto "Here, we report that FUS associates with the SMN complex, mediated by U1 snRNP and by direct interactions between FUS and SMN.|The FUS IP and pulldown revealed that FUS also associates with components of the SMN complex, including SMN and Gemins 4 and 6 |Remarkably, the number of SMN-stained nuclear bodies was dramatically reduced in the FUS knockdown cells" SIGNOR-262107 NTRK3 protein Q16288 UNIPROT PLCG1 protein P19174 UNIPROT up-regulates binding 9606 BTO:0000938 10235685 t gcesareni "Unglycosylated trka core protein is phosphorylated even in the absence of ligand stimulation and displays constitutive kinase activity as well as constitutive interaction with the signaling molecules shc and plc-gamma." SIGNOR-67404 "Cullin 1-RBX1-Skp1" complex SIGNOR-C529 SIGNOR BACE1 protein P56817 UNIPROT "down-regulates quantity by destabilization" polyubiquitination 10090 BTO:0000938 20854419 t miannu "SCFFbx2-E3-ligase-mediated degradation of BACE1 attenuates Alzheimer’s disease amyloidosis and improves synaptic function. We report that the SCF(Fbx2) -E3 ligase is involved in the binding and ubiquitination of BACE1 via its Trp 280 residue of F-box-associated domain. we found that overexpression of Fbx2 in the primary cortical and hippocampal neurons derived from Tg2576 transgenic mice significantly promoted BACE1 degradation and reduced β-amyloid production." SIGNOR-271903 H4C1 protein P62805 UNIPROT BRD4 protein O60885 UNIPROT "up-regulates activity" relocalization 9606 acetylation:Lys21;Lys17 GGAKRHRkVLRDNIQ;GLGKGGAkRHRKVLR 27991587 t lperfetto "BRD4 interacts with acetylated nucleosomes via both its BD1 and BD2 domains. Our results indicate that BRD4-BD1 binds to nucleosomes through the acetylated histone H4 tail and does not additionally interact with DNA." SIGNOR-262065 MAPK3 protein P27361 UNIPROT BCL2 protein P10415 UNIPROT up-regulates phosphorylation Ser70 RDPVARTsPLQTPAA 9606 10669763 t gcesareni "Erk1 and erk2 directly phosphorylate bcl2 exclusively at ser-70 p44mapk/extracellular signal-regulated kinase 1 (erk1) and p42 mapk/erk2 are activated by il-3, colocalize with mitochondrial bcl2, and can directly phosphorylate bcl2 on ser-70 in a stauro-resistant manner both in vitro and in vivo molecular association." SIGNOR-74935 PRKAA2 protein P54646 UNIPROT ACACA protein Q13085 UNIPROT down-regulates phosphorylation Ser80 LHIRSSMsGLHLVKQ 9606 BTO:0000887;BTO:0001103 SIGNOR-C15 12015362 t gcesareni "Significant negative linear correlations between phospho-acc and acc activity were observed in all models (p < 0.01). The decline in acc activity was related to the decrease in pcr and the rise in amp. A relationship between phospho-ampk (threonine 172) and activity of ampk immunoprecipitated with anti-alpha(2) subunit antibody preparation was also observed." SIGNOR-87583 PRKDC protein P78527 UNIPROT H2AX protein P16104 UNIPROT up-regulates phosphorylation 9606 23620287 t gcesareni "Dna-dependentprotein_ kinase_ (dna-pk) that phosphorylate h2ax at dsbs" SIGNOR-192443 ATF2 protein P15336 UNIPROT ST3GAL5 protein Q9UNP4 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0002335 21699754 f miannu "Our results identified the core promoter region in the hST3Gal V promoter and for the first time demonstrated that ATF2 binding to the CREB/ATF binding site at -143 is essential for transcriptional activation of hST3Gal V in VPA-induced ARPE-19 cells." SIGNOR-253745 RELA protein Q04206 UNIPROT PCK2 protein Q16822 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0000759 20137375 f miannu "NF-kappaB p65 was shown to inhibit transcription of phosphoenolpyruvate carboxykinase (PEPCK), a rate-limiting enzyme in gluconeogenesis in the liver" SIGNOR-255072 WNK3 protein Q9BYP7 UNIPROT SLC12A4 protein Q9UP95 UNIPROT "down-regulates activity" phosphorylation 21613606 t lperfetto "We have shown that with-no-lysine kinase 3 (WNK3) possesses several properties that suggest it could be the Cl−/volume-sensitive regulatory kinase that, in association with protein phosphatases, reciprocally modifies the phosphorylation/dephosphorylation states of the SLC12 proteins and thus their activities|WNK3 activates NKCC1/2 and NCC and inhibits the KCCs" SIGNOR-264627 FHL1 protein Q13642 UNIPROT RBPJ protein Q06330 UNIPROT down-regulates binding 9606 9418910 t "With differential splicing resulting in deletion of an exon, KyoT2 lacked two LIM domains from the C terminus and had a frameshift in the last exon, creating the RBP-J-binding region in the C terminus" gcesareni "It was demonstrated by emsa that kyot2 can form a complex with dna-bound rbp-j, but the dna-binding affinity of the kyot2rbp-j complex is greatly weakened and it exists mostly dissociated from dna" SIGNOR-54277 STK11 protein Q15831 UNIPROT AMPK complex SIGNOR-C15 SIGNOR up-regulates phosphorylation -1 14614828 t lperfetto "We demonstrated that lkb1 phosphorylates ampk on the activation loop threonine (thr172) within the catalytic subunit and activates ampk in vitro. Here, we have investigated whether lkb1 corresponds to the major ampkk activity present in cell extracts. Ampkk purified from rat liver corresponds to lkb1, and blocking lkb1 activity in cells abolishes ampk activation in response to different stimuli" SIGNOR-217469 GLI3 protein P10071 UNIPROT CCND1 protein P24385 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000150;BTO:0000551 19860666 f gcesareni "Gli activators bind to gaccaccca motif to regulate transcription of gli1, ptch1, ptch2, hhip1, mycn, ccnd1, ccnd2, bcl2, cflar, foxf1, foxl1, prdm1 (blimp1), jag2, grem1, and follistatin." SIGNOR-188878 GPR174 protein Q9BXC1 UNIPROT GNAS protein Q5JWF2 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-256757 "PD-153035 hydrochloride" chemical CHEBI:91075 ChEBI EGFR protein P00533 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-205716 ZNRF3 protein Q9ULT6 UNIPROT FZD5 protein Q13467 UNIPROT "down-regulates quantity" ubiquitination 9606 BTO:0000007 22575959 t "Here we show that the cell-surface transmembrane E3 ubiquitin ligase zinc and ring finger 3 (ZNRF3) and its homologue ring finger 43 (RNF43) are negative feedback regulators of Wnt signalling. ZNRF3 is associated with the Wnt receptor complex, and inhibits Wnt signalling by promoting the turnover of frizzled and LRP6." SIGNOR-260118 U2AF2 protein P26368 UNIPROT ZRSR2/U2AF2 complex SIGNOR-C81 SIGNOR "form complex" binding 9606 9237760 t miannu "Recognition of a functional 3' splice site in pre-mrna splicing requires a heterodimer of the proteins u2af65/u2af35." SIGNOR-50173 CORT protein O00230 UNIPROT GHSR protein Q92847 UNIPROT up-regulates binding 9606 12161511 t gcesareni "In human tissues cst-14 as well as cst-17 but not ss-14 bind the gh secretagogue receptor (ghs-r)." SIGNOR-91134 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR MCRIP1 protein C9JLW8 UNIPROT "down-regulates activity" phosphorylation 9606 BTO:0000007 25728771 t "inferred from 70% family members" lperfetto "When phosphorylated by ERK, MCRIP1 dissociates from CtBP, allowing CtBP to interact with ZEB1. In this manner, the CtBP co-repressor complex is recruited to, and silences, the E-cadherin promoter by inducing chromatin modifications.| While substitution of S4 or S18 with Ala did not affect the phosphorylation of MCRIP1 by ERK, substitution of either S21 or T30 significantly reduced MCRIP1 phosphorylation" SIGNOR-270188 HACD3 protein Q9P035 UNIPROT FASN protein P49327 UNIPROT "up-regulates activity" "chemical activation" 9606 18554506 t "Very long-chain fatty acids are produced through a four-step cycle. However, the 3-hydroxyacyl-CoA dehydratase catalyzing the third step in mammals has remained unidentified. Mammals have four candidates, HACD1-4, based on sequence similarities to the recently identified yeast Phs1, although HACD3 and HACD4 share relatively weak similarity. We demonstrate that all four of these human proteins are indeed 3-hydroxyacyl-CoA dehydratases," SIGNOR-267762 antigen smallmolecule CHEBI:59132 ChEBI BCR-Mk complex SIGNOR-C433 SIGNOR "up-regulates activity" binding 9606 BTO:0000776 32323266 t scontino "The recognition of antigen by the BCR initiates BCR signaling cascade." SIGNOR-268202 midostaurin chemical CHEBI:63452 ChEBI KDR protein P35968 UNIPROT "down-regulates activity" "chemical inhibition" 16969355 t lperfetto "Midostaurin (PKC412A), N-benzoyl-staurosporine, potently inhibits protein kinase C alpha (PKCalpha), VEGFR2, KIT, PDGFR and FLT3 tyrosine kinases" SIGNOR-261982 "2-(4-(4,4-Bis(4-fluorophenyl)butyl)-1-piperazinyl)-3-pyridinecarboxylic acid methyl ester" chemical CID:127728 PUBCHEM HTR1A protein P08908 UNIPROT "up-regulates activity" "chemical activation" 10029 BTO:0000246 9760039 t miannu "Several compounds proposed as ‘atypical’ antipsychoticagents were found to exhibit agonist activity at 5-HT1A EC values were greater than the respective Kvalues50i .21.8""5.8-fold difference,ns10 and a high degree of correlation was observed. All the compounds displayed high or marked bind-ing affinity at CHO-h5-HT1A receptors except for olanzapine, which exhibited a micromolar Kvalue at h5-HTi1A receptors (table3)." SIGNOR-258949 SIRT2 protein Q8IXJ6 UNIPROT PCK1 protein P35558 UNIPROT "up-regulates quantity by stabilization" deacetylation Lys594 KEVEDIEkYLEDQVN 9606 BTO:0000007 21726808 t lperfetto "Conversely, SIRT2 deacetylates and stabilizes PEPCK1.|Furthermore, coexpression of P300 increased acetylation levels of wild-type PEPCK1, but not PEPCK13K/R, indicating that P300 acts on these lysine residues of PEPCK1" SIGNOR-267602 SKP1 protein P63208 UNIPROT SCF-SKP2 complex SIGNOR-C136 SIGNOR "form complex" binding 9606 15340381 t gcesareni "The F-box family of proteins €” which are the substrate-recognition components of the Skp1€“Cul1€“F-box-protein (SCF) ubiquitin ligase €” are important players in many mammalian functions." SIGNOR-243554 INPPL1 protein O15357 UNIPROT PIP3 smallmolecule CHEBI:16618 ChEBI down-regulates "chemical modification" 9606 9111325 t gcesareni "Sip specifically and markedly reduced the level of phosphatidylinositol (3,4,5) triphosphate [ptdins(3,4,5)p3] generated in oocytes in response to insulin" SIGNOR-47537 SRC protein P12931 UNIPROT MPZL1 protein O95297 UNIPROT up-regulates phosphorylation Tyr241 SHQGPVIyAQLDHSG 9606 11751924 t lperfetto "Indeed, our studies indicated that cross-linking of pzr by cona lead to activation of c-src, which may be responsible for phosphorylation of pzr and possibly other proteins. Phosphorylation of pzr in turn recruits shp-2, which by itself is an essential signal transducertyrosine residues 241 and 263 embedded in the itims are responsible for the tyrosine phosphorylation of pzr" SIGNOR-113406 EGFR protein P00533 UNIPROT PI3K complex SIGNOR-C156 SIGNOR up-regulates binding 9606 BTO:0000093 BTO:0000150 26918608 t lperfetto "P85alpha promotes nucleolin transcription and subsequently enhances EGFR mRNA stability and EGF-induced malignant cellular transformation." SIGNOR-252671 "9-cis-retinoic acid" chemical CHEBI:50648 ChEBI RXRB protein P28702 UNIPROT "up-regulates activity" "chemical activation" 9606 18321241 t miannu "Alitretinoin (9-cis-retinoic acid) is a unique panagonist retinoid, capable of binding to all six known retinoid receptors (RAR-alpha, -beta, -gamma, and RXR-alpha, -beta, -gamma)." SIGNOR-259238 PPM1A protein P35813 UNIPROT IKBKB protein O14920 UNIPROT "down-regulates activity" dephosphorylation Ser181 DQGSLCTsFVGTLQY 9606 18930133 t "PPM1A and PPM1B act as IKKbeta phosphatases to terminate TNFalpha-induced IKKbeta-NF-kappaB activation|Overexpression of PPM1A or PPM1B results in dephosphorylation of IKKbeta at Ser177 and Ser181 and termination of IKKbeta-induced NF-kappaB activation." SIGNOR-248487 "SB 505124" chemical CHEBI:100922 ChEBI TGFBR1 protein P36897 UNIPROT down-regulates "chemical inhibition" 9606 14978253 t gcesareni "Sb-505124 is a selective inhibitor of transforming growth factor-beta type i receptors alk4, alk5, and alk7." SIGNOR-122910 TNF protein P01375 UNIPROT Inflammation phenotype SIGNOR-PH12 SIGNOR "up-regulates activity" 9606 23685857 f "Tumor necrosis factor α (TNF-α, also known as cachectin) is a strong pro-inflammatory cytokine which plays an important role in the immune system during inflammation, cell proliferation, differentiation and apoptosis" SIGNOR-258988 CTDSP2 protein O14595 UNIPROT SMAD2 protein Q15796 UNIPROT "down-regulates activity" dephosphorylation Thr220 QSNYIPEtPPPGYIS 9606 BTO:0000007 17035229 t "Dephosphorylation of Smad2/3 Linkers by SCP2 and SCP3|MAPK-mediated linker phosphorylation appears to have a dual role in Smad2/3 regulation. Mitogens and hyperactive Ras result in extracellular signal-regulated kinase (ERK)-mediated phosphorylation of Smad3 at Ser-204, Ser-208, and Thr-179 and of Smad2 at Ser-245/250/255 and Thr-220. Mutation of these sites increases the ability of Smad3 to activate target genes, suggesting that MAPK phosphorylation of Smad3 is inhibitory (11, 12). However, in contrast, ERK-dependent phosphorylation of Smad2 at Thr-8 enhances its transcriptional activity" SIGNOR-248296 VRK2 protein Q86Y07 UNIPROT BANF1 protein O75531 UNIPROT down-regulates phosphorylation Ser4 sQKHRDFV 9606 BTO:0000567 16371512 t gcesareni "We demonstrate that phosphorylation of ser4 and/or thr2/thr3 abrogates the interaction of baf with dna and reduces its interaction with the lem domain. Coexpression of vrk1 and gfp-baf greatly diminishes the association of baf with the nuclear chromatin/matrix and leads to its dispersal throughout the cell" SIGNOR-143368 ethanol chemical CHEBI:16236 ChEBI GlyR proteinfamily SIGNOR-PF62 SIGNOR "up-regulates activity" "chemical activation" 8355 BTO:0000964 8700149 t "inferred from family member" miannu "Pharmacologically relevant concentrations of ethanol (10-200 mM) reversibly potentiated the glycine receptor function in all receptors. Ethanol potentiation depended on the glycine concentration used, with decreased potentiation observed at higher glycine concentrations." SIGNOR-270260 VRK1 protein Q99986 UNIPROT "Histone H3" proteinfamily SIGNOR-PF69 SIGNOR unknown phosphorylation 9606 17938195 t gcesareni "We show that histone h3 is phosphorylated by vaccinia-related kinase 1 (vrk1). Direct phosphorylation of thr3 and ser10 in h3 by vrk1 both in vitro and in vivo was observed. Loss of vrk1 activity was associated with a marked decrease in h3 phosphorylation during mitosis." SIGNOR-265371 PRKCE protein Q02156 UNIPROT MGluR proteinfamily SIGNOR-PF55 SIGNOR "up-regulates activity" phosphorylation -1 15894802 t "inferred from family member" lperfetto "Thus, we showed that it is phosphorylation of Ser-839, not Thr-840, that is absolutely required for the unique Ca2+ oscillations produced by mGluR5 activation. The Thr-840 residue is important only in that it is permissive for the PKC-dependent phosphorylation of Ser-839." SIGNOR-270280 TEAD1 protein P28347 UNIPROT CCND1 protein P24385 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 BTO:0000165;BTO:0000222 BTO:0000887;BTO:0001103;BTO:0001760 20153295 f lperfetto "We found that the expression of myf5 and cyclind1 remained significantly elevated upon induction of differentiation in cells that were overexpressing hyap1 s127a compared to cells transfected with wildtype hyap and empty vector;yap directly induced the transcription of ccnd1 and foxm1, in cooperation with tead transcription factor." SIGNOR-235849 SPTB protein P11277 UNIPROT "Erythrocytic spectrin" complex SIGNOR-C384 SIGNOR "form complex" binding 9606 BTO:0000424 24302288 t lperfetto "Spectrin is a large, cytoskeletal, and heterodimeric protein composed of modular structure of alpha and beta subunits, it typically contains 106 contiguous amino acid sequence motifs called “spectrin repeats”. Spectrin is crucial for maintaining the stability and structure of the cell membrane and the shape of a cell" SIGNOR-266024 PRKACA protein P17612 UNIPROT HAND1 protein O96004 UNIPROT "down-regulates activity" phosphorylation Ser109 KERRRTEsINSAFAE 10116 BTO:0001556 14636580 t miannu "In vitro and in vivo phosphorylation studies show that both PKA and PKC can phosphorylate HAND1 and -2. T107; S109 within helix I and S98 within the basic domain, are the phosphorylated residues. We determined that modification of HAND1 at residues 107 and 109 affects dimerization affinities with E-proteins, thus changing the bHLH dimer equilibrium within the cell. These modifications also affect HAND1 function." SIGNOR-249989 PRKACB protein P22694 UNIPROT BAD protein Q92934 UNIPROT down-regulates phosphorylation Ser75 EIRSRHSsYPAGTED 9606 10949026 t gcesareni "Ser-155 is the major phosphoacceptor site for pka on bad, but that pka also phosphorylates ser-112 and ser-136." SIGNOR-81145 FGF12 protein P61328 UNIPROT SCN1A protein P35498 UNIPROT "down-regulates activity" binding 9606 20679355 t miannu "Sodium channel fast inactivation is modulated by alpha subunit interaction with a family of cytoplasmic proteins termed fibroblast growth factor homologous factors (FHFs). In this paper, we report that all A-type FHFs exert rapid onset long-term inactivation on Nav1.6 and other sodium channels." SIGNOR-253420 CDK2 protein P24941 UNIPROT CCNE1 protein P24864 UNIPROT down-regulates phosphorylation Ser387 LSEQNRAsPLPSGLL 9606 19561641 t gcesareni "Phosphorylation of threonine 395 has been linked to the proteasome-mediated degradation of full length cyclin e" SIGNOR-186414 EPHA3 protein P29320 UNIPROT EPHA3 protein P29320 UNIPROT "up-regulates activity" phosphorylation Tyr779 EDDPEAAyTTRGGKI 9606 11870224 t "Eph receptor activation leads to tyrosine phosphorylation of three major autophosphorylation sites. these residues function to regulate kinase activity, their phosphorylation being required for full intrinsic enzyme activity. these tyrosines (EphA3 Y596, Y602 and Y779) as the prominent autophosphorylation sites of EphA3" SIGNOR-251117 SRC protein P12931 UNIPROT RACK1 protein P63244 UNIPROT up-regulates phosphorylation Tyr228 LNEGKHLyTLDGGDI 9606 12400005 t gcesareni "We found that rack1 is a src substrate. Moreover, src activity is necessary for both the tyrosine phosphorylation of rack1 and the binding of rack1 to src's sh2 domain that occur following pkc activation. To identify the tyrosine(s) on rack1 that is phosphorylated by src, we generated and tested a series of rack1 mutants. We found that src phosphorylates rack1 on tyr 228 and/or tyr 246" SIGNOR-94796 STK4 protein Q13043 UNIPROT MOB1B protein Q7L9L4 UNIPROT up-regulates phosphorylation Thr35 LLKHAEAtLGSGNLR 9606 21808241 t "MOB1a and MOB1b are near identical to each other with protein sequence homology>90%, and more importantly, both of them are putative tumor suppressors." gcesareni "Mob1, which forms a complex with lats1/2, is also phosphorylated by mst1/2, resulting in an enhanced lats1/2mob1 interaction." SIGNOR-175841 PRKG1 protein Q13976 UNIPROT HRH1 protein P35367 UNIPROT down-regulates phosphorylation Ser398 WKRLRSHsRQYVSGL 9606 BTO:0000975 15107581 t "Translocation from Endosome to Lysosome" fspada "A specific pkg inhibitor inhibits h1r downregulation in cho cells (37). However, direct activation of pkg in these cells does not cause h1r down-regulation, indicating that more studies are required to clarify the role of pkg in h1r down-regulation." SIGNOR-124360 CTDSP1 protein Q9GZU7 UNIPROT POLR2A protein P24928 UNIPROT "up-regulates activity" dephosphorylation Ser1665 SPTSPSYsPTSPSYS -1 22137580 t "Phosphorylation and dephosphorylation of the C-terminal domain (CTD) of RNA polymerase II (Pol II) represent a critical regulatory checkpoint for transcription. Transcription initiation requires Fcp1/Scp1-mediated dephosphorylation of phospho-CTD. | This combined structure-function analysis discloses the residues in Scp1 involved in CTD binding and its preferential dephosphorylation of P.Ser5 of the CTD heptad repeat." SIGNOR-248783 PYGB protein P11216 UNIPROT "alpha-D-glucose 1-phosphate(2-)" smallmolecule CHEBI:58601 ChEBI "up-regulates quantity" "chemical modification" 9606 3346228 t miannu "Mammalian glycogen phosphorylases are found in at least three isozymic forms that can be distinguished by functional and structural properties as well as by the tissues in which they are preferentially expressed [√¢‚Ǩ¬¶] Each phosphorylase isozyme fulfills different physiological requirements even though all forms of the enzyme catalyze the same reaction, the phosphorolysis of glycogen to yield glucose 1-phosphate." SIGNOR-267396 MAPK3 protein P27361 UNIPROT BRAF protein P15056 UNIPROT down-regulates phosphorylation Thr753 YACASPKtPIQAGGY 9606 19933846 t gcesareni "Erk-induced phosphorylation of b-raf on t753 promoted the disassembly of raf heterodimers, and the mutation of t753 prolonged growth factor-induced heterodimerization. The b-raf t753a mutant enhanced differentiation of pc12 cells, which was previously shown to be dependent on sustained erk signaling. Site is critical for v-src dependent modulation of slk kinase activity." SIGNOR-161819 URI1 protein O94763 UNIPROT "URI1 prefoldin co-chaperone" complex SIGNOR-C514 SIGNOR "form complex" binding 9606 30484151 t miannu "In humans, the R2TP complex consists of orthologous proteins named RUVBL1, RUVBL2, RPAP3, and PIH1D1  and the PFDL module is composed of two α (UXT and URI1) and four β subunits (PFDN2, PFDN6, PDRG1, and one of them likely duplicated) as well as two additional members, the RNA polymerase II subunit POLR2E/RPB5, and WDR94" SIGNOR-270917 NEDD4L protein Q96PU5 UNIPROT SCN2A protein Q99250 UNIPROT "down-regulates quantity by destabilization" ubiquitination 10090 BTO:0000938 23778145 t miannu "The control of Nav density at the cell membrane is crucial to ensuring normal neuronal excitability. Navs are subject to posttranslational modifications that may influence their cell membrane availability. Ubiquitylation is a key process that orchestrates the internalization and subsequent degradation or recycling of Navs. This is accomplished by ubiquitin protein ligases, such as NEDD4-2 (neuronal precursor cell expressed developmentally downregulated-4 type 2)." SIGNOR-253459 NET1 protein Q7Z628 UNIPROT RHOA protein P61586 UNIPROT "up-regulates activity" "guanine nucleotide exchange factor" 9606 32203420 t Luana "We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2)." SIGNOR-260561 FBXO32 protein Q969P5 UNIPROT Muscle_atrophy phenotype SIGNOR-PH40 SIGNOR up-regulates 10090 25096180 f "Muscle RING finger 1 (MuRF1) and muscle atrophy F-box (MAFbx)/atrogin-1 were identified more than 10 years ago as two muscle-specific E3 ubiquitin ligases that are increased transcriptionally in skeletal muscle under atrophy-inducing conditions, making them excellent markers of muscle atrophy" SIGNOR-252072 ATF3 protein P18847 UNIPROT GDF15 protein Q99988 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 15670751 t lperfetto "In addition, DIM increased the expression of NAG-1 as well as activating transcription factor 3 (ATF3), and the induction of ATF3 was earlier than that of NAG-1. The DIM treatment increased luciferase activity of NAG-1 in HCT-116 cells transfected with NAG-1 promoter construct. The results suggest that I3C represses cell proliferation through up-regulation of NAG-1 and that ATF3 may play a pivotal role in DIM-induced NAG-1 expression in human colorectal cancer cells." SIGNOR-253725 Lewy_body_formation phenotype SIGNOR-PH56 SIGNOR Apoptosis phenotype SIGNOR-PH2 SIGNOR up-regulates 9606 BTO:0000938 20479780 f lperfetto "The genetic causes of PD seem to participate in con­ verging pathways to pathogenesis, but it is unclear whether all or only some of these pathways need to be activated for lewy body deposition and neuronal death to occur." SIGNOR-249703 PTAFR protein P25105 UNIPROT GNAL protein P38405 UNIPROT "up-regulates activity" binding 9606 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-256932 PIK3R4 protein Q99570 UNIPROT PIK3C3 protein Q8NEB9 UNIPROT "up-regulates activity" binding 10090 27411398 t lperfetto "Vps34 PI 3-kinase activity18 is stimulated by complex formation with the protein kinase Vps15|Rab5GTP binds Vps15, enhancing Vps34 activity" SIGNOR-260709 GABRA4 protein P48169 UNIPROT "GABA-A (a4-b3-d) receptor" complex SIGNOR-C327 SIGNOR "form complex" binding 9606 BTO:0000227 18790874 t "brain, See table 3 for identified complexes" lperfetto "The assembly of GABAA-R as heteropentamers produces complex subtype heterogeneity in structure, which is the major determinant of their pharmacological profile.|Evidence is greatly in favor of a pentameric receptor and most GABAA-R subtypes are formed from two copies of a single alpha, two copies of a single beta, and one copy of another subunit, such as gamma, delta, or epsilon." SIGNOR-263748 JUN protein P05412 UNIPROT SPI1 protein P17947 UNIPROT "up-regulates activity" binding 9606 BTO:0004136 12393465 t apalma "These results indicate that AML1-ETO competes c-Jun away from binding to the β3β4 domain of PU.1. Thus, the c-Jun coactivation function of PU.1 is down-regulated and this in turn down-regulates transcriptional activity of PU.1." SIGNOR-255660 PTGIR protein P43119 UNIPROT GNAL protein P38405 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-256949 MAP3K2 protein Q9Y2U5 UNIPROT MAP2K1 protein Q02750 UNIPROT up-regulates phosphorylation 9606 11343802 t gcesareni "Both mekk2 and mekk3 are able to activate the jun kinase pathway in vivo. However, following routine immunoprecipitation in triton x-100, mekk2 but not mekk3 is able to effectively phosphorylate both sek-1 and mek-1 and to undergo autophosphorylation" SIGNOR-107692 STAT3 protein P40763 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 BTO:0003298 BTO:0001103 30029643 f "In summary, our results indicate IL-15 can stimulate the proliferation of FAPs through Jak-STAT pathway." SIGNOR-256256 HNF4A protein P41235 UNIPROT F12 protein P00748 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0000599 9794469 f miannu "Orphan receptor hepatocyte nuclear factor-4 antagonizes estrogen receptor alpha-mediated induction of human coagulation factor XII gene. In conclusion, our findings address a direct role for HNF-4 in modulating estrogen-dependent transcription of the FXII gene promoter." SIGNOR-254073 DLX5 protein P56178 UNIPROT MYC protein P01106 UNIPROT "up-regulates quantity" "transcriptional regulation" 9606 19497851 t gcesareni "Here we demonstrate by luciferase assay that the MYC promoter is specifically activated by overexpression of DLX5 and that two DLX5 binding sites in the MYC promoter are important for transcriptional activation of MYC. We also show that DLX5 binds to the MYC promoter both in vitro and in vivo and that transfection of a DLX5 expression plasmid promotes the expression of MYC in a dose-dependent manner in mammalian cells" SIGNOR-241914 MAPK3 protein P27361 UNIPROT RXRA protein P19793 UNIPROT "down-regulates activity" phosphorylation Ser260 NMGLNPSsPNDPVTN 9606 17604322 t lperfetto "In colon cancer cells, the Ras/mitogen‐activated protein kinase (MAPK) pathway phosphorylates RXRalpha, which impairs its function as a heterodimeric partner for PPARgamma|A point‐mutated RXRalpha T82A/S260A, which mimics the unphosphorylated form of RXRalpha, can form a heterodimer with PPARgamma and thereby activate target gene expression by binding to the PPRE" SIGNOR-88662 RPS6K proteinfamily SIGNOR-PF26 SIGNOR H3-3A protein P84243 UNIPROT "down-regulates activity" phosphorylation Ser11 TKQTARKsTGGKAPR 9606 10464286 t "Ser 11 phosphorylation of H3 is either activatory and inhibitory as promotes DNA condensation (activatory) and induce transcription (inhibitory)." gcesareni "Phosphorylation at ser-11 (h3s10ph) by rps6ka4 and rps6ka5 is important during interphase because it enables the transcription of genes following external stimulation, like mitogens, stress, growth factors or uv irradiation and result in the activation of genes, such as c-fos and c-jun." SIGNOR-252815 MAPK14 protein Q16539 UNIPROT SP7 protein Q8TDD2 UNIPROT "up-regulates activity" phosphorylation 10090 20682789 t ggiuliani "We therefore propose that Osterix binds to Sp1 sequences on target gene promoters and that its phosphorylation by p38 enhances recruitment of coactivators to form transcriptionally active complexes" SIGNOR-255791 SMAD3/SMAD4 complex SIGNOR-C9 SIGNOR BCL2L11 protein O43521 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 17960585 f miannu "Transforming growth factor-beta (TGF-beta) signaling is known to depend on the formation of Smad2/3-Smad4 transcription regulatory complexes. Functional analysis revealed that Smad3 and Smad4 were the predominant mediators of TGF-beta-induced apoptosis in Hep3B cells. We provide evidence that up-regulation of Bcl-2-interacting mediator of cell death (Bim), under the transcriptional control of Smad3-Smad4 signaling, is crucial to TGF-beta-induced apoptosis in Hep3B cells." SIGNOR-260425 PRKCG protein P05129 UNIPROT STXBP1 protein P61764 UNIPROT unknown phosphorylation Ser306 VSQEVTRsLKDFSSS -1 12519779 t lperfetto "Munc18a is essential for neurotransmitter release by exocytosis and can be phosphorylated by PKC in vitro on Ser-306 and Ser-313. We demonstrate that it is phosphorylated on Ser-313 in response to phorbol ester treatment in adrenal chromaffin cells. Mutation of both phosphorylation sites to glutamate reduces its affinity for syntaxin and so acts as a phosphomimetic mutation." SIGNOR-249184 MMP9 protein P14780 UNIPROT PZP protein P20742 UNIPROT "down-regulates quantity by destabilization" cleavage Leu778 WKAGAFClSEDAGLG -1 9344465 t lperfetto "The complex formation was confirmed by the use of 125I-labeled matrix metalloproteinase-2. The cleavage sites in the ""bait"" regions following formation of high-molecular-weight complexes of matrix metalloproteinases with the alpha-macroglobulins were determined by protein sequence analysis. Pregnancy zone protein was cleaved at Thr693-Tyr694 and alpha2-macroglobulin at Gly679-Leu680 and Arg696-Leu697 by matrix metalloproteinase-2. Matrix metalloproteinase-9 cleaved alpha2-macroglobulin at the same site as matrix metalloproteinase-2, but cleavage of pregnancy zone protein was at Leu753-Ser754.|MMP-2 and MMP-9 cause a significant degradation of these bands and the background, a degradation which is prevented by both a2M and PZP." SIGNOR-261785 HAUS5 protein O94927 UNIPROT "HAUS complex" complex SIGNOR-C281 SIGNOR "form complex" binding 9606 BTO:0000567 19369198 t lperfetto "Here, by using mass spectrometry, we identified the full human augmin complex of 8 subunits and show that it interacts with the gamma-tubulin ring complex (gamma-TuRC)" SIGNOR-262317 CIITA protein P33076 UNIPROT HLA-DMA protein P28067 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9300700 f "The class II transactivator (CIITA) is a highly specific transcription factor that activates only genes known to be involved in the class II MHC processing pathway, including class II MHC, invariant chain, and HLA-DMA/B genes." SIGNOR-254004 COPS6 protein Q7L5N1 UNIPROT "COP9 signalosome variant 2" complex SIGNOR-C487 SIGNOR "form complex" binding 9606 18850735 t miannu "The COP9 signalosome (CSN) is a multiprotein complex that plays a critical role in diverse cellular and developmental processes in various eukaryotic organisms. we have performed a comprehensive proteomic analysis of the human CSN complex using a new purification method and quantitative mass spectrometry. Purification of the human CSN complex from a stable 293 cell line expressing N-terminal HBTH-tagged CSN5 subunit was achieved by high-affinity streptavidin binding with TEV cleavage elution." SIGNOR-270767 SPI1 protein P17947 UNIPROT ITGAM protein P11215 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 12393465 f apalma "CD11b is regulated by PU.1 and its promoter contains putative binding sites of AML1. In this case AML1-ETO interaction and down-regulation of important myeloid transcription factors like PU.1 and AML1 could explain the lower CD11b expression" SIGNOR-255661 PDGFB protein P01127 UNIPROT PDGFRB protein P09619 UNIPROT up-regulates binding 9606 11331882 t miannu "Pdgf-b activates both pdgfr-alpha and pdgfr-beta" SIGNOR-107400 KPNA3 protein O00505 UNIPROT NOTCH1 protein P46531 UNIPROT up-regulates relocalization 9606 20454918 t gcesareni "Nicd binds via one of its four potential nuclear localization signals to importins alfa3, alfa4, and alfa7." SIGNOR-165280 APC2 protein O95996 UNIPROT AXIN1 protein O15169 UNIPROT up-regulates binding 9606 SIGNOR-C110 9601641 t acerquone "Human axin (haxin) binds directly to beta-catenin, gsk3 beta, and apc in vitro, and the endogenous proteins are found in a complex in cells." SIGNOR-57673 TLR7 protein Q9NYK1 UNIPROT IFNA1 protein P01562 UNIPROT "up-regulates quantity" 9606 BTO:0004625 15661881 f miannu "TLR7 in pDC is functionally associated with the production of IFN-α- and IFN-regulated cytokines, similar to the role of TLR9." SIGNOR-259248 DOK1 protein Q99704 UNIPROT "AM/b2 integrin" complex SIGNOR-C170 SIGNOR "down-regulates activity" binding 9606 19118207 t miannu "Integrins also bind to many PTBdomain-containing proteins (Calderwood et al., 2003) – including Dok1 and integrincytoplasmic-domain-associated protein 1 (ICAP1) – and these can compete with talin for binding to integrin and so can impair activation" SIGNOR-257682 GFPT1 protein Q06210 UNIPROT Protein_glycosylation phenotype SIGNOR-PH144 SIGNOR up-regulates 9606 21310273 f miannu "GFPT1 is the key enzyme of the hexosamine pathway yielding the amino sugar UDP-N-acetylglucosamine, an essential substrate for protein glycosylation." SIGNOR-267820 GSK3A protein P49840 UNIPROT MAF protein O75444 UNIPROT up-regulates phosphorylation 9606 18042454 t miannu "We showed that c-maf and mafb, like mafa, are indeed phosphorylated by gsk-3/ we demonstrated that phosphorylation by gsk-3 is conserved among the large maf proteins. It couples ubiquitination/degradation and transcriptional activation and modulates maf biological activity." SIGNOR-159358 FKBP5 protein Q13451 UNIPROT NR3C1 protein P04150 UNIPROT down-regulates binding 9606 25790864 t gcesareni "When not associated with glucocorticoids, glucocorticoid receptors are predominantly found in the cytoplasm as part of a multimeric molecular chaperone complex that includes several heat shock proteins (HSPs), such as HSP70 and HSP90, the HSP90_binding protein p23 (also known as PTGES3) and proteins that help to bind HSP90 such as FK506_binding protein 5 (FKBP5)." SIGNOR-251666 HCFC1 protein P51610 UNIPROT "Set1-Ash2 HMT complex" complex SIGNOR-C352 SIGNOR "up-regulates activity" binding 9606 BTO:0000567 12670868 t miannu "Our analysis of HCF-1-associated proteins suggests that a K4 histone H3 HMT complex has been conserved from yeast to humans in both structure and activity: the Set1/Ash2 HMT. The results presented here show that this Set1/Ash2 HMT complex, in mutually exclusive interactions, can associate with HCF-1 bound to the repressive Sin3 HDAC or the transcriptional activator VP16, indicating a diversity of transcriptional regulatory roles." SIGNOR-264481 PDPK1 protein O15530 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR "up-regulates activity" phosphorylation Thr308 KDGATMKtFCGTPEY 10116 BTO:0000142 10226025 t lperfetto "Protein kinase B (PKB) is activated by phosphorylation of Thr308 and of Ser473. Thr308 is phosphorylated by the 3-phosphoinositide-dependent protein kinase-1 (PDK1) but the identity of the kinase that phosphorylates Ser473 (provisionally termed PDK2) is unknown." SIGNOR-244421 INS protein P01308 UNIPROT COMT protein P21964 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000542 17612537 f "Regulation of expression" miannu "Catechol O-methyltransferase expression in granulosa cells was up-regulated by insulin, DHT, and ATRA." SIGNOR-251961 "2-[[2-[[2-[[2-[[2-amino-3-(4-hydroxyphenyl)-1-oxopropyl]amino]-1-oxoethyl]amino]-1-oxoethyl]amino]-1-oxo-3-phenylpropyl]amino]-4-methylpentanoic acid" chemical CHEBI:91634 ChEBI OPRM1 protein P35372 UNIPROT "up-regulates activity" "chemical activation" 10029 BTO:0000246 9686407 t miannu "Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors." SIGNOR-258805 MECP2 protein P51608 UNIPROT AMPA proteinfamily SIGNOR-PF58 SIGNOR "down-regulates quantity by repression" "transcriptional regulation" 10116 BTO:0004102 22262897 t "inferred from family member" Luana "Bicuculline treatment also leads to an increase in the levels of the transcriptional repressor MeCP2, which binds to the GluR2 promoter along with the corepressors HDAC1 and mSin3A." SIGNOR-270237 SCRIB protein Q14160 UNIPROT Scribble_complex_DLG1-LLGL1_variant complex SIGNOR-C511 SIGNOR "form complex" binding 9606 23397623 t miannu "The Scribble polarity complex or module is one of the three polarity modules that regulate cell polarity in multiple epithelia including blood-tissue barriers. This protein complex is composed of Scribble, Lethal giant larvae (Lgl) and Discs large (Dlg), which are well conserved across species from fruitflies and worms to mammals." SIGNOR-270912 CSNK2A1 protein P68400 UNIPROT PPP1R2 protein P41236 UNIPROT up-regulates phosphorylation Ser122 RIQEQESsGEEDSDL 9606 9405437 t gcesareni "Recombinant inh2 was phosphorylated by kinases in cytosols prepared from g1 and s phase cells. The amount of inh2 kinase attributed to casein kinase 2, based on inhibition by heparin, increased 2.6-fold from g1 to s phase" SIGNOR-53861 BUB1 protein O43683 UNIPROT CDC20 protein Q12834 UNIPROT "down-regulates activity" phosphorylation Ser161 QKATPGSsRKTCRYI 9606 BTO:0000567 15525512 t llicata "Bub1 directly phosphorylates Cdc20 in vitro and inhibits the ubiquitin ligase activity of APC/C(Cdc20) catalytically. A Cdc20 mutant with all six Bub1 phosphorylation sites removed is refractory to Bub1-mediated phosphorylation and inhibition in vitro. " SIGNOR-250605 NDC1 protein Q9BTX1 UNIPROT NPC complex SIGNOR-C263 SIGNOR "form complex" binding 27016207 t lperfetto "The protein inventory of the NPC has been studied for a very diverse set of eukaryotes, including trypanosomes, fungi, plants, animals, and humans [4], [5], [6], [7], [8], [9]. In all cases, about 30 different Nups were found (Fig. 2)." SIGNOR-262073 ASH1L protein Q9NR48 UNIPROT H3C1 protein P68431 UNIPROT "up-regulates activity" trimethylation Lys37 APATGGVkKPHRYRP -1 21239497 t Gianni "We show that human ASH1L specifically methylates histone H3 Lys-36. Our data implicate that there may be a regulatory mechanism of ASH1L histone methyltransferases" SIGNOR-269055 MRGPRX2 protein Q96LB1 UNIPROT GNAL protein P38405 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-256930 "AP-2 complex" complex SIGNOR-C245 SIGNOR DAB2 protein P98082 UNIPROT "up-regulates activity" binding 9606 "BTO:0004784; BTO:0000567" 11247302 t Giorgia "Dab2 is alternatively spliced and its localization depends on a region of the protein that contains two DPF motifs that are present in the p96 Dab2 protein and absent in the p67 splice variant. This region is sufficient to confer Dab2 binding to the alpha‐adaptin subunit of the clathrin adaptor protein, AP‐2.|These findings suggest that in addition to previously reported signal-transduction functions, Dab2 could also act as an adaptor protein that may regulate protein trafficking." SIGNOR-260391 RPS6KA1 protein Q15418 UNIPROT ESR1 protein P03372 UNIPROT up-regulates phosphorylation Ser167 GGRERLAsTNDKGSM 9606 BTO:0000150 7838153 t gcesareni "Serine 167 is the major phosphorylation site on the human estrogen receptor. Phosphorylation is mediated by casein kinase ii." SIGNOR-34113 POLG protein P54098 UNIPROT "DNA polymerase gamma" complex SIGNOR-C378 SIGNOR "form complex" binding -1 19837034 t lperfetto "Here, we report a crystal structure of human DNA Pol gamma holoenzyme. The holoenzyme is a heterotrimer containing one Pol gammaA subunit and a dimeric Pol gammaB subunit." SIGNOR-265719 GSK3B protein P49841 UNIPROT GLI3 protein P10071 UNIPROT "down-regulates quantity by destabilization" phosphorylation 10090 16885213 t lperfetto "Gli2 and Gli3 (in vertebrates) are phosphorylated by protein kinase A and glycogen synthase kinase-3_ and are proteolytically processed" SIGNOR-148475 BCAR1 protein P56945 UNIPROT NAB2 protein Q15742 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000093 22431919 f miannu "In MCF-7 cells, we identified a positive feedback loop where p130(Cas) positively regulates EGR1 and NAB2, which in turn induce p130(Cas) expression." SIGNOR-253891 PCSK1 protein P29120 UNIPROT IAPP protein P10997 UNIPROT "up-regulates activity" cleavage Lys72 VGSNTYGkRNAVEVL -1 10931181 t lperfetto "The processing of proinsulin to insulin occurs in the secretory granules at the C-terminal end of pairs of basic amino acids, Arg31-Arg32 and Lys64-Arg65 [9,10]. Following cleavage, by the prohormone convertases, PC3 (also known as PC1) and PC2, the pair of basic amino acids are removed rapidly by carboxypeptidase E (CPE) to produce the mature insulin molecule" SIGNOR-261782 MAPK1 protein P28482 UNIPROT TNFRSF1A protein P19438 UNIPROT "down-regulates activity" phosphorylation Ser274 LAPNPSFsPTPGFTP -1 11606045 t lperfetto "Phosphorylation of murine CD120a by p42(mapk/erk2) has been shown to inhibit its ability to initiate apoptosis while preserving signaling events such as NF-kappaB activation.|Additionally, we demonstrated that (i) the p42(mapk/erk2)-dependent phosphorylation of CD120a and DR3 occurred on Ser and Thr residues, (ii) p42(mapk/erk2) phosphorylated residues located in the membrane proximal regions but not the death domains of CD120a and DR3, (iii) Ser 253 is a preferred site of phosphorylation on CD120a" SIGNOR-249452 EPAS1 protein Q99814 UNIPROT KDM7A protein Q6ZMT4 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 32938217 t SaraGualdi "To this end, we confirm that KDM3A, KDM4B, KDM4C, KDM5B, KDM5C, and KDM62 are direct targets of HIF-1a while extent the list of known targets to KDM2A, KDM2B, KDM4D, KDM5A, and KDM6A. The results demonstrated that majority of the KDMs were similarly induced (KDM2A, KDM2B, KDM3A, KDM4B, KDM4C, KDM4D, KDM5A, KDM5B, KDM5C, KDM6B, and KDM7A) or repressed (KDM NO66 and KDM1A) by both HIF-1a and HIF-2a." SIGNOR-271587 PTPRH protein Q9HD43 UNIPROT GHR protein P10912 UNIPROT "down-regulates activity" dephosphorylation 10029 BTO:0000246 12907755 t "Protein tyrosine phosphatases (PTPs) play key roles in switching off tyrosine phosphorylation cascades, such as initiated by cytokine receptors. We have used substrate-trapping mutants of a large set of PTPs to identify members of the PTP family that have substrate specificity for the phosphorylated human GH receptor (GHR) intracellular domain. Among 31 PTPs tested, T cell (TC)-PTP, PTP-beta, PTP1B, stomach cancer-associated PTP 1 (SAP-1), Pyst-2, Meg-2, and PTP-H1 showed specificity for phosphorylated GHR" SIGNOR-248802 KLHL21 protein Q9UJP4 UNIPROT AURKB protein Q96GD4 UNIPROT "up-regulates activity" binding 9606 BTO:0000567 19995937 t miannu "KLHL21 directly binds to Aurora B and mediates ubiquitination of Aurora B in vitro. In contrast to KLHL9 and KLHL13, KLHL21 localizes to midzone microtubules in anaphase and recruits Aurora B and Cul3 to this region. Together, our results suggest that different Cul3 adaptors nonredundantly regulate Aurora B during mitosis, possibly by ubiquitinating different pools of Aurora B at distinct subcellular localizations." SIGNOR-271848 RPS6KA3 protein P51812 UNIPROT HMGN2 protein P05204 UNIPROT "down-regulates activity" phosphorylation Ser25 KDEPQRRsARLSAKP 9606 BTO:0000567 11438671 t lperfetto "We report here that the NBD of the HMGN1 and -N2 protein family is highly and specifically phosphorylated during mitosis and that this phosphorylation has a major functional consequence: it abolishes the interaction of the proteins with its chromatin targets." SIGNOR-249102 AURKA protein O14965 UNIPROT KIF4A protein O95239 UNIPROT "up-regulates activity" phosphorylation Thr799 PPKLRRRtFSLTEVR -1 31881080 t miannu "We show that Aurora A phosphorylates the condensin I-dependent pool of KIF4A and thus actively promotes chromosome congression from the spindle poles to the metaphase plate. In vitro kinase assays showed that recombinant KIF4A can be phosphorylated by Aurora A and that this activity is inhibited by the specific Aurora A inhibitor MLN8537 (Fig. 7 C)." SIGNOR-265993 EEF1D protein P29692 UNIPROT "EEF1B complex" complex SIGNOR-C460 SIGNOR "form complex" binding 9606 23699257 t lperfetto "An inactive eEF1A-GDP moiety leaves the ribosome and must be recycled to eEF1A-GTP before binding another aa-tRNA. This GTP exchange process is the function of the nucleotide exchange factor eEF1B complex, which exchanges GDP for GTP to regenerate active eEF1A. The requirement for a guanine nucleotide exchange factor, the eEF1B complex, which in metazoans is composed of the subunits α, δ, and γ (also called eEF1B, eEF1D, and eEF1G, respectively)" SIGNOR-269392 HAND2 protein P61296 UNIPROT HAND2 protein P61296 UNIPROT "up-regulates activity" binding -1 11812799 t miannu "The basic helix-loop-helix factor, HAND2, functions as a transcriptional activator by binding to E-boxes as a heterodimer" SIGNOR-223476 3-(9-Fluoro-2-(piperidine-1-carbonyl)-1,2,3,4-tetrahydro-[1,4]diazepino[6,7,1-hi]indol-7-yl)-4-(imidazo[1,2-a]pyridin-3-yl)-1H-pyrrole-2,5-dione chemical CID:10029385 PUBCHEM GSK3B protein P49841 UNIPROT "down-regulates activity" "chemical inhibition" 9606 BTO:0000183 31562256 t miannu "Indeed, we demonstrated that the selective GSK3 inhibitor LY2090314 significantly reduced cell proliferation in control pancreatic cancer cell lines" SIGNOR-262539 PLCE1 protein Q9P212 UNIPROT HRAS protein P01112 UNIPROT up-regulates "guanine nucleotide exchange factor" 9606 11022047 t gcesareni "The presence of a rasgef motif in the n terminus of plcepsilon suggests that plcepsilon can activate ras by acting as an exchange factor by promoting the exchange of gtp for bound gdp." SIGNOR-82859 MRPL13 protein Q9BYD1 UNIPROT "39S mitochondrial large ribosomal subunit" complex SIGNOR-C285 SIGNOR "form complex" binding -1 25838379 t lperfetto "We have determined the structure of the intact mitoribosome to 3.5 angstrom resolution by single-particle electron cryo-microscopy. It reveals 80 extensively interconnected proteins, 36 of which are specific to mitochondria, and three rRNA molecules" SIGNOR-262380 levomilnacipran chemical CHEBI:136040 ChEBI SLC6A3 protein Q01959 UNIPROT "down-regulates activity" "chemical inhibition" 9606 BTO:0000007 18468895 t Luana "Studies on a series of milnacipran analogs containing a heteroaromatic group as potent norepinephrine and serotonin transporter inhibitors" SIGNOR-257944 PTPRA protein P18433 UNIPROT LYN protein P07948 UNIPROT "down-regulates activity" dephosphorylation Tyr397 RVIEDNEyTAREGAK 10116 15537644 t "We found that PTPα and SHP-1 both dephosphorylate Lyn exclusively at Tyr-397|Lyn expressed in CHO cells has a substantially higher specific activity than Lyn in RBL cells because of high levels of phosphorylation at its active site Tyr-397 (Fig. 1). Enhanced Lyn kinase activity in the CHO cells leads to spontaneous phosphorylation of multiple cellular proteins, including FcϵRI" SIGNOR-248436 selumetinib chemical CHEBI:90227 ChEBI MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR down-regulates "chemical inhibition" 9606 Other t Selleck lperfetto SIGNOR-244823 EZH2 protein Q15910 UNIPROT HOXA9 protein P31269 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 20565746 t miannu "These data support the proposed regulatory impact of particular PRC2-proteins in expression of HOXA9 and HOXA10 in NK/T-cells. In mammalian cells knockdown of PRC2 components EZH2 or PHF1 led to upregulated HOXA gene expression." SIGNOR-260068 CASP3 protein P42574 UNIPROT STK4 protein Q13043 UNIPROT "up-regulates activity" cleavage Asp349 RVASTMTdGANTMIE 9534 BTO:0004055 11517310 t lperfetto "In response to apoptotic stimuli, caspase cleavage of mst1 occurs at asp-326 and asp-349, resulting in the separation of its n-terminal kinase domain from the nes-containing c-terminal domain. Thus, caspase cleavage of mst1 serves two purposes: one is activation of mst1 kinase activity and the other is translocation of mst1 into the nucleus." SIGNOR-109878 NOTCH proteinfamily SIGNOR-PF30 SIGNOR Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates BTO:0001103 12361602 f apalma "Taken together, these results show that Notch-1 activity promotes myogenic cell proliferation and that attenuation of Notch-1 activity by its antagonist Numb causes cells to exit from the cell cycle, express MRFs, and undergo myogenic differentiation." SIGNOR-255376 CD79A protein P11912 UNIPROT BCR-Dl complex SIGNOR-C436 SIGNOR "form complex" binding 9606 BTO:0000776 32323266 t scontino "BCR consists of a pair of identical immunoglob- ulin heavy (IgH) and light (IgL) chains. though membrane BCR per se is not able to transduce downstream signaling, it does so by making BCR complex with CD79. The extracellular portion of the BCR is non-covalently coupled to a disulfide-linked heterodimer of the CD79A and CD79B. This association allows expression of BCR on the plasma membrane and BCR internalization after antigen recognition." SIGNOR-268200 MTOR protein P42345 UNIPROT RPS6KB1 protein P23443 UNIPROT "up-regulates activity" phosphorylation Thr412 NQVFLGFtYVAPSVL -1 SIGNOR-C3 10567431 t lperfetto "We report here that a mammalian recombinant p70alpha polypeptide, extracted in an inactive form from rapamycin-treated cells, can be directly phosphorylated by the mTOR kinase in vitro predominantly at the rapamycin-sensitive site Thr-412. mTOR-catalyzed p70alpha phosphorylation in vitro is accompanied by a substantial restoration in p70alpha kinase activity toward its physiologic substrate" SIGNOR-72357 IL17A protein Q16552 UNIPROT KLF2 protein Q9Y5W3 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 23332504 f fspada "Specifically, il-17 suppresses klf15, a pro-adipogenic tf, and enhances expression of klf2 and klf3, which are anti-adipogenic." SIGNOR-192477 SRC protein P12931 UNIPROT AP2B1 protein P63010 UNIPROT down-regulates phosphorylation Tyr737 THRQGHIyMEMNFTN 9606 18938240 t gcesareni "The phosphorylation of beta2-adaptin on tyrosine residue 737 (y737) negatively regulates its interaction with betaarrestin." SIGNOR-181743 RYK protein P34925 UNIPROT DVL2 protein O14641 UNIPROT up-regulates binding 9606 15454084 t gcesareni "Ryk also binds to dishevelled, through which it activates the canonical wnt, providing a link between wnt and dishevelled." SIGNOR-129571 CUDC-101 chemical CID:24756910 PUBCHEM EGFR protein P00533 UNIPROT "down-regulates activity" "chemical inhibition" -1 20143778 t miannu "By incorporating histone deacetylase (HDAC) inhibitory functionality into the pharmacophore of the epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (HER2) inhibitors, we synthesized a novel series of compounds with potent, multiacting HDAC, EGFR, and HER2 inhibition and identified 7-(4-(3-ethynylphenylamino)-7-methoxyquinazolin-6-yloxy)-N-hydroxyheptanamide 8 (CUDC-101) as a drug candidate, which is now in clinical development. 8 displays potent in vitro inhibitory activity against HDAC, EGFR, and HER2 with an IC(50) of 4.4, 2.4, and 15.7 nM, respectively." SIGNOR-262254 ADRB2 protein P07550 UNIPROT GNA14 protein O95837 UNIPROT "up-regulates activity" binding 9606 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257192 KIT protein P10721 UNIPROT SLA protein Q13239 UNIPROT "down-regulates activity" phosphorylation Tyr258 KKSISLMyGGSKRKS 9534 BTO:0001538 24284075 t miannu "Oncogenic c-Kit-D816V phosphorylates SLAP on residues Y120, Y258 and Y273. Mutation of the SLAP tyrosine phosphorylation sites rescues its activity" SIGNOR-263141 E2F4 protein Q16254 UNIPROT PPARG protein P37231 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 12110166 f fspada "We show here that e2f1 induces ppar gamma transcription during clonal expansion, whereas e2f4 represses pparg amma expression during terminal adipocyte differentiation" SIGNOR-90507 GSK3B protein P49841 UNIPROT TCAP protein O15273 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser157 GALRRSLsRSMSQEA 9606 32937135 t lperfetto "GSK-3beta phosphorylates FBXL21 and TCAP to activate FBXL21-mediated, phosphodegron-dependent TCAP degradation.|These results show direct GSK-3beta phosphorylation of TCAP S157 and FBXL21 T33 sites." SIGNOR-264852 PRRX1 protein P54821 UNIPROT MAFF protein Q9ULX9 UNIPROT "down-regulates activity" binding -1 11036080 t miannu "Hoxd12 and MHox, that interact with v-/c-Maf, using the phage display method. The Hox proteins also could associate with the other Maf protein family members, MafB, MafK, MafF, and MafG, but not with Jun and Fos. The Hox proteins negatively regulated the DNA binding, transactivation and cell-transforming abilities of Maf." SIGNOR-221890 CASP3 protein P42574 UNIPROT BAD protein Q92934 UNIPROT "up-regulates activity" cleavage 9606 BTO:0000938 15231831 t lperfetto "Casp3 cleaves bad at asp-61. In addition, caspases convert bad(l) into a pro-death fragment that resembles the short splice variant." SIGNOR-126727 TAF1 protein P21675 UNIPROT GTF2A1 protein P52655 UNIPROT up-regulates phosphorylation Ser321 LNSEDDVsDEEGQEL 9606 11278496 t llicata "Taf(ii) 250 phosphorylates human transcription factor iia on serine residues important for tbp binding and transcription activity." SIGNOR-105745 14-3-3 proteinfamily SIGNOR-PF7 SIGNOR RASSF1 protein Q9NS23 UNIPROT down-regulates binding 9606 21776416 t gcesareni "Basal inactivation of rassf1a is achieved by rassf1a self association and via 14-3-3 interactions (to isoforms s and e) at serine 175/178/179 of rassf1a." SIGNOR-175121 BMP7 protein P18075 UNIPROT ACVR2A protein P27037 UNIPROT up-regulates binding 9606 9748228 t fspada "We show that bmp7 and activin bind to the same type ii receptors, actrii and iib, but recruit distinct type i receptors into heteromeric receptor complexes" SIGNOR-60237 NR2F2 protein P24468 UNIPROT RXRA protein P19793 UNIPROT up-regulates binding 9606 10900149 t lperfetto "Arp-1/rxr, coup-tfi/rxr, and arp-1/coup-tfi heterodimers bound the fp330-3' site" SIGNOR-79446 BAIAP2 protein Q9UQB8 UNIPROT ENAH protein Q8N8S7 UNIPROT "up-regulates activity" binding 9606 BTO:0000452 11696321 t miannu "We conclude that the interaction of Cdc42 with the partial CRIB motif of IRSp53 relieves an intramolecular, autoinhibitory interaction with the N terminus, allowing the recruitment of Mena to the IRSp53 SH3 domain. This IRSp53:Mena complex initiates actin filament assembly into filopodia." SIGNOR-268423 SMAD3/SMAD4 complex SIGNOR-C9 SIGNOR AP1 complex SIGNOR-C154 SIGNOR "up-regulates activity" binding 9606 9732876 t lperfetto "Smad3 and smad4 also act together with c-jun and c-fos to activate transcription in response to tgf-beta, through a tgf-beta-inducible association of c-jun with smad3 and an interaction of smad3 and c-fos" SIGNOR-253332 AMPK complex SIGNOR-C15 SIGNOR RAF1 protein P04049 UNIPROT down-regulates phosphorylation Ser259 SQRQRSTsTPNVHMV 9606 11971957 t lperfetto "Mutation of serine 259 increased the basal raf-1 activity and rendered it largely resistant to inhibition by pka." SIGNOR-216523 "iron-sulfur cluster" smallmolecule CHEBI:30408 ChEBI "Mitochondrial respiratory chain complex III" complex SIGNOR-C279 SIGNOR "up-regulates activity" "chemical activation" 26083061 t lperfetto "Respiratory chain complexes I–III depend on Fe-S clusters for function" SIGNOR-262137 RET protein P07949 UNIPROT RET protein P07949 UNIPROT up-regulates phosphorylation Tyr1062 TWIENKLyGMSDPNW 9606 14711813 t lperfetto "Mass spectrometric analysis revealed that ret tyr806, tyr809, tyr900, tyr905, tyr981, tyr1062, tyr1090, and tyr1096 were autophosphorylation sitesret short and middle isoforms contain 16 tyrosine residues in their intracellular domains, and ret long isoforms have two additional tyrosines in the c-terminal tail. Among these tyrosines, tyr905, tyr1015, tyr1062, and tyr1096 are thought to be phosphorylated to become binding sites for grb7/grb10, phospholipase c_, shc/snt(frs2)/enigma, and grb2, respectively." SIGNOR-121141 INSR protein P06213 UNIPROT ADRB2 protein P07550 UNIPROT "down-regulates activity" phosphorylation Tyr350 RRSSLKAyGNGYSSN 10029 BTO:0000246 8557631 t "Insulin (10 nM)-stimulated rIR-catalyzed phosphorylation of β2-adrenergic receptor peptides was found prominently in peptides L339 (Tyr350 and Tyr354), T362 (Tyr364), and to a lesser extent peptides Y132 (Tyr132 and Tyr141), and I135 (Tyr141). G-protein-linked receptors and intrinsic tyrosine-kinase growth receptors represent two prominent modalities in cell signaling. Cross-regulation among members of both receptor superfamilies has been reported, including the counter-regulatory effects of insulin on β-adrenergic catecholamine action. Cells stimulated by insulin show loss of function and increased phosphotyrosine content of β2-adrenergic receptors." SIGNOR-251301 SIRT1 protein Q96EB6 UNIPROT PPARG protein P37231 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 21633182 t miannu "Interestingly, SIRT1 suppresses PPARγ but activates PGC-1α , and thus affects the clock network through multiple mechanisms." SIGNOR-268032 IRX1 protein P78414 UNIPROT ANPEP protein P15144 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 20440264 f Luana "We identified a number of target genes by global microarray analysis after IRX1 transfection combined with real-time PCR and chromatin immunoprecipitation assay.| Upregulation of PTGS2, ANPEP, KDR, UGT8, INHBA, ERMAP, RALGPS1 and SPON1 was confirmed." SIGNOR-261663 WNT7A protein O00755 UNIPROT FZD7 protein O75084 UNIPROT "up-regulates activity" binding 23290138 t "Simone Vumbaca" "Wnt7a-Fzd7 signaling stimulates symmetric stem cell divisions" SIGNOR-255646 CSF2 protein P04141 UNIPROT CSF3R protein Q99062 UNIPROT up-regulates binding 9606 BTO:0000130 16492764 t gcesareni "A g-csfr expression plasmid was introduced into interleukin-3 (il-3)-dependent mouse myeloid precursor fdc-p1 cells that normally do not respond to g-csf. G-csf stimulated proliferation of the transformants. These results suggested that the g-csfr, but not the il-3/gm-csf receptors, transduced the neutrophilic differentiation signal into cells" SIGNOR-144740 FABP6 protein P51161 UNIPROT "Fatty acid" stimulus SIGNOR-ST19 SIGNOR "up-regulates quantity" relocalization 9606 28457600 t miannu "Astrocytes and endothelial cells, two major components of the blood brain barrier, are the major contributors to the transportation of PUFAs from the circulation to brain. There are four classes of lipid transportation proteins involved in lipid synthesis and transportation in adult brain, including fatty acid translocase (FAT/CD36), caveolin-1, fatty acid binding proteins (FABPs) long chain acyl-coA synthase (ACS) and fatty acid transportation proteins (FATPs)." SIGNOR-264460 "MSL acetyltransferase" complex SIGNOR-C344 SIGNOR H2BC5 protein P58876 UNIPROT "down-regulates activity" monoubiquitination Lys35 KKRKRSRkESYSVYV 9606 21726816 t miannu "MSL1/2 ubiquitylates histone H2B on K 34. Importantly, only mono-ubiquitylation of H2B by MSL1/2 was detected in cells (data not shown), suggesting that MSL1/2, like RNF20/RNF40, was mainly a mono-ubiquitylase under physiological conditions.the MOF-MSL complex functions to promote both H4 K16ac and H2B K34ub. H2B K34ub, in turn, promotes H2B K120ub, H3 K4me3 and K79me2 to facilitate transcription elongation." SIGNOR-271985 CHUK protein O15111 UNIPROT RELA protein Q04206 UNIPROT "up-regulates activity" phosphorylation Ser536 SGDEDFSsIADMDFS 9606 BTO:0000876 SIGNOR-C14 SIGNOR-C13 15611276 t lperfetto "Our data suggest that the stimulation of nfkb by akt is dependent on the phosphorylation of p65 at s534, mediated by ikk (ikb kinase) alfa and beta." SIGNOR-132568 EDNRA protein P25101 UNIPROT GNAQ protein P50148 UNIPROT up-regulates binding 9606 BTO:0000887;BTO:0001260 15475516 t gcesareni "The response to endothelin-1 (et-1) consisted of two phases in both cell types. The initial, transient phase of contraction and phosphorylation of 20-kda myosin light chain (mlc20) was mediated additively by eta and etb receptors and initiated by galphaq-, ca2+/calmodulin-dependent activation of mlc kinase." SIGNOR-129817 MAPK3 protein P27361 UNIPROT BRAF protein P15056 UNIPROT down-regulates phosphorylation Thr753 YACASPKtPIQAGGY 9606 16508002 t gcesareni "Erk-induced phosphorylation of b-raf on t753 promoted the disassembly of raf heterodimers, and the mutation of t753 prolonged growth factor-induced heterodimerization. The b-raf t753a mutant enhanced differentiation of pc12 cells, which was previously shown to be dependent on sustained erk signaling. Site is critical for v-src dependent modulation of slk kinase activity." SIGNOR-144827 PPARG protein P37231 UNIPROT FABP4 protein P15090 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000975 8943212 f fspada "We report that insulin and a ppargamma ligand (thiazolidinedione (tzd)) stimulate in a synergistic manner the expression of an adipocyte-specific gene (ap2) in rat adipocytes and 3t3-l1 cells" SIGNOR-45294 CDK1 protein P06493 UNIPROT MASTL protein Q96GX5 UNIPROT "up-regulates activity" phosphorylation Thr207 PRQDYSRtPGQVLSL 8355 22354989 t gcesareni "We propose a model in which the initiating event for Gwl activation is phosphorylation by MPF of the proline-directed sites T193 and T206 in the presumptive activation loop" SIGNOR-249653 "Ionizing radiation" stimulus SIGNOR-ST16 SIGNOR ELE1-RET "fusion protein" SIGNOR-FP10 SIGNOR up-regulates 9606 23128507 f miannu "In PTC, genomic rearrangements juxtapose the RET tyrosine kinase domain to unrelated genes, thereby creating dominantly transforming oncogenes, denominated RET/PTC. The RET/PTC rearrangements are the 2nd most common genetic alteration described in PTC and observed in ∼13–43% of cases, mostly in pediatric cancers or in individuals exposed to ionizing radiation from nuclear accidents" SIGNOR-251984 CEBPB protein P17676 UNIPROT ABCB1 protein P08183 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000093 15044620 f miannu "C/EBPbeta activates the endogenous MDR1 gene of MCF-7 cells, and this activation was associated with a novel C/EBPbeta interaction region within the proximal MDR1 promoter (-128 to -75)." SIGNOR-253771 CCND3 protein P30281 UNIPROT Cell_cycle_exit phenotype SIGNOR-PH41 SIGNOR up-regulates 10090 BTO:0000165 21898542 f gcesareni "Our findings suggest that cyclin D3 primes myoblasts for differentiation by enhancing muscle specific gene expression and cell cycle exit" SIGNOR-241960 PTK7 protein Q13308 UNIPROT CTNNB1 protein P35222 UNIPROT down-regulates binding 9606 23151663 t gcesareni "Ptk7 has been strongly implicated in pcp and, like many pcp activators, is a negative regulator of beta-catenin-dependent wnt." SIGNOR-199536 AMPK complex SIGNOR-C15 SIGNOR FOXO proteinfamily SIGNOR-PF27 SIGNOR "up-regulates activity" phosphorylation Ser399 DNITLPPsQPSPTGG 9606 BTO:0000007 17711846 t gcesareni "Phosphorylation by AMPK leads to the activtion of FOXO3 transcriptional activity without affecting FOXO3 subcellular localization." SIGNOR-252880 MAPK8 protein P45983 UNIPROT ELK1 protein P19419 UNIPROT up-regulates phosphorylation Ser383 IHFWSTLsPIAPRSP 9606 8846788 t gcesareni "However, both of these stimuli strongly activate two other mapks, jnk1 and jnk2, and stimulate elk-1 transcriptional activity and phosphorylation jnk phosphorylation sites include ser383 and ser389, the major residues whose phosphorylation is responsible for enhancement of elk-1 trascriptional activity." SIGNOR-44356 PAK2 protein Q13177 UNIPROT RPS6 protein P62753 UNIPROT unknown phosphorylation Ser236 AKRRRLSsLRASTSK -1 1985906 t miannu "The synthetic peptide AKRRRLSSLRASTSKSESSQK (S6-21) which corresponds to the carboxyl-terminal 21 amino acids of human ribosomal protein S6 was synthesized and tested as a substrate for S6/H4 kinase purified from human placenta. The principal phosphorylation sites were serines in the acidic carboxyl-terminal domain of the peptide." SIGNOR-250232 KDM1A protein O60341 UNIPROT "CoREST-HDAC complex" complex SIGNOR-C105 SIGNOR "form complex" binding 9606 BTO:0000567 11171972 t miannu "Here we describe the components of a histone deacetylase (HDAC) complex that we term the CoREST-HDAC complex. CoREST Is a Component of an HDAC1/2 Complex. p40 is a Sox-like protein, p110b contains homology to polyamine oxidases, p110a is ZNF217, an eight-zinc finger protein, and p80 is a hypothetical protein of unknown function." SIGNOR-222121 CSNK2A2 protein P19784 UNIPROT WAS protein P42768 UNIPROT "up-regulates activity" phosphorylation Ser483 KRSRAIHsSDEGEDQ 9606 12769847 t llicata "We identify two phosphorylation sites in the VCA domain of WASP at serines 483 and 484. S483 and S484 are substrates for casein kinase 2 in vitro and in vivo. Phosphorylation of these residues increases the affinity of the VCA domain for the Arp2/3 complex 7-fold and is required for efficient in vitro actin polymerization by the full-length WASP molecule. " SIGNOR-251048 SLBP protein Q14493 UNIPROT H2AC14 protein Q99878 UNIPROT "up-regulates quantity by expression" "translation regulation" 9606 BTO:0001938 19155325 t lperfetto "Synthesis of mature histone mRNA requires only a single processing reaction: an endonucleolytic cleavage between a conserved stem-loop and a purine-rich downstream element to form the 3' end. The stem-loop binding protein (SLBP) is required for processing, and following processing, histone mRNA is transported to the cytoplasm, where SLBP participates in translation of the histone mRNA|We used radiolabeled probes generated by PCR targeting the open reading frame (ORF) to detect histones H2A, H2B, H3, H4, and H1 and used 7SK snRNA as a loading control (Fig. 2A). The abundance of histone H2A, H2B, H3, and H4 mRNAs is reduced to 37% to 70% of control levels in the SLBP knockdown cells when compared to the C2 control." SIGNOR-265404 CDK5 protein Q00535 UNIPROT AR protein P10275 UNIPROT up-regulates phosphorylation Ser83 QQQQQETsPRQQQQQ 9606 BTO:0001130 21799006 t gcesareni "Cdk5 enables phosphorylation of ar at ser-81 site through direct biochemical interaction and, therefore, results in the stabilization of ar proteins" SIGNOR-175696 APOA1 protein P02647 UNIPROT HDL_assembly phenotype SIGNOR-PH61 SIGNOR up-regulates 9606 23077142 f miannu "Cholesterol efflux is the first step in the formation of HDL, which is initiated through the action of ATP binding cassette transporter (ABC) A1 on apolipoprotein (apo) A-I that produces nascent HDL (nHDL)." SIGNOR-252110 PPM1D protein O15297 UNIPROT MAPK12 protein P53778 UNIPROT down-regulates dephosphorylation Thr183 RQADSEMtGYVVTRW 9606 15870257 t gcesareni "Ppm1d selectively inhibits p38 activation by dephosphorylating thr 180." SIGNOR-135976 PRKCA protein P17252 UNIPROT IL2RA protein P01589 UNIPROT unknown phosphorylation Thr271 RQRKSRRtI 9606 BTO:0000782 2303462 t lperfetto "The interleukin-2 (il-2) receptor, the leukocyte-specific membrane glycoprotein, t200, and the class i major histocompatibility antigens (hla) have been identified as substrates for protein kinase c from these studies, it was concluded that ser-247 is the major site of phosphorylation in the il-2 receptor and that thr-250 is a minor site." SIGNOR-22988 LPAR proteinfamily SIGNOR-PF2 SIGNOR GNAI1 protein P63096 UNIPROT up-regulates binding 9606 12393875 t "inferred from 70% family members" gcesareni "We conclude that lpa(1) receptors couple to a g(i)-phosphoinositide 3-kinase-tiam1 pathway to activate rac." SIGNOR-269964 ERRFI1 protein Q9UJM3 UNIPROT EGFR protein P00533 UNIPROT "down-regulates quantity by destabilization" binding 10090 BTO:0001867 20421427 t "We report here an additional mechanism of EGFR suppression mediated by RALT, demonstrating that RALT-bound EGF receptors undergo endocytosis and eventual degradation into lysosomes" SIGNOR-252073 APAF1 protein O14727 UNIPROT CASP9 protein P55211 UNIPROT "up-regulates activity" binding 9606 BTO:0000567 9390557 t lperfetto "Caspase-9 and Apaf-1 bind to each other via their respective NH2-terminal CED-3 homologous domains in the presence of cytochrome c and dATP, an event that leads to caspase-9 activation." SIGNOR-53576 MTR protein Q99707 UNIPROT homocysteine smallmolecule CHEBI:17230 ChEBI "down-regulates quantity" "chemical modification" 9606 10520212 t lperfetto "Methionine synthase is a vitamin B12-dependent enzyme that catalyses the remethylation of homocysteine to methionine. Therefore, defects in this enzyme may result in elevated homocysteine levels." SIGNOR-253142 TLN1 protein Q9Y490 UNIPROT "A5/b1 integrin" complex SIGNOR-C163 SIGNOR "up-regulates activity" binding 10090 BTO:0000132 19118207 t miannu "Over the past 10 years, the binding of talin to the cytoplasmic tail of integrin-β subunits has been established to have a key role in integrin activation. Binding of the phosphotyrosinebinding (PTB)-domain-like subdomain of the protein 4.1, ezrin, radixin, moesin (FERM) domain of talin to the conserved WxxxNP(I/L)Y motif of the β-integrin tail permits additional weaker interactions between talin and the membrane-proximal region of the tail that trigger integrin activation, probably through the disruption of inhibitory interactions between α- and β-subunit cytoplasmic tails." SIGNOR-257612 KEAP1 protein Q14145 UNIPROT NFE2L2 protein Q16236 UNIPROT "down-regulates quantity" ubiquitination 9606 31257023 t "Keap1 is a substrate receptor of a Cul3-RING ubiquitin ligase (CRL3) that, in physiological conditions, constitutively binds and targets Nrf2 for degradation" SIGNOR-259335 CDK2 protein P24941 UNIPROT RBL2 protein Q08999 UNIPROT unknown phosphorylation Ser952 DSRSHQNsPTELNKD 9606 BTO:0001938 11157749 t llicata "We now identify 22 in vivo phosphorylation sites of p130, targeted by diverse kinases, and present evidence for three cyclin-dependent kinase 4(6) [cdk4(6)] specific phosphorylations, which appear critical for controlling the growth-restraining activity of p130." SIGNOR-104691 "Cullin 1-RBX1-Skp1" complex SIGNOR-C529 SIGNOR GSTP1 protein P09211 UNIPROT "down-regulates quantity by destabilization" polyubiquitination 9606 BTO:0000675 31024008 t miannu "Here, we show that loss of FBX8 accelerates chemical-induced colon tumorigenesis. FBX8 directly targets GSTP1 for ubiquitin-mediated proteasome degradation in CRC." SIGNOR-272306 GlyR proteinfamily SIGNOR-PF62 SIGNOR chloride smallmolecule CHEBI:17996 ChEBI "up-regulates quantity" relocalization 9606 18721822 t miannu "The glycine receptor chloride channel (GlyR), a member of the pentameric Cys-loop ion channel receptor family, mediates inhibitory neurotransmission in the spinal cord, brainstem and retina." SIGNOR-264984 SMURF1 protein Q9HCE7 UNIPROT C9orf78 protein Q9NZ63 UNIPROT unknown ubiquitination -1 20804422 t miannu "Recombinant proteins were used to profile substrate ubiquitination by the Smurf1 ubiquitin ligase on a global scale using protein microarrays. T Proteins ubiquitinated on the protein microarray were confirmed as potential substrates of the Smurf1 activity using an off chip in vitro ubiquitination assay." SIGNOR-272674 SMURF1 protein Q9HCE7 UNIPROT ODF2 protein Q5BJF6 UNIPROT unknown ubiquitination -1 20804422 t miannu "Recombinant proteins were used to profile substrate ubiquitination by the Smurf1 ubiquitin ligase on a global scale using protein microarrays. T Proteins ubiquitinated on the protein microarray were confirmed as potential substrates of the Smurf1 activity using an off chip in vitro ubiquitination assay." SIGNOR-272683 SMURF1 protein Q9HCE7 UNIPROT UBXN6 protein Q9BZV1 UNIPROT unknown ubiquitination -1 20804422 t miannu "Recombinant proteins were used to profile substrate ubiquitination by the Smurf1 ubiquitin ligase on a global scale using protein microarrays. T Proteins ubiquitinated on the protein microarray were confirmed as potential substrates of the Smurf1 activity using an off chip in vitro ubiquitination assay." SIGNOR-272702 SYK protein P43405 UNIPROT LAX1 protein Q8IWV1 UNIPROT "up-regulates activity" phosphorylation Tyr193 SSEDSHDyVNVPTAE 9606 BTO:0000007 12359715 t miannu "Upon stimulation via the B or T cell receptors, LAX is rapidly phosphorylated by Src and Syk family tyrosine kinases and interacts with Grb2, Gads, and p85. " SIGNOR-273532 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR Macrophage_differentiation phenotype SIGNOR-PH99 SIGNOR up-regulates 9606 24890514 f apalma "The Erk1/2 pathway has a central role in CSF-1R-regulated myeloid differentiation. CSF-1 induces early (peaking at ‚àº5 min) and persistent (starting at 1 h) waves of MEK/Erk1/2 phosphorylation" SIGNOR-255573 rivaroxaban chemical CHEBI:68579 ChEBI F10 protein P00742 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-206550 MTA1 protein Q13330 UNIPROT CDH1 protein P12830 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0000812 18719363 f miannu "MTA1 overexpression resulted in downregulation of E-cadherin and MTA3 expression and enhanced expression of the transcriptional repressors SNAIL and SLUG." SIGNOR-254594 LCK protein P06239 UNIPROT ZAP70 protein P43403 UNIPROT "up-regulates activity" binding 9606 phosphorylation:Tyr319 TSVYESPySDPEELK 10318843 t lperfetto "Phosphopeptide encompassing the motif harboring tyr319, ysdp, interacted with lcksh2;tyr319-mediated binding of the sh2 domain of lck is crucial for zap-70 activation and consequently for the propagation of the signaling cascade leading to t-cell activation" SIGNOR-67443 CD3 complex SIGNOR-C432 SIGNOR NCK1 protein P16333 UNIPROT "up-regulates activity" relocalization 9606 12110186 t "We present strong evidence that ligand engagement of TCR-CD3 induces a conformational change that exposes a proline-rich sequence in CD3ϵ and results in recruitment of the adaptor protein Nck." SIGNOR-259935 PRKCB protein P05771 UNIPROT PA2G4 protein Q9UQ80 UNIPROT unknown phosphorylation Ser363 ALLQSSAsRKTQKKK 9606 BTO:0004737 11325528 t lperfetto "We found that Ebp1 was basally phosphorylated in AU565 breast cancer cells on serine/threonine residues and that this phosphorylation was enhanced by heregulin treatment. Both serine and threonine residues of a GST-Ebp1 fusion protein were phosphorylated by PKC in vitro. In vivo, we demonstrated that basal Ebp1 phosphorylation was dependent upon PKC." SIGNOR-249090 α-D-glucose smallmolecule CHEBI:17925 ChEBI Glycolysis phenotype SIGNOR-PH34 SIGNOR up-regulates 9606 23680095 t miannu "Glycolysis is a cytoplasmic non-oxidative reaction for glucose degradation that is composed of 9 pro cesses. A non-specific HK enzyme by using ATP phosphorylates glucose following entrance to the cell and converts it to G6P." SIGNOR-267959 TGFb proteinfamily SIGNOR-PF5 SIGNOR TGFBR2 protein P37173 UNIPROT "up-regulates activity" binding 9606 22326956 t miannu "TGF-beta signaling mediates a wide range of biological activities in development and disease. TGF-beta ligands signal through heterodimeric type I and type II receptors (TGF-beta receptor type I [TbetaRI, also known as ALK5 and TGFBR1] and TbetaRII) that are members of the serine/threonine kinase family." SIGNOR-256178 PRKACA protein P17612 UNIPROT ITGA4 protein P13612 UNIPROT "up-regulates activity" phosphorylation Ser1021 QEENRRDsWSYINSK 9606 BTO:0000782 11533025 t lperfetto "PKA phosphorylationin vitro blocks the binding of the alpha4 tail to paxillin. A mutation that mimics alpha4 phosphorylation disrupts paxillin binding and promotes cell spreading" SIGNOR-110119 PI3K complex SIGNOR-C156 SIGNOR IRS1 protein P35568 UNIPROT "down-regulates activity" 9606 11160134 f lperfetto "Ly294002 or wortmannin were used to determine whether pi 3-kinasedependent pathways mediate ser307 phosphorylation during insulin/igf-1 or TNF-alpha Stimulation. As expected, the pi-3 kinase inhibitors ly294002 or wortmannin inhibited activation of pkb/akt in insulin or igf-1 stimulated 3t3-l1 preadipocytes, but were without effect on erk1/2. these results suggest that elements of the pi 3-kinase cascade mediate insulin/igf-1stimulated phosphorylation of ser307" SIGNOR-252717 HDAC1 protein Q13547 UNIPROT GAD1 protein Q99259 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 19029285 f miannu "induction of the reelin and GAD67 mRNAs is accompanied by the dissociation of repressor complexes containing all three DNMTs, MeCP2, and HDAC1 from the corresponding promoters and by increased local histone acetylation." SIGNOR-254576 FOXO6 protein A8MYZ6 UNIPROT IDH1 protein O75874 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 25648147 t miannu "We identify FOXOs as transcriptional activators of IDH1. FOXOs promote IDH1 expression and thereby maintain the cytosolic levels of α-ketoglutarate and NADPH." SIGNOR-260092 PTPRE protein P23469 UNIPROT MAPK1 protein P28482 UNIPROT "down-regulates activity" dephosphorylation Tyr187 HTGFLTEyVATRWYR 9606 12754301 t llicata "The effect of PTP epsilon on ERKs is at least in part indirect because phosphorylation of the threonine residue in the ERK activation loop is reduced in the presence of PTP epsilon. Nonetheless, PTP epsilon is present in a molecular complex with ERK, providing PTP epsilon with opportunity to act on ERK proteins also directly. We conclude that PTP epsilon is a physiological inhibitor of ERK signaling|These enzymes are joined by the large family of dual-specificity phosphatases, which are structurally similar to tyrosine phosphatases but which can dephosphorylate both residues of the activation loop" SIGNOR-248448 "L-glutamine zwitterion" smallmolecule CHEBI:58359 ChEBI "carbamoyl phosphate(2-)" smallmolecule CHEBI:58228 ChEBI "up-regulates quantity" "precursor of" 9606 15096496 t "CPSase catalyzes the synthesis of carbamoyl phosphate from glutamine, bicarbonate, and two ATP molecules" SIGNOR-267191 EP300 protein Q09472 UNIPROT PLAGL2 protein Q9UPG8 UNIPROT up-regulates acetylation 9606 16207715 t miannu "Plag1 and plagl2 are also regulated by acetylation. They are acetylated and activated by p300 and deacetylated and repressed by hdac7." SIGNOR-140947 RPSA protein P08865 UNIPROT "40S cytosolic small ribosomal subunit" complex SIGNOR-C286 SIGNOR "form complex" binding -1 25901680 t lperfetto "Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins." SIGNOR-262414 TFIIH complex SIGNOR-C457 SIGNOR POLR2A protein P24928 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser1864 SPKYSPTsPKYSPTS 9606 14662762 t lperfetto "Although there is some inconsistency in the literature, it is generally thought that cdk7, a component of the transcription factor (tf) iih, is a major ser-5 kinase, whereas cdk9, a component of positive transcription elongation factor (p-tef) b, is a major ser-2 kinase within cells. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination." SIGNOR-269358 MYC protein P01106 UNIPROT HLA-C protein P10321 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0000848 8206526 f miannu "In melanoma, HLA class I expression is suppressed by overexpression of the c-myc oncogene." SIGNOR-254602 DAPK1 protein P53355 UNIPROT BECN1 protein Q14457 UNIPROT up-regulates phosphorylation Thr119 LSRRLKVtGDLFDIM 9606 BTO:0000007 19180116 t gcesareni "The activated form of DAPK triggers autophagy in a beclin-1-dependent manner. DAPK phosphorylates beclin 1 on Thr 119 located at a crucial position within its BH3 domain, and thus promotes the dissociation of beclin 1 from Bcl-XL and the induction of autophagy." SIGNOR-183548 NR3C1 protein P04150 UNIPROT NR3C2 protein P08235 UNIPROT up-regulates 9606 11154266 f lperfetto "These results indicate that functional interactions between the glucocorticoid and mineralocorticoid receptors in activating specific gene transcription are probably more complex than has been previously appreciated." SIGNOR-85987 DAPK3 protein O43293 UNIPROT MDM2 protein Q00987 UNIPROT "up-regulates quantity by stabilization" phosphorylation Ser166 SSRRRAIsETEENSD 9606 15001356 t gcesareni "Zip kinase was able to phosphorylate mdm2 at ser166, a site previously reported to be modified by akt kinase, thus demonstrating that zip kinase is a bona fide mdm2-binding protein." SIGNOR-123159 TLR4 protein O00206 UNIPROT p38 proteinfamily SIGNOR-PF16 SIGNOR "up-regulates activity" phosphorylation 9606 28137827 t miannu "Binding of S100A9 to TLR4 stimulates the phosphorylation of JNK, ERK1/2, and p38 MAPK, which leads to the activation of c-Jun, CREB, and NF-κB. Activation of neutrophils by S100A9 also proceeds via p38 MAPK, JNK, and ERK1/2 phosphorylation." SIGNOR-261928 "MSL acetyltransferase" complex SIGNOR-C344 SIGNOR H2BC3 protein P33778 UNIPROT "down-regulates activity" monoubiquitination Lys35 KKRKRSRkESYSIYV 9606 21726816 t miannu "MSL1/2 ubiquitylates histone H2B on K 34. Importantly, only mono-ubiquitylation of H2B by MSL1/2 was detected in cells (data not shown), suggesting that MSL1/2, like RNF20/RNF40, was mainly a mono-ubiquitylase under physiological conditions.the MOF-MSL complex functions to promote both H4 K16ac and H2B K34ub. H2B K34ub, in turn, promotes H2B K120ub, H3 K4me3 and K79me2 to facilitate transcription elongation." SIGNOR-271983 SHH protein Q15465 UNIPROT SMO protein Q99835 UNIPROT "up-regulates activity" 10090 16885213 f lperfetto "Binding of Hh to Ptch relieves the repression of Smo, allowing Smo to signal." SIGNOR-148481 SRC protein P12931 UNIPROT PTPN6 protein P29350 UNIPROT up-regulates phosphorylation Tyr536 QKGQESEyGNITYPP 9606 14699166 t llicata "Recombinant shp-1 had elevated activity subsequent to phosphorylation by src in vitro, and shp-1 variants with mutated phosphorylation sites in the c terminus, shp-1 y538f, and shp-1 y538f,y566f were less active toward src-generated phosphoproteins in intact cells." SIGNOR-120488 FST protein P19883 UNIPROT INHBA protein P08476 UNIPROT "down-regulates activity" binding 9606 22037168 t gcesareni "Blocking activin action by pre-treatment with its binding protein, follistatin, modifies the inflammatory cytokine cascade, and reduces the severity of the subsequent inflammatory response and mortality" SIGNOR-235134 terbutaline chemical CHEBI:9449 ChEBI ADRB2 protein P07550 UNIPROT "up-regulates activity" "chemical activation" 10030 20590599 t Luana "Of the agonists studied here, there was a general trend that those with highest intrinsic efficacy were so across all three receptor subtypes (i.e. at the top of Tables 3–5, e.g. fenoterol, terbutaline, metaproterenol and adrenaline)" SIGNOR-257872 PTPN2 protein P17706 UNIPROT STAT1 protein P42224 UNIPROT "down-regulates activity" dephosphorylation Tyr701 DGPKGTGyIKTELIS 9606 12138178 t "Upon interferon (IFN) stimulation, Stat1 becomes tyrosine phosphorylated and translocates into the nucleus, where it binds to DNA to activate transcription. The activity of Stat1 is dependent on tyrosine phosphorylation, and its inactivation in the nucleus is accomplished by a previously unknown protein tyrosine phosphatase (PTP). We have now purified a Stat1 PTP activity from HeLa cell nuclear extract and identified it as TC45, the nuclear isoform of the T-cell PTP (TC-PTP)." SIGNOR-248402 "Cullin 3-RBX1-Skp1" complex SIGNOR-C526 SIGNOR ULK1 protein O75385 UNIPROT "down-regulates quantity by destabilization" polyubiquitination 9606 BTO:0000007 26687681 t miannu "Cul3-KLHL20 Ubiquitin Ligase Governs the Turnover of ULK1 and VPS34 Complexes to Control Autophagy Termination. KLHL20 promotes ubiquitination of phagophore-residing VPS34 and Beclin-1" SIGNOR-272417 CHEK1 protein O14757 UNIPROT TP53 protein P04637 UNIPROT "up-regulates activity" phosphorylation Ser15 PSVEPPLsQETFSDL 9606 BTO:0001321 15659650 t lperfetto "CHK1 and CHK2 phosphorylate the p53 N terminus at Ser15, Thr18, Ser20, and Ser37" SIGNOR-217791 CAPN1 protein P07384 UNIPROT GSK3A protein P49840 UNIPROT "up-regulates activity" cleavage 9606 BTO:0000590 25969760 t lperfetto "Thus, it has been shown that calpain cleaves the inhibitory domain of GSK3 generating two fragments of 40 and 30 kDa. This cleavage enhanced activity of the kinase" SIGNOR-251585 SPAG9 protein O60271 UNIPROT MAPK11 protein Q15759 UNIPROT up-regulates binding 9606 BTO:0000222 17074887 t "p38 MAPK is activated by phosphorylation in response to CDO-BOC interactions. Activated p38 MAPK may translocate into the nucleus to further activate myogenic related transcription factors." gcesareni "Cdo, jlp, and p38alpha/beta form complexes in differentiating myoblasts, and cdo and jlp cooperate to enhance levels of active p38alpha/beta in transfectants." SIGNOR-150147 SRCAP protein Q6ZRS2 UNIPROT KLK3 protein P07288 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0003160 20432434 f miannu "ShRNA mediated knockdown of SRCAP resulted in decreased H2A.Z binding at the enhancer region of the PSA promoter and decreased expression of PSA in prostate cancer cells." SIGNOR-255220 PTPRG protein P23470 UNIPROT ABL1 protein P00519 UNIPROT "down-regulates activity" dephosphorylation Tyr413 TAPESLAyNKFSIKS -1 25624455 t miannu "PTPRG activation by the P1-WD peptide affected the tyrosine phosphorylation of several signaling molecules. Data analysis identified 31 molecules whose phosphorylation was modified in a statistically significant manner (Table I). inhibition of ABL1, BMX, BTK, DAB1, ITGB1, JAK2, KDR, KIT, LIMK1, MET, PDGFRB, SHC1, and VCL correlates with tyrosine dephosphorylation. In contrast, SRC inhibition correlates with hyperphosphorylation of the inhibitory Tyr530 residue and with dephosphorylation of the activatory Tyr419. Moreover, CDK2 and CTTN inhibition correlates with a hyperphosphorylation of the inhibitory Tyr15 and Tyr470, respectively. In contrast, a subgroup of 13 proteins, including BLNK, DOK2, ERBB2, GRIN2B, INSR, PDGFRA, PRKCD, PXN, STAT1, STAT2, STAT3, STAT5A, and ZAP70, appears to be activated by PTPRG activity." SIGNOR-254691 CBP/p300 complex SIGNOR-C6 SIGNOR MEF2C protein Q06413 UNIPROT up-regulates binding 9606 11062529 t gcesareni "Cbp/p300 and pcaf are coactivators for myod and mef-2c during myogenic commitment and differentiation" SIGNOR-83840 "trichostatin A" chemical CHEBI:46024 ChEBI HDAC6 protein Q9UBN7 UNIPROT "down-regulates activity" "chemical inhibition" -1 20139990 t Luana "Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1)." SIGNOR-258018 HTR2B protein P41595 UNIPROT GNAI3 protein P08754 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-256886 SMO protein Q99835 UNIPROT GNG2 protein P59768 UNIPROT up-regulates binding 9606 16885213 t gcesareni "Consistent with its predicted topology, smo couples to a specific family of inhibitory g protein (gis) to regulate hh signaling." SIGNOR-148595 MK-8245 chemical CID:24988881 PUBCHEM SCD protein O00767 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-194420 RPS6KA5 protein O75582 UNIPROT ATF1 protein P18846 UNIPROT "up-regulates activity" phosphorylation Ser63 GILARRPsYRKILKD 9606 12414794 t lperfetto "We find that activation of the c-jun promoter through the atf1 site requires phosphorylation of atf1 at serine 63. atf1 can be phosphorylated by mitogen- and stress-activated protein kinase 1 (msk1), which is activated by egf and erk1/2." SIGNOR-95318 3-[4-[4-[2-[3-[(dimethylamino)methyl]phenyl]-1H-pyrrolo[2,3-b]pyridin-4-yl]-1-ethyl-3-pyrazolyl]phenyl]-1,1-dimethylurea chemical CHEBI:91362 ChEBI AURKC protein Q9UQB9 UNIPROT "down-regulates activity" "chemical inhibition" 9606 BTO:0001109;BTO:0000018 19567821 t miannu "The protein kinases, Aurora A, B, and C have critical roles in the regulation of mitosis and are frequently overexpressed or amplified in human tumors. GSK1070916, is a novel ATP competitive inhibitor that is highly potent and selective for Aurora B/C kinases." SIGNOR-262226 1-methyl-5-[[2-[5-(trifluoromethyl)-1H-imidazol-2-yl]-4-pyridinyl]oxy]-N-[4-(trifluoromethyl)phenyl]-2-benzimidazolamine chemical CHEBI:91451 ChEBI BRAF protein P15056 UNIPROT "down-regulates activity" "chemical inhibition" -1 22037378 t Luana "Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here." SIGNOR-258097 TGFB1 protein P01137 UNIPROT KRT1 protein P04264 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 16258965 f Regulation miannu "TGFβ1 and TGFβ2 induce loss of epithelial morphology, cytokeratin, and membrane-associated Zonula Occludens-1 and increase the smooth muscle markers calponin and caldesmon" SIGNOR-251884 NUAK1 protein O60285 UNIPROT CASP6 protein P55212 UNIPROT "down-regulates activity" phosphorylation Ser257 TLVNRKVsQRRVDFC -1 15273717 t miannu "ARK5 negatively regulates procaspase-6 by phosphorylation at Ser257, leading to resistance to the FasL/Fas system." SIGNOR-250209 FOXA1 protein P55317 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR up-regulates 9606 19127412 f miannu "Overexpression of foxa1 promoted apoptosis" SIGNOR-183153 4-[6-[4-(1-piperazinyl)phenyl]-3-pyrazolo[1,5-a]pyrimidinyl]quinoline chemical CHEBI:91387 ChEBI ACVR1 protein Q04771 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-193639 GSK3B protein P49841 UNIPROT ZNF322 protein Q6U7Q0 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser391 SEKGLELsPPHASEA 9606 BTO:0002552 28581525 t lperfetto "CK1delta and GSK3beta kinases sequentially phosphorylate ZNF322A at serine-396 and then serine-391. Moreover, the doubly phosphorylated ZNF322A protein creates a destruction motif for the ubiquitin ligase FBXW7alpha leading to ZNF322A protein destruction." SIGNOR-264891 RPS6KA5 protein O75582 UNIPROT H3-4 protein Q16695 UNIPROT unknown phosphorylation Ser11 TKQTARKsTGGKAPR 10090 12773393 t "Ser 11 phosphorylation of H3 is either activatory and inhibitory as promotes DNA condensation (activatory) and induce transcription (inhibitory)." lperfetto "The results presented here show that MSK2 and, to a lesser extent, MSK1 are the major protein kinases required for the phosphorylation of histone H3 at both Ser10 and Ser28" SIGNOR-249213 S100A9 protein P06702 UNIPROT "Calprotectin complex" complex SIGNOR-C293 SIGNOR "form complex" binding 9867828 t "Using the two-hybrid system we analyzed the dimerization of MRP8 (S100A8) and MRP14 (S100A9), two S100 proteins expressed in myeloid cells. It is reported that the MRP8-MRP14 heteromer is the clearly preferred complex in both man and mouse." SIGNOR-262828 MBL2 protein P11226 UNIPROT MASP2 protein O00187 UNIPROT "up-regulates activity" binding 9606 9087411 t lperfetto "The results (Fig. 3A) show that the anti-MBL antibody, in addition to binding MBL captures both MASP-1 and MASP-2|Our results emphasize the similarity between complement activation through the MBL, or 'MBLectin' pathway of the innate immune system and the classical pathway of complement activation (Fig. 5)." SIGNOR-263415 ELANE protein P08246 UNIPROT AGT protein P01019 UNIPROT "up-regulates activity" cleavage Phe41 DRVYIHPfHLVIHNE -1 11747312 t miannu "Cathepsin G, elastase, and proteinase 3 are serine proteinases released by activated neutrophils. Cathepsin G can cleave angiotensinogen to release angiotensin II, but this activity has not been previously reported for elastase or proteinase 3. In this study we show that elastase and proteinase 3 can release angiotensin I from angiotensinogen and release angiotensin II from angiotensin I and angiotensinogen." SIGNOR-256313 JAK1 protein P23458 UNIPROT IRS1 protein P35568 UNIPROT "up-regulates activity" phosphorylation 10090 BTO:0002882 9305869 t "Janus kinase-dependent activation of insulin receptor substrate 1" SIGNOR-251343 ERG protein P11308 UNIPROT VIM protein P08670 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000093;BTO:0000815 8895512 f miannu "Our results suggest that PEA3 specifically transactivates vimentin promoter through PEA3 site. Among members of the ETS transcription factor family only Erg showed ability to transactivate vimentin promoter besides PEA3." SIGNOR-254069 Viral_replication stimulus SIGNOR-ST23 SIGNOR Viral_dsRNA stimulus SIGNOR-ST21 SIGNOR up-regulates 9606 31226023 f miannu "Double-stranded RNA (dsRNA), a common intermediate during the replication of DNA and RNA viruses." SIGNOR-260587 PDHX protein O00330 UNIPROT PDH complex SIGNOR-C402 SIGNOR "form complex" binding 9606 20160912 t miannu "The human (h) pyruvate dehydrogenase complex (hPDC) consists of multiple copies of several components: pyruvate dehydrogenase (E1), dihydrolipoamide acetyltransferase (E2), dihydrolipoamide dehydrogenase (E3), E3-binding protein (BP), and specific kinases and phosphatases. Mammalian PDC has a well organized structure with an icosahedral symmetry of the central E2/BP core to which the other component proteins bind non-covalently." SIGNOR-266543 TIGIT protein Q495A1 UNIPROT ARRB2 protein P32121 UNIPROT "up-regulates activity" binding 9606 BTO:0000914 24817116 t lperfetto "With TIGIT/PVR engagement, cytoplasmic TIGIT was phosphorylated at Tyr-225 and Tyr-231 residues. Phosphorylated Tyr-225 recruits adaptor protein beta arrestin 2|TIGIT/PVR signaling mediates suppression of IFN- gamma production via the NF-kappaB pathway. We identified a new adaptor β-arrestin 2 that associates with phosphorylated TIGIT and mediates recruitment of inositol phosphatase SHIP1 through the ITT-like motif (Fig. 7). Finally, SHIP1 impairs TRAF6 autoubiquitination to abolish NF-kappaB activation, leading to inhibition of IFN- gamma production in NK cells." SIGNOR-261482 ESR1 protein P03372 UNIPROT SCN11A protein Q9UI33 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 10090 BTO:0000938 BTO:0001264 22169964 f miannu "17β-Estradiol regulates the gene expression of voltage-gated sodium channels. . In this study, we investigate the mRNA expressions of Nav channel subtypes mediated differentially by the ERs in the DRGs of wild-type (WT) and estrogen receptor knockout (αERKO and βERKO) mice. In the present study, by means of quantitative real-time PCR, we found that the expressions of Nav1.1, Nav1.7, Nav1.8, and Nav1.9 subtypes were elevated in αERKO and βERKO mice" SIGNOR-253471 TRIM24 protein O15164 UNIPROT AR protein P10275 UNIPROT up-regulates binding 9606 BTO:0001130 19909775 t miannu "We found that trim24/transcriptional intermediary factor 1alpha (tif1alpha), which is known as a ligand-dependent nuclear receptor co-regulator, interacts with ar and enhances transcriptional activity of ar" SIGNOR-189113 FZR1 protein Q9UM11 UNIPROT APC-c complex SIGNOR-C150 SIGNOR "up-regulates activity" binding 16896351 t lperfetto "In addition to E2 enzymes, APC/C activity is also strictly dependent on one of several co-activator proteins that associate with APC/C during specific periods of the cell cycle. The best studied of these are Cdc20 and Cdh1" SIGNOR-252015 CyclinE/CDK2 complex SIGNOR-C16 SIGNOR SF3B1 protein O75533 UNIPROT up-regulates phosphorylation Thr248 GSETPGAtPGSKIWD 9606 12105215 t lperfetto "To map the set of phosphorylation sites in sap155-(223-322) that determine its interaction with nipp1, we have identified phosphorylation sites of cyclin e-cdk2 by the sequencing of proteolytically derived phosphopeptides. Three phosphorylation sites were identified as thr244, thr248, and thr313" SIGNOR-216666 PDK1 protein Q15118 UNIPROT PKN2 protein Q16513 UNIPROT "up-regulates activity" phosphorylation Thr816 GYGDRTStFCGTPEF 9606 BTO:0000007 10753910 t miannu "PDK1 phosphorylates the PRKs at their conserved activation loop threonines (Thr-774 and Thr-816 for PRK1 and PRK2, respectively) both in vitro and in vivo." SIGNOR-250265 LCK protein P06239 UNIPROT CD3 complex SIGNOR-C432 SIGNOR "up-regulates activity" phosphorylation 9606 8626561 t "The binding of Lck to the tyrosine-phosphorylated zeta chain of the TcR would serve to strengthen the interaction of the associated CD4 and the TcR complex, leading to increased avidity for the antigen-major histocompatibility protein complex" SIGNOR-252305 ADRB1 protein P08588 UNIPROT GNAS protein Q5JWF2 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-256758 diazepam chemical CHEBI:49575 ChEBI "GABA-A (a5-b1-g2) receptor" complex SIGNOR-C335 SIGNOR "up-regulates activity" "chemical activation" 9606 BTO:0000227 18790874 t brain lperfetto "The traditional BZ site agonists (GABA-enhancing CNS depressants such as diazepam) are active on the GABAA-Rs containing a gamma2 subunit (Pritchett et al., 1989), a beta subunit, and one of the alpha subunits, alpha1, 2, 3, or 5." SIGNOR-263799 ID1 protein P41134 UNIPROT TCF4 protein P15884 UNIPROT "down-regulates activity" binding 10090 BTO:0004058 SIGNOR-C129 9242638 t 2 miannu "All three Ids bound with high affinity to E proteins .Each Id was able to disrupt the ability of E protein-MyoD complexes to transactivate from a muscle creatine kinase reporter construct in vivo." SIGNOR-241385 PRKAA2 protein P54646 UNIPROT PPP1R12C protein Q9BZL4 UNIPROT down-regulates phosphorylation Ser452 AGLQRSAsSSWLEGT 9606 SIGNOR-C15 22137581 t lperfetto "Ampk-induced phosphorylation is necessary for ppp1r12c interaction with 14-3-3 and phosphorylation of myosin regulatory light chain. Both ampk activity and ppp1r12c phosphorylation are increased in mitotic cells and are important for mitosis completion. The interaction between ppp1r12c and 14-3-3_ may inactivate the ppp1r12c-containing phosphatase complex in vivo." SIGNOR-195148 trametinib chemical CHEBI:75998 ChEBI MAP2K2 protein P36507 UNIPROT "down-regulates activity" "chemical inhibition" 9606 26347206 t miannu "Trametinib (Mekinist™) is a reversible and highly selective allosteric inhibitor of MEK1 and MEK2 with anticancer activity against metastatic melanoma carrying the BRAF V600 mutation." SIGNOR-259448 AML1-ETO "fusion protein" SIGNOR-FP1 SIGNOR hsa-mir-223 mirna URS000037EC34_9606 RNAcentral "down-regulates quantity by repression" "transcriptional regulation" 10090 25477897 t miannu "The three miR-29 family members in mouse bone marrow cells reduced the level of TET2 as well as its metabolic by-product, 5hmC" SIGNOR-255797 P2RY14 protein Q15391 UNIPROT GNAI3 protein P08754 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-256866 PPP5C protein P53041 UNIPROT NR3C1 protein P04150 UNIPROT "down-regulates activity" dephosphorylation Ser211 PGKETNEsPWRSDLL 9606 BTO:0000093 19586900 t "Estrogen inhibits glucocorticoid action via protein phosphatase 5 (PP5)-mediated glucocorticoid receptor dephosphorylation.|Inhibition of GR phosphorylation at Ser-211 is associated with decreased nuclear retention of GR and decreased gene transcription." SIGNOR-248538 CDK4 protein P11802 UNIPROT RB1 protein P06400 UNIPROT down-regulates phosphorylation Ser811 IYISPLKsPYKISEG 9606 15809340 t gcesareni "Phosphorylated by cdk6 and cdk4, and subsequently by cdk2 at ser-567 in g1, thereby releasing e2f1 which is then able to activate cell growth. Here we show that although these cdks phosphorylate multiple residues in prb, they do so with different residue selectivities in vitro;thr821 and thr826 are preferentially phosphorylated by cdk6 and cdk4, respectively." SIGNOR-135185 ILK protein Q13418 UNIPROT PPP1R14B protein Q96C90 UNIPROT "up-regulates activity" phosphorylation Thr57 VRRQGKVtVKYDRKE -1 12144526 t lperfetto "We conclude that ILK may activate smooth-muscle contraction both directly, via phosphorylation of myosin, and indirectly, via phosphorylation and activation of CPI-17 and PHI-1, leading to inhibition of MLCP.|CPI-17 and PHI-1 thiophosphorylated by ILK at Thr(38) or Thr(57) respectively inhibited myosin light-chain phosphatase (MLCP) activity bound to myosin" SIGNOR-265741 ACSS3 protein Q9H6R3 UNIPROT acetyl-CoA(4-) smallmolecule CHEBI:57288 ChEBI "up-regulates quantity" "chemical modification" 10843999 t lperfetto "The gene encodes acetyl-CoA synthetase (ACS), the cytosolic enzyme that activates acetate so that it can be used for lipid synthesis or for energy generation. |The recombinant enzyme produced acetyl-CoA from acetate in a reaction that required ATP." SIGNOR-271832 CLK1 protein P49759 UNIPROT RBM17 protein Q96I25 UNIPROT "up-regulates activity" phosphorylation Ser291 EKDASKKsDSNPLTE 9534 23519612 t miannu "In this work, we show that Cdc2-like kinase 1 (Clk1) phosphorylates SPF45 on eight serine residues." SIGNOR-262710 gemfibrozil chemical CHEBI:5296 ChEBI PPARA protein Q07869 UNIPROT "up-regulates activity" "chemical activation" 9606 21889235 t Luana " The combination of stilbene scaffold and gemfibrozil enhances the PPARα agonistic activity." SIGNOR-258318 PPP4C protein P60510 UNIPROT NDEL1 protein Q9GZM8 UNIPROT "down-regulates activity" dephosphorylation Thr219 ASLSLPAtPVGKGTE 9606 18347064 t "Protein phosphatase 4 catalytic subunit regulates Cdk1 activity and microtubule organization via NDEL1 dephosphorylation|PP4c selectively dephosphorylates NDEL1 at Cdk1 sites. We also demonstrate that PP4c negatively regulates Cdk1 activity at the centrosome.|We next examined the ability of PP4c to dephosphorylate a Cdk1 phosphorylation site, phospho-T219" SIGNOR-248550 CFLAR protein O15519 UNIPROT CASP8 protein Q14790 UNIPROT "down-regulates activity" binding 9606 9794838 t amattioni "Flip can be incorporated into the disc complex and blocks processing and activation of pro-caspase8" SIGNOR-61122 MMP1 protein P03956 UNIPROT COL3A1 protein P02461 UNIPROT "down-regulates quantity by destabilization" cleavage Gly774 IGPPGPAgQPGDKGE -1 17318226 t lperfetto "In vitro, MMP1 initiates degradation of native fibrillar collagens, crucial components of vertebrate extracellular matrix (ECM), by cleaving the peptide bond between Gly775–Ile776 or Gly775–Lys776 in native type I, II or III collagen molecules3,4. " SIGNOR-272339 DOLK protein Q9UPQ8 UNIPROT "dolichyl beta-D-mannosyl phosphate" smallmolecule CHEBI:17624 ChEBI "up-regulates quantity" "chemical modification" -1 16923818 t lperfetto "Dolichol kinase (DK) catalyzes the CTP-dependent phosphorylation of dolichol in the biosynthesis de novo and possibly the recycling of dolichyl monophosphate in yeast and mammals." SIGNOR-262567 GATA3 protein P23771 UNIPROT GATA3 protein P23771 UNIPROT up-regulates 9606 16386358 t "Experimental data indeed supports the existence of a positive circuit involvingGATA-3 that excludes IL-4 and STAT-6, specifically in mouse cells" SIGNOR-254297 "eribulin mesylate" chemical CHEBI:70710 ChEBI TUBA4A protein P68366 UNIPROT "down-regulates activity" "chemical inhibition" 9606 16940412 t miannu "The complex marine natural product halichondrin B was compared with NSC 707389 (E7389), a structurally simplified, synthetic macrocyclic ketone analog, which has been selected for clinical trials in human patients. NSC 707389 was invariably more potent than halichondrin B in its interactions with tubulin. Both compounds inhibited tubulin assembly, inhibited nucleotide exchange on beta-tubulin, and were noncompetitive inhibitors of the binding of radiolabeled vinblastine and dolastatin 10 to tubulin." SIGNOR-259344 HSPA8 protein P11142 UNIPROT CFTR protein P13569 UNIPROT "down-regulates quantity" binding 9606 BTO:0000007 21148293 t miannu "JB12 cooperates with cytosolic Hsc70 and the ubiquitin ligase RMA1 to target CFTR and CFTRΔF508 for degradation. JB12 drives Hsc70 to associate with CFTR and the RMA1 E3 complex" SIGNOR-271492 axitinib chemical CHEBI:66910 ChEBI KIT protein P10721 UNIPROT down-regulates "chemical inhibition" 9606 BTO:0000150 21297102 t gcesareni "The inhibitory effect of four tkis (axitinib, imatinib, masitinib, and vatalanib) for proliferation and phosphorylation of c-kit receptor as well as the expression and function of abcb1 were investigated in three cmct cell lines (hrmc, vimc1, and cmmc1)." SIGNOR-171866 PRKCA protein P17252 UNIPROT ADRA1B protein P35368 UNIPROT "down-regulates activity" phosphorylation Ser412 DSLDDSGsCLSGSQR 9534 BTO:0000298 9353340 t lperfetto " Phorbol ester-induced phosphorylation of the Ser394 and Ser400 as well as GRK2-mediated phosphorylation of the Ser404, Ser408, and Ser410, resulted in the desensitization of alpha1BAR-mediated inositol phosphate response. " SIGNOR-248989 FLT3 protein P36888 UNIPROT FLT3 protein P36888 UNIPROT unknown phosphorylation Tyr955 ADAEEAMyQNVDGRV 10090 BTO:0001516 16627759 t lperfetto "In vitro mapping of FLT3 autophosphorylation sites|Tryptic peptides covering more than 80% of the FLT3 kinase domain were recovered, and 5 tyrosine residues (Y591, Y726, Y842, Y955, and Y969) within this region were phosphorylated." SIGNOR-271923 PTPN2 protein P17706 UNIPROT STAT3 protein P40763 UNIPROT down-regulates dephosphorylation Tyr705 DPGSAAPyLKTKFIC 9606 12138178 t gcesareni "The nuclear isoform of protein-tyrosine phosphatase tc-ptp regulates interleukin-6-mediated signaling pathway through stat3 dephosphorylation." SIGNOR-90818 D-threo-isocitrate(3-) smallmolecule CHEBI:15562 ChEBI IDH1 protein O75874 UNIPROT "up-regulates activity" "chemical activation" 9606 32943735 t "Wild-type IDH1 and IDH2 catalyze the reaction by converting isocitrate and NADP+ into α-KG and CO2 with the concomitant generation of NADPH in the cytosol and mitochondrial matrix" SIGNOR-267369 IL11 protein P20809 UNIPROT IL11RA protein Q14626 UNIPROT up-regulates binding 9606 10948192 t gcesareni "Il-11 has been shown to induce gp130-dependent signaling through the formation of a high affinity complex with the il-11 receptor (il-11r) and gp130" SIGNOR-81102 BRCA1 protein P38398 UNIPROT FANCD2 protein Q9BXW9 UNIPROT "up-regulates activity" ubiquitination 9606 BTO:0003323 SIGNOR-C297 12485996 t lperfetto "The major genetic evidence supporting ubiquitin ligase function for BRCA1 in vivo comes from studies on the FANCD2 protein. Whereas in wild‐type cells the FANCD2 protein co‐localizes with BRCA1 in nuclear foci and becomes monoubiquitylated in response to DNA damage, HCC1937 cells, which encode a mutated form of BRCA1, are largely defective for both monoubiquitylation of FANCD2 and foci formation" SIGNOR-263236 CSNK2A1 protein P68400 UNIPROT IL16 protein Q14005 UNIPROT "up-regulates activity" phosphorylation Ser743 MPLQPNAsLNEEEGT -1 12450396 t llicata "We now show that N-terminal to the NLS domain of pro-IL-16 are protein kinase CK2 substrate and cdc2 kinase substrate sites which, along with the NLS, constitute a dual phosphorylation-regulated CcN motif which regulates nuclear localization of pro-IL-16. In addition, we demonstrate that mutation of either site is associated with impairment of the N-terminal domain's ability to induce G(0)/G(1) cell cycle arrest. | Thus, we confirm that the N-terminal (42SLNEE46) sequence of pro-IL-16 is in fact a site for protein kinase CK2 phosphorylation." SIGNOR-250905 CDK2 protein P24941 UNIPROT ESR1 protein P03372 UNIPROT up-regulates phosphorylation Ser106 PLNSVSPsPLMLLHP 9606 SIGNOR-C83 10428798 t gcesareni "Within er af-1, serines 104, 106, and 118 represent potential cdk phosphorylation sites, and in this current study, we ascertain their importance in mediating cyclin a-cdk2-dependent enhancement of er transcriptional activity." SIGNOR-69714 SCF-SKP2 complex SIGNOR-C136 SIGNOR CDKN1B protein P46527 UNIPROT "down-regulates quantity by destabilization" ubiquitination 9606 BTO:0000567 phosphorylation:Thr187 NAGSVEQtPKKPGLR 10559916 t lperfetto "SKP2 is required for ubiquitin-mediated degradation of the CDK inhibitor p27|We conclude that the stable interaction of p27 with SKP2 is highly specific and dependent upon phosphorylation of p27 on T187." SIGNOR-267557 MAP3K1 protein Q13233 UNIPROT MAP2K4 protein P45985 UNIPROT "up-regulates activity" phosphorylation 9606 9712898 t lperfetto "The gck-ctd-mekk1 interaction is sufficiently stable to support mekk1 s phosphorylation of its substrate, SEK1" SIGNOR-236376 PRKCA protein P17252 UNIPROT SPAG1 protein Q07617 UNIPROT unknown phosphorylation Ser326 VERDLKNsEAASETQ -1 11517287 t lperfetto "In-vitro incubation with [_-32P]ATP showed that HSD-3.8 protein can be phosphorylated by PKC. The phosphate is probably linked to the serine residue presenting the sequence X LysXX SerX." SIGNOR-249109 "Histone H3" proteinfamily SIGNOR-PF69 SIGNOR Nucleosome complex SIGNOR-C371 SIGNOR "form complex" binding -1 21812398 t lperfetto "The elemental repeating unit of chromatin is the nucleosome core particle (NCP), which consists of 146 base pairs of DNA wrapped in 1.65 left-handed superhelical turns around the histone octamer. The histone octamer comprises two each of the core histones, H2A, H2B, H3 and H4, which form two H2A/H2B dimers and an H3/H4 tetramer, respectively, in the NCP." SIGNOR-265308 ALDH9A1 protein P49189 UNIPROT 4-(trimethylammonio)butanoate smallmolecule CHEBI:16244 ChEBI "up-regulates quantity" "chemical modification" 9606 11802770 t miannu "Aldolytic cleavage of HTML yields 4-trimethylaminobutyraldehyde (TMABA) and glycine, a reaction catalysed by HTML aldolase (HTMLA; EC 4.1.2.‘X’). Dehydrogenation of TMABA by TMABA dehydrogenase (TMABA-DH; EC 1.2.1.47) results in the formation of 4-Ntrimethylaminobutyrate (butyrobetaine)." SIGNOR-269693 PRKCD protein Q05655 UNIPROT ENOX2 protein Q16206 UNIPROT up-regulates phosphorylation Ser504 ENLKEKEsCASRLCA 9606 22659163 t lperfetto "Tnox is phosphorylated by protein kinase c_ (pkc_) both in vitro and in vivo. Replacement of serine-504 with alanine significantly reduces phosphorylation by pkc_. C. overexpression of the s504a tnox mutant leads to diminished cell proliferation and migration, reflecting reduced stability of the unphosphorylatable tnox mutant protein." SIGNOR-197706 PRKCA protein P17252 UNIPROT GRM5 protein P41594 UNIPROT "up-regulates activity" phosphorylation Thr841 RSAFTTStVVRMHVG -1 15894802 t lperfetto "Thus, we showed that it is phosphorylation of Ser-839, not Thr-840, that is absolutely required for the unique Ca2+ oscillations produced by mGluR5 activation. The Thr-840 residue is important only in that it is permissive for the PKC-dependent phosphorylation of Ser-839." SIGNOR-249285 CEP350 protein Q5VT06 UNIPROT FGFR1OP/CEP350 complex SIGNOR-C52 SIGNOR "form complex" binding 9606 16314388 t miannu "Here we show that cap350 and fop (fgfr1 oncogene partner) form a centrosomal complex required for mt anchoring." SIGNOR-142355 formestane chemical CHEBI:75172 ChEBI CYP19A1 protein P11511 UNIPROT "down-regulates activity" "chemical inhibition" -1 7083195 t miannu "Recently, it was discovered that 4-hydroxy-4-androstene-3,17-dione, 4-androstene-3,6,17-trione, and 1,4,6-androstatriene-3,17-dione, compounds previously reported to be competitive inhibitors of aromatase, cause a time-dependent loss of aromatase activity in human placental microsomes." SIGNOR-258407 HRH2 protein P25021 UNIPROT GNAS protein Q5JWF2 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-256777 F-actin_assembly phenotype SIGNOR-PH18 SIGNOR LATS1 protein O95835 UNIPROT down-regulates 9606 23450633 f gcesareni "Ga12/13 recruitment of rho-gefs causes rhoa activation and f-actin assembly, which promotes lats1/lat2 inactivation by an unknown, but myosin-independent mechanism." SIGNOR-201522 CCNK protein O75909 UNIPROT CyclinK/CDK13 complex SIGNOR-C38 SIGNOR "form complex" binding 9606 22012619 t miannu "We identified a 70-kda cyclin k (cyck) that binds cdk12 and cdk13 to form two different complexes (cyck/cdk12 or cyck/cdk13) in human cells" SIGNOR-176786 Cullin4-RBX1-DDB1 complex SIGNOR-C119 SIGNOR MAGEA6 protein P43360 UNIPROT "down-regulates quantity by destabilization" polyubiquitination 9606 BTO:0002806 31267705 t miannu " The CRL4‐DCAF12 E3 ubiquitin ligase degrades MAGE‐A3/6" SIGNOR-272266 PRKCA protein P17252 UNIPROT CFTR protein P13569 UNIPROT "up-regulates activity" phosphorylation Ser686 WTETKKQsFKQTGEF -1 1377674 t lperfetto "Direct amino acid sequencing and peptide mapping of CF-2 revealed that serines 660, 700, 737, and 813 as well as serine 768, serine 795, or both were phosphorylated by PKA and PKG, and serines 686 and 790 were phosphorylated by PKC." SIGNOR-248849 PTPRG protein P23470 UNIPROT PTK2 protein Q05397 UNIPROT "down-regulates activity" dephosphorylation Tyr861 PIGNQHIyQPVGKPD -1 25624455 t miannu "PTPRG activation by the P1-WD peptide affected the tyrosine phosphorylation of several signaling molecules. Data analysis identified 31 molecules whose phosphorylation was modified in a statistically significant manner (Table I). inhibition of ABL1, BMX, BTK, DAB1, ITGB1, JAK2, KDR, KIT, LIMK1, MET, PDGFRB, SHC1, and VCL correlates with tyrosine dephosphorylation. In contrast, SRC inhibition correlates with hyperphosphorylation of the inhibitory Tyr530 residue and with dephosphorylation of the activatory Tyr419. Moreover, CDK2 and CTTN inhibition correlates with a hyperphosphorylation of the inhibitory Tyr15 and Tyr470, respectively. In contrast, a subgroup of 13 proteins, including BLNK, DOK2, ERBB2, GRIN2B, INSR, PDGFRA, PRKCD, PXN, STAT1, STAT2, STAT3, STAT5A, and ZAP70, appears to be activated by PTPRG activity." SIGNOR-254720 BMP15 protein O95972 UNIPROT BMPR1A/1B/2 complex SIGNOR-C29 SIGNOR up-regulates binding 9606 BTO:0000975 16446785 t lperfetto "Here we have performed a detailed in situ hybridization analysis of the spatial and temporal expression patterns of the bmp ligands (bmp-2, -3, -3b, -4, -6, -7, -15), receptors (bmpr-ia, -ib, -ii), and bmp antagonist, follistatin, in rat ovaries over the normal estrous cycle." SIGNOR-217538 CSNK2A2 protein P19784 UNIPROT CCAR2 protein Q8N163 UNIPROT "up-regulates activity" phosphorylation Thr454 AAEAAPPtQEAQGET 9606 24962073 t lperfetto "CK2alphawas bound to DBC1 and phosphorylated DBC1. The phosphorylation of DBC1 by CK2alphawas evidenced by co-immunoprecipitation of CK2alphaand DBC1 in a GST pull-down assay, an in vitro kinase assay, and immunofluorescence staining. |In our results, CK2alpha affected the|These results suggest that DBC1 may be involved in the progression of gastric carcinoma by inducing the EMT and that it is closely associated with CK2alpha-mediated phosphorylation of DBC1. phosphorylation of Thr454 on DBC1" SIGNOR-267667 "LINC complex" complex SIGNOR-C303 SIGNOR "TTM complex" complex SIGNOR-C305 SIGNOR "up-regulates activity" relocalization 30718482 t lperfetto "Together, we conclude that both the TTM complex and SUN1 (the LINC complex) contribute to the stable telomere–NE association." SIGNOR-263305 4'-epidoxorubicin chemical CHEBI:47898 ChEBI TOP2A protein P11388 UNIPROT "down-regulates activity" "chemical inhibition" 9606 BTO:0002058 17639997 t miannu "The combinatory use of low concentrations of SM with low-toxic topoisomerase II inhibitor epirubicin accelerated apoptotic cell death." SIGNOR-259282 CDK12 protein Q9NYV4 UNIPROT PAK2 protein Q13177 UNIPROT "up-regulates activity" phosphorylation Thr134 LKFYDSNtVKQKYLS 9606 BTO:0004828 32483448 t lperfetto "Mechanistically, CDK12 directly binds to and phosphorylates PAK2 at T134/T169 to activate MAPK signaling pathway" SIGNOR-273109 ERBB4 protein Q15303 UNIPROT CBL protein P22681 UNIPROT up-regulates binding 9606 16829981 t gcesareni "Erbb4 might not be able to directly recruit cbl, and therefore downregulation of this receptor is slow." SIGNOR-147841 MAPK3 protein P27361 UNIPROT SP1 protein P08047 UNIPROT up-regulates phosphorylation Ser59 GGQESQPsPLALLAA 9606 19318349 t gcesareni "PKCalpha, which was activated in senescent cells by ROS strongly activated Erk1/2, and the SA-pErk1/2 in turn phosphorylated Sp1 on Ser(59). Sp1-enhanced transcription of p21(Sdi1) resulted in regulation of cellular senescence in primary human diploid fibroblast cells." SIGNOR-248079 MAP3K7 protein O43318 UNIPROT IKK-complex complex SIGNOR-C14 SIGNOR "up-regulates activity" phosphorylation 9606 21232017 t lperfetto "Tak1 become activated and then phosphorilates and activates ikk2 whic in turn now phosphorylates ikba, marking it for k48-ubiquitination and proteasomal degradation." SIGNOR-209759 CDC42 protein P60953 UNIPROT USP6 protein P35125 UNIPROT up-regulates relocalization 9606 12612085 t miannu "In quiescent cells, tre17 is localized to intracellular filamentous and punctate structures in the cytoplasm, folded in an inactive conformation. Upon growth factor addition, cdc42 and rac1 become activated and recruit tre17 to the plasma membrane. Stable membrane localization of tre17 also requires polymerized actin. This recruitment process leads to a conformational change in tre17, such that the n-terminal portion of the molecule further stimulates the accumulation of cortical actin." SIGNOR-98935 MC4R protein P32245 UNIPROT GNAI3 protein P08754 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257182 FRZB protein Q92765 UNIPROT WNT1 protein P04628 UNIPROT down-regulates binding 9606 BTO:0000671 9326585 t gcesareni "We and others demonstrated that fzb-1 blocks wnt-1 and xwnt-8 signaling in xenopus embryos," SIGNOR-51762 RPS6KA5 protein O75582 UNIPROT H3C1 protein P68431 UNIPROT "down-regulates activity" phosphorylation Ser11 TKQTARKsTGGKAPR 9606 10464286 t "Ser 11 phosphorylation of H3 is either activatory and inhibitory as promotes DNA condensation (activatory) and induce transcription (inhibitory)." gcesareni "Phosphorylation at ser-11 (h3s10ph) by rps6ka4 and rps6ka5 is important during interphase because it enables the transcription of genes following external stimulation, like mitogens, stress, growth factors or uv irradiation and result in the activation of genes, such as c-fos and c-jun." SIGNOR-70444 GDNF protein P39905 UNIPROT GFRA1 protein P56159 UNIPROT up-regulates binding 9606 BTO:0000938 BTO:0000142 9182803 t gcesareni "A receptor complex comprised of trnr1 (gdnfr alpha) and ret was recently identified and found to be capable of mediating both gdnf and ntn signaling" SIGNOR-49091 SMAD1/5/8/SMAD4 complex SIGNOR-C215 SIGNOR RUNX2 protein Q13950 UNIPROT "up-regulates activity" binding 9606 BTO:0000567 15573378 t ggiuliani "The Runx2 WT and deletion constructs (1 √¢‚Ǩ‚Äú495, 1√¢‚Ǩ‚Äú464, and 1√¢‚Ǩ‚Äú432) all physically interact with the BMP2 responsive Smad 1" SIGNOR-255834 TBX3 protein O15119 UNIPROT CDKN1A protein P38936 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0002267 25211658 t lperfetto "TBX2 and TBX3 function as transcriptional repressors and both have been shown to inhibit myogenesis (Carlson et al, 2002; Zhu et al, 2014). Abnormal expression of TBX2 has been reported in several cancers including breast, pancreas, and melanoma, where it has been shown to drive proliferation (reviewed in Abrahams et al (2010)). As has been previously shown in other cell types, TBX2 was found to induce a downregulation of p14/19ARF and function as a direct repressor of p21 in RMS" SIGNOR-249602 AURKA protein O14965 UNIPROT PARD3 protein Q8TEW0 UNIPROT up-regulates phosphorylation Ser962 SSRSGREsVSTASDQ 9606 BTO:0000938 19812038 t llicata "Aurora a interacts directly with the atypical protein kinase c binding domain of par3 and phosphorylates it at serine 962. The phosphorylation of par3 at serine 962 contributes to its function in the establishment of neuronal polarity." SIGNOR-188398 GNAQ protein P50148 UNIPROT ARHGEF12 protein Q9NZN5 UNIPROT "up-regulates activity" binding 10090 BTO:0000944 12024019 t "Leukemia-associated Rho guanine nucleotide exchange factor promotes G alpha q-coupled activation of RhoA." SIGNOR-256520 "Immunoglobulin mu heavy chain" protein P0DOX6 UNIPROT BCR-Mk complex SIGNOR-C433 SIGNOR "form complex" binding 9606 BTO:0000776 32323265 t scontino "An antibody is composed of two identical HCs and two identical LCs (either kappa or lambda ), consisting of variable (V) and constant (C) regions linked by disulfide bonds. Pro- genitor B cells rearrange their Ig heavy chain (HC) genes to differentiate into precursor B (pre- B) cells that express μ HCs." SIGNOR-268187 940929-33-9 chemical CID:49867937 PUBCHEM KIF11 protein P52732 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-206724 HACD proteinfamily SIGNOR-PF86 SIGNOR FASN protein P49327 UNIPROT "up-regulates activity" "chemical activation" 9606 18554506 t "Very long-chain fatty acids are produced through a four-step cycle. However, the 3-hydroxyacyl-CoA dehydratase catalyzing the third step in mammals has remained unidentified. Mammals have four candidates, HACD1-4, based on sequence similarities to the recently identified yeast Phs1, although HACD3 and HACD4 share relatively weak similarity. We demonstrate that all four of these human proteins are indeed 3-hydroxyacyl-CoA dehydratases," SIGNOR-267764 GSK3B protein P49841 UNIPROT GLI2 protein P10070 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser820 VSSAYTVsRRSSGIS 9606 BTO:0000007 16611981 t lperfetto "The degradation of Gli2 requires the phosphorylation of a cluster of numerous serine residues in its carboxyl terminus by protein kinase A and subsequently by casein kinase 1 and glycogen synthase kinase 3." SIGNOR-148472 L-tryptophan smallmolecule CHEBI:16828 ChEBI 5-hydroxy-L-tryptophan smallmolecule CHEBI:17780 ChEBI "up-regulates quantity" "precursor of" 9606 31024440 t brain lperfetto "In serotonergic neurons Trp serves as the precursor for 5-HT. The 5-HT metabolic pathway is initiated by Trp being hydroxylated to the intermediate 5-hydroxytryptophan (5-HTP), which is subsequently decarboxylated to become 5-HT|Thus, the rate limiting step in the biosynthesis of 5-HT is the hydroxylation of Trp which is catalyzed by the enzyme tryptophan hydroxylase (TPH) (Figure 1). This enzyme is specific for 5-HT producing cells, however, it is present in two different isoforms, TPH1 and TPH2 [reviewed in (22, 23)]." SIGNOR-264184 KAT6A/KAT6B complex SIGNOR-C54 SIGNOR TP53 protein P04637 UNIPROT up-regulates acetylation Lys382 QSTSRHKkLMFKTEG 9606 BTO:0001271 23431171 t lperfetto "We show here that moz is an acetyltransferase of p53 at k120 and k382 and colocalizes with p53 in promyelocytic leukemia (pml) nuclear bodies following cellular stress. The moz-pml-p53 interaction enhances moz-mediated acetylation of p53, and this ternary complex enhances p53-dependent p21 expression" SIGNOR-217198 GNG12 protein Q9UBI6 UNIPROT PLCE1 protein Q9P212 UNIPROT up-regulates binding 9606 17251915 t gcesareni "In the non-canonical wntpathway, frizzled uses galfaq or galfai and gbetagamma dimers to activate phospholipase c (plc), resulting in protein kinase c (pkc) activation and calcium mobilization that regulates the transcription factor nfat, and frizzled also signals through the small gtpases rho and rac to c-jun n-terminal kinase (jnk), which activates the ap1 transcription factor" SIGNOR-152612 PP1 proteinfamily SIGNOR-PF54 SIGNOR CFTR protein P13569 UNIPROT "up-regulates activity" dephosphorylation 10090 BTO:0000988 21317537 t lperfetto "WNK kinases acted as scaffolds to recruit SPAK, which phosphorylated CFTR and NBCe1-B, reducing their cell surface expression. IRBIT opposed the effects of WNKs and SPAK by recruiting PP1 to the complex to dephosphorylate CFTR and NBCe1-B, restoring their cell surface expression," SIGNOR-264646 CDK11A protein Q9UQ88 UNIPROT SPDEF protein O95238 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser238 SEESWTDsEVDSSCS 9606 BTO:0000007 26885618 t lperfetto "In this study we provide evidence that the cell cycle kinase CDK11p58, a protein involved in G2/M transition and degradation of several transcription factors, directly interacts with and phosphorylates SPDEF on serine residues|Western blot analysis demonstrated that only one of the mutant constructs, consisting of mutations of serine 238, 242 and 243, resulted in increased levels of SPDEF protein expression as compared to wild type SPDEF, leading to subsequent ubiquitination and degradation of SPDEF through the proteasome pathway.|" SIGNOR-273020 TEK protein Q02763 UNIPROT TEK protein Q02763 UNIPROT "down-regulates activity" phosphorylation Tyr897 GACEHRGyLYLAIEY -1 11080633 t lperfetto "The Tie2 nucleotide binding loop is in an inhibitory conformation, which is not seen in other kinase structures, while its activation loop adopts an activated-like conformation in the absence of phosphorylation. Tyr-897, located in the N-terminal domain, may negatively regulate the activity of Tie2 by preventing dimerization of the kinase domains or by recruiting phosphatases when it is phosphorylated." SIGNOR-246662 2-(6,7-dimethoxy-4-quinazolinyl)-5-(2-pyridinyl)-1,2,4-triazol-3-amine chemical CHEBI:91330 ChEBI ATM protein Q13315 UNIPROT "down-regulates activity" "chemical inhibition" -1 18794134 t Gianni "A targeted compound library was screened for potential inhibitors of the ATM kinase, and CP466722 was identified." SIGNOR-261975 CDK2 protein P24941 UNIPROT PRKAR1A protein P10644 UNIPROT up-regulates phosphorylation Ser83 DSREDEIsPPPPNPV 9606 SIGNOR-C16 16582606 t gcesareni "In this context, we have identified rialpha as a novel substrate for the g(1)/s-cyclin-dependent kinase, cdk2/cyclin e, and found that rialpha is specifically phosphorylated at the serine residue." SIGNOR-145577 SIK2 protein Q9H0K1 UNIPROT CEP250 protein Q9BV73 UNIPROT down-regulates phosphorylation Ser2392 AGLHHSLsHSLLAVA 9606 20708153 t lperfetto "Here, we show that the salt inducible kinase 2 (sik2) localizes at the centrosome, plays a key role in the initiation of mitosis, and regulates the localization of the centrosome linker protein, c-nap1, through s2392 phosphorylation" SIGNOR-167488 TFAP4 protein Q01664 UNIPROT SALL2 protein Q9Y467 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000452 21228219 f miannu "The transcription factor AP4 increases along with SALL2 in quiescent cells and positively regulates SALL2 expression." SIGNOR-255426 DNMT1 protein P26358 UNIPROT RELN protein P78509 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 19029285 f miannu "induction of the reelin and GAD67 mRNAs is accompanied by the dissociation of repressor complexes containing all three DNMTs, MeCP2, and HDAC1 from the corresponding promoters and by increased local histone acetylation." SIGNOR-254575 MAPK9 protein P45984 UNIPROT CTNNB1 protein P35222 UNIPROT up-regulates phosphorylation Ser191 SRHAIMRsPQMVSAI 9606 18423204 t amattioni "Beta-catenin, upon entering the nucleus, in turn activates transcription of downstream target genes. Jnk2 phosphorylates Beta-catenin on critical residues (ser191 and ser605). Jnk activity is required for Beta-catenin nuclear localization in response to wnt." SIGNOR-178258 VXJPSOQJNUZHDN-YJFQKBDPSA-N smallmolecule CID:118708139 PUBCHEM NMUR1 protein Q9HB89 UNIPROT "up-regulates activity" "chemical activation" 9606 BTO:0002524 31160049 t "Ligand-GPCR dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257591 SLC1A1 protein P43005 UNIPROT "glutamic acid" smallmolecule CHEBI:18237 ChEBI "up-regulates quantity" relocalization 9606 26687113 t miannu "After release from presynaptic nerve terminals, glutamate is quickly removed from the synaptic cleft by a family of five glutamate transporters, the so-called excitatory amino acid transporters (EAAT1-5)." SIGNOR-264804 TFIIH complex SIGNOR-C457 SIGNOR Nucleotide-excision_repair phenotype SIGNOR-PH209 SIGNOR up-regulates 9606 30860024 f lperfetto "Transcription factor IIH (TFIIH) is a heterodecameric protein complex critical for transcription initiation by RNA polymerase II and nucleotide excision DNA repair." SIGNOR-269322 SP1 protein P08047 UNIPROT HGF protein P14210 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 9223667 t lperfetto "Furthermore, in transient cotransfection assays, overexpression of Sp1 and/or Sp3 stimulated HGF promoter activity independently and additively through binding to the Sp1 binding site in the HGF gene promoter region." SIGNOR-251739 ketoprofen chemical CHEBI:6128 ChEBI PTGS1 protein P23219 UNIPROT "down-regulates activity" "chemical inhibition" 9606 BTO:0001061 18667313 t Luana "Profens, that is, Ketoprofen 1, Suprofen 2 (Fig. 1), were chosen because of their interesting inhibitory activity against cyclooxygenase and of their different selectivity versus the two isoforms COX-1/COX-2. " SIGNOR-257810 DUSP4 protein Q13115 UNIPROT MAPK9 protein P45984 UNIPROT down-regulates dephosphorylation 9606 BTO:0000782 8626452 t fstefani "We assayed the relative ability of mkp-2, pac1, and mkp-1 to dephosphorylate erk2 and the other related map kinases, jnk2 and p38. . Mkp-2 had detectable activity against jnk2, although full inactivation of jnk2 was not observed even at the higher phosphatase concentration." SIGNOR-40929 MAPK9 protein P45984 UNIPROT SH3BP5 protein O60239 UNIPROT unknown phosphorylation Ser351 PGSLDLPsPVSLSEF -1 15158451 t miannu "we have identified serine 321 as the major site of phosphorylation by both SAPK3 and JNK2. SAPK3 but not JNK2 also phosphorylates serine 391" SIGNOR-250142 RPL27A protein P46776 UNIPROT "60S cytosolic large ribosomal subunit" complex SIGNOR-C287 SIGNOR "form complex" binding -1 25901680 t lperfetto "Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins." SIGNOR-262473 KIT protein P10721 UNIPROT SRC_kinase_family proteinfamily SIGNOR-PF32 SIGNOR up-regulates phosphorylation 9606 15526160 t apalma "Binding of SCF to c-Kit leads to a rapid increase in SFK kinase activity" SIGNOR-254995 AKT proteinfamily SIGNOR-PF24 SIGNOR HK1 protein P19367 UNIPROT up-regulates binding 9606 16892082 t gcesareni "The glucose dependence of the antiapoptotic effects of growth factors and akt plus a strong correlation between akt-regulated mitochondrial hexokinase association and apoptotic susceptibility suggest a major role for hexokinases in these effects." SIGNOR-148675 JUN protein P05412 UNIPROT AP1 complex SIGNOR-C154 SIGNOR "form complex" binding -1 2467839 t irozzo "The protein products of the fos (Fos) and jun (Jun) proto-oncogenes have been shown to associate with a DNA element known as the transcription factor activator protein-1 (AP-1) binding site. Jun (previously known as the Fos-binding protein p39) and Fos form a protein complex in the nucleus. These data demonstrate a cooperative interaction between the protein products of two proto-oncogenes with a DNA element involved in transcriptional regulation." SIGNOR-256361 CHEK2 protein O96017 UNIPROT AATF protein Q9NY61 UNIPROT "up-regulates quantity by stabilization" phosphorylation Ser477 ELIERKTsSLDPNDQ 9606 BTO:0001109 17157788 t lperfetto "Three putative Chk2 phosphorylation sites (Stevens et al., 2003) are present in Che-1 at resides Ser141, Ser474, and Ser508. Thus, we performed in vitro Chk2 kinase assays utilizing the GST-Che-1 fusion peptides spanning these residues as substrates.| Taken together, these results indicate that Chk2 phosphorylates Che-1 and this phosphorylation contributes to increase Che-1 stability." SIGNOR-264417 GSK3B protein P49841 UNIPROT LGALS3 protein P17931 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 21821001 f miannu "Our study also showed that a number of K562 cells survived despite the apoptotic stimuli. Within these surviving cells, galectin-3 was upregulated through newly synthesized protein. Notably, inducible galectin-3, which stabilized the pro-survival Bcl-2 family proteins Mcl-1, Bcl-xL, and Bcl-2, was essential for anti-apoptosis. Unpredictably, GSK-3β was critical for inducible galectin-3 expression as well as for cell survival. As summarized in Fig. 4C, we not only found inducible galectin-3 has an anti-apoptotic effect, but we also identified a GSK-3β-regulated mechanism for apoptotic resistance in K562 cells." SIGNOR-261903 MAPK14 protein Q16539 UNIPROT MAX protein P61244 UNIPROT down-regulates phosphorylation 9606 7479834 t gcesareni "Mxi2 phosphorylates max both in vitro and in vivo. Phosphorylation by mxi2 may affect the ability of max to oligomerize with itself and its partners, bind dna, or regulate gene expression." SIGNOR-26511 SPI1 protein P17947 UNIPROT ACP5 protein P13686 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 11481336 f miannu "The combination of MITF and PU.1 synergistically activated the TRAP promoter in transient assays." SIGNOR-254585 SPAG9 protein O60271 UNIPROT MAPK14 protein Q16539 UNIPROT "up-regulates activity" binding 9606 BTO:0000222 17074887 t "Activation of p38alpha/beta MAPK in myogenesis via binding of the scaffold protein JLP" lperfetto "Cdo, jlp, and p38alpha/beta form complexes in differentiating myoblasts, and cdo and jlp cooperate to enhance levels of active p38alpha/beta in transfectants." SIGNOR-149979 axitinib chemical CHEBI:66910 ChEBI PDGFRA protein P16234 UNIPROT "down-regulates activity" "chemical inhibition" -1 22037378 t Luana "Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here." SIGNOR-258074 CCNA1 protein P78396 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 BTO:0001884 15829981 f miannu "SiRNA mediated silencing of cyclin A1 in highly cyclin A1 expressing ML1 leukemic cells significantly slowed S phase entry, decreased proliferation and inhibited colony formation. " SIGNOR-255734 GRIN2B protein Q13224 UNIPROT "NMDA receptor_2B" complex SIGNOR-C348 SIGNOR "form complex" binding 9606 BTO:0000938 12871085 t miannu "The NMDA receptor, a ligand-gated ion channel composed of the NR1 and NR2 subunits, is located mainly at synapses of CNS neurons. The NMDA receptor subtypes are encoded by three gene families that process mRNA transcripts to yield six distinct subunits (NR1, NR2A-2D, NR3A). Receptors are thought to be tetrameric complexes of two NR1 and two NR2 subunits" SIGNOR-264123 domperidone chemical CHEBI:31515 ChEBI DRD3 protein P35462 UNIPROT "down-regulates activity" "chemical inhibition" 10029 BTO:0000246 1975644 t miannu "Molecular cloning and characterization of a novel dopamine receptor (D3) as a target for neuroleptics. A dopamine receptor has been characterized which differs in its pharmacology and signalling system from the D1 or D2 receptor and represents both an autoreceptor and a postsynaptic receptor. Table1. pharmacology of D2 and D3 receptors expressed in CHO cells." SIGNOR-258381 RPS6K proteinfamily SIGNOR-PF26 SIGNOR IRS1 protein P35568 UNIPROT "down-regulates quantity by destabilization" phosphorylation 9606 BTO:0001103 21798082 t lperfetto "Negative feedback involves s6k, which inactivates irs by phosphorylation at multiple sites, thus inducing its degradation and altered cell localization." SIGNOR-252787 FBXW7 protein Q969H0 UNIPROT PSEN1 protein P49768 UNIPROT "down-regulates quantity by destabilization" binding 9606 BTO:0000007 12354302 t miannu "SEL-10 interacts with presenilin 1, facilitates its ubiquitination, and alters A-beta peptide production SEL-10 protein is a homologue of yeast Cdc4, a member of the SCF (Skp1-Cdc53/CUL1-F-box protein) E2-E3 ubiquitin ligase family. In this study, we show that human SEL-10 interacts with PS1 and enhances PS1 ubiquitination, thus altering cellular levels of unprocessed PS1 and its N- and C-terminal fragments. These observations suggest that SEL-10 mediated ubiquitination of PS1-CTF and PS1-NTF leads to their degradation." SIGNOR-272600 ATR protein Q13535 UNIPROT BRCA1 protein P38398 UNIPROT "up-regulates activity" phosphorylation Ser1423 AVLEQHGsQPSNSYP 9606 BTO:0000773 11278964 t lperfetto "Brca1 is phosphorylated at ser-1423 and ser-1524 after ir and uv;however, ser-1387 is specifically phosphorylated after ir, and ser-1457 is predominantly phosphorylated after uv.atr controls brca1 phosphorylation in vivo. Taken together, our results support a model in which atm and atr act in parallel but somewhat overlapping pathways of dna damage signaling but respond primarily to different types of dna lesion." SIGNOR-106436 PDGFRB protein P09619 UNIPROT PDGFRB protein P09619 UNIPROT "up-regulates activity" phosphorylation Tyr581 SDGHEYIyVDPMQLP 9606 BTO:0000599 9642269 t miannu "We used two platelet-derived growth factor beta-receptor (beta-PDGFR) mutants to identify events that are required for full engagement (autophosphorylation and activation of the kinase activity) of the beta-PDGFR kinase. The F79/81 receptor (Tyr to Phe substitution at 579 and 581 in the juxtamembrane domain of the receptor) was capable of only very modest ligand-dependent autophosphorylation and also failed to associate with numerous SH2 domain-containing proteins." SIGNOR-250255 PRKACA protein P17612 UNIPROT DYNLRB1 protein Q9NP97 UNIPROT up-regulates phosphorylation Ser73 LTFLRIRsKKNEIMV 9606 23333499 t llicata "Our results show that km23-1 is required for camp-responsive element (cre) transcriptional activation by tgf_, with s73-km23-1 being required for the cre-dependent tgf_ stimulation of fibronectin (fn) transcription." SIGNOR-200456 PRKCI protein P41743 UNIPROT LLGL1 protein Q15334 UNIPROT "up-regulates activity" phosphorylation Ser659 RVKSLKKsLRQSFRR 9615 12725730 t miannu "This finding indicates that both mLgl-2 and mLgl-1 are phosphorylated in vivo in an aPKC lambda activity-dependent manner." SIGNOR-263179 NfKb-p65/p50 complex SIGNOR-C13 SIGNOR FTH1 protein P02794 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0003212 19258503 f miannu "We show that inhibition of constitutively active NF-kappaB causes down-regulation of ferritin heavy chain (FHC) that leads to an increase of free intracellular iron, which, in turn, induces massive generation of ROS." SIGNOR-254792 PTPN22 protein Q9Y2R2 UNIPROT LCK protein P06239 UNIPROT down-regulates dephosphorylation Tyr394 RLIEDNEyTAREGAK 9606 BTO:0000007 16461343 t gcesareni "Native ptpn22 dephosphorylated lck at its activating tyrosine residues tyr-394." SIGNOR-144341 Hexokinase proteinfamily SIGNOR-PF76 SIGNOR Glycolysis phenotype SIGNOR-PH34 SIGNOR "up-regulates activity" 9606 18350175 f "inferred from family member" "The first step in metabolism of glucose (Glc) is usually phosphorylation, catalyzed by hexokinase." SIGNOR-270310 DYRK1B protein Q9Y463 UNIPROT CDKN1B protein P46527 UNIPROT up-regulates phosphorylation Ser10 NVRVSNGsPSLERMD 10090 15546868 t lperfetto "Mirk phosphorylates p27 at ser-10, thus stabilizing p27 and blocking its nuclear export and degradation" SIGNOR-235805 E2F1 protein Q01094 UNIPROT PPARG protein P37231 UNIPROT up-regulates "transcriptional regulation" 9606 12110166 f "During clonal expansion" fspada "We show here that e2f1 induces ppar gamma transcription during clonal expansion, whereas e2f4 represses pparg amma expression during terminal adipocyte differentiation" SIGNOR-210047 IMPDH2 protein P12268 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR "up-regulates activity" binding 9606 BTO:0001616 30518405 t miannu "We further demonstrated that IMPDH2 overexpression accelerated G1/S phase cell cycle transition by inducing increased expression of cyclin D1 and Ki-67 and downregulation of p21Cip1 and p27Kip1. More importantly, G1/S phase cell cycle transition was triggered by IMPDH2 through activation of AKT activity, downregulation of mTOR and FOXO1 transcriptional activity. There is evidence that IMPDH2 interacts with the pleckstrin homology domain of PKB/AKT in the regulation of GTP biosynthesis." SIGNOR-260961 HMOX2 protein P30519 UNIPROT HBA1 protein P69905 UNIPROT "down-regulates activity" 9606 10490932 t Regulation miannu "Heme oxygenase (HO), by catabolizing heme to bile pigments, down-regulates cellular hemoprotein, hemoglobin, and heme" SIGNOR-251814 "Cap-binding complex" complex SIGNOR-C440 SIGNOR PUM3 protein Q15397 UNIPROT "down-regulates quantity by repression" "post transcriptional regulation" 9606 31320643 t lperfetto "In addition to its role in bulk mRNA decay, CCR4-NOT can also catalyze the deadenylation or promote translational repression of specific mRNA targets to which it is recruited by RNA binding proteins, such as Nanos, Roquin and Puf/Pumilio proteins" SIGNOR-268352 SMAD7 protein O15105 UNIPROT SMURF2 protein Q9HAU4 UNIPROT "up-regulates activity" relocalization 9606 21791611 t lperfetto "One of the major mechanisms underlying the inhibitory effect of Smad7 on TGF-_ signaling operates through accelerating T_RI turnover by recruiting ubiquitin E3 ligases such as Smurf1 and Smurf2" SIGNOR-227556 AMPK complex SIGNOR-C15 SIGNOR CRY1 protein Q16526 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser71 ANLRKLNsRLFVIRG 9606 19833968 t miannu "We demonstrated that the nutrient-responsive adenosine monophosphate-activated protein kinase (AMPK) phosphorylates and destabilizes the clock component cryptochrome 1 (CRY1). In mouse livers, AMPK activity and nuclear localization were rhythmic and inversely correlated with CRY1 nuclear protein abundance. Stimulation of AMPK destabilized cryptochromes and altered circadian rhythms, and mice in which the AMPK pathway was genetically disrupted showed alterations in peripheral clocks. Phosphorylation of S71 or S280 by AMPK destabilizes CRY1" SIGNOR-268046 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR RPS6K proteinfamily SIGNOR-PF26 SIGNOR "up-regulates activity" phosphorylation Ser732 RRVRKLPsTTL 9534 BTO:0004055 9430688 t lperfetto "Several lines of evidence indicate that the mapkap-k1 isoforms are also activated by mapks in vivo via the ras-dependent protein kinase cascade that is triggered by growth factors or tumor-promoting phorbol esters, such as phorbol 12-myristate 13-acetate (pma). here we identify six sites in mapkap-k1a that become phosphorylated in transfected cos-1 cells. The inactive form of mapkap-k1a in unstimulated cells is partially phosphorylated at ser222 and ser733. Stimulation with phorbol 12-myristate 13-acetate induces the phosphorylation of thr360, ser364, thr574, and ser381 and increases the phosphorylation of ser222 and ser733." SIGNOR-252744 USP6 protein P35125 UNIPROT ARF6 protein P62330 UNIPROT up-regulates relocalization 9606 15509780 t miannu "Here we show that tre17 (also called tre-2 and usp6), a founding member of the tbc family, targets the arf family gtpase arf6, which regulates plasma membrane-endosome trafficking. Surprisingly, tre17 does not function as a gap for arf6 but rather promotes its activation in vivo. Forced expression of tre17 promotes the localization of arf6 to the plasma membrane, leading to arf6 activation, presumably due to facilitated access to membrane-associated guanine nucleotide exchange factors (gefs)." SIGNOR-130019 Serdemetan chemical CID:11609586 PUBCHEM MDM2 protein Q00987 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-193504 LRP5 protein O75197 UNIPROT DVL1 protein O14640 UNIPROT "up-regulates activity" binding 9606 23209147 t Gianni "The Wnt–FZD–LRP5/6 trimeric complex recruits Dishevelled (DVL) and Axin through the intracellular domains of FZD and LRP5/6, resulting in inhibition of β-catenin phosphorylation and thus ensuing β-catenin stabilization." SIGNOR-262525 MAPK10 protein P53779 UNIPROT BCL2L11 protein O43521 UNIPROT up-regulates phosphorylation Thr116 SCDKSTQtPSPPCQA 9606 18498746 t gcesareni "Jnk is the physiogically relevant uv-stimulated kinase that phosphorylates bimel on thr-112/jnk-induced bim apoptotic activity" SIGNOR-178683 UBE2N protein P61088 UNIPROT UBE2V1 protein Q13404 UNIPROT "up-regulates activity" binding 9606 20551964 t lperfetto "Ubc13, the partner of rnf8 and rnf168, usually cooperates with an e2-like protein, uev1 (also known as ube2v1) or mms2 (also known as ube2v2), for the synthesis of lys63-linked polyubiquitin chains." SIGNOR-166177 AMPK complex SIGNOR-C15 SIGNOR PFKFB2 protein O60825 UNIPROT "up-regulates activity" phosphorylation Ser466 PVRMRRNsFTPLSSS 9606 BTO:0000562 11069105 t lperfetto "Heart 6-phosphofructo-2-kinase activation by insulin results from ser-466 and ser-483 phosphorylation and requires 3-phosphoinositide-dependent kinase-1, but not protein kinase b." SIGNOR-216623 ATM protein Q13315 UNIPROT H2AX protein P16104 UNIPROT up-regulates phosphorylation Ser140 GKKATQAsQEY 9606 21690091 t gcesareni "Upon dna damage, h2ax is phosphorylated by ataxia telangiectasia mutated (atm) and atm-related kinases at serine 139, known as ?_?_?_-H2ax, which serves as a docking site to recruit the mediator of dna damage checkpoint protein 1 (mdc1) to sites of dna damage, named dna damage foci" SIGNOR-174442 "SB 203580" chemical CHEBI:90705 ChEBI MAPK14 protein Q16539 UNIPROT down-regulates "chemical inhibition" 9606 BTO:0000567 10702313 t gcesareni "Pretreatment of hela cells with sb 203580, a pyridinyl imidazole compound that specifically inhibits p38 mitogen-activated protein kinase (mapk). It has previously been established that sb 203580 acts primarily to block the catalytic activity of p38 mapk. However, it has been suggested that in cells, the compounds could also inhibit p38 mapk activation by virtue of their ability to bind to the inactive enzyme." SIGNOR-75389 CAMK4 protein Q16566 UNIPROT HDAC5 protein Q9UQL6 UNIPROT down-regulates phosphorylation Ser498 RPLSRTQsSPLPQSP 9606 BTO:0000887;BTO:0001103 12058061 t lperfetto "Recently, camkiv, a calcium-calmodulindependent protein kinase, was also shown to activate mef2s by dissociating class ii histone deacetylases (e.g., Hdac5) from mef2s, thus relieving the transcriptional repressive effect of hdacs." SIGNOR-236575 CREB1 protein P16220 UNIPROT UXT protein Q9UBK9 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0001033 17761951 f lperfetto "The DNA response elements that control the induction of ART-27 gene expression were also characterized. The major cis-acting element corresponds to a consensus cAMP-responsive element (CRE) and binds the CRE-binding protein (CREB) as shown by EMSA and chromatin immunoprecipitation assays. Furthermore, ART-27 promoter activity is induced upon CREB overexpression. Epidermal growth factor, which activates CREB via phosphorylation, also induces ART-27 expression, whereas a reduction in CREB phosphorylation or expression blocks this induction in prostate cells." SIGNOR-254092 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR LIPE protein Q05469 UNIPROT "up-regulates activity" phosphorylation 10090 BTO:0000944 11581251 t "inferred from 70% family members" lperfetto "Thus, activation of the ERK pathway appears to be able to regulate adipocyte lipolysis by phosphorylating HSL on Ser(600) and increasing the activity of HSL." SIGNOR-270207 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR MAP2K1 protein Q02750 UNIPROT "down-regulates activity" phosphorylation Thr292 ETPPRPRtPGRPLSS 9534 BTO:0004055 14993270 t lperfetto "We propose that activation of erk during adhesion creates a feedback system in which erk phosphorylates mek1 on t292, and this in turn blocks additional s298 phosphorylation in response to integrin signaling." SIGNOR-244557 CASP3 protein P42574 UNIPROT DFFA protein O00273 UNIPROT "up-regulates activity" cleavage 9606 9108473 t lperfetto "DFF, a heterodimeric protein that functions downstream of caspase-3 to trigger DNA fragmentation during apoptosis. We have identified and purified from HeLa cytosol a protein that induces DNA fragmentation in coincubated nuclei after it is activated by caspase-3." SIGNOR-47416 p38 proteinfamily SIGNOR-PF16 SIGNOR FH protein P07954 UNIPROT "up-regulates activity" phosphorylation Thr90 GVTERMPtPVIKAFG 9606 BTO:0002058 30683654 t miannu "In this study, we found that TGFβ induces FH Thr 90 phosphorylation by p38. Upon Notch activation, nuclear NICD promotes the interaction between CSL and p38-phosphorylated FH and thus FH/CSL/p53/Smad complex formation; this facilitates FH recruitment to p53-targed p21 promoter, where FH inhibits KDM2A-mediated demethylation of H3K36me2 through local production of fumarate" SIGNOR-266316 Ub:E2 complex SIGNOR-C497 SIGNOR RNF103 protein O00237 UNIPROT "up-regulates activity" ubiquitination 9606 34199813 t miannu "The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t" SIGNOR-271093 RFWD3 protein Q6PCD5 UNIPROT TP53 protein P04637 UNIPROT "up-regulates quantity by stabilization" ubiquitination 9606 BTO:0002552 20173098 t miannu "RFWD3 is a positive regulator of p53 abundance and regulates the G1 checkpoint in response to IR. We found that an E3 ubiquitin ligase RFWD3 (RNF201/FLJ10520) forms a complex with Mdm2 and p53 to synergistically ubiquitinate p53 and is required to stabilize p53 in the late response to DNA damage. " SIGNOR-271944 ASTN2 protein O75129 UNIPROT Neuron_migration phenotype SIGNOR-PH67 SIGNOR up-regulates 9606 BTO:0000142 28506896 f miannu "The role of astrotactin and Brinp proteins has been partially characterized, with ASTN1 and ASTN2 demonstrated to facilitate glial-guided neuronal migration during brain development" SIGNOR-269814 CIB1 protein Q99828 UNIPROT ITGA2B protein P08514 UNIPROT "up-regulates activity" binding 10029 BTO:0000246 11756406 t Gianni "The small GTPase Rac3 interacts with the integrin-binding protein CIB and promotes integrin alpha(IIb)beta(3)-mediated adhesion and spreading" SIGNOR-269061 TIMP3 protein P35625 UNIPROT Angiogenesis phenotype SIGNOR-PH46 SIGNOR down-regulates 17326328 f lperfetto "There are many naturally occurring proteins that can inhibit angiogenesis, including angiostatin, endostatin, interferon, platelet factor 4, thorombospondin, prolactin 16 kd fragment, and tissue inhibitor of metalloproteinase-1, -2, and -3" SIGNOR-252274 ATM protein Q13315 UNIPROT FBXO31 protein Q5XUX0 UNIPROT up-regulates phosphorylation Ser278 LMKFIYTsQYDNCLT 9606 BTO:0000150;BTO:0001130 19412162 t lperfetto "We find that dna damage induced by gamma-irradiation results in increased fbxo31 levels, which requires phosphorylation of fbxo31 by the ddr-initiating kinase atm" SIGNOR-185635 NFATC2 protein Q13469 UNIPROT GPC6 protein Q9Y625 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000150 21871017 t miannu "NFAT transcriptionally regulates GPC6 induction in breast cancer cells and binds to three regulatory elements in the GPC6 proximal promoter. Expression of GPC6 in response to NFAT signalling promotes invasive migration, whereas GPC6 silencing with shRNA (small-hairpin RNA) potently blocks this phenotype." SIGNOR-264021 MSTN protein O14793 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR "down-regulates activity" 9606 19357233 f miannu "In the current study, it was demonstrated that myostatin inhibits activation of Akt, in both myoblasts and myotubes." SIGNOR-255339 SALL4 protein Q9UJQ4 UNIPROT NANOG protein Q9H9S0 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 16840789 t Luana "We conclude that the Nanog enhancer activity is regulated by both Sall4 and Nanog. " SIGNOR-266079 APC protein P25054 UNIPROT CTNNB1 protein P35222 UNIPROT "down-regulates quantity" binding 9606 22083140 t amattioni "Apc binds to both b-catenin and axin, and could shuttle b-catenin from the plasma membrane and nucleus to the cytoplasmic axin complex. APC cooperates with Axin to promote the phosphorylation of _-catenin by GSK3 [which requires priming phosphorylation by casein kinase 1, _-isoform (CK1_)]." SIGNOR-177230 CSNK1D protein P48730 UNIPROT CTNNB1 protein P35222 UNIPROT down-regulates phosphorylation Ser45 GATTTAPsLSGKGNP 9606 12000790 t gcesareni "However, ckiepsilon has been recently shown to interact with axin (sakanaka et al. 1999;rubinfeld et al. 2001), and it was proposed that this kinase mediates axin-induced apc phosphorylation, thereby stabilizing the -catenin degradation complex (rubinfeld et al. 2001). We have, therefore, evaluated cki as a candidate s45-kinase in several assays, both in vitro and in vivo." SIGNOR-87441 LRRK2 protein Q5S007 UNIPROT LRRK2 protein Q5S007 UNIPROT up-regulates phosphorylation Thr1969 DKASLTRtLQHRIAL 9606 BTO:0000938 19824698 t lperfetto "We identified ser1403, thr1404, thr1410, thr1491 located within the roc domain, as well as thr1967 and thr1969 in the kinase domain, as the autophosphorylation sites. Substitution of thr1967, an autophosphorylation site located within the kinase domain, to ala caused a significant decrease in the kinase activity" SIGNOR-188421 "DCX DET1-COP1" complex SIGNOR-C24 SIGNOR CRTC2 protein Q53ET0 UNIPROT "down-regulates quantity by destabilization" ubiquitination Lys212 LDGEMDPkVPAIEEN 9606 BTO:0000007 17805301 t miannu " In the presence of relevant cofactors (DDB1, DET1), COP1 promoted the ubiquitination of wild-type but not COP1-interaction defective VP/AA TORC2 (Fig. 3e). COP1 also stimulated the ubiquitination of TORC2(K213R) but had no effect on TORC2(K628R), suggesting an important role for Lys 628 in this regard (Fig. 3e). We performed mass spectrometry studies to characterize residues in TORC2 that undergo COP1-mediated ubiquitination. This analysis revealed one major (Lys 628) and one minor (Lys 213) site on TORC2" SIGNOR-271666 "mono(2-ethylhexyl) phthalate" chemical CHEBI:17243 ChEBI PPARG protein P37231 UNIPROT "up-regulates activity" "chemical activation" 9606 19433246 t miannu "Phthalates are true ligands of PPARs. Mono-ethyl-hexyl-phthalate (MEHP), a metabolite of the widespread plasticizer di-ethyl-hexyl-phthalate (DEHP), has been found in exposed organisms and interacts with all three PPARs. A thorough analysis of its interactions with PPARgamma identified MEHP as a selective PPARgamma modulator, and thus a possible contributor to the obesity epidemic." SIGNOR-268747 ADAM17 protein P78536 UNIPROT TGFA protein P01135 UNIPROT "up-regulates activity" cleavage 9606 26284334 t miannu "ADAM17 is involved in the release and activation of several growth factors and cytokine receptor ligands. Among the growth factors activated by ADAM17 are TGF-alpha, amphiregulin, epiregulin and HB-EGF" SIGNOR-259841 STAT3 protein P40763 UNIPROT PLK1 protein P53350 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 22108192 t lperfetto "Stat3 directly activated transcription of PLK1 in esophageal cancer cells and mouse embryonic fibroblast cell NIH3T3." SIGNOR-271690 Delta(9)-tetrahydrocannabinol smallmolecule CHEBI:66964 ChEBI CNR1 protein P21554 UNIPROT "up-regulates activity" "chemical activation" 9606 BTO:0000142 29751001 t miannu "Endocannabinoids (eCBs) are the body’s natural agonists for cannabinoid receptors (G protein-coupled CB1 and CB2) that also recognize Δ9-tetrahydrocannabinol (Δ9-THC), the psychoactive component of marijuana." SIGNOR-264267 STK4 protein Q13043 UNIPROT FOXO3 protein O43524 UNIPROT up-regulates phosphorylation Ser209 SSAGWKNsIRHNLSL 9606 22898666 t gcesareni "Bonni and coworkers demonstrated that mst1 can phosphorylate foxo3 (and subsequently, foxo1) principally ser207 (ser212 in foxo1), a conserved site in the forkhead domain. This phosphorylation interdicts 14-3-3 binding, promotes foxo nuclear residence and transcriptional activity." SIGNOR-191851 PFKM protein P08237 UNIPROT "beta-D-fructofuranose 1,6-bisphosphate(4-)" smallmolecule CHEBI:32966 ChEBI "up-regulates quantity" "chemical modification" 9606 16051738 t miannu "Phosphofructokinase catalyzes the rate-limiting, ATP-mediated phosphorylation of F6P to FBP. PFK is a homo- or heterotetramer with a molecular mass of approximately 380 kDa, and the enzyme is allosterically regulated, among other metabolites, by 2,3-DPG.35." SIGNOR-266471 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR AMPH protein P49418 UNIPROT unknown phosphorylation Ser276 PLPSPTAsPNHTLAP -1 11113134 t llicata "Amphiphysin is phosphorylated by cdk5 in a region including serines 272, 276, and 285. Amphiphysin 1 is also phosphorylated by the cdc2/cyclin B kinase complex in the same region and undergoes mitotic phosphorylation in dividing cells. " SIGNOR-250645 SETD2 protein Q9BYW2 UNIPROT H3C1 protein P68431 UNIPROT "up-regulates activity" trimethylation Lys37 APATGGVkKPHRYRP 9606 16118227 t Gianni "Our results suggest that HYPB HMTase may coordinate histone methylation and transcriptional regulation in mammals and open perspective for the further study of the potential roles of HYPB protein in hematopoiesis and pathogenesis of HD." SIGNOR-269071 CARD11 protein Q9BXL7 UNIPROT MALT1 protein Q9UDY8 UNIPROT up-regulates binding 9606 BTO:0000785 20685844 t gcesareni "The carboxy-terminal part of the bcl10 card and a short stretch of 13 amino acids following the card are required for constitutive binding to malt1." SIGNOR-167393 Ub:E2 complex SIGNOR-C497 SIGNOR "RBR E3 ligase" proteinfamily SIGNOR-PF107 SIGNOR "up-regulates activity" ubiquitination 9606 34199813 t miannu "The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t" SIGNOR-270945 CDK2 protein P24941 UNIPROT CyclinA2/CDK2 complex SIGNOR-C83 SIGNOR "form complex" binding 9606 19056339 t lperfetto "We therefore compared human cyclin a1- and cyclin a2-containing cdk complexes in vitro by determining kinetic constants and by examining the complexes for their ability to phosphorylate prb and p53. Differences in biochemical activity were observed in cdk2 but not cdk1 when complexed with cyclin a1 versus cyclin a2. Further, cdk1/cyclin a1 is a better kinase complex for phosphorylating potentially physiologically relevant substrates prb and p53 than cdk2/cyclin a2." SIGNOR-182569 GATA1 protein P15976 UNIPROT KIT protein P10721 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 27858941 f miannu "DAB2IP suppresses transcription of stem cell factor receptor CD117, by interacting with GATA-1 on a silencer element on its gene" SIGNOR-254771 CYP17A1 protein P05093 UNIPROT 17alpha-hydroxypregnenolone smallmolecule CHEBI:28750 ChEBI "down-regulates quantity" "chemical modification" 9606 BTO:0001363;BTO:0000050;BTO:0000056 17192295 t lperfetto "THE MICROSOMAL ENZYME P450c17 catalyzes two reactions: the 17α-hydroxylation of progesterone and pregnenolone and the subsequent cleavage of the C17–20 carbon bond to produce dehydroepiandrosterone (DHEA) and androstenedione. Whereas only 17α-hydroxylase activity is necessary for the production of corticosteroids, both activities of P450c17 are required to synthesize sex hormones." SIGNOR-268655 Delta(9)-tetrahydrocannabinol smallmolecule CHEBI:66964 ChEBI CNR2 protein P34972 UNIPROT "up-regulates activity" "chemical activation" 9606 BTO:0000142 29751001 t miannu "Endocannabinoids (eCBs) are the body’s natural agonists for cannabinoid receptors (G protein-coupled CB1 and CB2) that also recognize Δ9-tetrahydrocannabinol (Δ9-THC), the psychoactive component of marijuana." SIGNOR-264268 SELENOS protein Q9BQE4 UNIPROT VCP protein P55072 UNIPROT "up-regulates activity" binding 9606 BTO:0000567 15215856 t miannu "VIMP mediates p97 binding to hDerlin-1. these data suggest that Derlin-1 and VIMP form a membrane protein complex that serves as a receptor for p97." SIGNOR-261371 TP53 protein P04637 UNIPROT MLH1 protein P40692 UNIPROT "up-regulates quantity" "transcriptional regulation" 9606 15781865 t ".... numerous potentially novel targets, including the DNA mismatch repair genes MLH1 and PMS2. Both of these genes were determined to be responsive to DNA damage and p53 activation in normal human fibroblasts, and have p53-response elements within their first intron." SIGNOR-257605 FUS protein P35637 UNIPROT HNRNPA2B1 protein P22626 UNIPROT "down-regulates quantity by repression" "post transcriptional regulation" 10090 28515487 f "This conclusion is also supported by the analysis of alternative splicing events in hFUS+/+; Smn+/− mice. As shown in Fig. 6b, the splicing of Dusp22, Mphosph9, Adarb1, hnRNP A2/B1, Gria4, Vps16, Atxn2 and Agrin, which are significantly affected in hFUS+/+ mice, is not further modified by SMN decrease" SIGNOR-262802 TFIIH complex SIGNOR-C457 SIGNOR RARA protein P10276 UNIPROT unknown phosphorylation Ser77 EIVPSPPsPPPLPRI 9606 11955452 t llicata "Thus, we demonstrate that the cdk7 kinase of tfiih phosphorylates the nuclear receptor, then allowing ligand-dependent control of the activation of the hormone-responsive genes." SIGNOR-269332 "NSL histone acetyltransferase" complex SIGNOR-C413 SIGNOR H4C1 protein P62805 UNIPROT "down-regulates activity" acetylation Lys17 GLGKGGAkRHRKVLR 9606 20018852 t miannu "Here we report an analysis of the subunit composition and substrate specificity of the NSL complex. Proteomic analyses of complexes purified through multiple candidate subunits reveal that NSL is composed of nine subunits. by comparing the substrate specificities of the MSL and NSL complexes, we obtain evidence that MOF HAT activity is differentially regulated by assembly into the MSL complex, where it acetylates nucleosomal histone H4 on lysine 16, and the NSL complex, where it also acetylates nucleosomal histone H4 on lysines 5 and 8." SIGNOR-267166 PRKCA protein P17252 UNIPROT VIM protein P08670 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser7 sSSSYRRM -1 2500966 t lperfetto "We reported that stoichiometric phosphorylation by either cAMP-dependent protein kinase or protein kinase C induces disassembly of vimentin filaments. In the present work, we attempted to identify the sites of vimentin phosphorylated by each protein kinase. Sequential analysis of the purified phosphopeptides, together with the known primary sequence, revealed that Ser-8, Ser-9, Ser-20, Ser-25, Ser-33, and Ser-41 were specifically phosphorylated by protein kinase C, whereas Ser-46 was phosphorylated preferentially by cAMP-dependent protein kinase. Both kinases reacted with Ser-6, Ser-24, Ser-38, Ser-50, and Ser-65." SIGNOR-248886 mTORC1 complex SIGNOR-C3 SIGNOR EIF4EBP1 protein Q13541 UNIPROT "down-regulates activity" phosphorylation Thr37 PPGDYSTtPGGTLFS 9606 23486913 t lperfetto "These results indicate that arg, leu, and gln act coordinately to stimulate proliferation of ptr cells through activation of the mtor-rps6k-rps6-eif4ebp1 signal transduction pathway. Specifically as part of mtorc1, mtor directly phosphorylates the ribosomal protein s6 kinases (s6k1 and s6k2) and the eukaryotic initiation factor 4e (eif4e)-binding proteins (4e-bp1 and 4e-bp2), both of which control specific steps in the initiation of cap-dependent translation" SIGNOR-217110 CDKN1A protein P38936 UNIPROT CDK3 protein Q00526 UNIPROT down-regulates binding 9606 7626805 t gcesareni "P21cip1 is a cyclin-dependent kinase (cdk) inhibitor that is transcriptionally activated by p53 in response to dna damage. We have explored the interaction of p21 with the currently known cdks. p21 effectively inhibits cdk2, cdk3, cdk4, and cdk6 kinases." SIGNOR-29954 LPAR2 protein Q9HBW0 UNIPROT GNA12 protein Q03113 UNIPROT up-regulates binding 9606 15856019 t gcesareni "Lysophosphatidic acid (lpa), a major g protein coupled receptor (gpcr)-activating ligand present in serum, elicits growth factor like responses by stimulating specific gpcrs coupled to heterotrimeric g proteins such as g(i), g(q), and g12/13. lpa2 also can couple to the gi/o, g12/13, and gqfamilies." SIGNOR-135834 GSK3B protein P49841 UNIPROT SNAI1 protein O95863 UNIPROT down-regulates phosphorylation Ser104 GKGSQPPsPPSPAPS 9606 20305697 t lperfetto "Snail is a well-known zn-finger transcription factor that promotes emt by repressing e-cadherin expression. It is known that snail is phosphorylated by gsk3beta and degraded by beta-trcp-mediated ubiquitination. A variant of snail (snail-6sa), which abolishes these phosphorylations, is much more stable and resides exclusively in the nucleus to induce emt" SIGNOR-164617 palmitoyl-CoA smallmolecule CHEBI:15525 ChEBI 3-hydroxyoctadecanoyl-CoA smallmolecule CHEBI:50583 ChEBI "up-regulates quantity" "precursor of" 9606 31616255 t miannu "The ELOVL family of enzymes in mammals is comprised of seven members that all reside in the endoplasmic reticulum (ER) and are thought to form a multimeric complex. Together, the ELOVL family is responsible for the elongation of saturated and unsaturated fatty acids.Fatty acid elongation occurs by cycling through a four step process (condensation, reduction, dehydration, and reduction), with two carbon atoms added through each cycle." SIGNOR-267881 BRAF protein P15056 UNIPROT MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR up-regulates phosphorylation 9606 8668348 t lperfetto "We show that, consequently, b-raf interacts with mek-1 and mek-2 with a better affinity than does c-raf-1, thus strengthening the notion that b-raf is a stronger mek activator than c-raf-l." SIGNOR-244843 PRKCA protein P17252 UNIPROT NR1H4 protein Q96RI1 UNIPROT up-regulates phosphorylation Ser145 VVCGDRAsGYHYNAL 9606 18755856 t llicata "Phosphorylation of farnesoid x receptor by protein kinase c promotes its transcriptional activity. pkcalpha phosphorylates in vitro fxr in its dna-binding domain on s135 and s154." SIGNOR-180537 gossypol chemical CHEBI:28584 ChEBI BCL2 protein P10415 UNIPROT down-regulates "chemical inhibition" 9606 23336025 t gcesareni "Bcl-2 inhibitors physically antagonize their anti-apoptotic actions to create a synergistic effect. Numerous compounds have been specifically developed or identified as bcl-2 inhibitors. These compounds include abt-737 and abt-263, obatoclax, gossypol." SIGNOR-200469 PHF2 protein O75151 UNIPROT H3C1 protein P68431 UNIPROT "down-regulates activity" demethylation Lys10 RTKQTARkSTGGKAP 9606 21532585 t miannu "PHF2, a jmjC demethylase, is enzymatically inactive by itself, but becomes an active H3K9Me2 demethylase through PKA-mediated phosphorylation. This modification leads to targeting of the PHF2–ARID5B complex to its target promoters, where it removes the repressive H3K9Me2 mark." SIGNOR-264521 MEF2D protein Q14814 UNIPROT DES protein P17661 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 BTO:0000222 25653159 t lperfetto "Ectopic expression of myogenin and a specific Mef2 isoform induced myogenic differentiation without activating endogenous MyoD expression. Under these conditions, the regulatory sequences of late gene loci were not in close proximity, and these genes were prematurely activated." SIGNOR-241504 ATM protein Q13315 UNIPROT RAD50 protein Q92878 UNIPROT unknown phosphorylation Ser635 KLFDVCGsQDFESDL 9606 17570479 t llicata "The ms/ms fragmentation spectra (figure s7) confirmed the phosphorylation of rad50 at the predicted atm substrate site, s635, in agreement with published data" SIGNOR-156077 PD173955 chemical CHEBI:49791 ChEBI SRC protein P12931 UNIPROT "down-regulates activity" "chemical inhibition" -1 22037378 t Luana "Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here." SIGNOR-258264 sunitinib chemical CHEBI:38940 ChEBI FLT3 protein P36888 UNIPROT down-regulates "chemical inhibition" 9606 21423276 t gcesareni "The vegfr/pdgfr inhibitor sunitinib (selleck) was used at 35 mg/kg in citrate-buffered water and administered daily by oral gavage for 7 days." SIGNOR-172911 CDK5RAP2 protein Q96SN8 UNIPROT CEP152 protein O94986 UNIPROT "up-regulates activity" relocalization 9606 BTO:0000567 26297806 t lperfetto "Primary microcephaly (MCPH) associated proteins CDK5RAP2, CEP152, WDR62 and CEP63 colocalize at the centrosome. We found that they interact to promote centriole duplication and form a hierarchy in which each is required to localize another to the centrosome, with CDK5RAP2 at the apex, and CEP152, WDR62 and CEP63 at sequentially lower positions. MCPH proteins interact with distinct centriolar satellite proteins; CDK5RAP2 interacts with SPAG5 and CEP72, CEP152 with CEP131, WDR62 with MOONRAKER, and CEP63 with CEP90 and CCDC14. These satellite proteins localize their cognate MCPH interactors to centrosomes and also promote centriole duplication. Consistent with a role for satellites in microcephaly, homozygous mutations in one satellite gene, CEP90, may cause MCPH. The satellite proteins, with the exception of CCDC14, and MCPH proteins promote centriole duplication by recruiting CDK2 to the centrosome." SIGNOR-271721 NOX5 protein Q96PH1 UNIPROT superoxide smallmolecule CHEBI:18421 ChEBI "up-regulates quantity" "chemical modification" 9606 17237347 t lperfetto "Over the last years, six homologs of the cytochrome subunit of the phagocyte NADPH oxidase were found: NOX1, NOX3, NOX4, NOX5, DUOX1, and DUOX2. Together with the phagocyte NADPH oxidase itself (NOX2/gp91phox), the homologs are now referred to as the NOX family of NADPH oxidases. These enzymes share the capacity to transport electrons across the plasma membrane and to generate superoxide and other downstream reactive oxygen species (ROS)." SIGNOR-264725 MAPK3 protein P27361 UNIPROT SP1 protein P08047 UNIPROT "up-regulates activity" phosphorylation Thr453 SGPIIIRtPTVGPNG 9606 14744793 t lperfetto "Transcriptional activation of p21(waf1/cip1) by alkylphospholipids: role of the mitogen-activated protein kinase pathway in the transactivation of the human p21(waf1/cip1) promoter by Sp1.|this activation promotes the phosphorylation of Sp1 in known mitogen-activated protein kinase residues (threonine 453 and 739), thereby leading to increased Sp1 binding and enhanced p21(waf1/cip1) transcription." SIGNOR-249480 DARS1 protein P14868 UNIPROT "Multiaminoacyl-tRNA synthetase" complex SIGNOR-C472 SIGNOR "form complex" binding 9606 32644155 t miannu "In mammalian cells, eight cytoplasmic aminoacyl-tRNA synthetases (AARS), and three non-synthetase proteins, reside in a large multi-tRNA synthetase complex (MSC). the MSC is suggested to be a super-complex of two identical, symmetrically arranged sub-units, each containing a single copy of the constituents, with the exception of LysRS which is present as a dimer in each sub-unit (Figure ​(Figure1B,1B, adapted from (27,28)). The sub-units are proposed to be joined by dimers of AspRS and the ProRS domain of GluProRS, and possibly by LysRS tetramers (20). Four AARSs containing GST-like domains important in protein-protein interactions form a MetRS-AIMP3–GluProRS–AIMP2 core of the complex (27,29). These proteins, together with AspRS, and possibly LeuRS and IleRS (30), form a distinct sub-complex denoted as sub-complex I (27). Sub-complex II consists of AIMP1, GlnRS, ArgRS, a dimer of LysRS, and AIMP2 (which is shared by both sub-complexes)." SIGNOR-270362 BRD4 protein O60885 UNIPROT POLR2A protein P24928 UNIPROT up-regulates phosphorylation Ser1616 TPQSPSYsPTSPSYS 9606 BTO:0000150;BTO:0001271;BTO:0000785 22509028 t llicata "We report that brd4 is an atypical kinase that binds to the carboxyl-terminal domain (ctd) of rna polymerase ii and directly phosphorylates its serine 2 (ser2) sites both in vitro and in vivo under conditions where other ctd kinases are inactive. our findings may provide a mechanistic basis for several functional studies that showed that loss of brd4 causes transcription termination and embryonic lethality" SIGNOR-197012 CPSF3 protein Q9UKF6 UNIPROT "CPSF complex" complex SIGNOR-C53 SIGNOR "form complex" binding 9606 BTO:0000007 19224921 t lperfetto "The CPSF complex consists of five subunits, named CPSF160, CPSF100, Fip1, CPSF73, and CPSF30." SIGNOR-268333 MAPK8 protein P45983 UNIPROT SYT4 protein Q9H2B2 UNIPROT "up-regulates activity" phosphorylation Ser135 EGEKESVsPESLKSS 10116 BTO:0001009 18046461 t done miannu "JNK phosphorylates Syt 4 at Ser135 in vitro and in vivo." SIGNOR-273673 6-O-phosphono-D-glucono-1,5-lactone smallmolecule CHEBI:16938 ChEBI 6-phospho-D-gluconate smallmolecule CHEBI:16863 ChEBI "up-regulates quantity" "precursor of" 9606 31586547 t miannu "The second enzyme in the oxiPPP, 6-phosphogluconolactonase (PGLS), converts 6PGL to 6-phosphogluconate (6PG)." SIGNOR-267056 PRKCA protein P17252 UNIPROT SDC2 protein P34741 UNIPROT unknown phosphorylation Ser188 LGERKPSsAAYQKAP -1 9244383 t lperfetto "We investigated phosphorylation of syndecan-2 cytoplasmic domain by PKC | Peptide mapping and substitution studies showed that both serines were phosphoacceptors, but each had slightly different affinity, with that of serine-197 being higher than serine-198." SIGNOR-248976 KIT protein P10721 UNIPROT STAP1 protein Q9ULZ2 UNIPROT "up-regulates activity" phosphorylation 9606 BTO:0000007 10679268 t miannu "STAP-1 was tyrosine-phosphorylated by activated c-kit. An in vitro binding assay suggested that the STAP-1 SH2 domain interacted with several tyrosine-phosphorylated proteins including c-kit and STAT5. These suggest that STAP-1 functions as an adaptor molecule downstream of c-kit in hematopoietic stem cells." SIGNOR-261820 CDK2 protein P24941 UNIPROT CCDC6 protein Q16204 UNIPROT up-regulates phosphorylation Ser244 QPVSAPPsPRDISME 9606 14712216 t amattioni "Serine 244 phosphorylation is required for h4 apoptotic function." SIGNOR-121198 BRAF protein P15056 UNIPROT MAP2K2 protein P36507 UNIPROT up-regulates phosphorylation Ser226 LIDSMANsFVGTRSY 9606 BTO:0000142 8668348 t gcesareni "We show that, consequently, b-raf interacts with mek-1 and mek-2 with a better affinity than does c-raf-1, thus strengthening the notion that b-raf is a stronger mek activator than c-raf-l." SIGNOR-42668 PPP2CA protein P67775 UNIPROT TNNI3 protein P19429 UNIPROT down-regulates dephosphorylation Ser23 PAPIRRRsSNYRAYA 9606 BTO:0000887 15769444 t lperfetto "The major phosphatase thought to dephosphorylate ctni and phospholamban is type 2a protein phosphatase (pp2a) [61]. Activation of pp2a and ensuing dephosphorylation of regulatory proteins is involved in the anti-adrenergic effects of adenosine and muscarinic receptor activation see also fig2." SIGNOR-134597 RPS6K proteinfamily SIGNOR-PF26 SIGNOR EEF2K protein O00418 UNIPROT "down-regulates activity" phosphorylation Ser366 SPQVRTLsGSRPPLL 9606 11500364 t lperfetto "We show that two such kinases, p70 s6 kinase (regulated via mtor) and p90(rsk1) (activated by erk), phosphorylate eef2k at a conserved serine and inhibit its activity" SIGNOR-252775 ARNTL protein O00327 UNIPROT CRY1 protein Q16526 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 22750052 f "Mammalian clocks are primarily based on a transcription and translation feedback loop in which a heterodimeric complex of the transcription factors CLOCK (circadian locomotor output cycles kaput) and BMAL1 (brain and muscle Arnt-like protein 1) activates the expression of its own repressors, the period (PER1-3) and cryptochrome (CRY1,2) proteins." SIGNOR-253626 AKT2 protein P31751 UNIPROT CASP9 protein P55211 UNIPROT down-regulates phosphorylation Ser196 KLRRRFSsLHFMVEV 9606 15004527 t gcesareni "Akt phosphorylated recombinant casp9 in vitro on serine-196 and inhibited its protease activity" SIGNOR-123243 RPS6KA5 protein O75582 UNIPROT ETV1 protein P50549 UNIPROT "up-regulates activity" phosphorylation Ser216 PMYQRQMsEPNIPFP 9606 BTO:0002181 12213813 t lperfetto "Activated, overexpressed MSK1 was able to phosphorylate ER81 at Ser191 and Ser216. Mutation of these residues strongly impairs ER81-responsive promoter activity." SIGNOR-262987 Kindlin proteinfamily SIGNOR-PF48 SIGNOR ITGB8 protein P26012 UNIPROT "up-regulates activity" binding 9606 29544897 t miannu "Kindlins bind with β-integrin cytoplasmic tails and execute broad biological functions including directed cell migration, proliferation, differentiation and survival." SIGNOR-259012 OPRK1 protein P41145 UNIPROT GNAI1 protein P63096 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-256710 calcium(2+) smallmolecule CHEBI:29108 ChEBI PLA2G4A protein P47712 UNIPROT up-regulates relocalization 9606 8027085 t gcesareni "Cytosolic phospholipase a2 (cpla2) is a calcium-sensitive 85-kda enzyme that hydrolyzes arachidonic acid-containing membrane phospholipids to initiate the biosynthesis of eicosanoids and platelet-activating factor, potent inflammatory mediators. The calcium-dependent activation of the enzyme is mediated by an n-terminal c2 domain, which is responsible for calcium-dependent translocation of the enzyme to membranes and that enables the intact enzyme to hydrolyze membrane-resident substrates. cytosolic phospholipase a2 (cpla2) associates with natural membranes in response to physiological increases in ca2+, resulting in the selective hydrolysis of arachidonyl phospholipids." SIGNOR-35874 FOXP1 protein Q9H334 UNIPROT SEMA5B protein Q9P283 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 10090 BTO:0001176 24023716 t Gianni "FoxP1 stimulates angiogenesis by repressing the inhibitory guidance protein semaphorin 5B in endothelial cells." SIGNOR-269050 MAPK9 protein P45984 UNIPROT TOB1 protein P50616 UNIPROT down-regulates phosphorylation Ser164 FGHSAAVsPTFMPRS 9606 BTO:0000782 12151396 t gcesareni "Biochemical analyses have then shown that erk mapk (erk2) and jnk/sapk (jnk2) bind to and phosphorylate tob in vitro." SIGNOR-91075 PRKAA1 protein Q13131 UNIPROT SIRT1 protein Q96EB6 UNIPROT up-regulates 9606 BTO:0000887;BTO:0001103 19262508 f gcesareni "The acute actions of ampk on lipid oxidation alter the balance between cellular nad+ and nadh, which acts as a messenger to activate sirt1" SIGNOR-184473 SKP2 protein Q13309 UNIPROT CYGB protein Q8WWM9 UNIPROT "down-regulates quantity by destabilization" binding 9606 BTO:0000007 28948618 t miannu "Skp2 induces ubiquitin-dependent degradation of Cygb. To this end, we performed an in vivo ubiquitination assay in HEK293T cells by transfecting relevant plasmids as indicated. The V5-Skp2DN was generated by deleting the N-terminal residues from 1 to 153 containing the F-box domain, which is involved in recruiting Skp2 to the SCF complex." SIGNOR-272792 NRG2 protein O14511 UNIPROT ERBB4 protein Q15303 UNIPROT up-regulates binding 9606 14967450 t gcesareni "The neuregulins (also called heregulins and neu differentiation factors) nrg-1 and nrg-2 bind erbb-3 and erbb-4;and nrg-3 and nrg-4 bind erbb-4." SIGNOR-122056 TNF protein P01375 UNIPROT PIK3CD protein O00329 UNIPROT up-regulates 9606 10485710 f gcesareni "Tnf activates phosphatidylinositol-3-oh kinase (pi(3)k)" SIGNOR-70622 ARID1A protein O14497 UNIPROT "Neural progenitor-specific SWI/SNF" complex SIGNOR-C477 SIGNOR "form complex" binding 9606 25195934 t miannu "The BAF (mammalian SWI/SNF) complexes are a family of multi-subunit ATP-dependent chromatin remodelers that use ATP hydrolysis to alter chromatin structure. Distinct BAF complex compositions are possible through combinatorial assembly of homologous subunit families and can serve non-redundant functions. In mammalian neural development, developmental stage-specific BAF assemblies are found in embryonic stem cells, neural progenitors and postmitotic neurons. In particular, the neural progenitor-specific BAF complexes are essential for controlling the kinetics and mode of neural progenitor cell division, while neuronal BAF function is necessary for the maturation of postmitotic neuronal phenotypes as well as long-term memory formation. " SIGNOR-270611 GRPR protein P30550 UNIPROT GNAQ protein P50148 UNIPROT up-regulates binding 9606 BTO:0000189 17251915 t gcesareni "Gastrin-releasing peptide receptors (grpr) are coupled primarily to galfaq, and are highly expressed in many cancers, including small-cell lung cancer" SIGNOR-152679 GLI1 protein P08151 UNIPROT Cell_growth phenotype SIGNOR-PH33 SIGNOR up-regulates 9606 3563490 f gcesareni "The gli gene is a member of a select group of cellular genes that are genetically altered in primary human tumors." SIGNOR-235196 NR3C1 protein P04150 UNIPROT TIMELESS protein Q9UNS1 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 19805059 t miannu "GR directly regulates transcription of circadian clock components in mouse and human primary MSCs. Per2, E4bp4, Per1, and Timeless rapidly respond to glucocorticoid stimulation. Primary glucocorticoid receptor (GR) target genes are those at which GR occupies a nearby genomic glucocorticoid response element (GRE) and regulates target gene transcription" SIGNOR-268052 CSNK2A2 protein P19784 UNIPROT SLC18A2 protein Q05940 UNIPROT unknown phosphorylation Ser511 PIGEDEEsESD -1 9045708 t llicata "Purified CKI and CKII phosphorylate the wild-type carboxyl terminus of VMAT2, but not a double mutant with both serines 512 and 514 replaced by alanine. The protein kinase inhibitor CKI-7 and unlabeled GTP both block in vitro phosphorylation by cell homogenates, indicating a role for CKII and possibly CKI in vivo. Both kinases phosphorylate the VMAT2 fusion protein to a much greater extent than a similar fusion protein containing the carboxyl terminus of VMAT1, consistent with differential phosphorylation of the two transporters observed in intact cells. " SIGNOR-251038 F2 protein P00734 UNIPROT F8 protein P00451 UNIPROT "up-regulates activity" cleavage Arg391 SPSFIQIrSVAKKHP -1 10350471 t lperfetto "Activation of factor VIII by thrombin occurs via limited proteolysis at R372, R740, and R1689." SIGNOR-263640 SLC38A9 protein Q8NBW4 UNIPROT mTORC1 complex SIGNOR-C3 SIGNOR "up-regulates activity" 9606 BTO:0000007 29053970 f "Activation of mTORC1 by arginine requires SLC38A9, a poorly understood lysosomal membrane protein with homology to amino acid transporters." SIGNOR-255311 ENPP1 protein P22413 UNIPROT Bone_mineralization phenotype SIGNOR-PH69 SIGNOR up-regulates 9606 19049325 f miannu "PC-1 and Tnap work together to produce normally mineralized bone matrix through the generation and hydrolysis of pyrophosphate." SIGNOR-252195 CDS1 protein Q92903 UNIPROT CDP-diacylglycerol(2-) smallmolecule CHEBI:58332 ChEBI up-regulates "chemical modification" 9606 25375833 t lperfetto "CDP-diacylglycerol synthases (CDS) are critical enzymes that catalyze the formation of CDP-diacylglycerol (CDP-DAG) from phosphatidic acid (PA)." SIGNOR-267017 RAB2A protein P61019 UNIPROT PRKCI protein P41743 UNIPROT "down-regulates activity" binding 9606 BTO:0000567 14570876 t Sara "Rab2 Binds to the PKCι/λ Regulatory Domain and Inhibits PKCι/λ-dependent GAPDH Phosphorylation" SIGNOR-261301 NANOG protein Q9H9S0 UNIPROT Pluripotency phenotype SIGNOR-PH43 SIGNOR up-regulates 9606 BTO:0001086 16153702 f flangone "Our results suggest that OCT4, SOX2, and NANOG contribute to pluripotency and self-renewal by activating their own genes and genes encoding components of key signaling pathways and by repressing genes that are key to developmental processes." SIGNOR-242076 PRKAA1 protein Q13131 UNIPROT NR2C2 protein P49116 UNIPROT down-regulates phosphorylation Ser351 HVISRDQsTPIIEVE 9606 SIGNOR-C15 21478464 t gcesareni "Tr4 transactivation is inhibited via phosphorylation bymetformin-induced amp-activated protein kinase (ampk) at the amino acid serine 351, which results in the suppression of scd1 gene expression" SIGNOR-173118 LPCAT2 protein Q7L5N7 UNIPROT acyl-CoA(4-) chemical CHEBI:58342 ChEBI "down-regulates quantity" "chemical modification" 9606 21498505 t miannu "Plasma-derived fatty acids are esterified to acyl-CoA by acyl-CoA synthetases and transferred to lysophospholipids by acyl-CoA:lysophospholipid acyltransferases. We report the characterization of three lysophosphatidylcholine (lysoPC) acyltransferases (LPCATs), products of the AYTL1, -2, and -3 genes. " SIGNOR-272767 TTK protein P33981 UNIPROT CDCA8 protein Q53HL2 UNIPROT up-regulates phosphorylation Thr88 QALEEAAtADLDITE 9606 19530738 t lperfetto "First, we confirmed that wild-type borealin is phosphorylated at the previously described sites t88, t94, t169, and t230 when present in complex with survivin borealin might be a substrate for mps1. In the case of wild-type borealin, the fast exchange between the monomeric and dimeric forms may allow mps1 to phosphorylate the monomer. In turn, mps1 may regulate borealin function by unfolding the c-terminal domain and/or shifting the population to the monomeric form." SIGNOR-186151 WT1 protein P19544 UNIPROT REN protein P00797 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 18496514 t "Here, we show that a splice variant of the Wilms' tumor protein lacking three amino acids WT1(-KTS) suppresses renin gene transcription" SIGNOR-252296 NRP1 protein O14786 UNIPROT PHACTR1 protein Q9C0D0 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 21939755 f miannu "Recently, we identified a new Vascular Endothelial Growth Factor (VEGF)-A(165)-induced gene Phactr-1, (Phosphatase Actin Regulator-1). We found that neuropilin-1 (NRP-1) and VEGF-R1 depletion inhibited Phactr-1 mRNA expression while NRP-2 and VEGF-R2 depletion had no effect." SIGNOR-260061 STAT1/STAT3 complex SIGNOR-C118 SIGNOR JAK1/STAT1/STAT3 complex SIGNOR-C120 SIGNOR "form complex" binding 10090 15284024 t lperfetto "Stimulation of EGFR induces Tyr701 phosphorylation of STAT1 and initiates complex formation of STAT1 and STAT3 with JAK1 and JAK2. Thereafter, the STATs translocate to the nucleus within 15 min." SIGNOR-235658 EGFR protein P00533 UNIPROT PLCG1 protein P19174 UNIPROT up-regulates phosphorylation Tyr783 EGRNPGFyVEANPMP 9606 9176240 t gcesareni "In contrast, egf-induced tyrosine phosphorylation of plc-gamma 1 was rather small, indicating that tyrosine phosphorylation of plc-gamma 1 is not proportional to changes in plc activity. These results suggest that autophosphorylation of theegfr may induce a conformational change of its kinase domain which enhances its kinase activity with exogenous substrates and may induce association with phospholipase c-gamma by increasing its affinity to a domain containing tyr-771." SIGNOR-48872 RPS6K proteinfamily SIGNOR-PF26 SIGNOR TSC2 protein P49815 UNIPROT down-regulates phosphorylation Ser1798 GQRKRLIsSVEDFTE 9606 BTO:0000007 15342917 t lperfetto "The mitogen-activated protein kinase (mapk)-activated kinase, p90 ribosomal s6 kinase (rsk) 1, was found to interact with and phosphorylate tuberin at a regulatory site, ser-1798, located at the evolutionarily conserved c terminus of tuberin. Rsk1 phosphorylation of ser-1798 inhibits the tumor suppressor function of the tuberin/hamartin complex, resulting in increased mtor signaling to s6k1" SIGNOR-252801 CDK3 protein Q00526 UNIPROT ESR1 protein P03372 UNIPROT "up-regulates activity" phosphorylation Ser104 FPPLNSVsPSPLMLL 26202215 t lperfetto "CDK3 was shown to be overexpressed in breast cancer and phosphorylate ERα at Ser104/116 and Ser118. Furthermore, we found that Mir-873 inhibits ER activity and cell growth via targeting CDK3" SIGNOR-273189 CyclinD1/CDK6 complex SIGNOR-C143 SIGNOR G0/G1_transition phenotype SIGNOR-PH219 SIGNOR up-regulates 12640120 f lperfetto "Transition through this point requires cdk6/4-cyclin D, since inhibition with TAT-p16INK4A during the first 3 to 5 h prevents cell cycle entry and maintains both naive and memory T cells in G0." SIGNOR-273192 MAGT1 protein Q9H0U3 UNIPROT "OST-B complex" complex SIGNOR-C536 SIGNOR "form complex" binding 9606 31831667 t miannu "Oligosaccharyltransferase (OST) catalyzes the transfer of a high-mannose glycan onto secretory proteins in the endoplasmic reticulum. Mammals express two distinct OST complexes that act in a cotranslational (OST-A) or posttranslocational (OST-B) manner. Here, we present high-resolution cryo-electron microscopy structures of human OST-A and OST-B. Although they have similar overall architectures, structural differences in the catalytic subunits STT3A and STT3B facilitate contacts to distinct OST subunits, DC2 in OST-A and MAGT1 in OST-B. In OST-A, interactions with TMEM258 and STT3A allow ribophorin-I to form a four-helix bundle that can bind to a translating ribosome, whereas the equivalent region is disordered in OST-B. " SIGNOR-272071 AURKC protein Q9UQB9 UNIPROT H3C1 protein P68431 UNIPROT "up-regulates activity" phosphorylation Ser11 TKQTARKsTGGKAPR 9606 14583461 t "Ser 11 phosphorylation of H3 is either activatory and inhibitory as promotes DNA condensation (activatory) and induce transcription (inhibitory)." gcesareni "Phosphorylation at ser-11 (h3s10ph) by aurkb is crucial for chromosome condensation and cell-cycle progression during mitosis and meiosis. Phosphorylation at ser-11 (h3s10ph) by aurkb is crucial for chromosome condensation and cell-cycle progression during mitosis and meiosis." SIGNOR-118898 TAF1 protein P21675 UNIPROT GTF2A1 protein P52655 UNIPROT "up-regulates activity" phosphorylation Ser316 VEEEPLNsEDDVSDE 9606 11278496 t lperfetto "Taf(ii) 250 phosphorylates human transcription factor iia on serine residues important for tbp binding and transcription activity." SIGNOR-105688 SQSTM1 protein Q13501 UNIPROT SOD1 protein P00441 UNIPROT "down-regulates quantity by destabilization" binding 10090 BTO:0002572 19765191 t "P00441:p.Ala5Val (mutation causing interaction)" " This study provides a novel molecular mechanism by which mutant SOD1 can be recognized by p62 in an ubiquitin-independent fashion and targeted for the autophagy-lysosome degradation pathway." SIGNOR-262801 PAK1 protein Q13153 UNIPROT ITGB3BP protein Q13352 UNIPROT up-regulates phosphorylation Ser28 SKITRKKsVITYSPT 9606 BTO:0000150 18521086 t lperfetto "Serine 28 phosphorylation of nrif3 confers its co-activator function for estrogen receptor-alpha transactivation. p21-activated protein kinase 1 (pak1) phosphorylates eralpha at ser305 and this modification is important in eralpha transactivation function." SIGNOR-178795 phenobarbital chemical CHEBI:8069 ChEBI NR1I2 protein O75469 UNIPROT "up-regulates activity" "chemical activation" 9534 BTO:0000318 9727070 t miannu "The antihypercholesterolemic drug lovastatin also activated hPXR as did phenobarbital and the organochlorine pesticide transnonachlor (Fig. 4 A). Thus, hPXR is activated by a remarkably diverse group of synthetic compounds that are known to induce CYP3A4 gene expression (Fig. 4 C)." SIGNOR-258830 NAE complex SIGNOR-C131 SIGNOR CUL7 protein Q14999 UNIPROT "up-regulates activity" neddylation 9606 25504797 t lperfetto "The family of cullin proteins is the most established target for NEDD8. In humans, it is composed of seven cullins (Cul1, 2, 3, 4A, 4B, 5 and 7), whereas PARC (CUL9) and APC2 (component of the anaphase promoting complex APC) contain a cullin-homology domain. All cullins are modified with NEDD8The role of cullin NEDDylation is to enhance the activity of the CRLs and subsequent ubiquitination and degradation of the regulated substrates." SIGNOR-243172 LLGL1 protein Q15334 UNIPROT Scribble_complex_DLG1-LLGL1_variant complex SIGNOR-C511 SIGNOR "form complex" binding 9606 23397623 t miannu "The Scribble polarity complex or module is one of the three polarity modules that regulate cell polarity in multiple epithelia including blood-tissue barriers. This protein complex is composed of Scribble, Lethal giant larvae (Lgl) and Discs large (Dlg), which are well conserved across species from fruitflies and worms to mammals." SIGNOR-270911 TEK protein Q02763 UNIPROT MYH1 protein P12882 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 BTO:0000222 26042050 f lperfetto "the effects of the angiopoietins are not specific for vascular endothelial cells, as their receptors (Tie1, Tie2) are known to be expressed in hematopoietic cells and they have also recently been shown to be expressed in skeletal muscle cellsExogenous Ang-1 enhanced myogenic (MyoD and Myogenin) mRNA in differentiating myoblasts and increased myosin heavy chain protein." SIGNOR-241541 S100A9 protein P06702 UNIPROT TLR4 protein O00206 UNIPROT "up-regulates activity" binding 9606 28137827 t miannu "RAGE and TLR4 are well-characterized S100A8 and S100A9 receptors and expressed in AML cells. S100A9 binds to TLR4 and induces signaling pathways,promoting leukemic cell differentiation and proliferation arrest. Binding of S100A9 to TLR4 stimulates the phosphorylation of JNK, ERK1/2, and p38 MAPK, which leads to the activation of c-Jun, CREB, and NF-kB." SIGNOR-261918 KDM4C protein Q9H3R0 UNIPROT JAG1 protein P78504 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 23698634 f miannu "The expression of KDM4C gene was increased in spheres from colorectal cancer (CRC) cells and the knockdown (KD) of KDM4C eliminated colonosphere formation. KDM4C KD decreased the expression of JAG1 gene, and the downregulation of JAG1 gene recapitulated the impaired colonosphere formation." SIGNOR-254542 MAPK3 protein P27361 UNIPROT GAB1 protein Q13480 UNIPROT "up-regulates activity" phosphorylation Ser567 DSSRFPMsPRPDSVH 10029 BTO:0000246 15379552 t lperfetto "Our results demonstrate that ERK1/2 phosphorylate Gab1 at six serine/threonine residues (T312, S381, S454, T476, S581, S597) in consensus motifs for MAP kinase phosphorylation. |serine and threonine phosphorylation are capable of modulating the initial signal" SIGNOR-249462 lurasidone chemical CHEBI:70735 ChEBI ADRA2A protein P08913 UNIPROT "down-regulates activity" "chemical inhibition" 10030 BTO:0000246 20404009 t Luana "Lurasidone was found to have potent binding affinity for dopamine D2, 5-hydroxytryptamine 2A (5-HT2A), 5-HT7, 5-HT1A, and noradrenaline 2C receptors." SIGNOR-257842 PTGER2 protein P43116 UNIPROT GNAS protein P63092 UNIPROT up-regulates binding 9606 16293724 t gcesareni "Pge2 receptors are coupled to the g protein gs, which causes accumulation of cyclic adenosine monophosphate (camp) and activates protein kinase a (pka), we confirmed that pge2 treatment or transfection of cells with the active catalytic subunit of pka also stimulated the activity of a camp-responsive-elementdriven reporter gene (cre-luc)." SIGNOR-141597 AKT1 protein P31749 UNIPROT PHB2 protein Q99623 UNIPROT down-regulates binding 10090 15173318 t lperfetto "Akt binds prohibitin 2 and relieves its repression of myod and muscle differentiation" SIGNOR-252541 NUAK1 protein O60285 UNIPROT LATS1 protein O95835 UNIPROT down-regulates phosphorylation Ser464 NIPVRSNsFNNPLGN 9606 19927127 t lperfetto "Moreover, we show that nuak1 phosphorylates lats1 at s464 and this has a role in controlling its stabilitycells that constitutively express nuak1 suffer gross aneuploidies and show diminished expression of the genomic stability regulator lats1" SIGNOR-161792 MITF protein O75030 UNIPROT TPSAB1 protein Q15661 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000830 20513998 t lperfetto "The transcription of tryptase gene in human mast cells is regulated by mi transcription factor |Using mutant constructs of tryptase promoter, we observed that two E-box (CANNTG) motifs including between -817 to -715 and -421 to -202 are able to involve in the transactivation of tryptase gene by MITF-A." SIGNOR-251725 PTGS2 protein P35354 UNIPROT "prostaglandin G2(1-)" smallmolecule CHEBI:82629 ChEBI "up-regulates quantity" "chemical modification" -1 7592599 t Luana "[14C]Arachidonate metabolism by oPGHS-1 and hPGHS-2 was examined in reactions with a series of GSP/Cox ratios (Fig. 3). The principal metabolite for both isoforms was the endoperoxide PGH2, with lesser amounts of PGF2a, PGE2, PGD2," SIGNOR-269770 MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR CASP9 protein P55211 UNIPROT "down-regulates activity" phosphorylation 12792650 t "inferred from 70% family members" lperfetto "Inhibition of caspase-9 through phosphorylation at Thr 125 by ERK MAPK|The opposing protein kinase activity is overcome by treatment with the broad-specificity kinase inhibitor staurosporine or with inhibitors of MEK1/2" SIGNOR-270222 DNM1L protein O00429 UNIPROT Mitochondrial_fission phenotype SIGNOR-PH143 SIGNOR up-regulates 9606 BTO:0000567 17301055 f Barakat "Mitotic phosphorylation of dynamin-related GTPase Drp1 participates in mitochondrial fission" SIGNOR-274132 FOXO3 protein O43524 UNIPROT TRIM63 protein Q969Q1 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000887 21798082 f lperfetto "Foxo factors are required for the transcriptional regulation of the ubiquitin ligases atrogin-1, also called muscle atrophy f-box (mafbx) and muscle ring finger 1 (murf1), leading to the ubiquitylation of myosin and other muscle proteins, and their degradation via the proteasome." SIGNOR-236551 GSK3B protein P49841 UNIPROT MAML1 protein Q92585 UNIPROT down-regulates phosphorylation 9606 19740771 t gcesareni "We found that gsk3beta inhibits maml1 transcriptional activity by directly targeting the n-terminal domain of maml1" SIGNOR-187896 ROCK1 protein Q13464 UNIPROT PPP1R12B protein O60237 UNIPROT down-regulates phosphorylation Thr646 ARQTRRStQGVTLTD 9606 22937917 t lperfetto "Phosphorylation of ppp1r12b on threonine 646 by rho kinase inhibits the activity of the pp1c-ppp1r12b complex." SIGNOR-198812 JUN protein P05412 UNIPROT MTHFR protein P42898 UNIPROT up-regulates 9606 18065414 f lperfetto "The induction of MTHFR was also observed after overexpression of inositol-requiring enzyme-1 (IRE1) and was inhibited by a dominant-negative mutant of IRE1. Because IRE1 triggers c-Jun signaling, we examined the possible involvement of c-Jun in up-regulation of MTHFR. Transfection of c-Jun and two activators of c-Jun (LiCl and sodium valproate) increased MTHFR expression" SIGNOR-253147 RNF8 protein O76064 UNIPROT DNA_repair phenotype SIGNOR-PH57 SIGNOR up-regulates 9606 31225475 f miannu "L3MBTL2 links RNF8 and RNF168 in the DNA double strand break response. The protein kinase ATM phosphorylates L3MBTL2, which recruits it to the DNA lesion by promoting the interaction between MDC1 and L3MBTL2. L3MBTL2 is subsequently ubiquitinated by RNF8, which acts as a docking site for RNF168, thereby recruiting the ubiquitin ligase to the damage site. RNF168, in turn, ubiquitinates H2A-type histones to amplify the DNA damage response and recruit downstream DNA repair proteins for proper DSB signaling." SIGNOR-266790 P2RY2 protein P41231 UNIPROT "Histone H3" proteinfamily SIGNOR-PF69 SIGNOR "up-regulates activity" demethylation 9606 30246379 t miannu "KDM5 subfamily is capable of removing tri‚Äê and di‚Äê methyl marks from lysine 4 on histone H3 (H3K4). Depending on the methylation site, its effect on transcription can be either activating or repressing." SIGNOR-265342 IL1RAP protein Q9NPH3 UNIPROT TOLLIP protein Q9H0E2 UNIPROT "down-regulates activity" binding 9606 BTO:0000007 10854325 t lperfetto "Binding of IL-1 to its receptor results in rapid assembly of a membrane-proximal signalling complex that consists of two different receptor chains (IL-1Rs), IL-1RI and IL-1RAcP, the adaptor protein MyD88, the serine/threonine kinase IRAK and a new protein, which we have named Tollip. Here we show that, before IL-1β treatment, Tollip is present in a complex with IRAK, and that recruitment of Tollip–IRAK complexes to the activated receptor complex occurs through association of Tollip with IL-1RAcP. Co-recruited MyD88 then triggers IRAK autophosphorylation, which in turn leads to rapid dissociation of IRAK from Tollip (and IL-1Rs)" SIGNOR-251979 RARA protein P10276 UNIPROT RXRG protein P48443 UNIPROT up-regulates binding 9606 1310351 t gcesareni "Here we report that the transcriptional activity of rar and rxr can be reciprocally modulated by direct interactions between the two proteins" SIGNOR-16466 GCK protein P35557 UNIPROT "alpha-D-glucose 6-phosphate(2-)" smallmolecule CHEBI:58225 ChEBI "up-regulates quantity" "chemical modification" 9606 16051738 t miannu "Hexokinase catalyzes the phosphorylation of glucose to G6P, using ATP as a phosphoryl donor." SIGNOR-266448 PAK1 protein Q13153 UNIPROT KIF2C protein Q99661 UNIPROT down-regulates phosphorylation Ser192 VNSVRRKsCLVKEVE 9606 23055517 t lperfetto "Here we found that mcak is a cognate substrate of pak1 wherein pak1 phosphorylates mcak on serines 192 and 111 both in vivo and in vitro. Furthermore, we found that pak1 phosphorylation of mcak on serines 192 and 111 preferentially regulates its microtubule depolymerization activity and localization to centrosomes" SIGNOR-199084 ATR protein Q13535 UNIPROT USP20 protein Q9Y2K6 UNIPROT "up-regulates quantity by stabilization" phosphorylation 9606 BTO:0000007 25355518 t miannu "USP20 phosphorylation by ATR is important for its stabilization and checkpoint activation" SIGNOR-272822 CALM1 protein P0DP23 UNIPROT GEM protein P55040 UNIPROT "up-regulates activity" binding 10116 14701738 t miannu "Inhibition of voltage-gated calcium channels by Gem requires GTP and calmodulin binding, but not phosphorylation of serine 261 or 289. Calmodulin binding in the C-terminal extension of Gem is required for maximal inhibition of HVA Ca2+ channels by ectopically expressed Gem, as determined by measurement of electrical activity in primary neurons and by Ca2+-evoked secretion in PC12 cells." SIGNOR-261716 TNF protein P01375 UNIPROT LPL protein P06858 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 3063839 f "Regulation of expression" miannu "Cytokines, notably TNF and IL-1, suppress synthesis of lipoprotein lipase which decreases the rate of TGFA clearance." SIGNOR-251853 BRIP1 protein Q9BX63 UNIPROT "BRCA1-B complex" complex SIGNOR-C298 SIGNOR "form complex" binding 25400280 t lperfetto "Another BRCA1 complex, the BRCA1–B complex containing BRCA1/TopBP1 and BACH1 (also known and BRIP1/FANCJ) has been reported to play a role in HR and S‐phase cell cycle arrest. The exact role of this complex in HR remains unclear, although it is assumed that BACH1, a DNA helicase, contributes to end resection (possibly through its helicase activity) and RPA loading, whereas TopBP1 is required for ATR activation and subsequent S‐phase checkpoint activation" SIGNOR-263219 MAPK8 protein P45983 UNIPROT FOXO4 protein P98177 UNIPROT up-regulates phosphorylation Thr455 ALGTPVLtPPTEAAS 9606 15538382 t lperfetto "Upon treatment of cells with h2o2, the small gtpase ral is activated and this results in a jnk-dependent phosphorylation of foxo4 on threonine 447 and threonine 451. This ral-mediated, jnk-dependent phosphorylation is involved in the nuclear translocation and transcriptional activation of foxo4 after h2o2 treatment." SIGNOR-130385 MAP3K5 protein Q99683 UNIPROT MAP2K6 protein P52564 UNIPROT "up-regulates activity" phosphorylation 9606 BTO:0000298 8974401 t lperfetto "A MAP kinase kinase kinase (MAPKKK), termed ASK1, was identified that activated two different subgroups of MAP kinase kinases (MAPKK), SEK1 (or MKK4) and MKK3/MAPKK6 (or MKK6), which in turn activated stress-activated protein kinase (SAPK, also known as JNK; c-Jun amino-terminal kinase) and p38 subgroups of MAP kinases, respectively." SIGNOR-45353 AHR protein P35869 UNIPROT CYP1A1 protein P04798 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" -1 9865727 t "Resveratrol inhibits transcription of CYP1A1 in vitro by preventing activation of the aryl hydrocarbon receptor|These data demonstrate that resveratrol inhibits CYP1A1 expression in vitro, and that it does this by preventing the binding of the AHR to promoter sequences that regulate CYP1A1 transcription." SIGNOR-253639 MARK2 protein Q7KZI7 UNIPROT RAB11FIP1 protein Q6WKZ4 UNIPROT "up-regulates quantity" phosphorylation Ser234 QKTPLSQsMSVLPTS -1 28396819 t done miannu "We have now found that MARK2 phosphorylates Rab11-FIP1B/C at serine 234 in a consensus site similar to that previously identified in Rab11-FIP2." SIGNOR-273676 POU2F1 protein P14859 UNIPROT HOXD11 protein P31277 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 25301728 f miannu "Knockdown of pou2f1 significantly reduced expression of hoxd10 and d11" SIGNOR-205564 TRIM28 protein Q13263 UNIPROT FBP1 protein P09467 UNIPROT "down-regulates quantity by destabilization" ubiquitination 9606 BTO:0000594 28394358 t lperfetto "In this study, we demonstrated that the tripartite motif-containing protein 28 (TRIM28) binds directly to and promotes FBP1 for ubiquitination and degradation. MAGE-A3 and MAGE-C2, which are known to be overexpressed in HCC, can enhance TRIM28-dependent degradation of FBP1 by forming ubiquitin ligase complexes with TRIM28." SIGNOR-267591 Frizzled proteinfamily SIGNOR-PF11 SIGNOR CTNNB1 protein P35222 UNIPROT up-regulates BTO:0001103 23209147 f apalma "The Wnt–FZD–LRP5/6 trimeric complex recruits Dishevelled (DVL) and Axin through the intracellular domains of FZD and LRP5/6, resulting in inhibition of β-catenin phosphorylation and thus ensuing β-catenin stabilization." SIGNOR-255687 SST protein P61278 UNIPROT SSTR4 protein P31391 UNIPROT up-regulates binding 9606 10433861 t gcesareni "The five receptor subtypes bind the natural SST peptides, SST-14 and SST-28, with low nanomolar affinity." SIGNOR-82496 vismodegib chemical CHEBI:66903 ChEBI SMO protein Q99835 UNIPROT down-regulates "chemical inhibition" 9606 BTO:0001271 21041712 t gcesareni "Cyclopamine with improved solubility (ipi-926), smo inhibitors that considerably differ in structure from cyclopamine (gdc-0499, lde225, bms-833923, xl-139, pf-0449913), inhibitors of the transformation of inactive smo into active smo (sant 74-75), and inhibitors of the transport of cytoplasmic inactive smo to cilia (sant 1-4) have been developed to date." SIGNOR-169194 CDK6 protein Q00534 UNIPROT RBL2 protein Q08999 UNIPROT unknown phosphorylation Ser1035 NMDAPPLsPYPFVRT 9606 BTO:0001938 11157749 t llicata "We now identify 22 in vivo phosphorylation sites of p130, targeted by diverse kinases, and present evidence for three cyclin-dependent kinase 4(6) [cdk4(6)] specific phosphorylations, which appear critical for controlling the growth-restraining activity of p130. all three residues selectively targeted by cdk4(6), t401 (n-terminus), s672 (spacer region) and s1035 (c-terminus)" SIGNOR-104711 PTK6 protein Q13882 UNIPROT EPS8 protein Q12929 UNIPROT "up-regulates activity" phosphorylation Tyr535 LKTQPKKyAKSKYDF 9606 BTO:0000007 28214294 t miannu "Eps8 which was identified by this method is phosphorylated by Myr-PTK6 in HEK293 cells. Mouse Eps8 expressed in HEK293 cells is phosphorylated by Myr-PTK6 at residues Tyr497, Tyr524, and Tyr534. These results indicate that plasma-membrane-associated PTK6 phosphorylates Eps8, which promotes cell proliferation, adhesion, and migration and, thus, tumorigenesis." SIGNOR-263191 GSK3B protein P49841 UNIPROT DPYSL3 protein Q14195 UNIPROT "up-regulates activity" phosphorylation Thr514 TTTPKGGtPAGSARG 10116 16611631 t lperfetto "Together, these results suggest that crmp4 is able to increase neurite formation and elongation in neurons, although not as potently as crmp2, and that this process is regulated by ser522/ser518/thr514/thr509 phosphorylation in both cases. We demonstrate that cdk5 primes crmp2 and crmp4 for subsequent phosphorylation by gsk3, whereas dyrk2, phosphorylates and primes only crmp4 in vitro" SIGNOR-146015 TP53 protein P04637 UNIPROT CDKN1A protein P38936 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000142 8242752 t lperfetto "The ability of p53 to activate transcription from specific sequences suggests that genes induced by p53 may mediate its biological role as a tumor suppressor. Using a subtractive hybridization approach, we identified a gene, named WAF1, whose induction was associated with wild-type but not mutant p53 gene expression in a human brain tumor cell line. The WAF1 gene was localized to chromosome 6p21.2, and its sequence, structure, and activation by p53 was conserved in rodents." SIGNOR-37145 "sphingosine 1-phosphate" smallmolecule CHEBI:37550 ChEBI LATS1 protein O95835 UNIPROT down-regulates 9606 BTO:0000007 22863277 f milica "Serum-borne lysophosphatidic acid (lpa) and sphingosine 1-phosphophate (s1p) act through g12/13-coupled receptors to inhibit the hippo pathway kinases lats1/2, thereby activating yap and taz transcription coactivators, which are oncoproteins repressed by lats1/2." SIGNOR-198550 UBA2 protein Q9UBT2 UNIPROT "SAE1/SAE2 complex" complex SIGNOR-C294 SIGNOR "form complex" binding -1 15660128 t lperfetto "E1 enzymes facilitate conjugation of ubiquitin and ubiquitin-like proteins through adenylation, thioester transfer within E1, and thioester transfer from E1 to E2 conjugating proteins. Structures of human heterodimeric Sae1/Sae2-Mg.ATP and Sae1/Sae2-SUMO-1-Mg.ATP complexes were determined at 2.2 and 2.75 A resolution, respectively." SIGNOR-263004 HDAC1 protein Q13547 UNIPROT KLK3 protein P07288 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 11994312 f "To define a mechanism for repression of AR function, we demonstrate that AR activity is specifically down-regulated by the histone deacetylase activity of HDAC1. Furthermore, using both mammalian two-hybrid and immunoprecipitation experiments, we show that AR and HDAC1 interact, suggestive of a direct role for down-regulation of AR activity by HDAC1. In chromatin immunoprecipitation assays, we provide evidence that AR, Tip60, and HDAC1 form a trimeric complex upon the endogenous AR-responsive PSA promoter, suggesting that acetylation and deacetylation of the AR is an important mechanism for regulating transcriptional activity." SIGNOR-253666 MIR1-1 mirna URS000075CF56_9606 RNAcentral PAX7 protein P23759 UNIPROT "down-regulates quantity" "post transcriptional regulation" 9606 24708856 t irozzo "In this study, bioinformatic prediction combined with pathway analysis and validation by qRT-PCR revealed that miR-155 expression positively correlates with the expression of the AP-1 genes c-JUN and FOS, which are known to induce myeloid differentiation" SIGNOR-256124 AURKB protein Q96GD4 UNIPROT TP53 protein P04637 UNIPROT down-regulates phosphorylation Ser215 DRNTFRHsVVVPYEP 9606 22611192 t gcesareni "We show that aurora b phosphorylates p53 at s183, t211, and s215 to accelerate the degradation of p53 through the polyubiquitination-proteasome pathway, thus functionally suppressing the expression of p53 target genes involved in cell cycle inhibition and apoptosis (e.g., p21 and puma)." SIGNOR-197602 SP3 protein Q02447 UNIPROT SCNN1A protein P37088 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0004299 12684058 f "Regulation of expression" miannu "Transcription factors Sp1 and Sp3 activate alpha-ENaC2 transcription through a GC-rich element (Sp1-binding site) in the promoter. Sp1 and Sp3 are essential for alpha-ENaC2 transcription in lung epithelial cells and that dephosphorylation of the Sp transcription factors by PP1 suppresses alpha-ENaC2 expression." SIGNOR-251951 PRKDC protein P78527 UNIPROT PRKDC protein P78527 UNIPROT "up-regulates activity" phosphorylation Thr2609 LTPMFVEtQASQGTL 9606 12186630 t lperfetto "We have identified seven in vitro autophosphorylation sites in DNA-PKcs. Six of these sites (Thr2609, Ser2612, Thr2620, Ser2624, Thr2638 and Thr2647) are clustered in a region of 38 amino acids in the central region of the protein. Five of these sites (Thr2609, Ser2612, Thr2638, Thr2647 and Ser3205) are conserved between six vertebrate species. Moreover, we show that DNA-PKcs is phosphorylated in vivo at Thr2609, Ser2612, Thr2638 and Thr2647 in okadaic acid-treated human cells. | Thus phosphorylation of DNA-PKcs at one or more of the autophosphorylation sites identified in this study is likely to be required for DNA-PKcs function." SIGNOR-249154 CDK4 protein P11802 UNIPROT SMAD3 protein P84022 UNIPROT "down-regulates activity" phosphorylation Thr179 PQSNIPEtPPPGYLS 9606 15241418 t lperfetto "We have mapped CDK4 and CDK2 phosphorylation sites to Thr 8, Thr 178 and Ser 212 in Smad3. Mutation of the CDK phosphorylation sites increases Smad3 transcriptional activity" SIGNOR-232146 FGFR1 protein P11362 UNIPROT FGFR1 protein P11362 UNIPROT up-regulates phosphorylation Tyr280 VEFMCKVySDPQPHI 9606 12601080 t lperfetto "Fgfr signaling is under the control of tyrosine phosphorylation to elicit activation of cellular signaling cascades. Ligand binding induces receptor dimerization and transphosphorylation. Fgfr1 contains eleven tyrosine residues (tyr154, tyr280, tyr307, tyr463, tyr585, tyr605, tyr653, tyr654, tyr730 and tyr766), some of which are directly involved regulating the activity of the receptor and others bind to activate substrates leading to the activation of various transduction pathways." SIGNOR-98626 acadesine chemical CHEBI:28498 ChEBI AMPK complex SIGNOR-C15 SIGNOR up-regulates "chemical activation" 9606 16879084 t lperfetto "The activation of the ampk pathway by exendin-4 was induced by aicar, which was inhibited by compound c." SIGNOR-217478 ARID2 protein Q68CP9 UNIPROT "SWI/SNF complex" complex SIGNOR-C92 SIGNOR "form complex" binding 9606 15627498 t lperfetto "We discuss recent insights in the functional differences between two evolutionary conserved subclasses of swi/snf-related chromatin remodeling factors. Onesubfamily comprises yeast swi/snf, fly bap and mammalian baf, whereas the other subfamily includes yeast rsc, fly pbap andmammalian pbaf. We review the subunit composition, conserved protein modules and biological functions of each of these subclasses ofswi/snf remodelers." SIGNOR-241756 GDNF protein P39905 UNIPROT TUBA1A protein Q71U36 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 10116 BTO:0002881 15212950 f miannu "We characterize the network of 43 genes induced by GDNF overproduction of neuronal progenitor cells (ST14A), which mainly regulate migration and differentiation of neuronal progenitor cells. GDNF down-regulates doublecortin, Paf-ah1b (Lis1), dynamin, and a-tubulin, which are involved in neocortical lamination and cytoskeletal reorganization." SIGNOR-252174 CELF6 protein Q96J87 UNIPROT CDKN1A protein P38936 UNIPROT "up-regulates quantity by stabilization" "post transcriptional regulation" 9606 BTO:0001109 31534127 t miannu "CELF6 binds to the 3'UTR of p21 transcript and increases its mRNA stability. Depletion of CELF6 promotes cell cycle progression, cell proliferation and colony formation whereas overexpression of CELF6 induces G1 phase arrest." SIGNOR-269044 CSNK2A1 protein P68400 UNIPROT CDC34 protein P49427 UNIPROT "down-regulates activity" phosphorylation Ser236 DDSGTEEs 9606 11546811 t lperfetto "The ubiquitin-conjugating enzyme, cdc34, has been implicated in the ubiquitination of a number of vertebrate substrates, including p27(kip1), ikappabalpha, wee1, and myod. We show that mammalian cdc34 is a phosphoprotein that is phosphorylated in proliferating cells. Phosphorylation of cdc34 by the associated kinase maps predominantly to residues 203 and 222. Mutation of cdc34 at ck2-targeted residues, ser-203, ser-222, ser-231, thr-233, and ser-236, abolishes the phosphorylation of cdc34 observed in vivo and markedly shifts nuclearly localized cdc34 to the cytoplasm." SIGNOR-110403 AURKA protein O14965 UNIPROT GSK3B/Axin/APC complex SIGNOR-C110 SIGNOR "down-regulates activity" phosphorylation 9606 BTO:0001225 19060929 t lperfetto "The recombinant human aurka protein phosphorylated the gsk-3beta protein at ser 9 in a concentration-dependent manner, in vitro. The phosphorylation of beta-catenin (ser33/37/thr41) by gsk-3beta is known to target beta-catenin towards degradation. In line with our findings, the increase in phospho-gsk-3beta level was accompanied by a significant decrease in beta-catenin phosphorylation (ser33/37/thr41) and accumulation of beta-catenin protein." SIGNOR-227923 PFAS protein O15067 UNIPROT "glutamic acid" smallmolecule CHEBI:18237 ChEBI "up-regulates quantity" "chemical modification" 9606 33179964 t miannu "The first two reactions catalyzed by TGART are sequential and produce FGAR, which is then acted upon by the third enzyme in the pathway, formylglycinamidine synthase (PFAS/FGAMS).The transferred ammonia is then used to convert FGAR to FGAM. The FGAMS protein exhibits interesting biophys ical properties and will be covered later in this review. The FGAM produced by FGAMS is then converted into AIR by the AIRS domain of TGART, resulting in a five membered ring closure." SIGNOR-267312 POU5F1 protein Q01860 UNIPROT LEFTY2 protein O00292 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 17068183 f miannu "To enhance our understanding of the molecular basis of this differentiation event in humans, we used a functional genomics approach involving RNA interference-mediated suppression of OCT4 function in a human ESC line and analysis of the resulting transcriptional profiles to identify OCT4-dependent genes in human cells. We detected altered expression of >1,000 genes, including targets regulated directly by OCT4 either positively (NANOG, SOX2, REX1, LEFTB, LEFTA/EBAF DPPA4, THY1, and TDGF1) or negatively (CDX2, EOMES, BMP4, TBX18, Brachyury [T], DKK1, HLX1, GATA6, ID2, and DLX5), as well as targets for the OCT4-associated stem cell regulators SOX2 and NANOG." SIGNOR-254940 BMS-754807 chemical CHEBI:88339 ChEBI IGF1R protein P08069 UNIPROT "down-regulates activity" "chemical inhibition" 9606 BTO:0001802 19996272 t lperfetto "BMS-754807, a small molecule inhibitor of insulin-like growth factor-1R/IR" SIGNOR-262027 MAPK3 protein P27361 UNIPROT KRT8 protein P05787 UNIPROT unknown phosphorylation Ser432 SAYGGLTsPGLSYSL 16554440 t lperfetto "Also, several probable in vivo K8 kinases have been identified including Erk1/2 for K8 Ser431 (Ku and Omary, 1997), and p38 and Jun kinases for K8 Ser73 (Ku et al., 2002a; He et al., 2002)." SIGNOR-249468 CRIPAK protein Q8N1N5 UNIPROT PAK1 protein Q13153 UNIPROT up-regulates binding 9606 BTO:0000150 BTO:0000149 16278681 t gcesareni "We further found that cripak interacted with pak1 through the n-terminal regulatory domain and inhibited pak1 kinase in both in vitro and in vivo assays." SIGNOR-141467 P2RY10 protein O00398 UNIPROT GNAZ protein P19086 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257121 PAK proteinfamily SIGNOR-PF13 SIGNOR VIM protein P08670 UNIPROT "down-regulates activity" phosphorylation -1 11895474 t "inferred from 70% family members" miannu "In vitro analyses revealed that vimentin served as an excellent substrate for PAK. This phosphorylated vimentin lost the potential to form 10 nm filaments. We identified Ser25, Ser38, Ser50, Ser65 and Ser72 in the amino-terminal head domain as the major phosphorylation sites on vimentin for PAK.¬†" SIGNOR-269975 "diisononyl phthalate" chemical CHEBI:35459 ChEBI "monoisononyl phthalate" chemical CHEBI:132593 ChEBI "up-regulates quantity" "precursor of" -1 33125036 t miannu "The primary metabolite of DiNP is monoisononyl-phthalate (MiNP) and the secondary metabolites include three oxidative derivatives of DiNP, which have been identified mainly in urine: mono-oxoisononyl phthalate (MOINP or oxo-MiNP), mono-carboxyisooctyl phthalate (MCIOP, MCOP or cx-MiNP), and mono-hydroxyisononyl phthalate (MHINP or OH-MiNP)." SIGNOR-268771 PHLPP1 protein O60346 UNIPROT PRKCA protein P17252 UNIPROT "down-regulates quantity" dephosphorylation Ser657 QSDFEGFsYVNPQFV 9606 BTO:0000067 18162466 t gcesareni "In addition, knockdown of PHLPP expression reduces the rate of phorbol ester-triggered dephosphorylation of the hydrophobic motif, but not turn motif, of PKC alpha" SIGNOR-237043 ATR protein Q13535 UNIPROT E2F1 protein Q01094 UNIPROT "up-regulates quantity by stabilization" phosphorylation Ser31 ALRLLDSsQIVIISA 10090 BTO:0001372 11459832 t lperfetto "These results thus suggest that this serine 31 residue is indeed an atm/atr phosphorylation site and in fact is the major site for atm/atr-mediated phosphorylation within e2f1. Thus, it is possible that the atm/atr-mediated phosphorylation inhibits the binding and function of skp2 and thus prevents the normal degradation of e2f1" SIGNOR-109420 IFNB1 protein P01574 UNIPROT IFNAR complex SIGNOR-C243 SIGNOR "up-regulates activity" binding 9606 11278538 t miannu "Ifn-alpha, ifn-beta, and ifn-omega, induce somewhat different cellular effects but act through a common receptor complex, ifnar, composed of subunits ifnar-1 and ifnar-2." SIGNOR-260335 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR AP1 complex SIGNOR-C154 SIGNOR up-regulates phosphorylation Thr331 CTPVVTCtPSCTAYT 9606 12972619 t lperfetto "In a previous study we have observed that exposure of nih 3t3 cells to pdgf or serum leads to c-fos phosphorylation by erk on specific residues, thr232, thr325, thr331, and ser374, within the cooh-terminal c-fos tad we have recently shown that erk phosphorylates multiple residues within the carboxylterminal transactivation domain (tad) of c-fos, thus resulting in its increased transcriptional activity." SIGNOR-252353 FBXO45 protein P0C2W1 UNIPROT PAWR protein Q96IZ0 UNIPROT "down-regulates quantity by destabilization" binding 9606 BTO:0000007 24992930 t miannu "Fbxo45 interacts with Par-4 in the cytoplasm and mediates its ubiquitylation and proteasomal degradation. Fbxo45 silencing results in stabilization of Par-4 with increased apoptosis.Fbxo45 forms an atypical ubiquitin ligase complex that contains Skp1 and the Ring-finger protein PAM (protein-associated with myc) also known as MYCBP2 (myc-binding protein 2)." SIGNOR-272223 AKT proteinfamily SIGNOR-PF24 SIGNOR FOXO4 protein P98177 UNIPROT down-regulates phosphorylation Thr32 QSRPRSCtWPLPRPE 9606 16272144 t lperfetto "Foxo4 transcription factor, also referred to afx, contains three putative phosphorylation motif sites for protein kinase b (pkb), thr32, ser197, and ser262, and it is proposed that phosphorylated foxo4 stays in the cytosol and is imported to the nucleus through dephosphorylation to induce target gene expression" SIGNOR-141424 NTRK1 protein P04629 UNIPROT SH2B2 protein O14492 UNIPROT up-regulates phosphorylation 9606 BTO:0000938 9856458 t lperfetto "Two substrates of trk kinases, raps and sh2-b. raps and sh2-b mediate trk signaling in developing neurons" SIGNOR-62619 GNAI1 protein P63096 UNIPROT Microtubule_polimerization phenotype SIGNOR-PH106 SIGNOR down-regulates -1 10224115 f "G protein alpha subunits Gi1alpha, Gsalpha, and Goalpha are shown to activate the GTPase activity of tubulin, inhibit microtubule assembly, and accelerate microtubule dynamics." SIGNOR-256523 CDK5/CDK5R1 complex SIGNOR-C144 SIGNOR DCX protein O43602 UNIPROT unknown phosphorylation Ser332 STPKSKQsPISTPTS 9606 14741103 t llicata "In order to determine the sites of phosphorylation by Cdk5, serine or threonine in the nine potential sites were substituted with alanine by site-directed mutagenesis to create mutant Dcx proteins. hese were analyzed by co-transfection of 293T cells with cdk5/p35. All-sites-A mutant Dcx showed no slower migrating species on Western analysis, indicating that removal of all nine possible sites is sufficient to block the phosphorylation by Cdk5/p35. However, each single mutant Dcx retains the slower migrating species similar to the wild-type Dcx, suggesting that any single mutation is not sufficient to block phosphorylation by Cdk5/p35." SIGNOR-250667 STAT4 protein Q14765 UNIPROT PRF1 protein P14222 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000914 12372421 f miannu "IL-12-induced expression of the perforin gene in NK cells is directly regulated by STAT4, which binds, most likely as a homo-tetramer, to the tandem STAT-binding sequences in the perforin gene promoter." SIGNOR-255245 PTPRG protein P23470 UNIPROT PDGFRB protein P09619 UNIPROT "down-regulates activity" dephosphorylation Tyr716 RPPSAELySNALPVG -1 25624455 t miannu "PTPRG activation by the P1-WD peptide affected the tyrosine phosphorylation of several signaling molecules. Data analysis identified 31 molecules whose phosphorylation was modified in a statistically significant manner (Table I). inhibition of ABL1, BMX, BTK, DAB1, ITGB1, JAK2, KDR, KIT, LIMK1, MET, PDGFRB, SHC1, and VCL correlates with tyrosine dephosphorylation. In contrast, SRC inhibition correlates with hyperphosphorylation of the inhibitory Tyr530 residue and with dephosphorylation of the activatory Tyr419. Moreover, CDK2 and CTTN inhibition correlates with a hyperphosphorylation of the inhibitory Tyr15 and Tyr470, respectively. In contrast, a subgroup of 13 proteins, including BLNK, DOK2, ERBB2, GRIN2B, INSR, PDGFRA, PRKCD, PXN, STAT1, STAT2, STAT3, STAT5A, and ZAP70, appears to be activated by PTPRG activity." SIGNOR-254715 Osmotic_stress stimulus SIGNOR-ST28 SIGNOR HNRNPA1 protein P09651 UNIPROT "down-regulates activity" relocalization 9606 BTO:0000312 33172210 f "We found that osmotic stress robustly induced nuclear loss of TDP-43, SPFQ, FUS, hnRNPA1 and hnRNPK, with characteristic changes in nucleocytoplasmic localisation in an RBP-dependent manne" SIGNOR-262816 CDK7 protein P50613 UNIPROT POLR2A protein P24928 UNIPROT down-regulates phosphorylation Ser1927 SPKYSPTsPTYSPTS 9606 14662762 t lperfetto "Although there is some inconsistency in the literature, it is generally thought that cdk7, a component of the transcription factor (tf) iih, is a major ser-5 kinase, whereas cdk9, a component of positive transcription elongation factor (p-tef) b, is a major ser-2 kinase within cells. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination." SIGNOR-120068 BVES protein Q8NE79 UNIPROT VAMP3 protein Q15836 UNIPROT "up-regulates activity" binding -1 20057356 t llicata "Taken together, these data demonstrate that Bves interacts with VAMP3 and facilitates receptor recycling both in vitro and during early development." SIGNOR-237771 SATB1 protein Q01826 UNIPROT MYB protein P10242 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 17343824 f miannu "We found 59 up-regulated and 75 down-regulated genes in the K562-SATB1 cells that were not observed in the K562 cells. Partial genes that have special biological functions are listed in Table 1." SIGNOR-255135 FYN protein P06241 UNIPROT CD300LF protein Q8TDQ1 UNIPROT "up-regulates activity" phosphorylation Tyr236 VDQVEVEyVTMASLP 17202342 t lperfetto "Y236 (YVTM) and Y263 (YCNM) fit with the consensus motif reported to bind the p85α regulatory subunit of PI3K (16). |The association between IREM-1 and p85α was only perceived in the presence of c-Fyn, suggesting that tyrosine phosphorylation of IREM-1 cytoplasmic tail of IREM-1 was required for the interaction." SIGNOR-275619 INSR protein P06213 UNIPROT INSR protein P06213 UNIPROT "up-regulates activity" phosphorylation Tyr1185 FGMTRDIyETDYYRK -1 2449432 t lperfetto "We identified the major autophosphorylation sites in the insulin receptor and correlated their phosphorylation with the phosphotransferase activity of the receptor on synthetic peptides. We conclude that 1) autophosphorylation of the insulin receptor begins by phosphorylation of Tyr-1146 and either Tyr-1150 or Tyr-1151;" SIGNOR-106510 HTR6 protein P50406 UNIPROT GNAQ protein P50148 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257340 SLBP protein Q14493 UNIPROT H2AC4 protein P04908 UNIPROT "up-regulates quantity by expression" "translation regulation" 9606 BTO:0001938 19155325 t lperfetto "Synthesis of mature histone mRNA requires only a single processing reaction: an endonucleolytic cleavage between a conserved stem-loop and a purine-rich downstream element to form the 3' end. The stem-loop binding protein (SLBP) is required for processing, and following processing, histone mRNA is transported to the cytoplasm, where SLBP participates in translation of the histone mRNA|We used radiolabeled probes generated by PCR targeting the open reading frame (ORF) to detect histones H2A, H2B, H3, H4, and H1 and used 7SK snRNA as a loading control (Fig. 2A). The abundance of histone H2A, H2B, H3, and H4 mRNAs is reduced to 37% to 70% of control levels in the SLBP knockdown cells when compared to the C2 control." SIGNOR-265397 NOTCH3 protein Q9UM47 UNIPROT RBPJ protein Q06330 UNIPROT up-regulates binding 9606 11404076 t gcesareni "Both notch 1 and notch 3 ics displace the co-repressor smrt from the dna-binding protein rbp-j kappa on the hes promoter. The latter observation suggests that both notch 3 ic and notch 1 ic can access rbp-j kappa in vivo, and that the difference in activation capacity instead stems from structural differences in the two ics when positioned on rbp-j kappa." SIGNOR-86128 INSR protein P06213 UNIPROT GAB1 protein Q13480 UNIPROT "up-regulates activity" phosphorylation Tyr589 SHDSEENyVPMNPNL 10090 BTO:0000944 10978177 t "HGab-1 was phosphorylated by IR at eight tyrosine residues (Y242, Y285, Y373, Y447, Y472, Y619, Y657, and Y689). t Gab-1 is the major binding partner of PI-3 kinase in 3T3L1 cells when stimulated with insulin" SIGNOR-251315 MEN1 protein O00255 UNIPROT MLL-ENL "fusion protein" SIGNOR-FP7 SIGNOR "up-regulates activity" binding 10090 BTO:0004730 16239140 t irozzo "We demonstrate here that oncogenic MLL fusion proteins retain an ability to stably associate with menin through a high-affinity, amino-terminal, conserved binding motif and that this interaction is required for the initiation of MLL-mediated leukemogenesis.These results demonstrate that a human oncoprotein is critically dependent on direct physical interaction with a tumor suppressor protein for its oncogenic activity[...]." SIGNOR-255866 SLIT2 protein O94813 UNIPROT ROBO2 protein Q9HCK4 UNIPROT "up-regulates activity" binding -1 16226035 t miannu "This observation suggests that Slit2 may require the Robo2 and Robo3 receptors in this process . Slit2 causes the miRNA miR-182 to release cofilin1 mRNA, potentiating cofilin1 local translation and resulting in growth cone collapse. The use of morpholinos or RNAi to knockdown robo2 and robo3 in X. laevis RGCs, would be useful to further confirm that Robo2 and Robo3 are the receptors involved in Slit2-dependent cofilin1 translation." SIGNOR-268380 GSK3B protein P49841 UNIPROT SNAI1 protein O95863 UNIPROT down-regulates phosphorylation Ser115 PAPSSFSsTSVSSLE 9606 15448698 t lperfetto "Snail is a well-known zn-finger transcription factor that promotes emt by repressing e-cadherin expression. It is known that snail is phosphorylated by gsk3beta and degraded by beta-trcp-mediated ubiquitination. A variant of snail (snail-6sa), which abolishes these phosphorylations, is much more stable and resides exclusively in the nucleus to induce emt" SIGNOR-129414 CREB1 protein P16220 UNIPROT FOXO4 protein P98177 UNIPROT "down-regulates activity" binding 9606 15126506 t lperfetto "We provide evidence that the acetyltransferase creb-binding protein (cbp) binds foxo resulting in acetylation of foxo. This acetylation inhibits foxo transcriptional activity" SIGNOR-124711 CSNK2A1 protein P68400 UNIPROT UBE2R2 protein Q712K3 UNIPROT "up-regulates activity" phosphorylation Ser233 DCYDDDDsGNEES 9606 12037680 t lperfetto "Ck2-dependent phosphorylation of the e2 ubiquitin conjugating enzyme ubc3b induces its interaction with beta-trcp and enhances beta-catenin degradation" SIGNOR-88050 OFD1 protein O75665 UNIPROT IFT88 protein Q13099 UNIPROT "up-regulates activity" binding 9606 BTO:0001086 20230748 t "Regulation of binding" miannu "Ofd1 acts at the distal centriole to build distal appendages, recruit Ift88, and stabilize centriolar microtubules at a defined length." SIGNOR-251973 DYRK1A protein Q13627 UNIPROT MAPT protein P10636 UNIPROT down-regulates phosphorylation Ser519 SGYSSPGsPGTPGSR 9606 21215781 t "The effect has been demonstrated using P10636-8" lperfetto "Dyrk1a phosphorylates tau at least at s202, t212 and s404, but t212 phosphorylation is known to initiate tau hyperphosphorylation by gsk3b (ryoo et al., 2007;woods et al., 2001) and has been demonstrated to have a role in alternative splicing of taumrna" SIGNOR-171030 frovatriptan chemical CHEBI:134991 ChEBI HTR1D protein P28221 UNIPROT "up-regulates activity" "chemical activation" -1 9986723 t miannu "As far as the selectivity against the 5-HT1A receptor, compound 10 shows similar selectivity as VML-251 (4) but has slightly lower selectivity as compared to sumatriptan (1), naratriptan (2), and rizatriptan (3). Although none of the 5-HT1D receptor agonists in the current study demonstrate as good selectivity versus the 5-HT1B receptor, the N-methyl-5-tert-butyltryptamine (10) remains the most selective (4-fold)." SIGNOR-259073 HSPA1A protein P0DMV8 UNIPROT APAF1 protein O14727 UNIPROT down-regulates binding 9606 10934467 t gcesareni "Here we show that the documented anti-apoptotic effect of the principal heat-shock protein, hsp70, is mediated through its direct association with the caspase-recruitment domain (card) of apaf-1 and through apoptosome formation" SIGNOR-80451 HECTD1 protein Q9ULT8 UNIPROT HSP90AA1 protein P07900 UNIPROT "down-regulates quantity" ubiquitination 9606 BTO:0000007 22431752 t Monia "We demonstrate that Hectd1 is a functional ubiquitin ligase and that one of its substrates is Hsp90, a chaperone protein with both intra- and extracellular clients. Identification of Hsp90 in both proteomic screens suggested that members of the Hsp90 superfamily may be substrates of Hectd1. Myc-Hectd1ANK and HA-Hsp90bd (the fragment identified in the yeast two-hybrid screen) bind in an in vitro binding assay (Fig. 3 D) and when coexpressed in HEK293T cells. Hectd1 is required for K63-linked Ubn of Hsp90. Together, these results demonstrate that Hectd1-dependent Ubn of Hsp90 targets it away from the membrane and the secretory pathway." SIGNOR-261199 PTPN2 protein P17706 UNIPROT MET protein P08581 UNIPROT down-regulates dephosphorylation Tyr1235 DMYDKEYySVHNKTG 9606 18819921 t gcesareni "We have identified ptp1b and tcptp as negative regulators of the hepatocyte growth factor receptor, the met receptor-tyrosine kinase. In vivo, loss of ptp1b or tcptp enhances hepatocyte growth factor-mediated phosphorylation of met." SIGNOR-181335 AKT2 protein P31751 UNIPROT BAD protein Q92934 UNIPROT down-regulates phosphorylation Ser99 PFRGRSRsAPPNLWA 9606 10949026 t gcesareni "Ser-136 is the major phosphoacceptor site for akt;akt can weakly phosphorilate ser-155." SIGNOR-81114 SRP54 protein P61011 UNIPROT U2AF1/U2AF2 complex SIGNOR-C78 SIGNOR "up-regulates activity" binding -1 8816452 t Monia "We have now demonstrated that p54 interacts not only with SC35 and ASF/SF2 but also with U2AF. Pairwise interactions between p54 and other RS domain-containing spliceosomal proteins in comparison with SC35 and ASF/SF2 as detected by the yeast two-hybrid interaction assay. . It is conceivable that p54 can mediate 59 and 39 splice site interaction by interacting directly with U2AF65 associated with the 39 splice site and at the same time interact with other SR proteins, such as ASF/SF2 and SC35, which in turn interact with U1-70K. In this scenario, p54 is different from SC35 or ASF/SF2 in that it cannot directly interact with the 59 component (U1-70K) but can interact with the protein associated with the 39 splice site (U2AF65)." SIGNOR-261162 GSK3A protein P49840 UNIPROT CAMKK2 protein Q96RR4 UNIPROT down-regulates phosphorylation Ser137 PVSSPQSsPRLPRRP 9606 22778263 t lperfetto "Cdk5 and gsk3 phosphorylate ser-129, ser-133, and ser-137. Mutation of ser-129, ser-133, and ser-137 increases autonomous activity with little change in ca2 /cam-dependent activity." SIGNOR-198130 NfKb-p65/p50 complex SIGNOR-C13 SIGNOR IL6 protein P05231 UNIPROT up-regulates "transcriptional regulation" 9606 BTO:0000801 20086235 f "Both NF-κBs bind to a conserved DNA motif (80) that is found in numerous IL-1–responsive genes, in particular the ones encoding IκBα (81), IL-6 (82), IL-8 (18, 83,84), monocyte chemoattractant protein 1 (MCP1) (28), and cyclooxygenase 2 (COX2)" SIGNOR-254511 PPARGC1A protein Q9UBK2 UNIPROT SLC2A4 protein P14672 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000887;BTO:0001103 17609368 f gcesareni "Pgc-1alpha protein is required for ampk action on glut4 gene expression and mitochondrial function." SIGNOR-156769 Ub:E2 complex SIGNOR-C497 SIGNOR BIRC8 protein Q96P09 UNIPROT "up-regulates activity" ubiquitination 9606 34199813 t miannu "The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t" SIGNOR-270957 PRKCQ protein Q04759 UNIPROT WIPF1 protein O43516 UNIPROT "up-regulates activity" phosphorylation Ser488 RNESRSGsNRRERGA -1 12504004 t lperfetto "TCR engagement also causes PKCtheta-dependent phosphorylation of WIP, causing the disengagement of WASP from the WIP-WASP complex, thereby releasing it from WIP inhibition. These results suggest that the ZAP-70-CrkL-WIP pathway and PKCtheta link TCR to WASP activation. | These results suggest that phosphorylation at S488 disrupts WIP binding to WASP." SIGNOR-249181 GPC4 protein O75487 UNIPROT WNT3A protein P56704 UNIPROT up-regulates binding 9606 22302992 t gcesareni "Gpc4 bound to wnt3a and wnt5a which activate the beta-catenin-dependent and -independent pathways, respectively, and colocalized with wnts on the cell surface. Expression of gpc4 enhanced the wnt3a-dependent beta-catenin pathway and the wnt5a-dependent beta-catenin-independent pathway, and knockdown of gpc4 suppressed both pathways" SIGNOR-195749 ACO2 protein Q99798 UNIPROT D-threo-isocitrate(3-) smallmolecule CHEBI:15562 ChEBI "up-regulates quantity" "chemical modification" 9606 24068518 t miannu "Citrate is converted to cis-aconitate. This is catalyzed by aconitase. Cis-aconitate is an intermediate and is further converted to isocitrate by aconitase. Aconitase is involved in both reactions. In which first dehydration and then rehydration occur and as a result final product isocitrate is obtained." SIGNOR-266246 ABL2 protein P42684 UNIPROT LGALS3 protein P17931 UNIPROT up-regulates phosphorylation Tyr118 AGPLIVPyNLPLPGG 9606 20150913 t llicata "The sh (src homology)3 domains of c-abl/arg bind to a p(80)gppsgp motif of gal3, and tyr79 and tyr118 are the major tyrosine phosphorylation sites. A consequence of this interaction and phosphorylation is the significant impairment of chaperone-mediated autophagy of gal3." SIGNOR-163743 MAPK9 protein P45984 UNIPROT TP53 protein P04637 UNIPROT up-regulates phosphorylation Ser20 PLSQETFsDLWKLLP 9606 11896587 t llicata "These findings strongly suggest that jnks are the major direct signaling mediators of uvb-induced p53 phosphorylation at serine 20. furthermore, phosphorylation of p53 at serine 20 by uvb-activated jnks and uvb-induced p53-dependent transcriptional activity were suppressed in jnk1 or jnk2 knockout (jnk1(-/-) or jnk2(-/-)) cells." SIGNOR-115835 ESR1 protein P03372 UNIPROT TFF1 protein P04155 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000356 11517191 f "ER beta and ER alpha induced the expression of several endogenous genes such as pS2, TGF alpha, or the cyclin kinase inhibitor p21 but, in contrast to ER alpha, ER beta was unable to regulate c-myc proto-oncogene expression" SIGNOR-253938 INHBA protein P08476 UNIPROT ACVR2A protein P27037 UNIPROT "up-regulates activity" binding 9606 1646080 t gcesareni "A protein of 494 amino acids comprising a ligand-binding extracellular domain, a single membrane-spanning domain, and an intracellular kinase domain with predicted serine/threonine specificity. 125I-activin A binds to transfected COS cells with an affinity of 180 pM and can be competed by activin A, activin B, and inhibin A, but not by transforming growth factor beta 1." SIGNOR-235138 CDK2 protein P24941 UNIPROT MCM4 protein P33991 UNIPROT "down-regulates activity" phosphorylation Thr19 GSRRGRAtPAQTPRS 9606 BTO:0000567 12714602 t lperfetto "We report here that human mcm4, a subunit of the putative dna replicative helicase, is extensively phosphorylated in hela cells when they are incubated in the presence of inhibitors of dna synthesis or are exposed to uv irradiation. The data presented here indicate that the consecutive actions of atr-chk1 and cdk2 kinases are involved in this phosphorylation in the presence of hydroxyurea. Phosphorylation of t19 correlates with lowered level of dna helicase activity of the purified mcm4,6,7 complex." SIGNOR-100893 DOK1 protein Q99704 UNIPROT ITGB7 protein P26010 UNIPROT "down-regulates activity" binding 9606 19118207 t miannu "Integrins also bind to many PTBdomain-containing proteins (Calderwood et al., 2003) – including Dok1 and integrincytoplasmic-domain-associated protein 1 (ICAP1) – and these can compete with talin for binding to integrin and so can impair activation" SIGNOR-257695 GSDMD protein P57764 UNIPROT Pyroptosis phenotype SIGNOR-PH105 SIGNOR up-regulates cleavage:Asp275 CLHNFLTdGVPAEGA 26375003 f lperfetto "These results establish that proteolytic cleavage at Asp275 in GSDMDis sufficient to instructmammalian cells to undergo pyroptosis" SIGNOR-256416 MGluR proteinfamily SIGNOR-PF55 SIGNOR Excitatory_synaptic_transmission phenotype SIGNOR-PH133 SIGNOR up-regulates 9606 BTO:0000938 24564659 f miannu "Excitatory synaptic transmission in the mammalian brain is mediated primarily by the amino acid glutamate, activating two different groups of glutamate receptors: ionotropic and metabotropic." SIGNOR-264690 GSK3B protein P49841 UNIPROT SCN2A protein Q99250 UNIPROT "down-regulates activity" phosphorylation Thr1966 TPEKTDMtPSTTSPP 9606 BTO:0000938 32599005 t lperfetto "Glycogen synthase kinase 3β (GSK3beta) phosphorylates the Nav1.2C-terminal tail at T1966, suppressing Na+ currents and channel trafficking to the plasma membrane" SIGNOR-275748 "bisphenol F" chemical CHEBI:34575 ChEBI AR protein P10275 UNIPROT "down-regulates activity" "chemical inhibition" -1 31995776 t miannu "This study investigated the endocrine-disrupting activity of BPA, BPF, and BPS alone or as a mixture and the agonistic and antagonistic activity of the BPs using an in vitro bioassay to detect ER-, AR-, and AhR-mediated activity. Here, we evaluated the endocrine-disrupting risks of the bisphenols by investigating their agonist and antagonist activities with the estrogen (ER), androgen (AR), and aryl hydrocarbon (AhR) receptors. Our results showed that BPA, BPS, and BPF (BPs) have estrogen agonist and androgen antagonist activities and decrease the ERα protein level. ." SIGNOR-268734 Calcineurin complex SIGNOR-C155 SIGNOR NFATC3 protein Q12968 UNIPROT up-regulates dephosphorylation 9606 21880741 t gcesareni "Calcineurin directly dephosphorylates nfat resulting in the nuclear import of nfat." SIGNOR-252312 SUN1 protein O94901 UNIPROT NXF1 protein Q9UBU9 UNIPROT "up-regulates activity" binding 9606 BTO:0000567 SIGNOR-C303 28831067 t lperfetto "SUN1, a component of the LINC (Linker of Nucleoskeleton and Cytoskeleton) complex, functions in mammalian mRNA export through the NXF1-dependent pathway. It associates with mRNP complexes by direct interaction with NXF1." SIGNOR-263296 SP7 protein Q8TDD2 UNIPROT Osteoblast_differentiation phenotype SIGNOR-PH9 SIGNOR up-regulates 10090 11792318 f "Giulio Giuliani" "Our results established that the novel transcription factor Osx is required for osteoblast differentiation and hence for bone formation." SIGNOR-255449 FLT3 protein P36888 UNIPROT ACAT1 protein P24752 UNIPROT "up-regulates activity" phosphorylation Tyr407 HALKQGEyGLASICN 9606 BTO:0001545 34289383 t "in mitochondria" lperfetto "We previously reported that the mitochondrial fraction of FLT3 activates acetyl-CoA acetyltransferase ACAT1 in mitochondria via Y407 phosphorylation to acetylate and inhibit mitochondrial pyruvate dehydrogenase A (PDHA) and PDH phosphatase 1 (PDP1) " SIGNOR-267628 MCU protein Q8NE86 UNIPROT MCU_MICUB_variant complex SIGNOR-C499 SIGNOR "form complex" binding 9606 32315830 t miannu "MCU is a Ca2+-selective channel that mediates mitochondrial Ca2+ influx. The human channel contains tetrameric pore-forming MCU, regulatory subunits MICU1/2, and EMRE that is required both for channel function and MICU1/2-mediated Ca2+ regulation." SIGNOR-270862 NOTCH1 protein P46531 UNIPROT HES1 protein Q14469 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 19165418 f lperfetto "Several lines of evidence have suggested that these genes are indeed direct notch target genes: a) the promoters of hes1, hes5 and hes7 as well as hey1, hey2 and heyl subfamily of hes, related with yrpw motif) can be activated by a constitutive active form of notch1." SIGNOR-183507 PPP3CA protein Q08209 UNIPROT DNM2 protein P50570 UNIPROT unknown dephosphorylation Ser764 LQSASSHsPTPQRRP 10116 20496096 t "CaN is activated, targeting a set of proteins for dephosphorylation, including dynamin II |We have recently discovered that the ubiquitously expressed dynamin isoform, dynII, is phosphorylated at S764 specifically during mitosis (unpublished data). We now show that S764 is phosphorylated throughout mitosis and is dephosphorylated at the time of cytokinesis(dynII)." SIGNOR-248677 PLK1 protein P53350 UNIPROT CEP55 protein Q53EZ4 UNIPROT up-regulates phosphorylation Ser436 PTAALNEsLVECPKC 9606 16198290 t lperfetto "Upon mitotic entry, centrosome dissociation of cep55 is triggered by erk2/cdk1-dependent phosphorylation at s425 and s428. s425/428 phosphorylation is required for interaction with plk1, enabling phosphorylation of cep55 at s436...enabling it to relocate to the midbody to function in mitotic exit and cytokinesis." SIGNOR-140898 KLHL2 protein O95198 UNIPROT WNK2 protein Q9Y3S1 UNIPROT "down-regulates quantity by destabilization" binding 9606 BTO:0000007 23838290 t miannu "We found that KLHL2, as well as KLHL3, was co-immunoprecipitated with all four WNK isoforms. The direct interaction of KLHL2 with WNKs was confirmed on fluorescence correlation spectroscopy. Co-expression of KLHL2 and Cullin3 decreased the abundance of WNK1, WNK3 and WNK4 within HEK293T cells, and a significant increase of WNK4 ubiquitination by KLHL2 and Cullin3 was observed both in HEK293T cells and in an in vitro ubiquitination assay. These results suggest that KLHL2-Cullin3 also functions as an E3-ligase for WNK isoforms within the body." SIGNOR-272120 MAPK1 protein P28482 UNIPROT PARVA protein Q9NVD7 UNIPROT "up-regulates activity" phosphorylation Ser8 MATSPQKsPSVPKSP 9606 BTO:0001938 22955285 t lperfetto "Actopaxin (alpha-parvin) is a paxillin, integrin-linked kinase, and F-actin binding focal adhesion protein with several serine phosphorylation sites in the amino terminus that contribute to the regulation of cell spreading and migration.|Actopaxin phosphorylation of Ser4/8 enhances cell migration whereas a nonphosphorylatable (Quint) mutant suppresses migration in U2OS osteosarcoma cells (7)." SIGNOR-265759 ARID1B protein Q8NFD5 UNIPROT "SWI/SNF complex" complex SIGNOR-C92 SIGNOR "form complex" binding 9606 15627498 t lperfetto "We discuss recent insights in the functional differences between two evolutionary conserved subclasses of swi/snf-related chromatin remodeling factors. Onesubfamily comprises yeast swi/snf, fly bap and mammalian baf, whereas the other subfamily includes yeast rsc, fly pbap andmammalian pbaf. We review the subunit composition, conserved protein modules and biological functions of each of these subclasses ofswi/snf remodelers." SIGNOR-241713 PRKCA protein P17252 UNIPROT NOS3 protein P29474 UNIPROT "down-regulates activity" phosphorylation Thr495 TGITRKKtFKEVANA 9606 BTO:0001853 24379783 t lperfetto "The phosphorylation of both S617 and S635 have also been shown to promote increased eNOS-derived NO release (Michell et al., 2002). The phosphorylaiton of S617 can be induced by PKA or Akt activity, and may serve to sensitize eNOS to calmodulin binding and modulate the phosphorylation of other eNOS sites" SIGNOR-251620 IKBKB protein O14920 UNIPROT DOK1 protein Q99704 UNIPROT up-regulates phosphorylation Ser439 EPGTATGsGIKSHNS 9606 15574499 t amattioni "Ikkbeta phosphorylates dok1 s(439)s(443) and s(446)s(450) after tnf-alpha, il-1, or gamma-radiation. mutant dok1 a(439), a(443), a(446), and a(450) differed from wild-type dok1 in not inhibiting platelet-derived growth factor-induced extracellular signal-regulated kinase 1/2 phosphorylation or cell growth. Mutant dok1 a(439), a(443), a(446), and a(450) also did not promote cell motility whereas wild-type dok1 promoted cell motility." SIGNOR-131447 CHUK protein O15111 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR down-regulates phosphorylation Ser644 GLDFNFDsLISTQNV 9606 BTO:0000150 SIGNOR-C14 15084260 t gcesareni "Ikappab kinase promotes tumorigenesis through inhibition of forkhead foxo3a. The tnf treatment of ht-29 cells increased ikk-dependent foxo3 ser644 phosphorylation." SIGNOR-252893 CREBBP protein Q92793 UNIPROT RELA protein Q04206 UNIPROT up-regulates acetylation 9606 SIGNOR-C6 16382138 t gcesareni "Rela is also acetylated at several sites by p300 and cbp" SIGNOR-143396 SPATA13 protein Q96N96 UNIPROT CDC42 protein P60953 UNIPROT "up-regulates activity" "guanine nucleotide exchange factor" 9606 BTO:0000007 32203420 t Luana "We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2)." SIGNOR-260576 CD28 protein P10747 UNIPROT GRB2 protein P62993 UNIPROT up-regulates binding 9606 24098653 t fspada "Binding of the py site in cd28 (py-m-n-m) by pi3k and grb2 through their sh2 domains is a key step that triggers the cd28 signal transduction for t cell activation and differentiation" SIGNOR-202706 USF1 protein P22415 UNIPROT FMR1 protein Q06787 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 "BTO:0001363; BTO:0000142" 11058604 f miannu "We have also shown that USF1, USF2, and alpha-Pal/Nrf-1 are the major transcription factors that bind the promoter in brain and testis extracts and suggest that elevated levels of these factors account in part for elevated FMR1 expression in these organs." SIGNOR-254882 GSK3B protein P49841 UNIPROT DPYSL2 protein Q16555 UNIPROT "down-regulates activity" phosphorylation Thr514 SVTPKTVtPASSAKT 9606 phosphorylation:Ser522 PASSAKTsPAKQQAP 25040932 t lperfetto "Cdk5 and DYRK2 phosphorylate CRMP2 and CRMP4, respectively, priming these proteins at S522 before their subsequent phosphorylation by GSK-3b at T509, T516 and S518|e CRMP2 phosphorylation by GSK-3b disrupts its interaction with tubulin (Yamashita & Goshima, 2012), leading to growth inhibition" SIGNOR-264840 DDB1 protein Q16531 UNIPROT "DCX DET1-COP1" complex SIGNOR-C24 SIGNOR "form complex" binding 9606 17452440 t lperfetto "Mammalian det1 regulates cul4a activity and forms stable complexes with e2 ubiquitin-conjugating enzymes" SIGNOR-154505 "SAGA complex" complex SIGNOR-C465 SIGNOR H3C15 protein Q71DI3 UNIPROT "down-regulates activity" acetylation Lys15 ARKSTGGkAPRKQLA 9606 34811519 t "Acetlyation of H3 causes transcriptional activation, thus has an inhibitory role on H3" lperfetto "The HAT module within the SAGA and ADA complexes acetylates histone H3, mainly on residues K9 and K14." SIGNOR-269643 GGCX protein P38435 UNIPROT F2 protein P00734 UNIPROT "up-regulates activity" carboxylation Glu72 CSYEEAFeALESSTA -1 10556651 t lperfetto "We analyzed the number of glutamic acid (Glu) residues and their positions in the Gla domain (GD) of DCP to investigate the gamma-carboxylation mechanism of VK-dependent carboxylase. Several DCPs were found in each subject studied. The 10 Gla residues of human prothrombin were carboxylated in order from the N-terminal (residues 26, 25, 16, 29, 20, 19, 14, 32, 7 and 6)|In the absence of VK or in the presence of VK antagonists, hepatic VKdependent carboxylase activity is inhibited and des-g-carboxyprothrombin (abnormal prothrombin or PIVKA; protein induced by vitamin K antagonist, prothrombin) is released into the blood." SIGNOR-263683 TNFAIP1 protein Q13829 UNIPROT RHOA protein P61586 UNIPROT "down-regulates quantity" binding 9606 19782033 t miannu "BACURDs form ubiquitin ligase complexes, which selectively ubiquitinate RhoA, with Cul3. Our studies reveal a previously unknown mechanism for controlling RhoA degradation and regulating RhoA function in various biological contexts, which involves a Cul3/BACURD ubiquitin ligase complex." SIGNOR-264235 SOCS6 protein O14544 UNIPROT KIT protein P10721 UNIPROT down-regulates ubiquitination 9606 21030588 t miannu "Suppressor of cytokine signaling 6 (socs6) is a member of the socs family of e3 ubiquitin ligases that can interact with c-kit and suppress c-kit-dependent pathways. / we demonstrate that socs6 has ubiquitin ligase activity toward c-kit and regulates c-kit protein turnover in cells" SIGNOR-169145 ALDH1A2 protein O94788 UNIPROT "all-trans-retinoic acid" smallmolecule CHEBI:15367 ChEBI "up-regulates quantity" "chemical modification" 9606 21621639 t lperfetto "All-trans-retinoic acid (atRA) provides essential support to diverse biological systems and physiological processes.| An accrual of biochemical, physiological and genetic data have identified specific functional outcomes for the retinol dehydrogenases, RDH1, RDH10, and DHRS9, as physiological catalysts of the first step in atRA biosynthesis, and for the retinal dehydrogenases RALDH1, RALDH2, and RALDH3, as catalysts of the second and irreversible step." SIGNOR-265126 DAXX protein Q9UER7 UNIPROT AIRE protein O43918 UNIPROT "down-regulates activity" binding 9606 BTO:0000567 20185822 t 1 miannu "The interaction between AIRE and DAXX has been validated by in vivo coimmunoprecipitation analysis and colocalization study in mammalian cells. The interaction has been further confirmed by showing in transactivation assays that DAXX exerts a strong repressive role on the transcriptional activity of AIRE." SIGNOR-239287 SSH1 protein Q8WYL5 UNIPROT CFL1 protein P23528 UNIPROT "up-regulates activity" dephosphorylation Ser3 sGVAVSDG 9606 14531860 t "Differential activities, subcellular distribution and tissue expression patterns of three members of Slingshot family phosphatases that dephosphorylate cofilin.|Cofilin, a key regulator of actin filament dynamics, is inactivated by phosphorylation at Ser-3 by LIM-kinases and is reactivated by dephosphorylation by a family of protein phosphatases, termed Slingshot (SSH)." SIGNOR-248762 NFYB protein P25208 UNIPROT GFI1B protein Q5VTD9 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 19965638 f miannu "HMGB2 binds to the GFI1B promoter in vivo and up-regulates its trans-activation most likely by enhancing the binding of Oct-1 and, to a lesser extent, of GATA-1 and NF-Y to the GFI1B promoter." SIGNOR-254431 F2RL3 protein Q96RI0 UNIPROT GNAI1 protein P63096 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257044 FBXO21 protein O94952 UNIPROT "Cullin 1-RBX1-Skp1" complex SIGNOR-C529 SIGNOR "up-regulates activity" binding -1 26299618 t miannu "Here we demonstrate that a ubiquitin E3-ligase, FBXO21, targets the multidrug resistance transporter, ABCB1, also known as P-glycoprotein (P-gp), for proteasomal degradation.Purified in vitro translated FLAG-tagged P-gp along with E2 (UbcH5c), E3 ligase FBXO21, Cul1, Skp1, Roc1 purified from Sf-9 insect cells were incubated in vitro." SIGNOR-272424 PTK6 protein Q13882 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates phosphorylation Tyr326 EVLEDNDyGRAVDWW 9606 BTO:0000150 BTO:0001129 20606012 t gcesareni "Here we demonstrate that AKT is a direct substrate of PTK6 and that AKT tyrosine residues 315 and 326 are phosphorylated by PTK6." SIGNOR-166510 CAMK2B protein Q13554 UNIPROT CAMK2B protein Q13554 UNIPROT "up-regulates activity" phosphorylation Thr287 SMMHRQEtVECLKKF 2842767 t llicata "Ca2+/calmodulin-dependent protein kinase II: identification of threonine-286 as the autophosphorylation site in the alpha subunit associated with the generation of Ca2+-independent activity." SIGNOR-250640 ROCK1 protein Q13464 UNIPROT DES protein P17661 UNIPROT unknown phosphorylation Thr77 RASRLGTtRTPSSYG 9606 BTO:0000971 10574968 t lperfetto "We developed antibodies specifically recognizing the kinase-dependent phosphorylation of desmin at Thr-16, Thr-75, and Thr-76. With these antibodies, phosphorylation of desmin was observed specifically at the cleavage furrow in late mitotic Saos-2 cells. We then found that treatment of the interphase cells with calyculin A revealed phosphorylation at all the three sites of desmin" SIGNOR-249033 JUNB protein P17275 UNIPROT IL4 protein P05112 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000782 21799768 f "Our results suggest that the prolonged IL-4 expression in NFAT1 deficient Th2 cells is mediated by preferential binding of JUNB/SATB1 to the IL-4 promoter with permissive chromatin architecture" SIGNOR-254503 CDK5 protein Q00535 UNIPROT STXBP2 protein Q15833 UNIPROT down-regulates phosphorylation Thr572 IGSSHILtPTRFLDD 9606 BTO:0000938 17716669 t lperfetto "It was shown that munc18 inhibition of neuronal syntaxin 1 can be overcome by cdk5 phosphorylation, indicating that structural change disrupts the syntaxin-munc18 interaction." SIGNOR-157528 EVL protein Q9UI08 UNIPROT Axonal_growth_cone_formation phenotype SIGNOR-PH199 SIGNOR up-regulates 9606 18508258 f miannu "Here we review recent findings into Ena/VASP function in neurite initiation, axon outgrowth and guidance." SIGNOR-268391 CACNA1E protein Q15878 UNIPROT Excitatory_synaptic_transmission phenotype SIGNOR-PH133 SIGNOR up-regulates 9606 BTO:0000227 30849329 f miannu "Voltage-gated calcium channels mediate the influx of calcium in response to membrane depolarization in excitable cells. In presynaptic nerve terminals, this calcium influx triggers transmitter release for synaptic transmission." SIGNOR-264327 PTK2 protein Q05397 UNIPROT PTK2 protein Q05397 UNIPROT up-regulates phosphorylation Tyr397 SVSETDDyAEIIDEE 9606 10816598 t miannu "Fak autophosphorylation site, tyr397. / extracellular matrix (ecm)-induced autophosphorylation of fak on tyr397 creates a high affinity binding site for the sh2 domain of c-src, and mutation (tyr to phe) of this residue inhibits association" SIGNOR-77434 HAUS7 protein Q99871 UNIPROT "HAUS complex" complex SIGNOR-C281 SIGNOR "form complex" binding 9606 BTO:0000567 19369198 t lperfetto "Here, by using mass spectrometry, we identified the full human augmin complex of 8 subunits and show that it interacts with the gamma-tubulin ring complex (gamma-TuRC)" SIGNOR-262318 TNF protein P01375 UNIPROT AKT2 protein P31751 UNIPROT up-regulates 9606 11287630 f lperfetto "Tumor necrosis factor (tnf) inhibited insulin-promoted tyrosine phosphorylation of irs-1 and activated the akt/protein kinase b serine-threonine kinase, a downstream target for phosphatidylinositol 3-kinase" SIGNOR-106596 SLC34A1 protein Q06495 UNIPROT phosphate(3-) smallmolecule CHEBI:18367 ChEBI "up-regulates quantity" relocalization 9606 BTO:0000671 20335586 t lperfetto "Genetic analysis revealed a homozygous in-frame duplication of 21 bp in SLC34A1, which encodes the renal sodium-inorganic phosphate cotransporter NaPi-IIa," SIGNOR-270576 ATG16L1 protein Q676U5 UNIPROT ATG12/5/16L1 complex SIGNOR-C109 SIGNOR "form complex" binding 9606 BTO:0000007 18321988 t lperfetto "Atg12 is conjugated to atg5 and forms an approximately 800-kda protein complex with atg16l (referred to as atg16l complex)." SIGNOR-226696 PRKCA protein P17252 UNIPROT HRH1 protein P35367 UNIPROT down-regulates phosphorylation Ser398 WKRLRSHsRQYVSGL 9606 BTO:0000975 15107581 t "Translocation from Endosome to Lysosome" fspada "The peptide p9-s396a/s398a (both ser396 and ser398 to alanines) was phosphorylated only slightly or not phosphorylated by these kinases. Thus both ser396 and ser398 can be phosphorylated by camk ii and pkc" SIGNOR-124352 NOG protein Q13253 UNIPROT BMPR1B protein O00238 UNIPROT "down-regulates activity" binding 9606 22298955 t lperfetto "Noggin binds the domain that is re-quired for bmp-7 to interact with bmp type i and type ii receptors.Noggin Inhibits bmp by blocking the molecular interfaces of the binding epitopes for both type i and type ii receptors (pmid 12478285)" SIGNOR-192802 KLF8 protein O95600 UNIPROT HBB protein P68871 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 10090 BTO:0000944 10756197 t Luana "These results establish KLF8 as a CACCC-box binding protein that associates with CtBP and represses transcription." SIGNOR-266052 TCEA1 protein P23193 UNIPROT UBR5 protein O95071 UNIPROT up-regulates binding 9606 21127351 t miannu "We show that the e3 ubiquitin ligase ubr5 associates with the cdk9 subunit of positive transcription elongation factor b to mediate its polyubiquitination in human cells. Tfiis also binds ubr5 to stimulate cdk9 polyubiquitination." SIGNOR-170258 CDK1 protein P06493 UNIPROT UBXN2B protein Q14CS0 UNIPROT "down-regulates activity" phosphorylation Ser56 PKATVFKsPRTPPQR 23500464 t lperfetto "At mitosis, Cdc2 kinase phosphorylates p47 on Serine-140 and p37 on Serine-56 and Threonine-59, respectively. The phosphorylated p47 and p37 are unable to bind to Golgi membranes, resulting in mitotic inhibition of the p97/p47 and the p97/p37 pathways, respectively." SIGNOR-265040 CDC42BPA protein Q5VT25 UNIPROT MYL2 protein P10916 UNIPROT "up-regulates activity" phosphorylation Ser19 GANSNVFsMFEQTQI BTO:0000567 9418861 t llicata "These approximately 190-kDa myotonic dystrophy kinase-related Cdc42-binding kinases (MRCKs) preferentially phosphorylate nonmuscle myosin light chain at serine 19, which is known to be crucial for activating actin-myosin contractility." SIGNOR-250723 PINK1 protein Q9BXM7 UNIPROT UBC protein P0CG48 UNIPROT "up-regulates activity" phosphorylation Ser65 DYNIQKEsTLHLVLR 9606 BTO:0000938 24784582 t lperfetto "Ubiquitin is phosphorylated by PINK1 to activate parkin|PINK1 phosphorylated ubiquitin at Ser65 both in vitro and in cells" SIGNOR-249691 MAPK1 protein P28482 UNIPROT PML protein P29590 UNIPROT up-regulates phosphorylation Ser40 RQPSPSPsPTERAPA 9606 BTO:0001271 15093545 t llicata "We report here that as(2)o(3) treatment induces phosphorylation of the pml protein through a mitogen-activated protein (map) kinase pathway. Increased pml phosphorylation is associated with increased sumoylation of pml and increased pml-mediated apoptosis." SIGNOR-124248 Olopatadine chemical CHEBI:7769 ChEBI HRH1 protein P35367 UNIPROT "down-regulates activity" "chemical inhibition" 9606 BTO:0002126 18446005 t Luana "We therefore tested how receptor internalization influenced the binding properties of a variety of H1-receptor antagonists. In this report, we present our findings that there were clear differences between the effect of histamineinduced H1-receptor internalization on the inhibition of [ 3 H]mepyramine binding by sedative and non-sedative H1-receptor antagonists in intact cells" SIGNOR-257782 PAK2 protein Q13177 UNIPROT ABL1 protein P00519 UNIPROT down-regulates phosphorylation Ser619 PTPPKRSsSFREMDG 9606 18161990 t lperfetto "The interaction of c-abl with the abl interactor protein abi2 is shown to be negatively regulated by phosphorylation of serines 637 and 638. These serines are adjacent to the pxxp motif (ptppkrs637s638sfr) that binds the sh3 domain of abi. phosphorylation of c-abl by pak2 inhibits the interaction between the sh3 domain of abi2 and the pxxp motif of c-abl." SIGNOR-160219 TSSK4 protein Q6SA08 UNIPROT CREB1 protein P16220 UNIPROT up-regulates phosphorylation Ser119 EILSRRPsYRKILND 9606 BTO:0000007 15964553 t gcesareni "Tssk5, a novel member of the testis-specific serine/threonine kinase family, phosphorylates creb at ser-133, and stimulates the cre/creb responsive pathway." SIGNOR-138289 HBEGF protein Q99075 UNIPROT ERBB4 protein Q15303 UNIPROT up-regulates binding 9606 BTO:0000887;BTO:0001260 9135143 t gcesareni "It was concluded that her4 is a newly described receptor for hb-egf and that hb-egf can activate two egf receptor subtypes, her1 and her4, but with different biological response." SIGNOR-47881 ASPA protein P45381 UNIPROT "acetic acid" smallmolecule CHEBI:15366 ChEBI "up-regulates quantity" "chemical modification" 9606 17194761 t miannu "N-acetyl-l-aspartate (NAA) is one of the most abundant amino acid derivatives found in the vertebrate brain, second only to glutamate. Aspartoacylase catalyzes hydrolysis of N-acetyl-l-aspartate to aspartate and acetate in the vertebrate brain." SIGNOR-267527 N-(2-chlorophenyl)-4-[[2-[4-[2-(4-ethyl-1-piperazinyl)-2-oxoethyl]anilino]-5-fluoro-4-pyrimidinyl]amino]benzamide chemical CHEBI:91365 ChEBI AURKA protein O14965 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-190029 GABA-A proteinfamily SIGNOR-PF61 SIGNOR CRHR2 protein Q13324 UNIPROT down-regulates 9606 BTO:0000614 33536967 f lperfetto "OT inhibits corticotropin-releasing factor (CRF) mRNA expression at the hypothalamus, resulting in antistress and anti-anxiety effects| It has been demonstrated that the inhibitory effect of OT on CRF mRNA expression is not a direct one on CRF neurons. GABAergic neurons are present in the surroundings of the PVN (peri-PVN). These GABA-projecting neurons into the PVN inhibits CRF expression via GABAA receptors" SIGNOR-268599 NUP98-HOXA9 "fusion protein" SIGNOR-FP15 SIGNOR RBPMS protein Q93062 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 17442773 f miannu "Over 102 cytoplasmic mRNAs were significantly altered in K562 myeloid leukemic cells transduced with NUP98‐HOXA9, 92 being increased and only 10 decreased. The gene for the RNA‐binding protein with multiple splicing (RBPMS) was upregulated in NUP98‐HOXA9–transduced cord blood CD34+ cells and also in the transcriptosomes of normal CD34+ and CD133+ cells." SIGNOR-261503 PPP1CC protein P36873 UNIPROT AKT1 protein P31749 UNIPROT "down-regulates activity" dephosphorylation Ser473 RPHFPQFsYSASGTA 9606 BTO:0002419 14633703 t "Here, we identify PP1 as a serine/threonine phosphatase that associates with and dephosphorylates AKT in breast cancer cells|The heat shock protein 90 inhibitor geldanamycin and the ErbB inhibitor ZD1839 promote rapid PP1 phosphatase-dependent inactivation of AKT in ErbB2 overexpressing breast cancer cells" SIGNOR-252605 PI4KB protein Q9UBF8 UNIPROT "phosphatidylinositol 4-phosphate" smallmolecule CHEBI:37530 ChEBI "up-regulates quantity" "chemical modification" 9534 22253445 t lperfetto "Interestingly, we found that PI4P, the product of PI4KB catalysis, creates a lipid microenvironment that is required for SARS-CoV S-mediated entry." SIGNOR-260732 PRKACB protein P22694 UNIPROT TENT2 protein Q6PIY7 UNIPROT "down-regulates activity" phosphorylation Ser116 LSGERRYsMPPLFHT 9606 31057087 t miannu "We found that Gld2 activity is regulated by site-specific phosphorylation in its disordered N-terminal domain. We identified two phosphorylation sites (S62, S110) where phosphomimetic substitutions increased Gld2 activity and one site (S116) that markedly reduced activity. Using mass spectrometry, we confirmed that HEK 293 cells readily phosphorylate the N-terminus of Gld2. We identified protein kinase A (PKA) and protein kinase B (Akt1) as the kinases that site-specifically phosphorylate Gld2 at S116, abolishing Gld2-mediated nucleotide addition." SIGNOR-259403 CASP3 protein P42574 UNIPROT GSN protein P06396 UNIPROT "down-regulates activity" cleavage Asp403 WRDPDQTdGLGLSYL 9606 9671712 t miannu "We showed that human gelsolin was cleaved during Fas-mediated apoptosis in vivo and that the caspase-3 cleavage site of human gelsolin was at D352 of DQTD352G. gelsolin seems to have dual functions, i.e., it both prevents and, once cleaved, induces cell death." SIGNOR-256357 CAMK2B protein Q13554 UNIPROT CTNNB1 protein P35222 UNIPROT down-regulates phosphorylation Thr332 VNIMRTYtYEKLLWT 9606 BTO:0000938 24117889 t lperfetto "Camkii represses transcriptionally active _-catenin to mediate acute ethanol neurodegeneration and can phosphorylate _-catenincamkii can directly phosphorylate _-catenin. Using targeted mutagenesis we identified camkii phosphorylation sites within human _-catenin at t332, t472, and s552." SIGNOR-202829 AMPK complex SIGNOR-C15 SIGNOR CHKA protein P35790 UNIPROT "up-regulates activity" phosphorylation Ser279 KKLHKLLsYNLPLEL 9606 BTO:0000527 34929314 t lperfetto "Glucose deprivation induces the binding of choline kinase α2 (CHKα2) to lipid droplets, followed by a continuous PTMs to promote lipolysis of lipid droplets, which are in turn mediated by AMPK-dependent CHKα2 Serine 279 phosphorylation and KAT5-dependent CHKα2 Lysine 247 acetylation." SIGNOR-267647 DVL3 protein Q92997 UNIPROT FRAT1 protein Q92837 UNIPROT up-regulates binding 9606 BTO:0000567 BTO:0000671 12556519 t gcesareni "These results indicate that cki epsilon-dependent phosphorylation of dvl enhances the formation of a complex of dvl-1 with frat-1 and that this complex leads to the activation of the wnt signaling pathway." SIGNOR-97877 LUBAC complex SIGNOR-C527 SIGNOR GLYR1 protein Q49A26 UNIPROT "down-regulates quantity by destabilization" ubiquitination Lys535 NEVYKRAkALDQSDN 9606 BTO:0000007 25278611 t miannu "Here, we analyzed changes in the ubiquitin landscape induced by prostate cancer-associated mutations of SPOP, an E3 ubiquitin ligase substrate-binding protein. SPOP mutants impaired ubiquitylation of a subset of proteins in a dominant-negative fashion. Of these, DEK and TRIM24 emerged as effector substrates consistently up-regulated by SPOP mutants. Up-regulation of DEK, TRIM24 and NCOA3 is a feature of prostate cancer SPOP mutations." SIGNOR-272840 GRIK3 protein Q13003 UNIPROT calcium(2+) smallmolecule CHEBI:29108 ChEBI "up-regulates quantity" relocalization 9606 29953871 t miannu "Ca2+ is arguably the most important second messenger in the brain because of its pivotal roles in presynaptic neurotransmitter release, postsynaptic responses, and plasticity induction. iGluRs and mGluRs can generate intracellular Ca2+ signals, albeit by different mechanisms, whose crosstalk has not been thoroughly explored (Figure 2C). iGluRs allow the influx of extracellular Ca2+ upon pore opening. This is widely acknowledged for NMDARs, which have a high Ca2+ conductance, but Ca2+ flux through AMPARs and KARs can still be substantial." SIGNOR-264944 PAK1 protein Q13153 UNIPROT BAD protein Q92934 UNIPROT down-regulates phosphorylation Ser74 VEIRSRHsSYPAGTE 9606 22096607 t lperfetto "Bad is a pro-apoptotic member of the bcl-2 family of proteins, which can be phosphorylated on numerous sites to modulate binding to bcl-2 and 14-3-3 proteins and inhibit its pro-apoptotic activities. Together, these findings demonstrate that pak1 phosphorylates bad directly at s111, but phosphorylated s112 through raf-1. These two sites of bad serve as redundant regulatory sites for bcl-2 binding" SIGNOR-177271 IKBKE protein Q14164 UNIPROT REL protein Q04864 UNIPROT up-regulates phosphorylation 9606 SIGNOR-C68 16888014 t miannu "The present results demonstrate that ikkepsilon- and tbk1-mediated phosphorylation of crel in the c-terminal td leads to cytoplasmic dissociation of a crel-ikb_ complex and nuclear accumulation of crel." SIGNOR-148620 DIDO1 protein Q9BTC0 UNIPROT ITGA5 protein P08648 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0001673 22469980 t Luana "Dido1 upregulates the expression of Integrin αV, thereby influencing the attachment, apoptosis and migration of melanoma cells." SIGNOR-261580 CDK11A protein Q9UQ88 UNIPROT SPDEF protein O95238 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser243 TDSEVDSsCSGQPIH 9606 BTO:0000007 26885618 t lperfetto "In this study we provide evidence that the cell cycle kinase CDK11p58, a protein involved in G2/M transition and degradation of several transcription factors, directly interacts with and phosphorylates SPDEF on serine residues|Western blot analysis demonstrated that only one of the mutant constructs, consisting of mutations of serine 238, 242 and 243, resulted in increased levels of SPDEF protein expression as compared to wild type SPDEF, leading to subsequent ubiquitination and degradation of SPDEF through the proteasome pathway.|" SIGNOR-273022 GADD45B protein O75293 UNIPROT CDK11A protein Q9UQ88 UNIPROT "down-regulates activity" binding 9606 BTO:0000007 26885618 t lperfetto "Western blot analysis for SPDEF revealed that overexpression of GADD45α, β and γ prevents SPDEF degradation mediated by CDK11p58 |We identified CDK11p58 as an interaction partner of GADD45α by co-immunoprecipitation analysis. We corroborated these data by co-immunoprecipitation in vitro translation assays, showing that all three members of the GADD45 family interact with CDK11p58." SIGNOR-273024 dobutamine chemical CHEBI:4670 ChEBI YAP1 protein P46937 UNIPROT down-regulates 9606 23431053 f "These results suggest that the activity of YAP/TAZ can be either up-regulated or down-regulated by GPCR signaling,depending on which Galfa protein is activated" gcesareni "Dobutamine is an agonist for the beta1 adrenergic receptor, which likely inhibits yap by activating gaalfas." SIGNOR-201259 RET protein P07949 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates phosphorylation Tyr315 TFCGTPEyLAPEVLE 9606 15994200 t lperfetto "The PKB Y315 residue, which is known to be phosphorylated by Src tyrosine kinase, was also a major site of phosphorylation by RET/PTC. RET/PTC-mediated tyrosine phosphorylation results in the activation of PKB kinase activity" SIGNOR-166514 serotonin smallmolecule CHEBI:28790 ChEBI HTR3D protein Q70Z44 UNIPROT "up-regulates activity" "chemical activation" 9606 BTO:0000938 25601315 t miannu "Serotonin or 5-hydroxytryptamine (5-HT) remains one of the most widely studied chemical messengers. Serotonin produces a myriad of physiological effects in humans, mediated through 14 distinct receptor subtypes, of which 13 are G protein coupled receptors (GPCRs), and one ligand-gated cation channel" SIGNOR-264292 PPM1D protein O15297 UNIPROT RPS6KA3 protein P51812 UNIPROT "down-regulates activity" dephosphorylation Ser227 DHEKKAYsFCGTVEY 10090 15206906 t "RSK2 (p90 ribosomal S6 kinase 2) is activated via the ERK (extracellular-signal-regulated kinase) pathway by phosphorylation on four sites: Ser227 in the activation loop of the N-terminal kinase domain, Ser369 in the linker, Ser386 in the hydrophobic motif and Thr577 in the C-terminal kinase domain of RSK2. In the present study, we demonstrate that RSK2 is associated in vivo with PP2Cdelta (protein phosphatase 2Cdelta). In epidermal growth factorstimulated cells, RSK2 is partially dephosphorylated on all four sites in an Mn2+-dependent manner, leading to reduced protein kinase activity" SIGNOR-248320 DZIP3 protein Q86Y13 UNIPROT H2AC18 protein Q6FI13 UNIPROT "up-regulates activity" monoubiquitination Lys119 IQAVLLPkKTESHHK 9606 BTO:0000007 18206970 t miannu " 2A-HUB catalyzes monoubiquitination of H2A at lysine 119, functioning as a combinatoric component of the repression machinery required for specific gene regulation programs. Thus, 2A-HUB mediates a selective repression of a specific set of chemokine genes in macrophages, critically modulating migratory responses to TLR activation. H2A monoubiquitination acts to prevent FACT recruitment at the transcriptional promoter region, blocking RNA polymerase II release at the early stage of elongation." SIGNOR-271755 PRKCG protein P05129 UNIPROT RAF1 protein P04049 UNIPROT up-regulates phosphorylation Ser497 ATVKSRWsGSQQVEQ 9606 8288587 t gcesareni "Pkc can effectively phosphorylate raf-1, this is a direct effect of activated pkc and not the result of raf-1 autophosphorylation." SIGNOR-37541 PRKAA1 protein Q13131 UNIPROT CRY1 protein Q16526 UNIPROT down-regulates phosphorylation Ser71 ANLRKLNsRLFVIRG 9606 SIGNOR-C15 phosphorylation:Ser71 ANLRKLNsRLFVIRG 21892142 t gcesareni "Ampk was shown to regulate the stability of the core clock component cry1 though phosphorylation of cry1 ser71, which stimulates the direct binding of the fbox protein fbxl3 to cry1, targeting it for ubiquitin-mediated degradation" SIGNOR-176472 NEDD4L protein Q96PU5 UNIPROT SCN9A protein Q15858 UNIPROT "down-regulates quantity by destabilization" ubiquitination 10090 BTO:0000938 23778145 t miannu "The control of Nav density at the cell membrane is crucial to ensuring normal neuronal excitability. Navs are subject to posttranslational modifications that may influence their cell membrane availability. Ubiquitylation is a key process that orchestrates the internalization and subsequent degradation or recycling of Navs. This is accomplished by ubiquitin protein ligases, such as NEDD4-2 (neuronal precursor cell expressed developmentally downregulated-4 type 2)." SIGNOR-253458 E2F1 protein Q01094 UNIPROT CyclinE/CDK2 complex SIGNOR-C16 SIGNOR "up-regulates quantity by expression" "transcriptional regulation" 9606 8649818 f lperfetto "We have found that cell cycle regulation of cyclin E transcription is mediated by E2F binding sites present in the promoter. The activity of this promoter can be regulated negatively by pRB." SIGNOR-245471 GPHN protein Q9NQX3 UNIPROT ARHGEF9 protein O43307 UNIPROT "up-regulates activity" binding 9606 25882190 t miannu "Gephyrin is believed to act as a scaffold at inhibitory synapses, in a manner analogous to that of the prototypic excitatory synaptic scaffold, PSD-95. The best-known function of gephyrin is to bring the inhibitory synaptic receptors and to stabilize them at the inhibitory synapses. gephyrin interacts with NL-2 and collybistin, suggesting that it may be critical for the maturation or maintenance of inhibitory synapses." SIGNOR-264973 PRRX1 protein P54821 UNIPROT MAFB protein Q9Y5Q3 UNIPROT "down-regulates activity" binding -1 11036080 t miannu "Hoxd12 and MHox, that interact with v-/c-Maf, using the phage display method. The Hox proteins also could associate with the other Maf protein family members, MafB, MafK, MafF, and MafG, but not with Jun and Fos. The Hox proteins negatively regulated the DNA binding, transactivation and cell-transforming abilities of Maf." SIGNOR-221899 GTF2B protein Q00403 UNIPROT FOXF2 protein Q12947 UNIPROT "up-regulates activity" binding 9534 BTO:0004055 9722567 t miannu "The human forkhead protein FREAC-2 contains two functionally redundant activation domains and interacts with TBP and TFIIB. FREAC-2 dependent activation of transcription by TFIIB." SIGNOR-220317 ENO1 protein P06733 UNIPROT phosphonatoenolpyruvate smallmolecule CHEBI:58702 ChEBI "up-regulates quantity" "chemical modification" 9606 29767008 t miannu "Alpha-enolase (ENO1), also known as 2-phospho-D-glycerate hydrolase, is a metalloenzyme that catalyzes the conversion of 2-phosphoglyceric acid to phosphoenolpyruvic acid in the glycolytic pathway. Subsequent studies have shown that three types of enolase isoenzymes exist in mammals: Œ±-enolase (ENO1) is present in almost all mature tissues; Œ≤-enolase (ENO3) exists primarily in muscle tissues; and Œ≥-enolase (ENO2) occurs mainly in nervous and neuroendocrine tissues. All enolases are composed of two identical subunits." SIGNOR-266524 ITGB4 protein P16144 UNIPROT PI3K complex SIGNOR-C156 SIGNOR up-regulates binding 9606 9428518 t gcesareni "Stable expression of alpha6beta4 increased carcinoma invasion in a pi3k-dependent manner, and transient expression of a constitutively active pi3k increased invasion in the absence of alpha6beta4. Ligation of alpha6beta4 stimulated significantly more pi3k activity than ligation of beta1 integrins, establishing specificity among integrins for pi3k activation." SIGNOR-252697 NFIX protein Q14938 UNIPROT WNT5A protein P41221 UNIPROT "down-regulates quantity" "transcriptional regulation" 10090 31838646 t Gianni "By integrating transcriptomic profiling (RNA-seq) of Nfia- and Nfix-deficient GNPs with epigenomic profiling (ChIP-seq against NFIA, NFIB and NFIX, and DNase I hypersensitivity assays), we reveal that these transcription factors share a large set of potential transcriptional targets, suggestive of complementary roles for these NFI family members in promoting neural development" SIGNOR-268889 Aflibercept chemical SID:134445687 ChEBI VEGFA protein P15692 UNIPROT "down-regulates activity" "chemical inhibition" 9606 22813448 t miannu "Aflibercept, a fusion protein with binding domains from native VEGF receptors, binds VEGF-A, VEGF-B, and placental growth factors 1 and 2 with high affinity.This soluble decoy receptor is produced by fusing all-human DNA sequences of the second immunoglobulin (Ig) domain of human VEGF receptor (VEGFR) 1 to the third Ig domain of human VEGFR-2, which then is fused to the Fc region of human IgG-1.2 Aflibercept binds to all VEGF-A and VEGF-B isoforms, as well as the highly related placental growth factor." SIGNOR-259386 PTPN1 protein P18031 UNIPROT CTTN protein Q14247 UNIPROT "up-regulates activity" dephosphorylation Tyr446 GTEPEPVySMEAADY 9534 BTO:0004055 18387954 t "Here, we have identified cortactin, a central regulator of actin cytoskeletal dynamics, as a substrate of PTP1B. A trapping mutant of PTP1B binds cortactin at the phosphorylation site Tyr446, |Cortactin exerts its effects on the actin cytoskeleton by interacting directly with the Arp2/3 complex , F-actin |Src phosphorylates murine cortactin predominantly at three key sites in vitro, Tyr421, Tyr466, and Tyr482 (corresponding to Tyr421, Tyr470, and Try486 in human cortactin), resulting in decreased actin cross-linking activity" SIGNOR-248432 "mono(2-ethylhexyl) phthalate" chemical CHEBI:17243 ChEBI PPARA protein Q07869 UNIPROT "up-regulates activity" "chemical activation" 9606 19433246 t miannu "Phthalates are true ligands of PPARs. Mono-ethyl-hexyl-phthalate (MEHP), a metabolite of the widespread plasticizer di-ethyl-hexyl-phthalate (DEHP), has been found in exposed organisms and interacts with all three PPARs. A thorough analysis of its interactions with PPARgamma identified MEHP as a selective PPARgamma modulator, and thus a possible contributor to the obesity epidemic." SIGNOR-268745 SRC protein P12931 UNIPROT WWOX protein Q9NZC7 UNIPROT up-regulates phosphorylation Tyr33 TTKDGWVyYANHTEE 9606 15070730 t llicata "The tyrosine kinase, src, phosphorylates wwox at tyrosine 33 in the first ww domain and enhances its binding to p73." SIGNOR-123819 STAT5A protein P42229 UNIPROT Cell_death phenotype SIGNOR-PH109 SIGNOR down-regulates 9606 BTO:0001096 14530308 f apalma "Specific inhibition of Stat5a/b promotes apoptosis of IL-2-responsive primary and tumor-derived lymphoid cells" SIGNOR-256663 FANCD2 protein Q9BXW9 UNIPROT "Fanconi anemia ID complex" complex SIGNOR-C302 SIGNOR "form complex" binding 9606 BTO:0000007 17412408 t lperfetto "Immunoprecipitation of HA-FLAG-tagged FANCI expressed in 293T cells with antibodies against either HA or FLAG, but not MYC, resulted in coimmunoprecipitation of endogenous FANCD2|The FANCI protein associates with FANCD2 and, together, as the FANCI-FANCD2 (ID) complex, localize to chromatin in response to DNA damage." SIGNOR-263268 PAK5 protein Q9P286 UNIPROT GATA1 protein P15976 UNIPROT "up-regulates activity" phosphorylation Ser161 SSLPVPNsAYGGPDF 9606 BTO:0000150 25726523 t lperfetto "GATA1 is a new substrate of p21-activated kinase 5 (PAK5), which is phosphorylated on serine 161 and 187 (S161 and S187). GATA1 recruits HDAC3/4 to E-cadherin promoter, which is reduced by GATA1 S161A S187A mutant. These data indicate that phosphorylated GATA1 recruits more HDAC3/4 to promote transcriptional repression of E-cadherin, leading to the EMT of breast cancer cells." SIGNOR-275655 MCHR1 protein Q99705 UNIPROT GNAI1 protein P63096 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257034 CDK8 protein P49336 UNIPROT SMAD1 protein Q15797 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser206 SSSTYPHsPTSSDPG 9606 19914161 t lpetrilli "Phosphorylation of the linker region of smad1, a receptor-activated smad (r-smad), at serine 206 (s206) and s214 induced by bmp and mediated by cdk8/9 is critical for binding of the e3 ubiquitin ligase smurf1. Binding of smurf1 leads to polyubiquitination of smad1 and its degradation by the proteasome;cdk8 and cyclint-cdk9 showed a preference for s206 and s214 but also phosphorylated s186 and s195 in the case of smad1;and t179, s208 and s213 in the case of smad3." SIGNOR-189137 PKA proteinfamily SIGNOR-PF17 SIGNOR SCN2A protein Q99250 UNIPROT "down-regulates activity" phosphorylation 9606 BTO:0000938 32599005 t lperfetto "For example, protein kinase A (PKA) and protein kinase C (PKC) have been shown to phosphorylate multiple serine residues on the interdomain I-II and III-IV linkers of Nav1.2, significantly reducing current and increasing firing thresholds" SIGNOR-275749 Netrin proteinfamily SIGNOR-PF97 SIGNOR NEO1 protein Q92859 UNIPROT "up-regulates activity" binding 9606 BTO:0001484 21558366 t miannu "In mammals, three secreted netrins, netrin 1, 3 and 4, and two membrane-tethered glycophosphatidylinositol (GPI)-linked (see Glossary, Box 1) netrins, netrin G1 and G2, have been identified. In mammals, receptors for the secreted netrins include deleted in colorectal cancer (DCC), the DCC paralogue neogenin, the UNC-5 homologues UNC5A-D, and Down syndrome cell adhesion molecule (DSCAM)." SIGNOR-268172 EIF4E2 protein O60573 UNIPROT "EIF4E2/GIGYF1 complex" complex SIGNOR-C256 SIGNOR "form complex" binding 9606 30917308 t lperfetto "4EHP forms complexes with the GYF domain-containing proteins GIGYF1 and GIGYF2, which are critical for this translational repression" SIGNOR-261010 CAMK2A protein Q9UQM7 UNIPROT RCHY1 protein Q96PM5 UNIPROT down-regulates phosphorylation Ser155 CLEDIHTsRVVAHVL 9606 17568776 t lperfetto "Phosphorylation of pirh2 by calmodulin-dependent kinase ii impairs its ability to ubiquitinate p53" SIGNOR-156064 CSNK2A1 protein P68400 UNIPROT IRS1 protein P35568 UNIPROT unknown phosphorylation Thr811 ADDSSSStSSDSLGG -1 8349691 t llicata "These data suggest that casein kinase II mediates a portion of the insulin-stimulated serine/threonine phosphorylation of overexpressed IRS-1 in vivo. | Thr-502 was identified as the major casein kinase II-catalyzed phosphorylation site in rat IRS-1." SIGNOR-250910 PRKN protein O60260 UNIPROT SNCA protein P37840 UNIPROT "down-regulates quantity by destabilization" ubiquitination 9606 BTO:0000938 12666095 t lperfetto "Parkin is a protein of 465 amino acids, and its structure includes a ubiquitin homologous domain in its N terminus and two RING finger domains in its C terminus. Molecular studies have determined that parkin is an E3 ubiquitin ligase function, implicating parkin in the ubiquitin-proteasome system, and raising the possibility that mutations in the gene lead to loss or diminished function. Three substrates for the ubiquitin-ligase function of parkin have been identified to date.1. A 22kDa glycosolated form of alpha-synuclei|2. Parkin-associated endothelin receptor-like receptor (Pael-R)." SIGNOR-249705 PAK5 protein Q9P286 UNIPROT GATA1 protein P15976 UNIPROT "up-regulates activity" phosphorylation Ser187 LNSAAYSsPKLRGTL 9606 BTO:0000150 25726523 t lperfetto "GATA1 is a new substrate of p21-activated kinase 5 (PAK5), which is phosphorylated on serine 161 and 187 (S161 and S187). GATA1 recruits HDAC3/4 to E-cadherin promoter, which is reduced by GATA1 S161A S187A mutant. These data indicate that phosphorylated GATA1 recruits more HDAC3/4 to promote transcriptional repression of E-cadherin, leading to the EMT of breast cancer cells." SIGNOR-275656 RNF146 protein Q9NTX7 UNIPROT AXIN1 protein O15169 UNIPROT "down-regulates quantity by destabilization" ubiquitination 9606 21478859 t lperfetto "Here, we identify RNF146, a RING-domain E3 ubiquitin ligase, as a positive regulator of Wnt signalling. RNF146 promotes Wnt signalling by mediating tankyrase-dependent degradation of axin. Mechanistically, RNF146 directly interacts with poly(ADP-ribose) through its WWE domain, and promotes degradation of PARsylated proteins. Using proteomics approaches, we have identified BLZF1 and CASC3 as further substrates targeted by tankyrase and RNF146 for degradation." SIGNOR-263335 CSNK2B protein P67870 UNIPROT IRS1 protein P35568 UNIPROT unknown phosphorylation Ser330 SFRVRASsDGEGTMS -1 8349691 t llicata "These data suggest that casein kinase II mediates a portion of the insulin-stimulated serine/threonine phosphorylation of overexpressed IRS-1 in vivo. | Thr-502 was identified as the major casein kinase II-catalyzed phosphorylation site in rat IRS-1." SIGNOR-251073 PRKCA protein P17252 UNIPROT SNAP23 protein O00161 UNIPROT unknown phosphorylation Ser23 ITDESLEsTRRILGL 9606 12930825 t lperfetto "Ion trap mass spectrometry revealed that platelet SNAP-23 was phosphorylated at Ser23/Thr24 and Ser161, after cell activation by thrombin; these sites were also identified in PKC-phosphorylated r-SNAP-23. SNAP-23 mutants that mimic phosphorylation at Ser23/Thr24 inhibited syntaxin 4 interactions, whereas a phosphorylation mutant of Ser161 had only minor effects. | Because mutants that mimic SNAP-23 phosphorylation affect syntaxin 4 interactions, we hypothesize that SNAP-23 phosphorylation may be important for modulating SNARE-complex interactions during membrane trafficking and fusion." SIGNOR-249228 ZAP70 protein P43403 UNIPROT LCP2 protein Q13094 UNIPROT up-regulates phosphorylation Tyr113 SSFEEDDyESPNDDQ 9606 8702662 t lperfetto "A fourth peptide derived from slp-76 encompassing tyr residues 423 and 426 was also phosphorylated by zap-70 but with a 10-15-fold lesser efficiency compared to tyr-113, _128, and _145. Phosphorylation of slp-76 by the zap-70 protein-tyrosine kinase is required for t-cell receptor function" SIGNOR-42956 RUNX2 protein Q13950 UNIPROT BGLAP protein P02818 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 11331591 f gcesareni "Tgf-beta inhibited the expression of the cbfa1 and osteocalcin genes, whose expression is controlled by cbfa1 in osteoblast-like cell lines. This inhibition was mediated by smad3, which interacts physically with cbfa1 and represses its transcriptional activity at the cbfa1-binding ose2 promoter sequence" SIGNOR-107160 AMPK complex SIGNOR-C15 SIGNOR LIPE protein Q05469 UNIPROT down-regulates phosphorylation Ser855 EPMRRSVsEAALAQP 9606 9636039 t lperfetto "Phosphorylation of bovine hormone-sensitive lipase by the amp-activated protein kinase." SIGNOR-216507 CASP3 protein P42574 UNIPROT RAD51 protein Q06609 UNIPROT "down-regulates quantity by destabilization" cleavage 9606 BTO:0002882 11684015 t lperfetto "The RAD51 protein has been shown to be a substrate for caspase-3|he activated caspase-3 fragments (19 kDa and 17 kDa) and caspase-3 cleaved RAD51 fragment (∼23 kDa) was detected by Western analysis (Figure 3E). Activation of caspase-3 and the signature proteolytic degradation product of RAD51 only occurred in parental 32Dcl3 cells after treatment with cisplatin" SIGNOR-271709 HIF1A protein Q16665 UNIPROT EPO protein P01588 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 8663540 t lperfetto "Hypoxia-inducible factor 1 (HIF-1) is a heterodimeric basic helix-loop-helix transcription factor that regulates hypoxia-inducible genes including the human erythropoietin (EPO) gene." SIGNOR-253695 PRKCA protein P17252 UNIPROT HMGN2 protein P05204 UNIPROT down-regulates phosphorylation Ser25 KDEPQRRsARLSAKP 9606 10739259 t lperfetto "Protein kinases that phosphorylate hmg-14 17 at the major sites have been implicated from previous in vitro studies. Protein kinase c and a similar calcium phospholipid-dependent kinase have been reported to phosphorylate both proteins in vitro, where the phosphorylation of hmg-17 occurs predominantly at ser24 and to a lesser degree at ser28. Phosphorylation of hmg-14 at ser6 by camp- or cgmp-dependent kinases has also been reported. Thus, other kinases may contribute to phosphorylation at ser6 in response to oa. Ser88 and ser98 on hmg-14 are also phosphorylated by casein kinase ii in vitro. we conclude that the correlation we observe reflects a causal relationship, in which phosphorylation somehow facilitates the redistribution of hmg-14 and -17 toward non-nuclear pools." SIGNOR-76320 PPP2CA protein P67775 UNIPROT BCL2 protein P10415 UNIPROT "up-regulates activity" dephosphorylation Ser87 AAAGPALsPVPPVVH 9606 15225643 t "The phosphorylation of Bcl-2 resulted in a reduction in anti-apoptotic function, implying that dephosphorylation promoted the anti-apoptotic activity of Bcl-2 protein in human tumor cell lines. Thus, the present findings suggest that ERK and PP2A are physiological regulators of Bcl-2 phosphorylation, and these enzymes exert an influence on the anti-apoptotic function of Bcl-2.phosphorylation of Bcl2 at Ser70 is proposed to be a dynamic process regulated by the sequential action of an agonist-activated Bcl2 kinase and PP2A." SIGNOR-248624 PAK5 protein Q9P286 UNIPROT RELA protein Q04206 UNIPROT "up-regulates activity" phosphorylation 9606 BTO:0000150 29041983 t lperfetto "PAK5-mediated phosphorylation and nuclear translocation of NF-κB-p65 promotes breast cancer cell proliferation in vitro and in vivo|We characterized that PAK5 could promote the phosphorylation and the nuclear translocation of p65 subunit of nuclear factor-kappaB, and demonstrated that p65 could directly bind to the promoter of Cyclin D1" SIGNOR-275657 MAPK9 protein P45984 UNIPROT SFN protein P31947 UNIPROT down-regulates phosphorylation Ser186 FHYEIANsPEEAISL 9606 15071501 t "JNK1 and JNK2 are required for apoptosis of thymocites,Ser residues in the reagion between alpha-helices 7 and 8" gcesareni "Jnk phosphorylates 14-3-3zeta_ at ser-184 and 14-3-3sigma_ at ser-189" SIGNOR-124027 solifenacin chemical CHEBI:135530 ChEBI CHRM2 protein P08172 UNIPROT "down-regulates activity" "chemical inhibition" -1 21524581 t Luana "The IC50 values for solifenacin, YM-46303, tiotropium bromide and ipratropium bromide were also determined for reference" SIGNOR-258311 AKT proteinfamily SIGNOR-PF24 SIGNOR ACAP1 protein Q15027 UNIPROT unknown phosphorylation Ser554 SIRPRPGsLRSKPEP 9606 16256741 t llicata "Akt phosphorylates s554 in acap1" SIGNOR-141343 Autophagy phenotype SIGNOR-PH31 SIGNOR Protein_aggregates phenotype SIGNOR-PH142 SIGNOR up-regulates 32218723 f lperfetto "In many neurodegenerative conditions protein aggregation may occurs without specific GOF mutations in genes encoding aggregate-prone proteins. In these conditions protein aggregation is associated to the decline of cellular degradative functions, specifically of the autophagy-lysosomal pathway (ALP) (Figure 1)." SIGNOR-262269 CDK5/CDK5R1 complex SIGNOR-C144 SIGNOR DCX protein O43602 UNIPROT unknown phosphorylation Thr326 TSSSQLStPKSKQSP 9606 14741103 t llicata "In order to determine the sites of phosphorylation by Cdk5, serine or threonine in the nine potential sites were substituted with alanine by site-directed mutagenesis to create mutant Dcx proteins. hese were analyzed by co-transfection of 293T cells with cdk5/p35. All-sites-A mutant Dcx showed no slower migrating species on Western analysis, indicating that removal of all nine possible sites is sufficient to block the phosphorylation by Cdk5/p35. However, each single mutant Dcx retains the slower migrating species similar to the wild-type Dcx, suggesting that any single mutation is not sufficient to block phosphorylation by Cdk5/p35." SIGNOR-250659 MAPK1 protein P28482 UNIPROT POU5F1 protein Q01860 UNIPROT down-regulates phosphorylation Ser111 ESNSDGAsPEPCTVT 9606 23024368 t miannu "We demonstrate that oct4a interacts with erk1/2 by using both in vitro gst pulldown and in vivo co-immunoprecipitation assays. Ms analysis identified phosphorylation of oct4a at ser-111. / serine 111 phosphorylation regulates oct4a protein subcellular distribution and degradation." SIGNOR-192097 GADD45A protein P24522 UNIPROT CyclinB/CDK1 complex SIGNOR-C17 SIGNOR down-regulates binding 9606 10362260 t lperfetto "Gadd45 has now been found to directly inhibit the activity of cdc2/cyclin b1 complex" SIGNOR-217508 DKK1 protein O94907 UNIPROT KREMEN1 protein Q96MU8 UNIPROT up-regulates binding 9606 12050670 t gcesareni "Dkk1 has been shown to inhibitwnt by binding to and antagonizing lrp5/6. Here we show that the transmembrane proteins kremen1 and kremen2 are high-affinity dkk1 receptors that functionally cooperate with dkk1 to blockwnt/betBeta-catenin. Kremen2 forms a ternary complex with dkk1 and lrp6, and induces rapid endocytosis and removal of thewntreceptor lrp6 from the plasma membrane." SIGNOR-88838 PARP1 protein P09874 UNIPROT SNAIL/RELA/PARP1 complex SIGNOR-C198 SIGNOR "form complex" binding 9606 22223884 t alessandro "Therefore, we conclude that the endogenous proteins PARP1, p65NF-κB and Snail1 form a ternary complex in the nuclei of cells that are actively expressing fibronectin" SIGNOR-254528 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR CAD protein P27708 UNIPROT "up-regulates activity" phosphorylation Thr456 KVYFLPItPHYVTQV -1 17485345 t miannu "The multifunctional protein CAD initiates de novo pyrimidine biosynthesis in mammalian cells. CAD is activated by MAP kinase (Erk1/2) just prior to the S phase of the cell cycle, when the demand for pyrimidine nucleotides is greatest, and down-regulated as the cells emerge from S phase by protein kinase A (PKA) phosphorylation. MAP kinase phosphorylates Thr456, while PKA phosphorylates Ser1406 and Ser1859, although only Ser1406 is involved in regulation. " SIGNOR-267441 MTOR protein P42345 UNIPROT Neurogenesis phenotype SIGNOR-PH168 SIGNOR up-regulates 29789464 f Luana "The mTOR complexes are essential to neurogenesis and the establishment of neural circuits. | Activation of mTOR complexes exerts profound effects on all the processes of neurogenesis, including dendrite formation." SIGNOR-265771 AKT1 protein P31749 UNIPROT MAP3K11 protein Q16584 UNIPROT down-regulates phosphorylation Ser674 PGRERGEsPTTPPTP 9606 BTO:0000938 12458207 t lperfetto "Negative regulation of mixed lineage kinase 3 by protein kinase b/akt leads to cell survivalthe expression of activated akt1 inhibits mlk3-mediated cell death in a manner dependent on serine 674 phosphorylation." SIGNOR-252592 BMP7 protein P18075 UNIPROT PPARGC1A protein Q9UBK2 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 18719589 f "induction of mitochondrial biogenesis" fspada "Bmp7 activates a full program of brown adipogenesis including induction of early regulators of brown fat fate prdm16 (pr-domain-containing 16;ref. 4) and pgc-1alpha (peroxisome proliferator-activated receptor-gamma (ppargamma) coactivator-1alpha;ref. 5), increased expression of the brown-fat-defining marker uncoupling protein 1 (ucp1) and adipogenic transcription factors ppargamma and ccaat/enhancer-binding proteins (c/ebps), and induction of mitochondrial biogenesis via p38 mitogen-activated protein (map) kinase-(also known as mapk14) and pgc-1-dependent pathways" SIGNOR-180314 GH1 protein P01241 UNIPROT GHR protein P10912 UNIPROT "up-regulates activity" binding 9606 7862673 t miannu "Although growth hormone (GH) receptors (GHRs) in many species bind human (h) GH as well as their own GH, the hGHR only binds primate GH." SIGNOR-255451 Gbeta proteinfamily SIGNOR-PF4 SIGNOR ETV6 protein P41212 UNIPROT down-regulates phosphorylation 10090 15060146 t "inferred from 70% family members" miannu "Tel became phosphorylated by erk on two serine residues, ser213 and ser257, in the internal domain between the hlh and ets domains. Tel lost its abilities to repress transcription through the phosphorylation." SIGNOR-270120 PRKACA protein P17612 UNIPROT IRS1 protein P35568 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser1223 SSSTRRSsEDLSAYA 9606 BTO:0000975 17360977 t lperfetto "Tyrosine phosphorylation of IRS-1 initiates insulin signaling, whereas serine/threonine phosphorylation alters the ability of IRS-1 to transduce the insulin signalInsulin increased the phosphorylation of Ser312, Ser616, Ser636, Ser892, Ser1101, and Ser1223" SIGNOR-236603 NPM1 protein P06748 UNIPROT CDKN2A protein Q8N726 UNIPROT "up-regulates activity" binding 10090 16199867 t gcesareni "The Arf-NPM interaction seems to be critical in regulating the stability of both proteins. Arf, in fact, induces polyubiquitination and degradation of NPM and inhibits its effects on ribogenesis (18). NPM, instead, protects Arf from degradation and, surprisingly, antagonizes its ability to inhibit cell division" SIGNOR-245073 PKC proteinfamily SIGNOR-PF53 SIGNOR SCN2A protein Q99250 UNIPROT "down-regulates activity" phosphorylation 9606 BTO:0000938 32599005 t lperfetto "For example, protein kinase A (PKA) and protein kinase C (PKC) have been shown to phosphorylate multiple serine residues on the interdomain I-II and III-IV linkers of Nav1.2, significantly reducing current and increasing firing thresholds" SIGNOR-275750 SOD1 protein P00441 UNIPROT Protein_aggregates phenotype SIGNOR-PH142 SIGNOR "up-regulates quantity" 9606 BTO:0000312 22051914 f lperfetto "SOD1 inclusions are found in motor neurons of patients with FALS," SIGNOR-262279 CTTN protein Q14247 UNIPROT ARP2/3 complex SIGNOR-C146 SIGNOR "up-regulates activity" binding 9606 11231575 t "Cortactin binds directly to the Arp2/3 complex and activates it to promote nucleation of actin filaments." SIGNOR-251519 AKT2 protein P31751 UNIPROT PPARGC1A protein Q9UBK2 UNIPROT "down-regulates activity" phosphorylation Ser571 RMRSRSRsFSRHRSC 10090 17554339 t miannu "Here we describe a mechanism by which insulin, through the intermediary protein kinase Akt2/protein kinase B (PKB)-beta, elicits the phosphorylation and inhibition of the transcriptional coactivator peroxisome proliferator-activated receptor-coactivator 1alpha (PGC-1alpha), a global regulator of hepatic metabolism during fasting.  Akt phosphorylates PGC-1α at Ser 570." SIGNOR-262626 CSNK2A1 protein P68400 UNIPROT SNCA protein P37840 UNIPROT up-regulates phosphorylation Ser87 KTVEGAGsIAAATGF 9606 BTO:0000938 10617630 t lperfetto "In vitro experiments and two-dimensional phosphopeptide mapping provided further evidence that serine 129 was phosphorylated by ck-1 and ck-2. Moreover, phosphorylation of serine 129 was reduced in vivo upon inhibition of ck-1 or ck-2. These data demonstrate that alpha-synuclein is constitutively phosphorylated within its c terminus and may indicate that the function of alpha-synuclein is regulated by phosphorylation/dephosphorylation.From these data we conclude that _-synuclein is predominantly phosphorylated at serine residue 129. However, a second serine at position 87 is also used for phosphorylation to some extent. together, these data may indicate that ck-1 and ck-2 are involved in the regulation of neuronal function and one may speculate that phosphorylation of _-synuclein could affect its binding to membranes." SIGNOR-73807 LIF protein P15018 UNIPROT MYH7 protein P12883 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10116 10212267 f "Regulation of expression" miannu "Increase of protein synthesis rate and β-MHC gene expression in cardiac myocytes by ET-1 and LIF." SIGNOR-251959 NOTCH1 protein P46531 UNIPROT HEY1 protein Q9Y5J3 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 11486044 t lperfetto "These data establish that HERP2 is a novel primary target gene of Notch that, together with HES, may effect diverse biological activities of Notch" SIGNOR-235397 MECP2 protein P51608 UNIPROT DLX5 protein P56178 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 10090 19195802 f "Expression of DLX5 is controlled by MECP2, and defect in MECP2 induced an over-expression of DLX5 in lymphocytes as well as in the brain" SIGNOR-254034 MAPK3 protein P27361 UNIPROT BAD protein Q92934 UNIPROT down-regulates phosphorylation 9606 BTO:0000567 19777442 t gcesareni "Erk-1 map kinase prevents tnf-induced apoptosis through bad phosphorylation and inhibition of bax translocation in hela cells." SIGNOR-188172 adenosine smallmolecule CHEBI:16335 ChEBI ADORA3 protein P0DMS8 UNIPROT "up-regulates activity" "chemical activation" 9606 BTO:0002524 31160049 t "Ligand-GPCR dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257449 MECP2 protein P51608 UNIPROT GAD1 protein Q99259 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 19029285 f miannu "induction of the reelin and GAD67 mRNAs is accompanied by the dissociation of repressor complexes containing all three DNMTs, MeCP2, and HDAC1 from the corresponding promoters and by increased local histone acetylation." SIGNOR-254579 GSK3B protein P49841 UNIPROT NFKB1 protein P19838 UNIPROT "up-regulates quantity by stabilization" phosphorylation Ser903 KTTSQAHsLPLSPAS 10090 BTO:0000452 12871932 t "GSK-3 beta forms an in vivo complex with and specifically phosphorylates NF-kappa B1/p105 at Ser-903 and Ser-907 in vitro. GSK-3 beta has a dual effect on p105: it stabilizes p105 under resting conditions and primes p105 for degradation upon tumor necrosis factor (TNF)-alpha treatment. Indeed, constitutive processing of p105 to p50 occurs at a higher rate in cells lacking GSK-3 beta with respect to wild-type cells and can be reduced upon reintroduction of GSK-3 beta by transfection. S903A and S907A point mutations impair p105 proteolysis in response to TNF-α." SIGNOR-251251 CXCL1 protein P09341 UNIPROT GLI1 protein P08151 UNIPROT up-regulates 9606 16885213 f gcesareni "The data suggest that smo is in fact the source of two signals relevant to the activation of gli: one involving g(i) and the other involving events at smo's c-tail independent of g(i)." SIGNOR-148454 SSU72 protein Q9NP77 UNIPROT POLR2A protein P24928 UNIPROT "up-regulates activity" dephosphorylation Ser1693 SPTSPSYsPTSPSYS -1 15125841 t "Phosphorylation of serine-2 (S2) and serine-5 (S5) of the C-terminal domain (CTD) of RNA polymerase II (RNAP II) is a dynamic process that regulates the transcription cycle and coordinates recruitment of RNA processing factors. The Fcp1 CTD phosphatase catalyzes dephosphorylation of S2-P.| Depletion of Ssu72 impairs transcription in vitro" SIGNOR-248821 "heparan sulfate octasaccharide" smallmolecule CHEBI:142519 ChEBI ECM_synthesis phenotype SIGNOR-PH8 SIGNOR up-regulates 9606 27241222 f miannu "Many observations in animal models deficient for HSPGs and recent observations of human genetic mutations for biosynthesis of HSPGs have identified the importance of HSPGs for normal embryonic development and ECM organization." SIGNOR-264017 CSNK1E protein P49674 UNIPROT BID protein P55957 UNIPROT "up-regulates activity" phosphorylation Thr59 EGYDELQtDGNRSSH 9606 BTO:0000567 11583622 t llicata "Here we report that Bid is phosphorylated by casein kinase I (CKI) and casein kinase II (CKII). Inhibition of CKI and CKII accelerated Fas-mediated apoptosis and Bid cleavage, whereas hyperactivity of the kinases delayed apoptosis. | These results suggest that residues S61, S64, and to a much lesser extent T58 are sites of phosphorylation of Bid." SIGNOR-250806 DUSP3 protein P51452 UNIPROT MAPK3 protein P27361 UNIPROT "down-regulates activity" dephosphorylation Tyr204 HTGFLTEyVATRWYR 9606 BTO:0004419 12840032 t lperfetto "The activation of the mapk activity requires the dual phosphorylation of the ser/thr and tyr residues in the txy kinase activation motif (1113), and deactivation occurs through the action of either ser/thr protein phosphatase (14), protein-tyrosine phosphatase (ptp) (14, 15), or dual specificity phosphatases" SIGNOR-103035 N-(cyanomethyl)-4-[2-[4-(4-morpholinyl)anilino]-4-pyrimidinyl]benzamide chemical CHEBI:91407 ChEBI JAK1 protein P23458 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-191244 TRIM27 protein P14373 UNIPROT ULK1 protein O75385 UNIPROT "down-regulates quantity by destabilization" ubiquitination Lys569 DLHVVRPkLPKPPTD 10090 35670107 t lperfetto "TRIM27 directly polyubiquitinates ULK1 at K568 and K571 sites with K48-linked ubiquitin chains, with proteasomal turnover maintaining control over basal ULK1 levels" SIGNOR-272540 SNAI1 protein O95863 UNIPROT SERPINE1 protein P05121 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 19055748 f lperfetto "We demonstrated by both cDNA microarrays and real-time quantitative RT-PCR that the functional blockade of SNAI1 induces a significant decrease of PAI-1 and uPA transcripts." SIGNOR-252262 IFNA2 protein P01563 UNIPROT HLA-B protein P01889 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 2507660 f Regulation miannu "HLA-B (class I) and C13 gene expression was transcriptionally activated by IFN-gamma and IFN-alpha 2" SIGNOR-251925 SLC9A3 protein P48764 UNIPROT hydron chemical CHEBI:15378 ChEBI "down-regulates quantity" relocalization 9606 BTO:0000938 31507243 t miannu "Na+/H+ exchangers play pivotal roles in the control of cell and tissue pH by mediating the electroneutral exchange of Na+ and H+ across cellular membranes. " SIGNOR-265593 Cullin4-RBX1-DDB1 complex SIGNOR-C119 SIGNOR IKZF1 protein Q13422 UNIPROT "down-regulates quantity by destabilization" polyubiquitination 9606 BTO:0003933 24292625 t miannu "We found that lenalidomide causes selective ubiquitination and degradation of two lymphoid transcription factors, IKZF1 and IKZF3, by the CRBN-CRL4 ubiquitin ligase. IKZF1 and IKZF3 are essential transcription factors in multiple myeloma." SIGNOR-272083 PIM1 protein P11309 UNIPROT FOXO3 protein O43524 UNIPROT down-regulates phosphorylation Ser253 APRRRAVsMDNSNKY 9606 18593906 t tpavlidou "Pim-mediated phosphorylation and inactivation of forkhead transcription factors, foxo1a and foxo3a, was involved in the transcriptional repression of the p27(kip1) gene." SIGNOR-179304 PTPN11 protein Q06124 UNIPROT GAB1 protein Q13480 UNIPROT down-regulates dephosphorylation Tyr659 VADERVDyVVVDQQK 9606 10068651 t lperfetto "Tyrosine phosphorylation of gab2 was induced by stimulation through gp130, il-2r, il-3r, tpor, scfr, and tcr. Gab1 and gab2 were shown to be substrates for shp-2 in vitro." SIGNOR-236254 POU2F1 protein P14859 UNIPROT MYH10 protein P35580 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 15728583 t lperfetto "Myocyte enhancer factor-2 and serum response factor binding elements regulate fast Myosin heavy chain transcription in vivo. We show that the upstream promoter region of the gene most abundantly expressed in mouse skeletal muscles, IIb MyHC, retains binding activity and transcriptional activation for three positive transcription factors, the serum response factor, Oct-1, and myocyte enhancer factor-2, whereas the other two genes (IIa and IId/x) have nucleotide substitutions in these sites that reduce binding and transcriptional activation" SIGNOR-238772 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR SCNN1G protein P51170 UNIPROT "down-regulates quantity by destabilization" phosphorylation -1 11805112 t "inferred from 70% family members" lperfetto "Using a number of different approaches it was demonstrated that the protein kinase acting on betaThr-613 and gammaThr-623 is the extracellular regulated kinase (ERK). It is suggested that an ERK-mediated phosphorylation of betaThr-613 and gammaThr-623 down-regulates the channel by facilitating its interaction with Nedd4." SIGNOR-270171 GATA2 protein P23769 UNIPROT KLF1 protein Q13351 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 8195185 f irozzo "Regulation of the Erythroid Kruppel-like Factor (EKLF) Gene Promoter by the Erythroid Transcription Factor GATA-l.Accordingly,we have also demonstrated that GATA-2, like GATA-1, is able to activate the EKLF promoter in NIH3T3." SIGNOR-256052 PTPRF protein P10586 UNIPROT INSR protein P06213 UNIPROT down-regulates dephosphorylation Tyr999 YASSNPEyLSASDVF 9606 10734133 t lperfetto "Many cellular receptors signal via tyrosine phosphorylation. The tyrosine kinases required for this activity are often recruited upon ligand bindingAlternatively, receptors themselves have kinase activity, like insulin receptors. In either case, the receptors are returned to their original state through the activity of protein-tyrosine phosphatases (PTPs)The major candidate PTPs previously implicated in IRK dephosphorylation are PTP-1b and LAR." SIGNOR-76017 Ub:E2 complex SIGNOR-C497 SIGNOR TRIM46 protein Q7Z4K8 UNIPROT "up-regulates activity" ubiquitination 9606 34199813 t miannu "The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t" SIGNOR-271182 CSNK1A1 protein P48729 UNIPROT TP53 protein P04637 UNIPROT unknown phosphorylation Ser20 PLSQETFsDLWKLLP 9606 20041275 t llicata "Our data support the concept that non-primed phosphorylation of p53 by ck1 is an isoform-specific reaction preferentially affecting s20" SIGNOR-162648 FFAR4 protein Q5NUL3 UNIPROT GNAI1 protein P63096 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257045 CSNK2B protein P67870 UNIPROT EIF5 protein P55010 UNIPROT "up-regulates activity" phosphorylation Ser389 LKEAEEEsSGGEEED 9606 BTO:0001938 11861906 t llicata "Mass spectrometric analysis of maximally in vitro phosphorylated eIF5 localized the major phosphorylation sites at Ser-387 and Ser-388 near the C-terminus of eIF5. These serine residues are embedded within a cluster of acidic amino acid residues and account for nearly 90% of the total in vitro eIF5 phosphorylation. A minor phosphorylation site at Ser-174 was also observed. | The results suggest that phosphorylation of eIF5 may have a role in stimulating the rate of eIF5-promoted GTP hydrolysis." SIGNOR-251069 CSNK1E protein P49674 UNIPROT AXIN1 protein O15169 UNIPROT up-regulates phosphorylation 9606 SIGNOR-C110 12000790 t gcesareni "We conclude that a major role of axin in the wnt is to provide the kinase activity that initiates the betBeta-catenin phosphorylation cascade at s45. This process is mediated by cki, the alfa, delta, or ? Isoform, all detected in association with axin by lc/ms." SIGNOR-87444 CDK1 protein P06493 UNIPROT MDM4 protein O15151 UNIPROT down-regulates phosphorylation Ser96 SFSVKDPsPLYDMLR 9606 15735705 t lperfetto "Cdc2p34 phosphorylates mdmx on ser 96 in vitro. Mutation within this site (mdmx(s96a)) impairs, whereas phosphomimic substitution (mdmx(s96d)) increases the cytoplasmic localization of mdmx, suggesting that cdk2/cdc2p34 phosphorylation is required for export of mdmx from the nucleus" SIGNOR-134388 "NMDA receptor_2D" complex SIGNOR-C350 SIGNOR CAMK2A protein Q9UQM7 UNIPROT "up-regulates activity" binding 9606 BTO:0000938 11052931 t miannu "The most abundant signaling protein in the PSD fraction is Ca2+/calmodulin–dependent protein kinase II (CaMKII), which makes up 1 to 2% of the total protein in the forebrain (21). CaMKII is a target for Ca2+ flowing through the NMDA receptor and is necessary for normal synaptic plasticity in pyramidal neurons. The cytosolic tails of the NR2 subunits of the NMDA receptor bind to CaMKII and thus can serve as docking sites for it in the PSD" SIGNOR-264217 CSNK2A1 protein P68400 UNIPROT HMGN1 protein P05114 UNIPROT down-regulates phosphorylation Ser8 MPKRKVSsAEGAAKE 9606 10739259 t gcesareni "Peptide mass and sequence analysis showed major and minor phosphorylation sites, respectively, at ser24 and ser28 in hmg-17, and ser20 and ser24 in hmg-14 a third phosphorylation site in hmg-14 was located at either ser6 or ser7phosphorylation of ser6 and ser7 may compromise the binding of hmgn1 protein to the binding domain of importin proteins, which in turn affects the nuclear transport and sub-cellular localization of hmgn1 protein. Protein kinase ck2 could potentially be an enzyme that regulates this process." SIGNOR-76270 BCOR protein Q6W2J9 UNIPROT HOXA5 protein P20719 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 10090 26847029 f irozzo "Importantly, our results showed that BCOR is a repressor of HoxA cluster of genes (HoxA5, HoxA7 and HoxA9) in myeloid cells. Knock-down of HoxA5, HoxA7 and HoxA9 significantly decreased the clonogenic growth of Bcor mutant and wild type cells, demonstrating the Hox genes, as targets of BCOR, played an important role in mediating BCOR’s function in regulating myeloid cell proliferation." SIGNOR-256012 TLN1 protein Q9Y490 UNIPROT "A11/b1 integrin" complex SIGNOR-C168 SIGNOR "up-regulates activity" binding 10090 BTO:0000132 19118207 t miannu "Over the past 10 years, the binding of talin to the cytoplasmic tail of integrin-β subunits has been established to have a key role in integrin activation. Binding of the phosphotyrosinebinding (PTB)-domain-like subdomain of the protein 4.1, ezrin, radixin, moesin (FERM) domain of talin to the conserved WxxxNP(I/L)Y motif of the β-integrin tail permits additional weaker interactions between talin and the membrane-proximal region of the tail that trigger integrin activation, probably through the disruption of inhibitory interactions between α- and β-subunit cytoplasmic tails." SIGNOR-257617 BCORL1 protein Q5H9F3 UNIPROT CTBP1 protein Q13363 UNIPROT "up-regulates activity" binding 9606 BTO:0002181 17379597 t irozzo "BCoR-L1 also interacts with the CtBP corepressor through a CtBP-interacting motif in its amino terminus. Furthermore, BCoR-L1 is located on the E-cadherin promoter, a known CtBP-regulated promoter, and represses the E-cadherin promoter activity in a reporter assay." SIGNOR-259193 PTPN12 protein Q05209 UNIPROT JAK2 protein O60674 UNIPROT "down-regulates activity" dephosphorylation Tyr1007 VLPQDKEyYKVKEPG 9606 BTO:0003892 11731619 t "PTP-PEST-Containing Lysates from EGF-Treated HC11 Cells Dephosphorylate JAK2 More Efficiently than Lysates from Control Cells|phospho-JAK2-specific rabbit polyclonal antiserum (44-426, BioSource Technologies, Inc., Camarillo, CA) which recognizes Tyr1007/1008 in the activation site" SIGNOR-248657 Hexocyclium chemical CHEBI:5707 ChEBI CHRM2 protein P08172 UNIPROT "down-regulates activity" "chemical inhibition" 10029 BTO:0000246 2704370 t miannu "In order to investigate the pharmacological properties of the individual muscarinic receptors, we have transfected each of these genes into Chinese hamster ovary cells (CHO-K1) and have established stable cell lines expressing each receptor. In the present study we have examined the antagonist binding properties of each muscarinic receptor. Antagonists were chosen that had previously been proposed to be selective for muscarinic receptor subtypes and included pirenzepine, AF-DX 116, methoctramine, dicyclomine, hexohydrodifenidol, hexahydrosiladifenidol, hexocyclium, and silahexocyclium." SIGNOR-258389 FGR protein P09769 UNIPROT ACO2 protein Q99798 UNIPROT unknown phosphorylation Tyr665 VVIGDENyGEGSSRE -1 17997986 t miannu "Here, we provide evidence that the flavoprotein of succinate dehydrogenase and aconitase are ""in vitro"" substrates of Fgr tyrosine kinase. Fgr phosphorylates flavoprotein of succinate dehydrogenase at Y535 and Y596 and aconitase at Y71, Y544 and Y665. Further experiments will be necessary to verify if Fgr is the tyrosine kinase responsible for the tyrosine phosphorylation of these proteins in vivo and to elucidate the role of these phosphorylations." SIGNOR-262870 Gbeta proteinfamily SIGNOR-PF4 SIGNOR KRT8 protein P05787 UNIPROT unknown phosphorylation 16554440 t "inferred from 70% family members" lperfetto "Also, several probable in vivo K8 kinases have been identified including Erk1/2 for K8 Ser431 (Ku and Omary, 1997), and p38 and Jun kinases for K8 Ser73 (Ku et al., 2002a; He et al., 2002)." SIGNOR-270003 FLT3 protein P36888 UNIPROT RUNX1 protein Q01196 UNIPROT "up-regulates activity" 9606 28213513 f "Our finding that RUNX1 protein levels are dependent on FLT3-ITD signaling in AML cells and that, together, they synergize to generate AML. […]Our work demonstrated that Tyr phosphorylation within the ID region of RUNX1 is critical for its oncogenic potential," SIGNOR-256307 "Non-structural protein 10" protein P0C6X7-PRO_0000037317 UNIPROT MT-CO2 protein P00403 UNIPROT "down-regulates activity" binding 9606 16157265 t lperfetto "This result suggests that the nsp10 protein could affect the activities of NADH and cytochrome oxidase II via a direct interaction while being involved in viral replication." SIGNOR-260254 BECN1 protein Q14457 UNIPROT "Vps34 Complex II" complex SIGNOR-C241 SIGNOR "form complex" binding -1 30397185 t lperfetto "PtdIns3P recruits specific recognition modules that are common in protein-sorting pathways, such as autophagy and endocytic sorting. It is best characterized in two heterotetramers, complexes I and II. Complex I is composed of VPS34, VPS15, Beclin 1, and autophagy-related gene (ATG)14L, whereas complex II replaces ATG14L with UVRAG. |Complexes I and II are critical for early events in autophagy and endocytic sorting, respectively." SIGNOR-260319 ABL1 protein P00519 UNIPROT PPARG protein P37231 UNIPROT "up-regulates quantity" phosphorylation Tyr78 SSISTPHyEDIPFTR 10090 25368164 t "We show that the tyrosine kinase Abelson murine leukemia viral oncogene (cAbl) is an adipogenic key regulator. c-Abl promotes adipogenesis by phosphorylation and subsequent stabilization of PPARγ." SIGNOR-255912 HECTD2 protein Q5U5R9 UNIPROT PIAS1 protein O75925 UNIPROT "down-regulates quantity by destabilization" polyubiquitination 9606 BTO:0000007 26157031 t miannu "We discovered a ubiquitin E3 ligase, HECTD2, which ubiquitinated and mediated the degradation of PIAS1, thus increasing inflammation in an experimental pneumonia model." SIGNOR-272421 ACVR1B protein P36896 UNIPROT TDP2 protein O95551 UNIPROT "up-regulates activity" phosphorylation Thr92 VDLTNEEtTDSTTSK 9606 BTO:0000007 18039968 t miannu "ALK4 phosphorylated TTRAP in vitro (Fig. 6A). The band migrating at the position of TTRAP was excised and analyzed by LC-MS/MS. One TTRAP peptide was phosphorylated either on T88 and T92, or on T92 only (Fig. 6B).We tested in vivo phosphorylation of Strep-TTRAP by co-expression with mouse Alk4 in HEK293T cells, and affinity-purified TTRAP. In this preparation TTRAP-specific peptides were reproducibly found in both the singly (T92) and doubly phosphorylated form (T88/T92). mutant TTRAPT88A,T92A is not able to rescue the TtrapMO phenotype, suggesting that phosphorylation of Ttrap on Thr88 and Thr92 is essential for Ttrap function." SIGNOR-262612 MAOA protein P21397 UNIPROT serotonin smallmolecule CHEBI:28790 ChEBI "down-regulates quantity" "chemical modification" 9606 31024440 t brain lperfetto "Following release, 5-HT receptor activation and reuptake by 5-HT transporter (5-HTT), serotonin is degraded by MAO (monoamine oxidase) and ALDH (aldehyde dehydrogenase) into 5-hydroxyindole-3-acetic acid (5-HIAA)." SIGNOR-264014 PPP4C protein P60510 UNIPROT HDAC3 protein O15379 UNIPROT "down-regulates activity" dephosphorylation Ser424 DHDNDKEsDVEI 9606 15805470 t "Here we demonstrate that, in addition to protein-protein interactions with NCoR/SMRT, the activity of HDAC3 is regulated by both phosphorylation and dephosphorylation. A protein kinase CK2 phosphoacceptor site in the HDAC3 protein was identified at position Ser424, which is a nonconserved residue among the class I HDACs. Mutation of this residue was found to reduce deacetylase activity.|Significantly, both overexpression and siRNA knock-down approaches, and analysis of cells devoid of PP4c, unequivocally show that HDAC3 activity is inversely proportional to the cellular abundance of PP4(c)." SIGNOR-248548 SOX9 protein P48436 UNIPROT PRAME protein P78395 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0000849 19273910 f miannu "Overexpression of SOX9 in both human and mouse melanoma cell lines induced cell cycle arrest by increasing p21 transcription and restored sensitivity to RA by downregulating expression of PRAME, a melanoma antigen." SIGNOR-255191 SEC13 protein P55735 UNIPROT NPC complex SIGNOR-C263 SIGNOR "form complex" binding 27016207 t lperfetto "The protein inventory of the NPC has been studied for a very diverse set of eukaryotes, including trypanosomes, fungi, plants, animals, and humans [4], [5], [6], [7], [8], [9]. In all cases, about 30 different Nups were found (Fig. 2)." SIGNOR-262091 Gbeta proteinfamily SIGNOR-PF4 SIGNOR RPS3 protein P23396 UNIPROT unknown phosphorylation 9606 15950189 t "inferred from 70% family members" llicata "Erk phosphorylates threonine 42 residue of ribosomal protein s3." SIGNOR-270019 "pemetrexed disodium" chemical CHEBI:63722 ChEBI DHFR protein P00374 UNIPROT "down-regulates activity" "chemical inhibition" 9606 BTO:0002058 14596699 t miannu "Thymidylate synthase, the primary target of pemetrexed,9 is a fo-late-dependent enzyme that catalyzes the transformation of deoxyuri-dine monophosphate to deoxythymidine monophosphate. Inhibi-tion of TS results in decreased levels of thymidine, which is necessary for DNA synthesis. In addition to TS, pemetrexed inhibits DHFR, aminoimidazole carboxamide ribonucleotide formyltransferase (AICARFT), and glycinamide ribonucleotide formyltransferase (GARFT)." SIGNOR-259290 NCAPH protein Q15003 UNIPROT "Condensin I" complex SIGNOR-C341 SIGNOR "form complex" binding 9606 32445620 t miannu "The majority of higher eukaryotes, including humans, have two condensins, condensin I (CI) and II (CII) Although sharing the same SMC subunits (SMC2 and SMC4), condensin I and II have distinct non-SMC regulatory subunits, including the kleisin subunit (CAP-H and CAP-H2, respectively) and a pair of HEAT repeat subunits (CAP-D2/G and CAP-D3/G2, respectively; Figure 1B). the combined actions of both condensins contribute to formation of a nested-loop architecture necessary to achieve the highest level of chromosome compaction." SIGNOR-263906 PTPN12 protein Q05209 UNIPROT PTK2 protein Q05397 UNIPROT "down-regulates activity" dephosphorylation Tyr397 SVSETDDyAEIIDEE 10090 BTO:0000944 19595712 t "We demonstrate here that activated Ras induces tyrosine dephosphorylation and inhibition of FAK mediated by the Ras downstream Fgd1-Cdc42-PAK1-MEK-ERK signaling cascade.| PIN1 binding and prolyl isomerization of FAK cause PTP-PEST to interact with and dephosphorylate FAK Y397. Inhibition of FAK mediated by this signal relay promotes Ras-induced cell migration, invasion, and metastasis." SIGNOR-248661 RXRB protein P28702 UNIPROT RAR proteinfamily SIGNOR-PF45 SIGNOR up-regulates binding 9606 1310351 t "inferred from 70% of family members" gcesareni "Here we report that the transcriptional activity of rar and rxr can be reciprocally modulated by direct interactions between the two proteins" SIGNOR-269852 PRKCD protein Q05655 UNIPROT DNM1L protein O00429 UNIPROT up-regulates phosphorylation Ser616 PIPIMPAsPQKGHAV 9606 17301055 t gcesareni "Drp1 was specifically phosphorylated in mitosis by cdk1/cyclin b on ser-585. Exogenous expression of unphosphorylated mutant drp1s585a led to reduced mitotic mitochondrial fragmentation." SIGNOR-153148 CSNK2A1 protein P68400 UNIPROT SIRT1 protein Q96EB6 UNIPROT unknown phosphorylation Ser661 GAEVYSDsEDDVLSS 9606 19236849 t llicata "We demonstrate that sirt1 is a substrate for protein kinase ck2 both in vitro and in vivo. Both, deletion construct analyses and serine-to-alanine mutations identified sirt1 ser-659 and ser-661 as major ck2 phosphorylation sites that are phosphorylated in vivo as well." SIGNOR-184155 MAPK3 protein P27361 UNIPROT STK11 protein Q15831 UNIPROT "down-regulates activity" phosphorylation Ser428 SSKIRRLsACKQQ 9606 25846811 t lperfetto "Directly and/or through the activation of p90RSK, ERK phosphorylates LKB-1 at Ser325 and Ser428. The phosphorylation of LKB-1 causes the dissociation of LKB-1 from AMPK, resulting in the impaired activation of AMPK." SIGNOR-209880 Ub:E2 complex SIGNOR-C497 SIGNOR RNF146 protein Q9NTX7 UNIPROT "up-regulates activity" ubiquitination 9606 34199813 t miannu "The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t" SIGNOR-271078 MEN1 protein O00255 UNIPROT KMT2A protein Q03164 UNIPROT "up-regulates activity" binding 9606 BTO:0000567 15640349 t irozzo "However, menin dramatically increases the amount of MLL bound at the p27Kip1 and p18Ink4c loci, suggesting that it either directly or indirectly promotes MLL recruitment to these targets. Once recruited, MLL could enhance transcription by a number of mechanisms.Overall, the data suggest that transcriptional regulation by menin involves increasing MLL protein association with target loci." SIGNOR-255890 PIH1D1 protein Q9NWS0 UNIPROT "R2TP core co-chaperone" complex SIGNOR-C515 SIGNOR "form complex" binding 9606 29662061 t miannu " Here we use cryo-EM and biochemical studies on the human R2TP core (RUVBL1-RUVBL2-RPAP3-PIH1D1) which reveal the distinctive role of RPAP3, distinguishing metazoan R2TP from the smaller yeast equivalent. RPAP3 spans both faces of a single RUVBL ring, providing an extended scaffold that recruits clients and provides a flexible tether for HSP90. " SIGNOR-270926 SOD1 protein P00441 UNIPROT S100A4 protein P26447 UNIPROT "up-regulates quantity" 10116 BTO:0000452;BTO:0000099 BTO:0001279 31623154 f "P00441:p.Gly94Ala (mutation increasing interaction)" "We found that S100A4 was significantly up-regulated in astrocytes and microglia in the spinal cord of a transgenic rat SOD1-G93A model of amyotrophic lateral sclerosis" SIGNOR-262783 FZD3 protein Q9NPG1 UNIPROT CXCL1 protein P09341 UNIPROT up-regulates binding 9606 14977528 t gcesareni "In the non-canonical wnt pathway, frizzled uses galfaq or galfai and gbetagamma dimers to activate phospholipase c (plc), resulting in protein kinase c (pkc) activation and calcium mobilization that regulates the transcription factor nfat, and frizzled also signals through the small gtpases rho and rac to c-jun n-terminal kinase (jnk), which activates the ap1 transcription factor gpcrs signal through four relatively small families of galfa proteins (galfas, galfai/o, galfaq, and galfa12/13), and if fzd receptors are classic gpcrs, they should signal through one of these four galfa families." SIGNOR-122886 NFATC1 protein O95644 UNIPROT IL2 protein P60568 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 10022916 t Barakat "Together, our results demonstrate that dnNFAT inhibits the production of IL-2. Thus, the NFAT transcription factor contributes to the regulation of IL-2 gene expression and therefore plays a critical role in the initiation of immune responses." SIGNOR-275405 PAK2 protein Q13177 UNIPROT PAK2 protein Q13177 UNIPROT "up-regulates activity" phosphorylation Ser20 APPVRMSsTIFSTGG -1 10075701 t miannu "Eight autophosphorylation sites were identified in Cdc42-activated gamma-PAK, six of which are in common with those previously reported in alpha-PAK, while Ser-19 and Ser-165 appear to be uniquely phosphorylated in the gamma-form. Further, the phosphorylation of Ser-141, Ser-165, and Thr-402 was found to correlate with gamma-PAK activation. Autophosphorylation of γ-PAK with MgATP alone takes place at Ser-19, Ser-20, Ser-55, Ser-192, and Ser-197." SIGNOR-250227 MYC protein P01106 UNIPROT BCR protein P11274 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000664;BTO:0004465 26179066 t lperfetto "In the present study we demonstrate that MYC and its partner MAX bind to the BCR promoter, leading to up-regulation of BCR and BCR/ABL1 at both transcriptional and protein levels.|Here we describe a regulatory pathway modulating BCR and BCR/ABL1 expression, showing that the BCR promoter is under the transcriptional control of the MYC/MAX heterodimer." SIGNOR-272144 BCL10 protein O95999 UNIPROT NFKB1 protein P19838 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 14695475 f Barakat "The adaptor protein Bcl10 promotes activation of NF-κB transcription factors through paracaspase- and UBC13-dependent ubiquitination of NEMO." SIGNOR-274145 BCL2L11 protein O43521 UNIPROT BCL2 protein P10415 UNIPROT down-regulates binding 9606 15694340 t gcesareni "Bim can induce apoptosis by interacting with anti-apoptotic members of the bcl2 family, including bcl2, bcl-xl and mcl-1.. Bim binds prosurvival proteins comparably. The members that promote cell survival, including mammalian bcl-2, bcl-xl,bcl-w, mcl-1, and a1" SIGNOR-133823 "WAVE complex" complex SIGNOR-C271 SIGNOR ARP2/3 complex SIGNOR-C146 SIGNOR "up-regulates activity" binding 9606 BTO:0000132 27871158 t lperfetto "Cdc42 can induce Arp2/3-mediated filopodia formation through the activation of WASp (Wiskott-Aldrich syndrome proteins) and neuronal N-WASp (Rohatgi et al., 1999). Similarly, Rac1-enhanced lamellipodia formation is related to Arp2/3 activation by the WAVE (WASP-family verprolin-homologous) complex" SIGNOR-261876 PCC complex SIGNOR-C414 SIGNOR (S)-methylmalonyl-CoA(5-) smallmolecule CHEBI:57327 ChEBI "up-regulates quantity" "chemical modification" 9606 15890657 t miannu "Propionyl-CoA carboxylase (PCC) is a biotin-dependent mitochondrial enzyme that catalyzes the conversion of propionyl-CoA to D-methylmalonyl-CoA. PCC consists of two heterologous subunits, alpha PCC and beta PCC, which are encoded by the nuclear PCCA and PCCB genes, respectively." SIGNOR-267186 canertinib chemical CHEBI:61399 ChEBI ERBB2 protein P04626 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-191012 GART protein P22102 UNIPROT 2-formamido-N(1)-(5-O-phosphonato-beta-D-ribosyl)acetamidine smallmolecule CHEBI:147287 ChEBI "down-regulates quantity" "chemical modification" 9606 33179964 t miannu "The second enzyme in the DNPB pathway is trifunc tional GART (TGART), whose domains and activities include: glycinamide ribonucleotide synthase (GARS) that catalyzes the ATP-dependent process that uses 5- PRA and Gly to make glycinamide ribonucleotide (GAR); glycinamide ribonucleotide transformylase (GART) that transfers the formyl group of N10-formyltetrahydrofolate to GAR, generating formylglycinamide ribonucleotide (FGAR); and aminoimidazole ribonucleotide synthase (AIRS) that converts formylglycinamidine ribonucleotide (FGAM) to aminoimidazole ribonucleotide (AIR) in an ATP-dependent manner." SIGNOR-267314 SMAD6 protein O43541 UNIPROT TGFBR1 protein P36897 UNIPROT "down-regulates activity" binding 9606 20663871 t lperfetto "The inhibitory Smads (I-Smads), i.e. Smad6 and Smad7, are negative regulators of transforming growth factor-_ (TGF-_) family signaling. I-Smads inhibit TGF-_ family signaling principally through physical interaction with type I receptors (activin receptor-like kinases), so as to compete with receptor-regulated Smads (R-Smads) for activation." SIGNOR-167160 GLS protein O94925 UNIPROT L-glutamate(1-) smallmolecule CHEBI:29985 ChEBI "up-regulates quantity" "chemical modification" 9606 22049910 t miannu "Glutaminase (GLS1/2) catalyzes the conversion of L-glutamine to L-glutamate and ammonia." SIGNOR-266910 LYN protein P07948 UNIPROT LYN protein P07948 UNIPROT "up-regulates activity" phosphorylation Tyr397 RVIEDNEyTAREGAK -1 8530369 t "Lyn is a member of the Src family of protein-tyrosine kinases that can readily undergo autophosphorylation in vitro. The site of autophosphorylation is Tyr397. Autophosphorylation results in a 17-fold increase in protein-tyrosine kinase activity." SIGNOR-251402 PRKCB protein P05771 UNIPROT RAF1 protein P04049 UNIPROT up-regulates phosphorylation Ser497 ATVKSRWsGSQQVEQ 9606 8288587 t gcesareni "Pkc can effectively phosphorylate raf-1, this is a direct effect of activated pkc and not the result of raf-1 autophosphorylation. the sites of pkc-mediated raf-1 phosphorylation are deduced to be ser497 and ser619." SIGNOR-37474 Ub:E2 complex SIGNOR-C497 SIGNOR RNF141 protein Q8WVD5 UNIPROT "up-regulates activity" ubiquitination 9606 34199813 t miannu "The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t" SIGNOR-271204 CARM1 protein Q86X55 UNIPROT SMARCC1 protein Q92922 UNIPROT "up-regulates activity" methylation Arg1064 PGNILGPrVPLTAPN 9606 BTO:0000007;BTO:0000356 24434208 t "CARM1-mediated BAF155 methylation affects gene expression by directing methylated BAF155 to unique chromatin regions (e.g., c-Myc pathway genes). Collectively, our studies uncover a mechanism by which BAF155 acquires tumorigenic functions via arginine methylation." SIGNOR-251708 APC-c complex SIGNOR-C150 SIGNOR CCNB1 protein P14635 UNIPROT "down-regulates quantity by destabilization" ubiquitination 21596315 t lperfetto "Complexed with the activator proteins CDC20 or CDH1 (Fang et al., 1998, Visintin et al., 1997), the APC/C recognizes, ubiquitinates, and targets for proteasomal degradation a multitude of cell cycle regulators containing KEN or D box degrons, including securin, cyclin A, and cyclin B." SIGNOR-265051 ATM protein Q13315 UNIPROT BRCA1 protein P38398 UNIPROT up-regulates phosphorylation Ser1387 EDCSGLSsQSDILTT 9606 BTO:0000150 12183412 t gcesareni "Phosphorylation of serine 1387 in brca1 is specifically required for the atm-mediated s-phase checkpoint after ionizing irradiation.We recently reported that brca1 function is required for appropriate cell cycle arrests after ionizing irradiation in both the s-phase and the g2 phase of the cell cycle. We also found that mutation of serine 1423 in brca1, a target of atm phosphorylation, abrogates the g2-m checkpoint but not the ionizing irradiation-induced s-phase checkpoint. Here we demonstrate that mutation of serine 1387 in brca1, another target of atm phosphorylation, conversely abrogates the radiation-induced s-phase arrest but does not affect the g2-m checkpoint." SIGNOR-91482 "Complement C1 complex" complex SIGNOR-C309 SIGNOR C4B protein P0C0L5 UNIPROT "up-regulates activity" cleavage Arg679 EKTTRKKrNVNFQKA -1 9087411 t lperfetto "The classical complement activation pathway, like the MELinitiated pathway, involves the generation of a C3-converting complex, C4b2b, through enzymatic activation of C4 and C2. In the C1 complex (C1qr2s2), this specific protease activity is exhibited by C1s after activation of this enzyme by C1r. When C4 is activated, its reactive thiol ester is exposed and C4b binds covalently to nearby amino or hydroxyl groups. The C4-activating abilities of MASP-1 and MASP-2 were compared.|Activation of C4 by Ct sand MASP-2 on western blots." SIGNOR-263424 DAB2 protein P98082 UNIPROT LRP6 protein O75581 UNIPROT down-regulates binding 9606 22491013 t gcesareni "Wnt stimulation induces the casein kinase 2 (ck2)-dependent phosphorylation of lrp6 at s1579, promoting its binding to dab2 and internalization with clathrin." SIGNOR-196925 ROCK1 protein Q13464 UNIPROT MYL12B protein O14950 UNIPROT up-regulates phosphorylation Thr19 KKRPQRAtSNVFAMF 9606 12185584 t gcesareni "Here we found that rho-kinase has an activity for mrlc diphosphorylation at both threonine 18 and serine 19 in nonmuscle cells using sequential column chromatographies." SIGNOR-91546 MAPK1 protein P28482 UNIPROT MITF protein O75030 UNIPROT down-regulates phosphorylation Ser180 PGSSAPNsPMAMLTL 9606 10673502 t "The effect has been demonstrated using O75030-9" gcesareni "The current study reveals that c-kit signaling triggers two phosphorylation events on mi, which up-regulate transactivation potential yet simultaneously target mi for ubiquitin-dependent proteolysis. The specific activation/degradation signals derive from mapk/erk targeting of serine 73the results suggested that s1p reduced melanin synthesis via s1p(3) receptor-mediated erk and rsk-1 activation, and subsequent mitf dual phosphorylation and degradation." SIGNOR-75030 FLT3 protein P36888 UNIPROT BCL2L1 protein Q07817 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 15626738 f "FLT3-ITD-TKD dual mutants induce hyperactivation of STAT5 and up-regulation of its downstream targets Bcl-x(L) and RAD51 in Ba/F3 cells" SIGNOR-261549 SELENOF protein O60613 UNIPROT UGGT2 protein Q9NYU1 UNIPROT "up-regulates activity" binding 9606 24415556 t miannu "The enzymatic activity of UGGT2 is enhanced by complex formation with Sep15" SIGNOR-261373 PPP2CB protein P62714 UNIPROT MDM2 protein Q00987 UNIPROT "up-regulates activity" dephosphorylation Thr216 RSSSSEStGTPSNPD 10090 11983168 t "cyclin G also binds in vivo and in vitro to Mdm2 and markedly stimulates the ability of PP2A to dephosphorylate Mdm2 at T216. Consistent with these data, cyclin G null cells have both Mdm2 that is hyperphosphorylated at T216 and markedly higher levels of p53 protein when compared to wild-type cells" SIGNOR-248593 SARS1 protein P49591 UNIPROT diphosphate(3-) smallmolecule CHEBI:33019 ChEBI "up-regulates quantity" "chemical modification" 9606 24095058 t miannu "As a member of the aminoacyl-tRNA synthetase family, seryl-tRNA synthetase (SerRS) catalyzes the aminoacylation reaction that charges serine onto its cognate tRNA for protein synthesis" SIGNOR-270496 MAPK14 protein Q16539 UNIPROT GSK3B protein P49841 UNIPROT down-regulates phosphorylation Ser389 ARIQAAAsTPTNATA 9606 BTO:0000142 17726008 t gcesareni "However p38alfa also inactivates gsk3b by direct phosphorilation of the c-terminal residue ser389. this non-canonicl p38 mapk-dependent phosphorilation of gsk3b seems to occur primarily in the brain and thymocytes." SIGNOR-157548 "CAK complex" complex SIGNOR-C456 SIGNOR CDK2 protein P24941 UNIPROT "up-regulates activity" phosphorylation Thr160 GVPVRTYtHEVVTLW -1 10085115 t llicata "Phosphorylation of monomeric human CDK2 by CAK1 is more efficient than phosphorylation of the binary CDK2-cyclin A complex. Phosphorylated CDK2 exhibits histone H1 kinase activity corresponding to approximately 0.3% of that observed with the fully activated phosphorylated CDK2-cyclin A complex. Fluorescence measurements have shown that Thr160 phosphorylation increases the affinity of CDK2 for both histone substrate and ATP and decreases its affinity for ADP." SIGNOR-269330 CHIR-98014 chemical CID:53396311 PUBCHEM GSK3B protein P49841 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-190988 LRRK2 protein Q5S007 UNIPROT LRRK2 protein Q5S007 UNIPROT unknown phosphorylation Thr1410 STHPHFMtQRALYLA 9606 BTO:0000938 19824698 t lperfetto "We identified ser1403, thr1404, thr1410, thr1491 located within the roc domain, as well as thr1967 and thr1969 in the kinase domain, as the autophosphorylation sites." SIGNOR-188437 barium(2+) chemical CHEBI:37136 ChEBI KCNJ13 protein O60928 UNIPROT "down-regulates activity" "chemical inhibition" 9606 BTO:0000007 9620703 t miannu "Figure 4 shows the response of Kir7.1 to increasing [Ba2+]o. The EC50 for Ba2+ block was 1 mM (Figure 4C), independent of the type of cell in which the channel was expressed. Other known inward rectifier K+ channels are sensitive to inhibition at much lower concentrations" SIGNOR-258925 PPM1D protein O15297 UNIPROT TP53 protein P04637 UNIPROT down-regulates dephosphorylation Ser15 PSVEPPLsQETFSDL 9606 15870257 t lperfetto "PPM1D also dephosphorylates p53 at phospho-Ser 15. PPM1D dephosphorylations are correlated with reduced cellular intra-S and G2/M checkpoint activity in response to DNA damage induced by ultraviolet and ionizing radiation. Thus, a primary function of PPM1D may be to reverse the p53 and Chk1-induced DNA damage and cell cycle checkpoint responses and return the cell to a homeostatic state following completion of DNA repair." SIGNOR-135980 EXOSC1 protein Q9Y3B2 UNIPROT Exosome_Complex complex SIGNOR-C255 SIGNOR "form complex" binding -1 24189234 t miannu "The RNA exosome is an evolutionarily conserved multi-protein complex involved in the 3' degradation of a variety of RNA transcripts. In the nucleus, the exosome participates in the maturation of structured RNAs, in the surveillance of pre-mRNAs and in the decay of a variety of noncoding transcripts. In the cytoplasm, the exosome degrades mRNAs in constitutive and regulated turnover pathways. The eukaryotic exosome, however, is composed of nine different subunits that are still somewhat related in sequence to the archaeal Rrp41-like subunits (Rrp41, Rrp46 and Mtr3), the archaeal Rrp42-like subunits (Rrp45, Rrp43 and Rrp42) and the cap proteins (Rrp4, Csl4 and Rrp40)." SIGNOR-261381 PCDH19 protein Q8TAB3 UNIPROT GABRA4 protein P48169 UNIPROT "up-regulates quantity by stabilization" binding 10116 BTO:0003102 SIGNOR-C327,SIGNOR-C326,SIGNOR-C333 29360992 t miannu "Here, we found that PCDH19 binds the alpha subunits of GABAAR and regulates its surface availability and currents in cultured hippocampal neurons. The PCDH19 gene (Xp22.1) encodes the cell-adhesion protein protocadherin-19 (PCDH19) and is responsible for a neurodevelopmental pathology characterized by female-limited epilepsy, cognitive impairment and autistic features, the pathogenic mechanisms of which remain to be elucidated. Here, we identified a new interaction between PCDH19 and GABAA receptor (GABAAR) alpha subunits in the rat brain. PCDH19 shRNA-mediated downregulation reduces GABAAR surface expression and affects the frequency and kinetics of miniature inhibitory postsynaptic currents (mIPSCs) in cultured hippocampal neurons. " SIGNOR-267220 BRAP protein Q7Z569 UNIPROT CDC14A protein Q9UNH5 UNIPROT "up-regulates activity" polyubiquitination 9606 BTO:0000007 19152073 t k63 miannu "Brap2 promotes Lys-63 linked ubiquitination of HsCdc14A. Collectively, these results support the idea that Brap2 facilitates Lys-63 linked ubiquitin modification of HsCdc14A, which may not be targeted for degradation, but mainly for protein–protein interactions or other regulatory functions." SIGNOR-271777 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR FGFR1 protein P11362 UNIPROT down-regulates phosphorylation Ser777 SMPLDQYsPSFPDTR 9606 23405013 t lperfetto "Erk-mediated phosphorylation of fibroblast growth factor receptor 1 on ser777 inhibits signaling" SIGNOR-244541 DRAP1 protein Q14919 UNIPROT BTAF1 protein O14981 UNIPROT "up-regulates activity" binding 9986 15509807 t miannu "We present evidence that the NC2alpha subunit interacts with BTAF1. Addition of NC2alpha or the NC2 complex can stimulate the ability of BTAF1 to interact with TBP." SIGNOR-263918 RPS6K proteinfamily SIGNOR-PF26 SIGNOR Translational_regulation phenotype SIGNOR-PH202 SIGNOR up-regulates 9606 17360704 f gianni "Mutation of rpS6 at Ser(235/236) reveals that phosphorylation of these sites promotes its recruitment to the 7-methylguanosine cap complex, suggesting that Ras/ERK signaling regulates assembly of the translation preinitiation complex. These data demonstrate that RSK provides an mTOR-independent pathway linking the Ras/ERK signaling cascade to the translational machinery." SIGNOR-268527 PTPN11 protein Q06124 UNIPROT PDGFRB protein P09619 UNIPROT "down-regulates activity" dephosphorylation Tyr771 ADIESSNyMAPYDNY -1 7545675 t "Upon activation, the βPDGFR is phosphorylated at multiple tyrosine residues and thereby becomes a docking site for SH2-domain-containing signal transduction proteins.|While all phosphotyrosine sites on the βPDGFR are equally good targets for rPTP1B, maps of the βPDGFR dephosphorylated by rSyp showed that rSyp had a distinct preference for certain sites (Fig. 4 D-F). The low dose of rSyp primarily dephosphorylated spots 1, 6, 7, 9, and to a lesser extent 8a|Spot 1 corresponds to tyrosine 751; spot 3 corresponds to tyrosine 1009; spot 6 corresponds to tyrosine 740; spot 8b corresponds to tyrosine 1021; spot 9 corresponds to tyrosine 771, and spots 2, 7, and 8a are as yet unidentified phosphopeptides" SIGNOR-248669 ACOX1 protein Q15067 UNIPROT TP73 protein O15350 UNIPROT "down-regulates quantity by destabilization" binding 9606 31401980 t miannu "Downregulation of ACOX1 increased p73, but not p53, expression. p73 expression was critical for apoptosis induction induced by ACOX1 downregulation. ACOX1 reduced p73 expression by destabilizing p73 protein. We also found that ACOX1 interacted with p73 protein" SIGNOR-261056 MAPK1 protein P28482 UNIPROT PARP1 protein P09874 UNIPROT up-regulates phosphorylation Thr373 AATPPPStASAPAAV 9606 BTO:0000938 BTO:0000142 16627622 t esanto "Parp1 phosphorylation by erk1/2 is required for maximal parp-1 activation after dna damage. S372a and t373a mutations impaired parp-1 activation." SIGNOR-146224 ATF6 protein P18850 UNIPROT "Chaperone-mediated protein folding" phenotype SIGNOR-PH120 SIGNOR up-regulates 9606 31226023 f miannu "Apart from ER protein chaperones, ATF6 also induces the expression of CHOP and XBP1, thereby connecting the three UPR branches into an integrated signaling network" SIGNOR-260182 PPP3CA protein Q08209 UNIPROT NFATC2 protein Q13469 UNIPROT up-regulates dephosphorylation 9606 21880741 t gcesareni "Calcineurin directly dephosphorylates nfat resulting in the nuclear import of nfat." SIGNOR-176373 SOD1 protein P00441 UNIPROT ERN1 protein O75460 UNIPROT "up-regulates activity" binding 10090 BTO:0004488 18519638 t "P00441:p.Gly94Ala (mutation causing interaction); P00441:p.Gly86Arg (mutation causing interaction); P00441:p.Ala5Val (mutation causing interaction)" "SOD1mut-induced ER stress |we first examined whether SOD1mut induces ER stress in NSC34 motor neurons, as assessed by band-shift analyses of the ER transmembrane kinase receptors IRE1 and PERK. Adenovirus (Ad)-mediated expression of ALS-linked SOD1mut (SOD1G93A) was detectable within 48 h of infection (Supplemental Fig. S1A). SOD1mut (SOD1A4V, SOD1G85R, and SOD1G93A) but not wild-type SOD1 (SOD1wt) activated IRE1 and PERK" SIGNOR-262786 2-oxoglutarate(2-) smallmolecule CHEBI:16810 ChEBI succinate(2-) smallmolecule CHEBI:30031 ChEBI "up-regulates quantity" "precursor of" 9606 11431483 t miannu "Epsilon-N-Trimethyllysine hydroxylase (EC ) is the first enzyme in the biosynthetic pathway of l-carnitine and catalyzes the formation of beta-hydroxy-N-epsilon-trimethyllysine from epsilon-N-trimethyllysine, a reaction dependent on alpha-ketoglutarate, Fe(2+), and oxygen." SIGNOR-269686 CSNK2A1 protein P68400 UNIPROT SPIB protein Q01892 UNIPROT down-regulates phosphorylation Ser37 KHSSYPDsEGAPDSL 9606 10618498 t lperfetto "Serine residues 37 in the transactivation domain and 129, 144 and 146 in the pest domain of spi-b are phosphorylated by ckii in vitro. The ckii phosphorylation sites mapped in vitro are phosphorylated in vivo. Mutations of the ckii phosphorylation sites increase the ability of spi-b to transactivate. Spi-b phosphorylation by ckii reduces its stability" SIGNOR-73891 PPP3CA protein Q08209 UNIPROT NFATC1 protein O95644 UNIPROT up-regulates dephosphorylation 9606 BTO:0000782 14722106 t gcesareni "Once activated, calcineurin directly dephosphorylates NFAT proteins that are present in a hyperphosphorylated latent form in the cytoplasm and induces their rapid translocation into the nucleus, where in concert with nuclear partner proteins such as the AP-1 transcription factor complex, they are able to bind cooperatively to their target promoter elements and activate the transcription of specific NFAT target genes" SIGNOR-84038 PPP2R5A protein Q15172 UNIPROT TGFBR1 protein P36897 UNIPROT up-regulates binding 9606 9774674 t gcesareni "In this report, we show that another wd-40 repeat protein, the balpha subunit of protein phosphatase 2a, associates with the cytoplasmic domain of type i tgf-beta receptors..[..] Furthermore, balpha enhances the growth inhibition activity of tgf-beta in a receptor-dependent manner" SIGNOR-60743 PLK1 protein P53350 UNIPROT ANAPC1 protein Q9H1A4 UNIPROT up-regulates phosphorylation Ser355 AALSRAHsPALGVHS 9606 14657031 t gcesareni "Our analysis revealed an unexpected and unprecedented complexity of mitotic phosphorylation sites and suggests that other kinases than cdk1 and plk1 also contribute to apc phosphorylation." SIGNOR-119881 PPM1B protein O75688 UNIPROT IKBKB protein O14920 UNIPROT "down-regulates activity" dephosphorylation Ser181 DQGSLCTsFVGTLQY 9606 18930133 t "PPM1A and PPM1B act as IKKbeta phosphatases to terminate TNFalpha-induced IKKbeta-NF-kappaB activation|Overexpression of PPM1A or PPM1B results in dephosphorylation of IKKbeta at Ser177 and Ser181 and termination of IKKbeta-induced NF-kappaB activation." SIGNOR-248344 TGFB1 protein P01137 UNIPROT PI3K complex SIGNOR-C156 SIGNOR "up-regulates activity" binding 9606 19114990 t lperfetto "While association of the TGF_RI receptor with p85 requires TGF-_ stimulation." SIGNOR-252729 SUFU protein Q9UMX1 UNIPROT GLI2 protein P10070 UNIPROT "down-regulates activity" relocalization 10090 16316410 t lperfetto "We demonstrate here that Su(fu) prevents the nuclear accumulation of Gli1 and Gli2 through multiple mechanisms" SIGNOR-129065 sapitinib chemical CHEBI:132986 ChEBI ERBB3 protein P21860 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-190155 PLK1 protein P53350 UNIPROT SUN1 protein O94901 UNIPROT "down-regulates activity" phosphorylation Ser138 RPPVLDEsWIREQTT 9606 25482198 t miannu "Here, we show that SUN1, located in the INM, undergoes mitosis-specific phosphorylation on at least 3 sites within its nucleoplasmic N-terminus. We further identify Cdk1 as the kinase responsible for serine 48 and 333 phosphorylation, while serine 138 is phosphorylated by Plk1. Together, these data support a model whereby mitotic phosphorylation of SUN1 disrupts interactions with nucleoplasmic binding partners, promoting disassembly of the nuclear lamina and, potentially, its chromatin interactions." SIGNOR-263098 FUS protein P35637 UNIPROT SNRNP70 protein P08621 UNIPROT "up-regulates activity" binding 9606 26124092 t "FUS functions in coupling transcription to splicing by mediating an interaction between RNAP II and U1 snRNP" SIGNOR-262823 YAP1 protein P46937 UNIPROT RUNX2 protein Q13950 UNIPROT down-regulates binding 9606 14765127 t "Regulation of Runx activity by TAZ or YAP affects mesenchymal stem cell differentiation." gcesareni "Here we show that the endogenous yes-associated protein (yap), a mediator of src/yes signaling, interacts with the native runx2 protein, an osteoblast-related transcription factor, and suppresses runx2 transcriptional activity in a dose-dependent manner." SIGNOR-121803 PIAS4 protein Q8N2W9 UNIPROT SMAD3 protein P84022 UNIPROT down-regulates binding 9606 SIGNOR-C9 12904571 t gcesareni "Piasy binds most strongly with smad3 and also associates with other receptor-regulated smads and smad4. smad3, smad4, and piasy can form a ternary complex. Piasy does not inhibit smad complex binding to dna, but it represses smad transcriptional activity." SIGNOR-104538 PRKAA2 protein P54646 UNIPROT ACACB protein O00763 UNIPROT "down-regulates activity" phosphorylation Ser222 PTMRPSMsGLHLVKR 9606 9148944 t miannu "The results suggest that the decrease in ACC activity during muscle contraction is caused by an increase in its phosphorylation, most probably due, at least in part, to activation of the alpha2 isoform of AMPK." SIGNOR-250318 AKT1S1 protein Q96B36 UNIPROT mTORC1 complex SIGNOR-C3 SIGNOR "form complex" binding 9606 25628925 t lperfetto "Depending on their binding partners and sensitivities to rapamycin, mtor resides in at least two distinct complexes, termed mtor complex 1 (mtorc1, containing raptor, fkbp12, pras40 and mlst8) and mtor complex 2 (mtorc2, containing rictor, sin1, protor and mlst8)" SIGNOR-205597 PAX5 protein Q02548 UNIPROT PRDM1 protein O75626 UNIPROT "down-regulates quantity" "transcriptional regulation" 10090 9120274 t Gianni "Overexpression of BSAP reduced Blimp-1 expression in CH12.LX.A2 clones but not in MPC11 clones. In addition, overexpression of BSAP in CH12.LX.A2 cells suppressed spontaneous appearance of cells with high Syndecan-1 expression and high amounts of intracytosolic as well as secreted Ig synthesi" SIGNOR-269085 H4C1 protein P62805 UNIPROT "Nucleosome_H3.1t variant" complex SIGNOR-C325 SIGNOR "form complex" binding -1 20498094 t miannu "A histone H3 variant, H3T, is highly expressed in the testis, suggesting that it may play an important role in the chromatin reorganization required for meiosis and/or spermatogenesis. In the present study, we found that the nucleosome containing human H3T is significantly unstable both in vitro and in vivo, as compared to the conventional nucleosome containing H3.1." SIGNOR-263726 RB1 protein P06400 UNIPROT ITGA10 protein O75578 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 24287699 f lperfetto "Integrin α10 expression is pRb-dependent in mouse osteoblasts|pRb-activated expression of integrin α10 mRNA is effectively translated into higher levels of integrin α10 protein as visualized by immunofluorescence" SIGNOR-253348 LYN protein P07948 UNIPROT PRKCD protein Q05655 UNIPROT "up-regulates activity" phosphorylation Tyr52 VQKKPTMyPEWKSTF -1 9692543 t "Lyn was found to phosphorylate Lyn-associated and recombinant PKC-delta in vitro and the tyrosine 52 phosphorylated PKC-delta was recruited to associate with the Lyn SH2 domain." SIGNOR-251408 budesonide chemical CHEBI:3207 ChEBI NR3C1 protein P04150 UNIPROT up-regulates "chemical activation" 9606 6958488 t "nasal polyposys" gcesareni SIGNOR-251688 GRPR protein P30550 UNIPROT GNAL protein P38405 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-256917 PRKAA1 protein Q13131 UNIPROT RRN3 protein Q9NYV6 UNIPROT down-regulates phosphorylation Ser635 DTHFRSPsSSVGSPP 9606 SIGNOR-C15 19815529 t llicata "We show that ampk down-regulates rrna synthesis under glucose restriction by phosphorylating the rna polymerase i (pol i)-associated transcription factor tif-ia at a single serine residue (ser-635)." SIGNOR-188403 FCAR protein P24071 UNIPROT Cytokine_production phenotype SIGNOR-PH166 SIGNOR up-regulates 9606 BTO:0000130;BTO:0000801;BTO:0000876;BTO:0000399 30766540 f lperfetto "IgA-mediated immune effector responses such as phagocytosis, antibody-dependent cell-mediated cytotoxicity, respiratory burst and cytokine release are mediated through FcalphaRI (CD89), an IgA-specific receptor that is expressed on monocytes, eosinophils, neutrophils and macrophages" SIGNOR-264860 CBX1 protein P83916 UNIPROT H3-3A protein P84243 UNIPROT "up-regulates activity" binding 9606 methylation:Lys10 RTKQTARkSTGGKAP 19111658 t miannu "A core characteristic of heterochromatin is its association with heterochromatin protein 1 (HP1) proteins, a highly conserved family of chromosomal proteins that bind to di- and trimethylated H3K9 via a conserved N-terminal domain called the chromodomain (CD) HP1 proteins are a highly conserved family of eukaryotic proteins that bind to methylated histone H3 lysine 9 (H3K9) and are required for heterochromatic gene silencing." SIGNOR-264491 PPP1R3B protein Q86XI6 UNIPROT GYS1 protein P13807 UNIPROT up-regulates binding 9606 BTO:0000759 36551183 t miannu "In the liver, PTG and PPP1R3B(GL)are expressed at roughly equivalent levels [55], and they jointly promote hepatic glycogen mobilization and storage. PTG overexpression significantly increased glycogen content, mainly due to its ability to promote the redistribution of PP1 and glycogen synthase to glycogen granules, significantly increasing GS activity and glycogen synthesis (Figure 2)" SIGNOR-271734 PRDM1 protein O75626 UNIPROT PAX5 protein Q02548 UNIPROT "down-regulates quantity" "transcriptional regulation" 10090 12052884 t Gianni "Blimp-1 binds a site on the Pax-5 promoter in vitro and in vivo and represses the Pax-5 promoter in a binding-site-dependent manner." SIGNOR-269089 USP8 protein P40818 UNIPROT BACE1 protein P56817 UNIPROT "up-regulates quantity" deubiquitination 9606 BTO:0003704 27302062 t "Here, we report that RNAi-mediated depletion of USP8 reduced levels of both ectopically expressed and endogenous BACE1 in H4 human neuroglioma cells. Moreover, USP8 depletion increased BACE1 ubiquitination, promoted BACE1 accumulation in the early endosomes and late endosomes/lysosomes, and decreased levels of BACE1 in the recycling endosomes." SIGNOR-266905 PRKCD protein Q05655 UNIPROT NCF1 protein P14598 UNIPROT up-regulates phosphorylation Ser304 GAPPRRSsIRNAHSI 9606 12056906 t esanto "Pkc alpha, beta ii, delta, and zeta expressed in human neutrophils can individually phosphorylate p47(phox) and induce both its translocation and nadph oxidase activation. The use of p47phox mutants identified serines 303, 304, 315, 320, 328, 359, 370, and 379 as targets of pkc?, ???, And ?." SIGNOR-89221 ZAP70 protein P43403 UNIPROT SH2B3 protein Q9UQQ2 UNIPROT up-regulates phosphorylation Tyr273 LEMPDNLyTFVLKVK 9606 BTO:0000782 9169414 t lperfetto "In vitro tyrosine phosphorylation of lnk by lck and zap-70. Tyrosine 297 would appear to be an attractive target for phosphorylation within the c-terminal domain. Our studies suggest that although lnk may participate in tcr signaling, its functions are in no way limiting during t cell development or activation." SIGNOR-48854 MAPK1 protein P28482 UNIPROT POLR2A protein P24928 UNIPROT down-regulates phosphorylation Ser1892 TPKYSPTsPTYSPTS 9606 14662762 t lperfetto "Erk1/2 are major ser-5 kinases after h2o2 treatment. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination." SIGNOR-120140 FBXO22 protein Q8NEZ5 UNIPROT BACH1 protein O14867 UNIPROT "down-regulates quantity" ubiquitination 9606 31257023 t "Here, we show that heme triggers the degradation of Bach1, a pro-metastatic transcription factor, by promoting its interaction with the ubiquitin ligase Fbxo22." SIGNOR-259331 ITGB1 protein P05556 UNIPROT "Av/b1 integrin" complex SIGNOR-C175 SIGNOR "form complex" binding 16988024 t lperfetto "Integrins are one of the major families of cell adhesion receptors (Humphries, 2000; Hynes, 2002). All integrins are non-covalently-linked, heterodimeric molecules containing an α and a β subunit. Both subunits are type I transmembrane proteins, containing large extracellular domains and mostly short cytoplasmic domains (Springer and Wang, 2004; Arnaout et al., 2005). Mammalian genomes contain 18 α subunit and 8 β subunit genes, and to date 24 different α,β combinations have been identified at the protein level. Although some subunits only appear in a single heterodimer, twelve integrins contain the β1 subunit, and five contain αV." SIGNOR-253202 NEUROG3 protein Q9Y4Z2 UNIPROT ASH1L protein Q9NR48 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 19028584 f miannu "Ngn3 overexpression altered the expression of a number of regulatory genes, including ash1, ath3, ath5, chx10, neuroD, ngn1, ngn2, and NSCL1. Early gene ngn1 was induced, but ash1, ngn2, ath3, and chx10, whose expressions persist through later phases of neurogenesis, were down-regulated." SIGNOR-254629 AR protein P10275 UNIPROT SERPINB5 protein P36952 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 16304843 t lperfetto "In addition, androgen receptor (AR) can recognize and bind to the ARE element, and then inhibit the activity of maspin promoter" SIGNOR-253685 bortezomib chemical CHEBI:52717 ChEBI PSMB1 protein P20618 UNIPROT "down-regulates activity" "chemical inhibition" 9606 BTO:0000898 21504411 t miannu "Proteasome inhibition is a modern and surprisingly successful approach how to cancer treatment. Bortezomib (Velcade®) is a first-in-class proteasome inhibitor and has been approved for first-line treatment of multiple myeloma and second-line treatment of mantle cell lymphoma." SIGNOR-259306 MAPK3 protein P27361 UNIPROT RPS6KA3 protein P51812 UNIPROT up-regulates phosphorylation Ser227 DHEKKAYsFCGTVEY 9606 10980595 t llicata "We have generated two monoclonal antibodies that recognize two phosphorylated sites, p-ser227 and p-thr577, in the n- and c-terminal kinase domains of rsk2, respectively. phosphorylation and activation of rsk2 by uv light involves the erk pathway" SIGNOR-81460 H2AX protein P16104 UNIPROT NBN protein O60934 UNIPROT up-regulates binding 9606 15635255 t esanto "Nbs1 physically interacts with ?-H2ax to form nuclear foci at dna damage sites. The inhibition of this interaction by introduction of anti-?-H2ax antibody into cells abolishes nbs1 foci formation in response to dna damage." SIGNOR-133020 CAMK2A protein Q9UQM7 UNIPROT HOMER3 protein Q9NSC5 UNIPROT "down-regulates activity" phosphorylation Ser120 ARLAREKsQDGGELT -1 18480293 t miannu "Homer3 is phosphorylated at Ser120, Ser159, and Ser176 by CaMKII in vitro. Homer3 phosphorylation reduces its affinity for target molecules and modulates the Ca2+ signaling patterns induced by mGluR1α activation" SIGNOR-262684 ILK protein Q13418 UNIPROT PPP1R14A protein Q96A00 UNIPROT "up-regulates activity" phosphorylation Thr38 QKRHARVtVKYDRRE 9606 12144526 t miannu "Phosphopeptide mapping, phospho amino acid analysis and immunoblotting using phospho-specific antibodies indicated that ilk predominantly phosphorylated the site critical for potent inhibition, i.e. Thr(38) of cpi-17" SIGNOR-90828 LIMS4 protein P0CW20 UNIPROT "IPP complex" complex SIGNOR-C380 SIGNOR "form complex" binding 16493410 t lperfetto "Integrin-linked kinase (ILK), PINCH and parvin form a ternary complex (the IPP complex) that binds to ECM-ligated integrins. This complex regulates signalling pathways and connects the ECM with the actin cytoskeleton." SIGNOR-265766 TNFSF12 protein O43508 UNIPROT MYH3 protein P11055 UNIPROT "down-regulates quantity by destabilization" polyubiquitination 10090 BTO:0000165 17314137 t miannu "TWEAK induces ubiquitination of MyHCf and expression of atrogin-1 and MuRF1 in myotubes. our data show that TWEAK rapidly increases the conjugation of ubiquitin to MyHCf (Fig. 3A) and ubiquitination preceded the degradation of MyHCf (Fig. 2C and Fig. 3A)." SIGNOR-272628 CHUK protein O15111 UNIPROT NFKBIA protein P25963 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser32 LLDDRHDsGLDSMKD 9606 BTO:0000567 SIGNOR-C14 9346241 t lperfetto "We described the purification of a 900 kda protein kinase complex, the ikb kinase (ikk), that phosphorylates ikbalfa and ikbbeta at the sites that mediate their ubiquitination and degradation" SIGNOR-52875 RNF128 protein Q8TEB7 UNIPROT ARHGDIB protein P52566 UNIPROT "up-regulates quantity by stabilization" polyubiquitination 9606 BTO:0000661 17114425 t miannu "We found that RhoGDIα and RhoGDIβ are ubiquitin E3 substrates of GRAIL. GRAIL uses nonlysine 48-ubiquitin linkage in polyubiquitinating RhoGDI. GRAIL was subsequently demonstrated to bind and ubiquitinate RhoGDI, although GRAIL-mediated ubiquitination of RhoGDI did not result in proteosomal degradation. Our data suggest that ubiquitination of RhoGDI by GRAIL does not result in proteolytic degradation. In fact, GRAIL activity appeared to increase RhoGDI stability." SIGNOR-271621 3-[4-[4-[2-[3-[(dimethylamino)methyl]phenyl]-1H-pyrrolo[2,3-b]pyridin-4-yl]-1-ethyl-3-pyrazolyl]phenyl]-1,1-dimethylurea chemical CHEBI:91362 ChEBI AURKC protein Q9UQB9 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-192814 NPAS2 protein Q99743 UNIPROT BMAL1/NPAS2 complex SIGNOR-C431 SIGNOR "form complex" binding 9606 20817722 t miannu "The mammalian clock is regulated at the cellular level by a transcriptional/translational feedback loop. BMAL1/clock (or NPAS2) heterodimers activate the expression of the period (PER) and cryptochrome (CRY) genes acting as transcription factors directed to the PER and CRY promoters via E-box elements." SIGNOR-267966 NfKb-p65/p50 complex SIGNOR-C13 SIGNOR BIRC2 protein Q13490 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 9916987 f gcesareni "The iaps have been shown to be induced by nf-kappab or v-rel in multiple cell lines and conversely, hiap1 and hiap2 have been shown to activate nf-kappab possibly forming a positive feed-back loop." SIGNOR-64100 ERG protein P11308 UNIPROT TDRD1 protein Q9BXT4 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0003215 23319146 f miannu "In the prostate cancer cell line VCaP, downregulation of ERG by shRNA lead to a lower expression level of TDRD1 and resulted in a decreased activity of the TDRD1 promoter." SIGNOR-254067 mTORC1 complex SIGNOR-C3 SIGNOR RPS6KB1 protein P23443 UNIPROT up-regulates phosphorylation Thr412 NQVFLGFtYVAPSVL 9606 17510057 t lperfetto "Mtorc1 promotes protein synthesis by phosphorylating the eukaryotic initiation factor 4e (eif4e)- binding protein 1 (4e-bp1) and the p70 ribosomal s6 kinase 1 (s6k1). In vitro activation of p70alfa by mtor-catalyzed phosphorylation involving p70alfa thr-412. Mtor-catalyzed p70alfa phosphorylation in vitro is accompanied by a substantial restoration in p70alfa kinase activity toward its physiologic substrate, the 40 s ribosomal protein s6. in response to insulin and nutrients, mtorc1, consisting of mtor, raptor (regulatory-associated protein of mtor), and mlst8, is activated and phosphorylates eukaryotic initiation factor 4e-binding protein (4ebp) and p70 s6 kinase to promote protein synthesis and cell size." SIGNOR-217071 L-serine chemical CHEBI:17115 ChEBI D-serine smallmolecule CHEBI:16523 ChEBI "up-regulates quantity" "precursor of" 10090 BTO:0000142 12393813 t lperfetto "High levels of d-serine occur in the brain, challenging the notion that d-amino acids would not be present or play a role in mammals. d-serine levels in the brain are even higher than many l-amino acids, such as asparagine, valine, isoleucine, and tryptophan, among others. d-serine is synthesized by a serine racemase (SR) enzyme, which directly converts l- to d-serine. We now report that SR is a bifunctional enzyme, producing both d-serine and pyruvate in cultured cells and in vitro. Transfection of SR into HEK 293 cells elicits synthesis of d-serine and augmented release of pyruvate to culture media." SIGNOR-268271 ACTR3 protein P61158 UNIPROT ARP2/3 complex SIGNOR-C146 SIGNOR "form complex" binding 9606 12479800 t "The subunits in mammalian cells are named Arp3, Arp2, p41-Arc, p34-Arc, p21-Arc, p20-Arc and p16-Arc" SIGNOR-251513 CNBP protein P62633 UNIPROT MYC protein P01106 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0000567 23774591 t Luana "These data verified that the binding of CNBP with c-myc promoter G-quadruplex can indeed down-regulate its associated gene expression for a certain period of time. This result with human CNBP is somehow consistent with previous reports that c-myc G-quadruplex serves as a silencer of c-myc transcription [7] and CNBP promotes the formation of c-myc G-quadruplex." SIGNOR-261571 EPAS1 protein Q99814 UNIPROT KDM4B protein O94953 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 32938217 t SaraGualdi "To this end, we confirm that KDM3A, KDM4B, KDM4C, KDM5B, KDM5C, and KDM62 are direct targets of HIF-1a while extent the list of known targets to KDM2A, KDM2B, KDM4D, KDM5A, and KDM6A. The results demonstrated that majority of the KDMs were similarly induced (KDM2A, KDM2B, KDM3A, KDM4B, KDM4C, KDM4D, KDM5A, KDM5B, KDM5C, KDM6B, and KDM7A) or repressed (KDM NO66 and KDM1A) by both HIF-1a and HIF-2a." SIGNOR-271584 PRKCZ protein Q05513 UNIPROT WWC1 protein Q8IX03 UNIPROT unknown phosphorylation Ser975 VRMKRPSsVKSLRSE -1 15081397 t lperfetto "PKCzeta phosphorylates KIBRA at serine 975 and 978" SIGNOR-249262 ABL1 protein P00519 UNIPROT DGCR8 protein Q8WYQ5 UNIPROT "up-regulates activity" phosphorylation Tyr267 KRRTEEKyGGDSDHP 9606 BTO:0000007 26126715 t miannu "The kinase ABL phosphorylates the microprocessor subunit DGCR8 to stimulate primary microRNA processing in response to DNA damage. When coexpressed in HEK293T cells, ABL phosphorylated DGCR8 at Tyr(267)." SIGNOR-262604 LEPR protein P48357 UNIPROT AMPK complex SIGNOR-C15 SIGNOR "down-regulates activity" 9606 BTO:0003336 25343030 f miannu "Leptin exerts an inhibitory effect on AMPK in the hypothalamus, thereby stimulating ACC and subsequently suppressing food intake." SIGNOR-263510 KIF5A protein Q12840 UNIPROT Organelle_transport phenotype SIGNOR-PH159 SIGNOR up-regulates 9606 BTO:0000938 9438838 f miannu "The kinesin superfamily of proteins plays a major role in this complex organelle transport. Kinesin is primarily associated with anterogradely transported membranous organelles in nerve axons. KIF5B and HsuKHC are expressed ubiquitously in many tissues, whereas KIF5A, KIF5C, and HsnKHC are specific to nerve tissue." SIGNOR-264067 DUSP5 protein Q16690 UNIPROT MAPK1 protein P28482 UNIPROT down-regulates dephosphorylation 9606 15713638 t fstefani "Here we demonstrate that dusp5, an inducible nuclear phosphatase, interacts specifically with erk2 via a kinase interaction motif (kim) within its amino-terminal noncatalytic domain. This binding determines the substrate specificity of dusp5 in vivo, as it inactivates erk2 but not jun n-terminal protein kinase or p38 map kinase." SIGNOR-134049 TPO protein P07202 UNIPROT 3-iodo-L-tyrosine smallmolecule CHEBI:27847 ChEBI "up-regulates quantity" "chemical modification" 9606 16098474 t scontino "TPO plays a key role in thyroid hormone synthesis by catalyzing both the iodination of tyrosine residues to form monoiodotyrosine (MIT) and diiodotyrosine (DIT) residues. The first step in the process of thyroid hormone synthesis is the binding of iodine to tyrosine residues in Tg, which yields MIT and DIT residues." SIGNOR-266957 CDK1 protein P06493 UNIPROT PIK3C3 protein Q8NEB9 UNIPROT down-regulates phosphorylation Thr159 DGSEPTKtPGRTSST 9606 20513426 t llicata "We show that vps34 is phosphorylated on thr159 by cdk1, thr159 phosphorylation negatively regulates the ptdins3 kinase activity of vps34 and autophagy" SIGNOR-165768 MAP3K14 protein Q99558 UNIPROT CHUK protein O15111 UNIPROT "up-regulates activity" phosphorylation 9606 20651737 t lperfetto "Once activated by autophosphorylation, nik activates ikkalpha, which in turn phosphorylates nf-kb2. This stimulates limited proteasome-mediated proteolysis of nf-kb2 to p52. Removal of the carboxy-terminal ankyrin repeats from nf-kb2 releases the p52/RELB heterodimer, allowing its translocation to the nucleus where it instigates the expression of nf-kb target genes." SIGNOR-167060 BUB3 protein O43684 UNIPROT MCC complex SIGNOR-C382 SIGNOR "form complex" binding 9606 BTO:0000567 25092294 t miannu "The mitotic (or spindle assembly) checkpoint system delays anaphase until all chromosomes are correctly attached to the mitotic spindle. When the checkpoint is active, a Mitotic Checkpoint Complex (MCC) assembles and inhibits the ubiquitin ligase Anaphase-Promoting Complex/Cyclosome (APC/C). MCC is composed of the checkpoint proteins Mad2, BubR1, and Bub3 associated with the APC/C activator Cdc20." SIGNOR-265975 MAP2K4 protein P45985 UNIPROT MAP2K4 protein P45985 UNIPROT "up-regulates activity" phosphorylation Ser257 ISGQLVDsIAKTRDA -1 9162092 t "Ser221 and, to a lesser extent, Thr225 in MKK4 as necessary sites for basal and MEKK-induced autophosphorylation and activation of MKK4." SIGNOR-251420 SRC protein P12931 UNIPROT GTF2I protein P78347 UNIPROT "up-regulates activity" phosphorylation Tyr248 EESEDPDyYQYNIQA 9534 BTO:0004055 11934902 t lperfetto "c-Src-dependent transcriptional activation of TFII-ITFII-I is a multifunctional transcription factor that is also involved in signal transduction. Here we show that TFII-I undergoes a c-Src-dependent tyrosine phosphorylation on tyrosine residues 248 and 611 and translocates to the nucleus in response to growth factor signaling" SIGNOR-247185 PTEN protein P60484 UNIPROT PI3K complex SIGNOR-C156 SIGNOR "down-regulates activity" 9606 BTO:0000938 18794881 f lperfetto "The pten tumour suppressor is a lipid and protein phosphatase that inhibits phosphoinositide 3-kinase (pi3k)-dependent by dephosphorylating phosphatidylinositol 3,4,5-trisphosphate (ptdinsp(3))." SIGNOR-252725 GNAS protein Q5JWF2 UNIPROT Adenylate_cyclase proteinfamily SIGNOR-PF92 SIGNOR "up-regulates activity" binding 9606 12145344 t lperfetto "HETEROTRIMERIC G PROTEINS are essential for cell signaling throughout the body. The stimulatory G protein, Gs, couples activation of a host of different transmembrane receptors to adenylyl cyclase stimulation, leading to intracellular generation of cAMP" SIGNOR-268693 MAPK3 protein P27361 UNIPROT BRAF protein P15056 UNIPROT "down-regulates activity" phosphorylation Ser151 VARSNPKsPQKPIVR 9606 BTO:0000848 21478863 t "We show that overactivation of the MAPK pathway, induced by the oncogenic Ras in melanoma, induces constitutive phosphorylation of BRAF on Ser151 by ERK, which inhibits NRAS-BRAF interaction" SIGNOR-259921 EGFR protein P00533 UNIPROT EGFR protein P00533 UNIPROT "up-regulates activity" phosphorylation Tyr1092 TFLPVPEyINQSVPK 9606 BTO:0000567 10653583 t "Dimerization mediated by a beta hairpin, which protudes from the S1 domains of each ligand bound monomer" lperfetto "After binding of epidermal growth factor (EGF), the EGF receptor (EGFR) becomes autophosphorylated via tyrosine." SIGNOR-236479 PRDM14 protein Q9GZV8 UNIPROT POU5F1 protein Q01860 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0001086 20953172 f miannu "We showed that PRDM14 regulates directly the expression of key pluripotency gene POU5F1 through its proximal enhancer." SIGNOR-255067 IKBKB protein O14920 UNIPROT COMT protein P21964 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0000100 19291302 f "Regulation of expression" miannu "TNFα-dependent COMT downregulation was indeed mediated by the NF-κB pathway. Transient expression of p65, the essential component of NF-κB complexes, or IKKβ, the major positive regulator of NF-κB activition, significantly decreased P2-COMT reporter expression." SIGNOR-251965 SRPK1 protein Q96SB4 UNIPROT SRPK1 protein Q96SB4 UNIPROT up-regulates phosphorylation Ser33 SETQHRGsAPHSESD 9606 22727668 t llicata "We found that activated akt binds and induces srpk1 autophosphorylation because akt-mediated phosphorylation depends on the kinase activity of srpk1" SIGNOR-197989 MAPK1 protein P28482 UNIPROT PTTG1 protein O95997 UNIPROT up-regulates phosphorylation Ser165 LFQLGPPsPVKMPSP 9606 10906323 t gcesareni "Pttg is phosphorylated in vitro on ser(162) by map kinase and this phosphorylation site plays an essential role in pttg transactivation function." SIGNOR-79515 ATR protein Q13535 UNIPROT CDS1 protein Q92903 UNIPROT up-regulates 9606 15530773 f gcesareni "The pikk kinases serve as transducers of the damege signel, ultimately phosphorylating and activating the downstream effector kinases: checkpoint kinases 1 and 2." SIGNOR-130187 PRKACA protein P17612 UNIPROT CCND1 protein P24385 UNIPROT unknown phosphorylation Ser90 NYLDRFLsLEPVKKS -1 8058338 t miannu "PKA phosphorylates three distinct serine residues in cyclin D1 at positions 90, 197 and 234." SIGNOR-250347 "beta-D-fructofuranose 1,6-bisphosphate(4-)" smallmolecule CHEBI:32966 ChEBI "D-glyceraldehyde 3-phosphate(2-)" smallmolecule CHEBI:59776 ChEBI "up-regulates quantity" "precursor of" 9606 16051738 t miannu "Aldolase catalyzes the reversible conversion of FBP to glyceraldehyde-3-phosphate and dihydroxyacetone phosphate (DHAP; Figure 1). Aldolase is a tetramer of identical subunits of 40 kDa each, and 3 distinct isoenzymes have been identified: aldolase A, B, and C." SIGNOR-266478 indometacin chemical CHEBI:49662 ChEBI PTGS1 protein P23219 UNIPROT "down-regulates activity" "chemical inhibition" -1 9057869 t miannu "Naproxen had similar activity against both COX-1 and COX-2 enzymes (IC50s of 3.2 and 2.5 μM, respectively), whereas ibuprofen was approximately 100-fold more potent for COX-2 (IC50 = 0.1 μM) than for COX-1 (IC50 = 11 μM), and indomethacin was about 50-fold more potent for COX-1 (IC50 = 0.012 μM) than for COX-2 (IC50 = 0.56 μM)." SIGNOR-258607 FCHO2 protein Q0JRZ9 UNIPROT "AP-2/clathrin vescicle" complex SIGNOR-C249 SIGNOR "up-regulates quantity by stabilization" binding 24789820 t lperfetto "Early recruitment of FCHo1/2, Eps15, epsin, and intersectin to the rims of assembling coated pits is essential for their stability and further growth" SIGNOR-260717 PIM2 protein Q9P1W9 UNIPROT PK proteinfamily SIGNOR-PF80 SIGNOR "up-regulates quantity by stabilization" phosphorylation 9606 24142698 t "inferred from family member" Manara "Importantly, we found that PIM2 could directly phosphorylate PKM2 on the Thr-454 residue, resulting in an increase of PKM2 protein levels." SIGNOR-270287 MAPK1 protein P28482 UNIPROT CASP8 protein Q14790 UNIPROT down-regulates phosphorylation Ser387 YLEMDLSsPQTRYIP 9606 BTO:0000149 24342355 t lperfetto "We demonstrate that perk 1/2 can phosphorylate pro-caspase-8 at s387 by knocking-down the endogenous pro-caspase-8 using rnai and replacing it with its non-phosphorylatable counterpart (s387a), a significant increase in caspase-8 activity" SIGNOR-203473 PLK1 protein P53350 UNIPROT WEE1 protein P30291 UNIPROT down-regulates phosphorylation Ser53 GHSTGEDsAFQEPDS 9606 BTO:0000567 15070733 t gcesareni "Phosphorylation of serines 53 and 123 (s53 and s123) of wee1a by polo-like kinase 1 (plk1) and cdk, respectively, are required for binding to beta-trcp." SIGNOR-123832 Ub:E2 complex SIGNOR-C497 SIGNOR RNF180 protein Q86T96 UNIPROT "up-regulates activity" ubiquitination 9606 34199813 t miannu "The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t" SIGNOR-271028 SOD3 protein P08294 UNIPROT dioxygen smallmolecule CHEBI:15379 ChEBI "up-regulates quantity" "chemical modification" 9606 29301787 t lperfetto "Oxidative stress contributes to diabetes mellitus (DM)–induced endothelial dysfunction, which is one of the most common causes of cardiovascular morbidity and mortality.1,2 The major cellular defense against superoxide (O2•−) is SODs (superoxide dismutases), which consists of the SOD1 (cytoplasmic copper zinc SOD [Cu/ZnSOD]), the SOD2 (mitochondrial MnSOD), and the SOD3 (extracellular Cu/ZnSOD)." SIGNOR-272272 PPARG protein P37231 UNIPROT CEBPA protein P49715 UNIPROT "up-regulates activity" "transcriptional regulation" 10090 BTO:0002572;BTO:0000011;BTO:0005065 16431920 f "Dislodging hdac1 from the promoter" lperfetto "These data suggest that c/ebp beta activates a single unified pathway of adipogenesis involving its stimulation of ppargamma expression, which then activates c/ebp alpha expression by dislodging hdac1 from the promoter for degradation in the proteasome" SIGNOR-235358 CASP8 protein Q14790 UNIPROT CASP8AP2 protein Q9UKL3 UNIPROT up-regulates binding 9606 17245429 t gcesareni "The caspase-8-binding protein flice-associated huge protein (flash) would form a molecular complex with caspase-8, thereby presumably activating the mitochondrial apoptosis pathway by regulating caspase-8 activity." SIGNOR-152473 MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR MAPK3 protein P27361 UNIPROT up-regulates phosphorylation Tyr204 HTGFLTEyVATRWYR 9606 9677429 t "MAPK3/ERK1 is a MAPK which plays an important role in the MAPK/ERK cascade." lperfetto "The mek1 proline-rich insert is required for efficient activation of the mitogen-activated protein kinases erk1 and erk2 in mammalian cells." SIGNOR-244806 PTPRJ protein Q12913 UNIPROT MET protein P08581 UNIPROT down-regulates dephosphorylation Tyr1365 NVKCVAPyPSLLSSE 9606 BTO:0000150;BTO:0000551 12475979 t gcesareni "Hepatocyte growth factor receptor tyrosine kinase met is a substrate of the receptor protein-tyrosine phosphatase dep-1" SIGNOR-96347 CTBP1 protein Q13363 UNIPROT BHLHE41 protein Q9C0J9 UNIPROT up-regulates binding 9606 16287852 t gcesareni "We identify the ctip and ctbp corepressors as novel components of the human rbp-jkappa/sharp-corepressor complex and show that ctip binds directly to the sharp repression domain. Functionally, ctip and ctbp augment sharp-mediated repression." SIGNOR-141613 MAPK1 protein P28482 UNIPROT PARVA protein Q9NVD7 UNIPROT "up-regulates activity" phosphorylation Ser4 sPQKSPSV 9606 22955285 t lperfetto "Actopaxin (alpha-parvin) is a paxillin, integrin-linked kinase, and F-actin binding focal adhesion protein with several serine phosphorylation sites in the amino terminus that contribute to the regulation of cell spreading and migration.|Actopaxin phosphorylation of Ser4/8 enhances cell migration whereas a nonphosphorylatable (Quint) mutant suppresses migration in U2OS osteosarcoma cells (7)." SIGNOR-265760 RMDN3 protein Q96TC7 UNIPROT "VAPB-PTPIP51 complex" complex SIGNOR-C275 SIGNOR "form complex" binding 10116 BTO:0000142 30841933 t lperfetto "Here, we demonstrate that the VAPB-PTPIP51 tethers regulate synaptic activity. VAPB and PTPIP51 localise and form contacts at synapses, and stimulating neuronal activity increases ER-mitochondria contacts and the VAPB-PTPIP51 interaction." SIGNOR-262119 belinostat chemical CHEBI:61076 ChEBI HDAC3 protein O15379 UNIPROT "down-regulates activity" "chemical inhibition" -1 17868033 t Luana "Our findings suggest that hydroxamic acid-derived compounds such as TSA, NVP-LAQ824, panobinostat, ITF2357, vorinostat and belinostat act as potent pan-HDAC isoform inhibitors. A notable observation was the similarity between belinostat and vorinostat in the biochemical isoform assays; both compounds exhibit similar EC50 values in all but the HDAC8 assay." SIGNOR-257746 CDK1 protein P06493 UNIPROT LATS1 protein O95835 UNIPROT up-regulates phosphorylation Ser613 EKKQITTsPITVRKN 9606 SIGNOR-C17 12372621 t lperfetto "Warts is a serine/threonine kinase and a dynamic component of the mitotic apparatus. We have found that cdc2/cyclin b forms a complex with a fraction of warts in the centrosome and phosphorylates the ser613 site of warts during mitosisit can be speculated that phosphorylation of warts by cdc2/cyclin b promotes a protein complex formation on the mitotic apparatus at early mitosis, which may be required for subsequent activation of warts kinase at the metaphase-anaphase transition." SIGNOR-94160 SERPINE1 protein P05121 UNIPROT Fibrinolysis phenotype SIGNOR-PH6 SIGNOR down-regulates 9606 10368279 f gcesareni "Pai-1 is the physiological inhibitor of the fibrinolytic pathway" SIGNOR-68481 "UVB radiation" stimulus SIGNOR-ST17 SIGNOR PAH protein P00439 UNIPROT up-regulates 9606 9204951 f miannu "UVB light induces GTP-CH.-1 to increase the de novo synthesis of 6-BH4 in association with a concomitant increase in PAH activities, thus providing more L-tyrosine." SIGNOR-252207 RIMS2 protein Q9UQ26 UNIPROT RAB3A protein P20336 UNIPROT "up-regulates activity" relocalization 9606 BTO:0000938 31679900 t miannu "N-terminal interactions of RIMs with RAB3 and MUNC13 regulate DCV fusion. Through N-terminal interactions, RIMs position MUNC13 and recruit DCVs via RAB3, which is located on the vesicle" SIGNOR-264377 PTGDR protein Q13258 UNIPROT GNAL protein P38405 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-256898 AKT1 protein P31749 UNIPROT ZFP36L1 protein Q07352 UNIPROT down-regulates phosphorylation Ser92 RFRDRSFsEGGERLL 9606 15538381 t llicata "Here we report that protein kinase b (pkb/akt) stabilizes are transcripts by phosphorylating brf1 at serine 92 (s92). Recombinant brf1 promoted in vitro decay of are-containing mrna (are-mrna), yet phosphorylation by pkb impaired this activity." SIGNOR-130376 RPS6KA3 protein P51812 UNIPROT WWC1 protein Q8IX03 UNIPROT up-regulates phosphorylation Thr929 STIIRSKtFSPGPQS 9606 BTO:0000149 24269383 t llicata "Moreover, we found that rsk1/2 specifically phosphorylates kibra at two highly conserved sites (thr(929) and ser(947)) in vitro and in cells. Rsk-mediated phosphorylation is required for kibra binding to rsk1, but not rsk2." SIGNOR-203306 PRKCA protein P17252 UNIPROT PFKFB2 protein O60825 UNIPROT "up-regulates activity" phosphorylation Thr475 TPLSSSNtIRRPRNY -1 1322130 t lperfetto "The phosphorylation sites for both cAMP-dependent protein kinase and protein kinase C were located in a single peptide whose sequence was Arg-Arg-Asn-Ser-(P)-Phe-Thr-Pro-Leu-Ser-Ser-Ser-Asn-Thr(P)-Ile-Arg-Arg-Pro. The seryl residue nearest the N terminus was the residue specifically phosphorylated by cAMP-dependent protein kinase, whereas the threonine residue nearest the C terminus was phosphorylated by protein kinase C. | Phosphorylation of bovine heart Fru-6-P,B-kinase by either protein kinase C or CAMP-dependent protein kinase results in activation of the enzyme." SIGNOR-248844 PTPN12 protein Q05209 UNIPROT BCAR1 protein P56945 UNIPROT down-regulates dephosphorylation 9606 BTO:0000782 11432829 t gcesareni "Ptp-pest is an efficient negative regulator of lymphocyte activation. This function correlated with the ability of ptp-pest to induce dephosphorylation of shc, pyk2, fak and cas, and inactivate the ras pathway." SIGNOR-109032 N-(5-{[(5-tert-butyl-1,3-oxazol-2-yl)methyl]sulfanyl}-1,3-thiazol-2-yl)piperidine-4-carboxamide chemical CHEBI:91399 ChEBI CDK9 protein P50750 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-207090 ATF1 protein P18846 UNIPROT FTH1 protein P02794 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 17565989 f miannu "Here we found that ATF1 (activating transcription factor 1) is a transcriptional repressor of the ferritin H ARE." SIGNOR-253741 KNG1 protein P01042 UNIPROT BDKRB2 protein P30411 UNIPROT "up-regulates activity" binding 9606 cleavage:Arg381;Arg389 GMISLMKrPPGFSPF;PPGFSPFrSSRIGEI 28966616 t lperfetto "BK binds receptor B2 (B2R) and triggers inflammation, edema, and symptoms of anaphylaxis." SIGNOR-263554 "Membrane attack complex" complex SIGNOR-C313 SIGNOR Cell_killing phenotype SIGNOR-PH149 SIGNOR up-regulates -1 30552328 f lperfetto "Our work provides a structural basis for understanding how β-pore forming proteins breach the membrane and reveals a mechanism for how MAC kills pathogens and regulates cell functions." SIGNOR-263454 AURKA protein O14965 UNIPROT TP53 protein P04637 UNIPROT up-regulates phosphorylation Ser106 SQKTYQGsYGFRLGF 9606 23201157 t gcesareni "Ser-106 phosphorylation of p53 decreases its interaction with mdm2 and prolongs the half-life of p53" SIGNOR-199939 NR3C1 protein P04150 UNIPROT PPARG protein P37231 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 BTO:0000011 10649448 f gcesareni "The dose of DEX required to promote maximal expression of PPARg mRNA is approximately 10 nM, which is within the range of the Kd for the association of DEX with the glucocorticoid receptor in 3T3-L1 cells" SIGNOR-255753 CSNK1E protein P49674 UNIPROT PER1 protein O15534 UNIPROT down-regulates phosphorylation 9606 15917222 t miannu "Ck1_ and ck1_2 can promote proteasome-dependent per1 degradation in mammalian tissue culture cells, and their removal by rnai leads to an increased abundance of per1." SIGNOR-137706 CyclinD3/CDK6 complex SIGNOR-C234 SIGNOR RUNX1 protein Q01196 UNIPROT "up-regulates activity" phosphorylation Ser276 VHPATPIsPGRASGM 9606 21059642 t "The effect has been demonstrated using Q01196-8" gcesareni "Phosphorylation of runx1 on ser-303 by cdks leads its ubiquitin-mediated degradation during g2/m (19). We developed additional evidence that cdks phosphorylate ser-303 and found that ser-48 and ser-424 are also substrates of cdk1/cyclin b and cdk6/cyclin d3. Moreover, we demonstrated that phosphorylation of ser-48, ser-303, and ser-424 strengthens the ability of runx1 to activate transcription and to stimulate proliferation of the ba/f3 hematopoietic cell line (20)." SIGNOR-273029 CyclinD3/CDK6 complex SIGNOR-C234 SIGNOR RUNX1 protein Q01196 UNIPROT "up-regulates activity" phosphorylation Ser397 SMVGGERsPPRILPP 9606 BTO:0000007 21059642 t "The effect has been demonstrated using Q01196-8" gcesareni "Phosphorylation of runx1 on ser-303 by cdks leads its ubiquitin-mediated degradation during g2/m (19). We developed additional evidence that cdks phosphorylate ser-303 and found that ser-48 and ser-424 are also substrates of cdk1/cyclin b and cdk6/cyclin d3. Moreover, we demonstrated that phosphorylation of ser-48, ser-303, and ser-424 strengthens the ability of runx1 to activate transcription and to stimulate proliferation of the ba/f3 hematopoietic cell line (20)." SIGNOR-273030 COL4A2 protein P08572 UNIPROT "A1/b1 integrin" complex SIGNOR-C159 SIGNOR "up-regulates activity" binding 35267698 t lperfetto "Integrins constitute a major group of receptors for extracellular matrix components, including collagens.|Among the four types, the signaling mechanism of α1β1 and α2β1 integrins has especially been reported. These integrins bind to both collagen types I and IV; however, their affinities differ: α1β1 has a higher affinity for collagen type IV, while α2β1 preferentially binds to collagen type I [13,23]." SIGNOR-272348 CDK1 protein P06493 UNIPROT CDC25B protein P30305 UNIPROT up-regulates phosphorylation Ser160 PVRLLGHsPVLRNIT 9606 SIGNOR-C17 12107172 t lperfetto "We demonstrate that serine 146 is required for two crucial features of cdc25b1. It is essential for cdc25b1 to function as a mitotic inducer and to prevent cdc25b1 export from the nucleus. We also show that serine 146 is phosphorylated in vitro by cdk1-cyclin b. Serine 146 phosphorylation is proposed to be a key event in the regulation of the cdc25b function" SIGNOR-90451 AKT2 protein P31751 UNIPROT PKP1 protein Q13835 UNIPROT "up-regulates quantity by stabilization" phosphorylation Thr179 LGSKGQKtTQNRYSF -1 23444369 t miannu "Akt2 phosphorylates PKP1 in vitro. Phosphorylated PKP1 is more resistant to degradation. PKP1 phosphorylation sites identified by peptide microarray analyses and mass spectrometry." SIGNOR-273489 F7 protein P08709 UNIPROT F9 protein P00740 UNIPROT "up-regulates activity" binding 9606 BTO:0000131 SIGNOR-C319 29880919 t lperfetto "TF has a high affinity for FVII and enables the trace levels (∼1% of the total FVII) of activated FVII (FVIIa) in the blood to cleave specific sites in the serine proteases FIX and FX, activating them into FIXa and FXa, respectively." SIGNOR-263544 F2RL1 protein P55085 UNIPROT CTSD protein P07339 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0000007 21072196 f miannu "PAR-2 activation up-regulated four genes more than 5 fold (DUSP6, WWOX, AREG, SERPINB2) and down-regulated another six genes more than 3 fold (TXNIP, RARG, ITGB4, CTSD, MSC and TM4SF15)." SIGNOR-254860 HK1 protein P19367 UNIPROT α-D-glucose smallmolecule CHEBI:17925 ChEBI "down-regulates quantity" "chemical modification" 9606 16051738 t miannu "Hexokinase catalyzes the phosphorylation of glucose to G6P, using ATP as a phosphoryl donor." SIGNOR-266455 TWIST1 protein Q15672 UNIPROT mir-10b mirna URS00004CAC40_9606 RNAcentral "up-regulates quantity by expression" "transcriptional regulation" 9606 23132946 f irozzo "We then showed that ectopic expression of MLL fusion genes in both human and mouse normal hematopoietic stem/progenitor cells could significantly down-regulate endogenous expression of miR-495 and that the depletion of MLL fusions resulted in the up-regulation of miR-495. Thus, our data suggest that there is an MLL-fusion–mediated negative regulation of the production of miR-495 in hematopoietic cells." SIGNOR-255887 MMP21 protein Q8N119 UNIPROT ECM stimulus SIGNOR-ST20 SIGNOR down-regulates 17318226 f lperfetto "Historically, MMPs were thought to function mainly as enzymes that degrade structural components of the ECM." SIGNOR-272389 MYF5 protein P13349 UNIPROT MIR1-1 mirna URS000075CF56_9606 RNAcentral "up-regulates quantity" "transcriptional regulation" 10090 21730352 f miannu "We provide evidence that PU.1 directly controls expression of at least 4 of these miRs (miR-146a, miR-342, miR-338, and miR-155) through temporally dynamic occupation of binding sites within regulatory chromatin regions adjacent to their genomic coding loci. We conclude that PU.1 bound to open chromatin near 4 of its induced miR loci with 2 types of kinetics: (1) permanent (miR-146a, miR-342, and miR-338) and (2) transient (miR-155) during myeloid differentiation." SIGNOR-256241 IQSEC2 protein Q5JU85 UNIPROT AMPA proteinfamily SIGNOR-PF58 SIGNOR "up-regulates quantity" relocalization 9606 BTO:0000142 27009485 t miannu "BRAG1 increases the synaptic recycling pool of AMPARs.these data suggest that the BRAG1 enhancement of AMPAR transmission is mediated by the increased expression of the recycling pool of synaptic GluA2/3 receptors." SIGNOR-264916 BMP7 protein P18075 UNIPROT PPARG protein P37231 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 18719589 f lperfetto "Bmp7 activates a full program of brown adipogenesis including induction of early regulators of brown fat fate prdm16 (pr-domain-containing 16;ref. 4) and pgc-1alpha (peroxisome proliferator-activated receptor-gamma (ppargamma) coactivator-1alpha;ref. 5), increased expression of the brown-fat-defining marker uncoupling protein 1 (ucp1) and adipogenic transcription factors ppargamma and ccaat/enhancer-binding proteins (c/ebps), and induction of mitochondrial biogenesis via p38 mitogen-activated protein (map) kinase-(also known as mapk14) and pgc-1-dependent pathways" SIGNOR-180311 MAPK3 protein P27361 UNIPROT SP3 protein Q02447 UNIPROT up-regulates phosphorylation Ser73 CSKIGPPsPGDDEEE 9606 17685427 t gcesareni "Here, we show that sp3, which, as sp1, belongs to the gc-rich binding transcription factor family, is also phosphorylated by erk in vitro on serine 73." SIGNOR-157276 "CFII complex" complex SIGNOR-C387 SIGNOR "messenger RNA" smallmolecule CHEBI:33699 ChEBI "up-regulates quantity" cleavage 9606 30139799 t lperfetto "Cleavage factor II (CF II) is a poorly characterized component of the multiprotein complex catalyzing 3' cleavage and polyadenylation of mammalian mRNA precursors. We have reconstituted CF II as a heterodimer of hPcf11 and hClp1. The heterodimer is active in partially reconstituted cleavage reactions" SIGNOR-266121 GNG3 protein P63215 UNIPROT PI3K complex SIGNOR-C156 SIGNOR up-regulates binding 9606 16537363 t gcesareni "Gbetagamma subunits released from gi can activate pi3k (phosphoinositide 3-kinase), and can be therefore implicated in smo-dependent activation of akt" SIGNOR-252684 FOXO proteinfamily SIGNOR-PF27 SIGNOR Apoptosis phenotype SIGNOR-PH2 SIGNOR up-regulates 9606 BTO:0000007 14976264 f lperfetto "Sirt1 inhibited foxo3's ability to induce cell death." SIGNOR-252939 PELI3 protein Q8N2H9 UNIPROT JUN protein P05412 UNIPROT up-regulates 9606 12874243 f gcesareni "Pellino3 leads to activation of c-jun and elk-1, but not nf-kappab" SIGNOR-103989 RAP1GDS1 protein P52306 UNIPROT RAC2 protein P15153 UNIPROT up-regulates binding 9606 21242305 t miannu "Smggds has been previously shown to activate a wide variety of small gtpases, including the ras family members rap1a, rap1b, and k-ras, as well as the rho family members cdc42, rac1, rac2, rhoa, and rhob" SIGNOR-171421 PRKCE protein Q02156 UNIPROT CHAT protein P28329 UNIPROT up-regulates phosphorylation Ser464 LLKHVTQsSRKLIRA 9606 15381704 t "The effect has been demonstrated using P28329-3" gcesareni "We show that chat is differentially phosphorylated by protein kinase c (pkc) isoforms on four serines (ser-440, ser-346, ser-347, and ser-476) and one threonine (thr-255). This phosphorylation is hierarchical, with phosphorylation at ser-476 required for phosphorylation at other serines. Phosphorylation at some, but not all, sites regulates basal catalysis and activation" SIGNOR-129300 ARFGAP1 protein Q8N6T3 UNIPROT LRRK2 protein Q5S007 UNIPROT up-regulates binding 9606 BTO:0000938 BTO:0000142 22363216 t "The effect has been demonstrated using Q8N6T3-2" flangone "The gtp hydrolysis activity of lrrk2 is markedly enhanced by arfgap1 supporting a role for arfgap1 as a gtpase-activating protein for lrrk2.Lrrk2 and arfgap1 interact in vitro in mammalian cells and in vivo in brain, and co-localize in the cytoplasm and at golgi membranes" SIGNOR-196264 SREBF2 protein Q12772 UNIPROT PON2 protein Q15165 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 19497963 f miannu "UPA upregulated PON2 expression in a sterol regulatory binding protein-2 (SREBP-2)-dependent manner, since blocking SREBP-2 maturation by 4-(2-aminoethyl)-benzenesulfonyl fluoride abolished uPA-stimulation of PON2, whereas inhibition of SREBP-2 catabolism by N-acetyl-leucyl-norleucinal had an opposite effect." SIGNOR-255225 PKC proteinfamily SIGNOR-PF53 SIGNOR ABCB1 protein P08183 UNIPROT "up-regulates activity" dephosphorylation Ser661 SSNDSRSsLIRKRST 9606 BTO:0000007 24333728 t "Protein phosphatase complex PP5/PPP2R3C dephosphorylates P-glycoprotein/ABCB1 and down-regulates the expression and function|P-gp is known to be phosphorylated at Ser667, Ser671, and Ser683 by PKA; at Ser661, Ser667, and Ser671 by PKC; and at Ser683 by Pim-1|simultaneous expression of PP5 and PPP2R3C reduced the phosphorylation detected by the antibodies that specifically recognize serine/threonine phosphorylated by PKA or serine phosphorylated by PKC. These results suggest that the PP5/PPP2R3C complex dephosphorylates PKA- and PKC-phosphorylated serine residues on P-gp" SIGNOR-272512 PTPN12 protein Q05209 UNIPROT GIT2 protein Q14161 UNIPROT down-regulates dephosphorylation Tyr592 NSTPESDyDNTPNDM 9606 16317044 t fspada "Conversely, a gfp-pkl phosphorylation mutant, y286/392/592f (gfp-pkl triple yf) (brown et al., 2005), was not phosphorylated during adhesion and the addition of ptp-pest had no effect, suggesting one or more of these tyrosine residues are dephosphorylated by ptppest. Taken together, these data strongly suggest pkl as a direct substrate for ptp-pest." SIGNOR-142719 MMP24 protein Q9Y5R2 UNIPROT ECM stimulus SIGNOR-ST20 SIGNOR down-regulates 17318226 f lperfetto "Historically, MMPs were thought to function mainly as enzymes that degrade structural components of the ECM." SIGNOR-272391 MMP25 protein Q9NPA2 UNIPROT ECM stimulus SIGNOR-ST20 SIGNOR down-regulates 17318226 f lperfetto "Historically, MMPs were thought to function mainly as enzymes that degrade structural components of the ECM." SIGNOR-272392 85375-15-1 chemical CID:6917797 PUBCHEM SLC6A1 protein P30531 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-206960 NCL protein P19338 UNIPROT MYB protein P10242 UNIPROT "down-regulates activity" binding 9606 BTO:0000007 10660576 t miannu "We identify nucleolin as one of the nuclear polypeptides that interact specifically with the A-Myb and c-Myb. We show that the interaction of nucleolin with Myb is functional because co-transfection of nucleolin down-regulates Myb transcriptional activity." SIGNOR-221236 "Caspase 3 complex" complex SIGNOR-C221 SIGNOR PTCH1 protein Q13635 UNIPROT "down-regulates activity" cleavage Asp1405 CPGYPETdHGLFEDP 9606 12907805 t lperfetto "Like other dependence receptors, ptc1 contains a dependence-as-associated receptor c-terminal motif that is cleaved by caspases at a conserved aspartic acid (asp 1392) in the absence of shh, to expose a proapoptotic domain." SIGNOR-256438 IKBKE protein Q14164 UNIPROT TBK1 protein Q9UHD2 UNIPROT "up-regulates activity" binding 9606 24622840 t miannu "STING recruits TBK1 and IKKε and forms the TBK1-IKKε complex via the association with TRAF3. The TBK1 complex induces the phosphorylation, dimerization, and nuclear translocation of IRF3." SIGNOR-260155 (2R,3S,4S,5R)-2-(6-amino-2-fluoro-9-purinyl)-5-(hydroxymethyl)oxolane-3,4-diol chemical CHEBI:94701 ChEBI RRM2 protein P31350 UNIPROT "down-regulates activity" "chemical inhibition" -1 7048062 t miannu "In vitro biological activity of 9-beta-D-arabinofuranosyl-2-fluoroadenine and the biochemical actions of its triphosphate on DNA polymerases and ribonucleotide reductase from HeLa cells. 2-F-araATP was a potent inhibitor of ribonucleotide reductase" SIGNOR-258405 PRKACA protein P17612 UNIPROT CACNB2 protein Q08289 UNIPROT "up-regulates activity" phosphorylation Ser533 KKSQHRSsSSAPHHN 10441130 t miannu "Voltage-dependent L-type calcium (Ca) channels are heteromultimeric proteins that are regulated through phosphorylation by cAMP-dependent protein kinase (PKA) Mutagenesis of a single residue at Ser459 resulted in the loss of one site of phosphorylation by PKA, and mutagenesis of two residues at Ser478/479 resulted in the loss of approximately two sites of PKA-mediated phosphorylation" SIGNOR-250340 FOXJ1 protein Q92949 UNIPROT TEKT2 protein Q9UIF3 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000939 23822649 t miannu "FOXJ1 expression in basal cells induced the expression of a panel of cilia-associated genes, including centrin 2 (CETN2); dynein, axonemal, heavy chain 11 (DNAH11); dynein, axonemal, intermediate chain 1 (DNAI1); dynein, axonemal, light intermediate chain 1 (DNALI1); EF-hand domain, C-terminal, containing 1 (EFHC1); sperm associated antigen 6 (SPAG6); tektin 1 (TEKT1), TEKT2 and tubulin, alpha 1a (TUBA1A; Figure 3C and Additional file 2: Table S1)." SIGNOR-266937 SRC protein P12931 UNIPROT STAP2 protein Q9UGK3 UNIPROT "up-regulates activity" phosphorylation Tyr22 GVLPSHYyESFLEKK 9606 12540842 t lperfetto "To examine this possibility, STAP-2 was co-transfected with constitutively active tyrosine kinases in HEK-293 cells. STAP-2 was strongly phosphorylated by various tyrosine kinases, including v-Src (Fig.2 A-a), a JAK2 tyrosine kinase Tyr-22 and Tyr-322 are the major tyrosine phosphorylation sites by v-Src." SIGNOR-247333 EPHA2 protein P29317 UNIPROT EPHA2 protein P29317 UNIPROT up-regulates phosphorylation Tyr772 EDDPEATyTTSGGKI 9606 18387945 t lperfetto "The binding of ephrin ligands to eph receptors induces the transphosphorylation of the cytoplasmic domains and initiates kinase activity.Taken together, these results suggest that tyr587, tyr593, tyr771, and tyr734 are likely to be autophospho-rylated in vascular endothelial cells." SIGNOR-178181 PAK1 protein Q13153 UNIPROT VIM protein P08670 UNIPROT unknown phosphorylation Ser56 SRSLYASsPGGVYAT 9606 BTO:0000887;BTO:0001260 15766329 t llicata "In the present study, pak1 was able to phosphorylate vimentin on ser-56 in vitro." SIGNOR-134520 "Cullin 7-RBX1-Skp1" complex SIGNOR-C528 SIGNOR IRS1 protein P35568 UNIPROT "down-regulates quantity by destabilization" polyubiquitination 10090 23142081 t miannu " We provide evidence that mTORC2 can stabilize Fbw8, the substrate-targeting subunit of the CUL7 E3 ligase complex that has been shown to mediate degradation of IRS-1 ." SIGNOR-271941 "sorafenib tosylate" chemical CHEBI:50928 ChEBI FGFR1 protein P11362 UNIPROT "down-regulates activity" "chemical inhibition" -1 16757355 t miannu "Further characterization of sorafenib revealed that this molecule was a multikinase inhibitor that targeted the vascular endothelial growth factor receptor family (VEGFR-2 and VEGFR-3) and platelet-derived growth factor receptor family (PDGFR-beta and Kit), which play key roles in tumor progression and angiogenesis. The in vitro and cellular profile of sorafenib is summarized in Table I." SIGNOR-259221 IFNAR complex SIGNOR-C243 SIGNOR JAK1 protein P23458 UNIPROT "up-regulates activity" binding 9606 15120645 t miannu "Despite signaling through distinct receptor complexes, type I IFNs and IFN-lambda activate similar signaling events and biological activities, consistent with their common ability to mediate an antiviral state in cells (Fig. 6). In both cases, receptor engagement leads via the activation of the Jak kinases Jak1 and Tyk2 to the activation of the IFN-stimulated gene factor 3 (ISGF3) transcription complex, composed of latent transcriptional factors of the Signal Transducers and Activators of Transcription (STAT) family, Stat1 and Stat2, and of the interferon regulatory factor (IRF) IRF9 (ISGF3g or p48)." SIGNOR-260147 KIF20B protein Q96Q89 UNIPROT "Plus-end directed sliding movement" phenotype SIGNOR-PH216 SIGNOR up-regulates 9606 19773780 f "In general, N-kinesins and C-kinesins drive microtubule plus end- and minus end-directed motilities, respectively, and M-kinesins depolymerize microtubules1,9 (Box 1).|Forty-five genes that encode kinesin superfamily proteins (also known as KIFs) have been discovered in the mouse and human genomes.|KIFs are molecular motors that directionally transport various cargos, including membranous organelles, protein complexes and mRNAs, along the microtubule system." SIGNOR-272528 LPAR1 protein Q92633 UNIPROT GNAI1 protein P63096 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-256696 RAB38 protein P57729 UNIPROT "Neuronal AP-3" complex SIGNOR-C445 SIGNOR "up-regulates activity" relocalization 9606 23247405 t miannu "Rab32 and Rab38 interact physically and colocalize with BLOC-2, AP-1 and AP-3|These results indicate that Rab32 and Rab38 operate in the same pathways previously defined for AP-1, AP-3 and BLOC-2 and suggest they are the specific proteins that divert AP-1, AP-3 and BLOC-2-dependent cargoes to maturing melanosomes and away from lysosomes." SIGNOR-268526 SGK3 protein Q96BR1 UNIPROT GSK3B protein P49841 UNIPROT "down-regulates activity" phosphorylation Ser9 SGRPRTTsFAESCKP 9606 BTO:0000007 16543730 t lperfetto "Phosphorylation of GSK3 by PKB or SGK1 inhibits GSK3 activity|estern blotting using an antibody specific for the PKB/SGK1 consensus phosphorylation site in GSK3a/beta (serine 21 and 9 respectively) revealed an increase in GSK3a/beta phosphorylation in human embryonic kidney 293 (HEK293) cells overexpressing wild type SGK1, constitutively active SGK1, but not catalytically inactive SGK1.|The effect of SGK1 was mimicked by PKB and SGK3." SIGNOR-249167 PRKAA1 protein Q13131 UNIPROT GFPT1 protein Q06210 UNIPROT up-regulates phosphorylation Ser261 CNLSRVDsTTCLFPV 9606 17941647 t gcesareni "Amp-activated protein kinase and calcium/calmodulin-dependent kinase ii were identified to phosphorylate specifically ser243 in vitro. Phosphorylation by these two kinases results in an increase of enzymatic activity by 1.4-fold. These findings suggest for the first time that hgfat1 may be regulated by kinases other than pka." SIGNOR-158490 CSNK1E protein P49674 UNIPROT PER3 protein P56645 UNIPROT "down-regulates activity" phosphorylation Thr635 SQCGYSStIVHVPPP 9534 BTO:0000298 11865049 t llicata "The CKI phosphorylation of mPer1 and mPer3 proteins results in their rapid degradation, which is dependent on the ubiquitin-proteasome pathway. Moreover, CKIepsilon and CKIdelta are able to induce nuclear translocation of mPer3, which requires its nuclear localization signal. The mutation in potential phosphorylation sites on mPer3 decreased the extent of both nuclear translocation and degradation of mPer3 that are stimulated by CKIepsilon. | In mut7 in which all of the conserved serine and threonine residues in this region were mutated, the ratio of the shifted band was greatly reduced reproducibly. " SIGNOR-250820 CSNK1A1 protein P48729 UNIPROT NFATC3 protein Q12968 UNIPROT "down-regulates activity" phosphorylation Ser215 PLTSPGGsPGGCPGE 9606 BTO:0001131 9630228 t lperfetto "Dominant-negative cki alpha Induces nuclear import of nf-at4 these results demonstrated that the cki alpha Phosphorylation sites identified in vitro were also specifically phosphorylated by cki alpha In vivo, and that these residues were crucial for the masking of the nls of nf-at4." SIGNOR-109781 DAB2IP protein Q5VWQ8 UNIPROT MAP3K5 protein Q99683 UNIPROT "up-regulates activity" binding 9606 27858941 t miannu "DAB2IP also mediates recruitment of PP2A to ASK1, binding both proteins through its C2 domain; this favors removal of the inhibitory S967 phosphorylation and further activation of ASK1" SIGNOR-254748 MAPK1 protein P28482 UNIPROT GRB10 protein Q13322 UNIPROT up-regulates phosphorylation Ser476 MNILGSQsPLHPSTL 9606 15952796 t lperfetto "We show that grb10 is a direct substrate of the p42/44 mitogen-activated protein kinase (mapk)we identified ser(150), ser(418), and ser(476) of human grb10zeta as mapk-mediated in vitro phosphorylation sites. Replacing ser(150) and ser(476) with alanines reduced the inhibitory effect of human grb10zeta on insulin-stimulated irs1 tyrosine phosphorylation. Taken together, our findings suggest that phosphorylation of the adaptor protein may provide a feedback inhibitory mechanism by which grb10 regulates insulin signaling." SIGNOR-138167 NHS protein Q6T4R5 UNIPROT ARP2/3 complex SIGNOR-C146 SIGNOR "up-regulates activity" relocalization 9606 20332100 t miannu "NHS knockdown also resulted in the mislocalization of the Arp2/3 complex and disruption of the actin cytoskeleton. in the absence of NHS, Arp2/3 localization and F-actin distribution are disrupted, suggesting that Arp2/3 actin-nucleation activity is mediated, in part, by NHS providing an additional functional link between NHS and actin." SIGNOR-253566 phenylalanine smallmolecule CHEBI:28044 ChEBI GCHFR protein P30047 UNIPROT "down-regulates activity" "chemical inhibition" 9606 11361142 t miannu "The enzyme activity of GTP cyclohydrolase I is controlled by a regulatory protein for this enzyme, GFRP, which is a pentamer of identical subunits. GFRP mediates feedback inhibition of GTP cyclohydrolase I activity by BH4, and the inhibition by BH4 is reversed by phenylalanine" SIGNOR-252205 PAK1 protein Q13153 UNIPROT ARHGEF2 protein Q92974 UNIPROT down-regulates phosphorylation Ser886 PVDPRRRsLPAGDAL 9606 19667072 t gcesareni "We identify gef-h1 as a binding target and substrate for p21-activated kinase 1 (pak1), we show that phosphorylation of gef-h1 at ser(885) by pak1 induces 14-3-3 binding to the exchange factor and relocation of 14-3-3 to microtubules." SIGNOR-187573 AKT proteinfamily SIGNOR-PF24 SIGNOR GSK3B protein P49841 UNIPROT "down-regulates activity" phosphorylation Ser9 SGRPRTTsFAESCKP 9606 23552696 t lperfetto "Active AKT, a common mediator of cell survival signals induced by radiation through multiple intracellular signaling pathways,11, 12 suppresses apoptosis. AKT positively regulates cyclin D1 expression through inactivation of glycogen synthase kinase 3_ (GSK3_). The AKT-mediated phosphorylation of glycogen synthase kinase 3_ on serine9 decreases its kinase activity for Thr286 of cyclin D1, which inhibits the nuclear export and the cytoplasmic proteasomal degradation of cyclin D1" SIGNOR-245428 CDK1 protein P06493 UNIPROT PP1 proteinfamily SIGNOR-PF54 SIGNOR "down-regulates activity" phosphorylation 9606 12202491 t lperfetto "Both of these pp1 isoforms contain an arg-pro-ile/val-thr-pro-pro-arg sequence near the c terminus, a known site of phosphorylation by cdc/cdk kinases, and phosphorylation attenuates phosphatase activity." SIGNOR-264648 SRC protein P12931 UNIPROT SRC protein P12931 UNIPROT up-regulates phosphorylation Tyr419 RLIEDNEyTARQGAK 9606 7578094 t lperfetto "These data are consistent with autophosphorylation on y-419 as predicted. Intermolecular autophosphorylation is consistent with the ability of srctk to dimerize, which is analogous to activation of receptor tyrosine kinases such as the egf receptor kinase in response to growth factors." SIGNOR-29369 ATXN2L protein Q8WWM7 UNIPROT DDX6 protein P26196 UNIPROT unknown binding 9606 23209657 t miannu "Ataxin-2-like associates with known interaction partners of ataxin-2, the rna helicase ddx6" SIGNOR-199948 959122-11-3 chemical CID:24768261 PUBCHEM DGAT1 protein O75907 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-205695 PRKACA protein P17612 UNIPROT RYR2 protein Q92736 UNIPROT "up-regulates activity" phosphorylation Ser2808 YNRTRRIsQTSQVSV -1 14532276 t miannu "PKA-mediated hyperphosphorylation of a conserved serine, Ser-2843 in skeletal RyR and Ser-2809 in cardiac RyR, results in an aberrant SR function during heart failure. hyperphosphorylated RyRs are leaky and therefore lead to a reduced SR Ca2+ load and impaired contractile function in heart failure" SIGNOR-250079 IL12B protein P29460 UNIPROT IL12RB1 protein P42701 UNIPROT up-regulates binding 9606 7527811 t fspada "Characterization of the p40 proteins for binding and bioactivity showed that both the p40 monomer and dimer inhibited 125i-labeled il-12 binding to il-12r, but the 80-kda species, having a 50% inhibitory concentration (ic50) of 20 to 70 ng/ml, was at least 20-fold more effective than the monomer. The results suggest that the il-12 p40 subunit contains the essential epitopes for receptor binding." SIGNOR-27690 AKT1 protein P31749 UNIPROT LONP1 protein P36776 UNIPROT "up-regulates activity" phosphorylation Ser173 VFLKRDDsNESDVVE 9606 BTO:0001061 31406245 t lperfetto "In mitochondria, LonP1 is phosphorylated by Akt on Ser173 and Ser181, enhancing its protease activity." SIGNOR-265724 CTDSPL protein O15194 UNIPROT SMAD2 protein Q15796 UNIPROT "down-regulates activity" dephosphorylation Ser245 NQSMDTGsPAELSPT 9606 BTO:0000007 17035229 t "Dephosphorylation of Smad2/3 Linkers by SCP2 and SCP3|MAPK-mediated linker phosphorylation appears to have a dual role in Smad2/3 regulation. Mitogens and hyperactive Ras result in extracellular signal-regulated kinase (ERK)-mediated phosphorylation of Smad3 at Ser-204, Ser-208, and Thr-179 and of Smad2 at Ser-245/250/255 and Thr-220. Mutation of these sites increases the ability of Smad3 to activate target genes, suggesting that MAPK phosphorylation of Smad3 is inhibitory (11, 12). However, in contrast, ERK-dependent phosphorylation of Smad2 at Thr-8 enhances its transcriptional activity" SIGNOR-248310 PRKG1 protein Q13976 UNIPROT TRPC7 protein Q9HCX4 UNIPROT "up-regulates activity" phosphorylation Thr15 KNMQRRHtTLREKGR 9534 BTO:0000298 21402151 t miannu "In vitro and in vivo kinase assays have revealed that cGK-Iα phosphorylates mouse TRPC7 but not mouse TRPC3. Site-directed mutagenesis analysis revealed that TRPC7 was phosphorylated by cGK-Iα at threonine 15. Phosphorylation of TRPC7 significantly suppressed carbachol-induced calcium influx and CREB phosphorylation. These data indicate that cGK-Iα interacts with and phosphorylates TRPC7, contributing to the quick and accurate regulation of calcium influx and CREB phosphorylation." SIGNOR-263184 ESR1 protein P03372 UNIPROT SCN1A protein P35498 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 10090 BTO:0000938 BTO:0001264 22169964 f miannu "17β-Estradiol regulates the gene expression of voltage-gated sodium channels. . In this study, we investigate the mRNA expressions of Nav channel subtypes mediated differentially by the ERs in the DRGs of wild-type (WT) and estrogen receptor knockout (αERKO and βERKO) mice. In the present study, by means of quantitative real-time PCR, we found that the expressions of Nav1.1, Nav1.7, Nav1.8, and Nav1.9 subtypes were elevated in αERKO and βERKO mice" SIGNOR-253468 NOX3 protein Q9HBY0 UNIPROT ROS stimulus SIGNOR-ST2 SIGNOR up-regulates 9606 17237347 t lperfetto "Over the last years, six homologs of the cytochrome subunit of the phagocyte NADPH oxidase were found: NOX1, NOX3, NOX4, NOX5, DUOX1, and DUOX2. Together with the phagocyte NADPH oxidase itself (NOX2/gp91phox), the homologs are now referred to as the NOX family of NADPH oxidases. These enzymes share the capacity to transport electrons across the plasma membrane and to generate superoxide and other downstream reactive oxygen species (ROS)." SIGNOR-264715 ACVR1 protein Q04771 UNIPROT VPS39 protein Q96JC1 UNIPROT "up-regulates activity" binding 9534 12941698 t miannu "TLP interacts with TGF-β and activin receptors in vivo. Endogenous TLP associates with both active and kinase-deficient TGF-beta and activin type II receptors, but interacts with the common-mediator Smad4 only in the presence of TGF-beta/activin signaling." SIGNOR-261376 LCK protein P06239 UNIPROT NFKBIA protein P25963 UNIPROT "down-regulates quantity by destabilization" phosphorylation Tyr42 DSMKDEEyEQMVKEL 14534291 t lperfetto "Loss of tyrosine kinase p56lck in Jurkat cells abolished NFkappaB activation and partially suppressed and delayed phosphorylation of Tyr-42 of IkappaB upon pervanadate treatment. |Transfection of these cells with wild type Lck but not with mutant Lck F394 followed by H/R induces the tyrosine phosphorylation of inhibitor of nuclear factor kappaB (IkappaBalpha) and transcriptional activation of NFkappaB, and these are inhibited by Lck inhibitors" SIGNOR-249374 TWIST1 protein Q15672 UNIPROT CD44 protein P16070 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0002590 17487558 f miannu "Immunoblot analysis showed that HEY/si-TWIST cells exhibited decreased expression levels of CD29, CD44 and CD54 compared to those of HEY/si-scrambled cells" SIGNOR-255512 "L-glutamine zwitterion" smallmolecule CHEBI:58359 ChEBI "2-ammonio-2-deoxy-D-glucopyranose 6-phosphate(1-)" smallmolecule CHEBI:58725 ChEBI "up-regulates quantity" "precursor of" 9606 21310273 t miannu "GFPT1 catalyzes the transfer of an amino group from glutamine onto fructose-6-phosphate, yielding glucosamine-6-phosphate (GlcN-6-P) and glutamate. This transamidase reaction has been identified as the first and rate-limiting step of the hexosamine biosynthesis pathway, which is the obligatory source of essential amino sugars for the synthesis of glycoproteins, glycolipids, and proteoglycans" SIGNOR-268097 STK11 protein Q15831 UNIPROT MARK2 protein Q7KZI7 UNIPROT up-regulates phosphorylation 9606 17573348 t gcesareni "Here we show in vitro that lkb1 phosphorylates and activates mark2" SIGNOR-156126 ATM protein Q13315 UNIPROT RNF40 protein O75150 UNIPROT up-regulates phosphorylation 9606 21763684 t gcesareni "E3 ubiquitin ligase, a heterodimeric complex of the ringfinger rfn20/rfn40 is phosphorylated by atm." SIGNOR-175003 TP53 protein P04637 UNIPROT Hexokinase proteinfamily SIGNOR-PF76 SIGNOR "down-regulates quantity by repression" "transcriptional regulation" 9606 27692180 t "inferred from family member" miannu "P53 regulates basal expression of AIF and SCO2 and facilitates oxidative phosphorylation. The expression of GLUT1, GLUT4, and HK2 is negatively regulated by p53, whereas TIGAR expression is induced by p53. The net result of p53-mediated regulation of these glycolytic enzymes is the suppression of glycolysis. In addition, p53 directly binds and inhibits G6PD activity and downregulates the pentose phosphate pathway." SIGNOR-270272 Ub:E2 complex SIGNOR-C497 SIGNOR DTX4 protein Q9Y2E6 UNIPROT "up-regulates activity" ubiquitination 9606 34199813 t miannu "The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t" SIGNOR-271108 FBXO6 protein Q9NRD1 UNIPROT ERO1A protein Q96HE7 UNIPROT "down-regulates quantity by destabilization" binding 9606 BTO:0000007 27855403 t miannu "Ero1L is a ubiquitination substrate of FBXO6. FBXO6 mediates the degradation of Ero1L through a ubiquitylation-dependent pathway. Overexpression of FBXO6 increased the polyubiquitination and decreased the stability of Ero1L, whereas inhibition of FBXO6 prolonged the half-life of Ero1L. FBXO6 is the substrate recognition component of a Skp1-Cullin1-F-box protein (SCF) ubiquitin E3 ligase complex" SIGNOR-272326 glucose chemical CHEBI:17234 ChEBI AMPK complex SIGNOR-C15 SIGNOR "down-regulates activity" 10090 BTO:0000222 18477450 f "Glucose restriction (GR) impaired differentiation of skeletal myoblasts and was associated with activation of the AMP-activated protein kinase (AMPK)." SIGNOR-256137 HAUS6 protein Q7Z4H7 UNIPROT NEDD1 protein Q8NHV4 UNIPROT "up-regulates activity" binding 9606 BTO:0000567 19029337 t miannu "FAM29A recruits NEDD1 to spindle MTs. Ectopically expressed NEDD1 and FAM29A interact with each other." SIGNOR-261421 ZFHX3 protein Q15911 UNIPROT AFP protein P02771 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 11314020 f miannu "We investigated AFP gene regulation in AFP-GC by an active transcription factor, HNF1 (hepatocyte nuclear factor 1) and a repressive transcription factor, ATBF1 (AT motif binding factor 1). CAT assays showed the direct inhibition of AFP gene expression by ATBF1." SIGNOR-254436 WNT1 protein P04628 UNIPROT PRKACA protein P17612 UNIPROT "up-regulates activity" 9606 BTO:0001103 21902831 f gcesareni "Wnt1 and wnt7a stimulation of precursor cells activates protein kinase a (pka), which, through the phosphorylation of creb, induces the expression of the myogenic transcription factors myf5, myod and pax3, resulting in the myogenic commitment of embryonic precursors." SIGNOR-176572 STK3/4 proteinfamily SIGNOR-PF41 SIGNOR MOB1B protein Q7L9L4 UNIPROT up-regulates phosphorylation 9606 21808241 t "The regulation of MOB1 and LATS1/2 by MST1/2 may be organ and disease-specific." gcesareni "Mob1, which forms a complex with lats1/2, is also phosphorylated by mst1/2, resulting in an enhanced lats1/2 mob1 interaction." SIGNOR-270221 CDK1 protein P06493 UNIPROT AR protein P10275 UNIPROT up-regulates phosphorylation Ser83 QQQQQETsPRQQQQQ 9606 BTO:0001130 21799006 t gcesareni "At first, the data show that cdk5 enables phosphorylation of ar at ser-81 site through direct biochemical interaction and, therefore, results in the stabilization of ar proteins although ar was reported as substrates for cdk9 (5) as well as cdk1" SIGNOR-175692 EGFR protein P00533 UNIPROT SHC1 protein P29353 UNIPROT "up-regulates activity" binding 9606 11350724 t lperfetto "Adaptors such as Shc, Grb2, Crk or the recently characterised Dok-R protein (Jones Dumont 1999) show a modular structure containing protein– protein interaction domains and putative phosphorylation sites and act as signalling platforms which extend the receptor’s repertoire of activated intracellular pathways." SIGNOR-107712 N-hydroxy-3-[4-[[2-hydroxyethyl-[2-(1H-indol-3-yl)ethyl]amino]methyl]phenyl]-2-propenamide chemical CHEBI:94063 ChEBI HDAC7 protein Q8WUI4 UNIPROT "down-regulates activity" "chemical inhibition" -1 17868033 t Luana "Our findings suggest that hydroxamic acid-derived compounds such as TSA, NVP-LAQ824, panobinostat, ITF2357, vorinostat and belinostat act as potent pan-HDAC isoform inhibitors. A notable observation was the similarity between belinostat and vorinostat in the biochemical isoform assays; both compounds exhibit similar EC50 values in all but the HDAC8 assay." SIGNOR-257927 L-serine chemical CHEBI:17115 ChEBI pyruvate smallmolecule CHEBI:15361 ChEBI "up-regulates quantity" "precursor of" 10090 BTO:0000142 12393813 t lperfetto "High levels of d-serine occur in the brain, challenging the notion that d-amino acids would not be present or play a role in mammals. d-serine levels in the brain are even higher than many l-amino acids, such as asparagine, valine, isoleucine, and tryptophan, among others. d-serine is synthesized by a serine racemase (SR) enzyme, which directly converts l- to d-serine. We now report that SR is a bifunctional enzyme, producing both d-serine and pyruvate in cultured cells and in vitro. Transfection of SR into HEK 293 cells elicits synthesis of d-serine and augmented release of pyruvate to culture media." SIGNOR-268269 CDK2 protein P24941 UNIPROT PELP1 protein Q8IZL8 UNIPROT up-regulates phosphorylation Ser991 PALPPPEsPPKVQPE 9606 20807815 t llicata "We identified ser(477) and ser(991) of pelp1 as cdk phosphorylation sites. we conclude that pelp1 is a novel substrate of interphase cdks and that its phosphorylation is important for the proper function of pelp1 in modulating hormone-driven cell cycle progression and also for optimal e2f transactivation function." SIGNOR-167766 PIK3CD protein O00329 UNIPROT PIK3CD protein O00329 UNIPROT down-regulates phosphorylation Ser1039 NWLAHNVsKDNRQ 9606 10064595 t gcesareni "Autophosphorylation of p110delta phosphoinositide 3-kinase: a new paradigm for the regulation of lipid kinases in vitro and in vivo in vitro autophosphorylation of p110delta completely down-regulates its lipid kinase activity." SIGNOR-65186 PKI-587 chemical CID:44516953 PUBCHEM PI3K complex SIGNOR-C156 SIGNOR down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-252650 SPTAN1 protein Q13813 UNIPROT ERCC4 protein Q92889 UNIPROT "up-regulates activity" 19102630 f lperfetto "We have shown that in the nucleus alphaRIISp is involved in repair of DNA interstrand cross-links (13,14). It binds to purified DNA containing an interstrand crosslink; it colocalizes with the cross-link repair protein, XPF, in damage-induced nuclear foci after treatment of cells with a DNA interstrand cross-linking agent, and it is needed for the production of incisions by XPF at the site of an interstrand cross-link" SIGNOR-263276 PCM1 protein Q15154 UNIPROT NIN protein Q8N4C6 UNIPROT up-regulates relocalization 9606 12403812 t miannu "Rna silencing of pcm-1 leads to reduced assembly of centrin, pericentrin, and ninein at the centrosome" SIGNOR-95077 PRKACB protein P22694 UNIPROT GPKOW protein Q92917 UNIPROT "up-regulates activity" phosphorylation Ser27 SFGFTRTsARRRLAD -1 21880142 t miannu "Using yeast two-hybrid screening with the PKA Cβ2 subunit as bait we identified GPKOW, also known as MOS2 homolog or T54 protein, as an interaction partner for Cβ2. PKA phosphorylates GPKOW at S27 and T316 in vitro. GPKOWs ability to bind RNA is sensitive to mutations of its PKA phosphorylation sites." SIGNOR-266311 JNK proteinfamily SIGNOR-PF15 SIGNOR JUN protein P05412 UNIPROT "up-regulates activity" phosphorylation Ser73 VGLLKLAsPELERLI 9606 17158707 t lperfetto "The JNK-mediated phosphorylation of both Ser63 and Ser73 within the transactivation domain of c-Jun (Table _(Table1)1) potentiates its transcriptional activity" SIGNOR-36466 RPS16 protein P62249 UNIPROT "40S cytosolic small ribosomal subunit" complex SIGNOR-C286 SIGNOR "form complex" binding -1 25901680 t lperfetto "Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins." SIGNOR-262435 vorinostat chemical CHEBI:45716 ChEBI HDAC6 protein Q9UBN7 UNIPROT "down-regulates activity" "chemical inhibition" -1 17868033 t Luana "Our findings suggest that hydroxamic acid-derived compounds such as TSA, NVP-LAQ824, panobinostat, ITF2357, vorinostat and belinostat act as potent pan-HDAC isoform inhibitors. A notable observation was the similarity between belinostat and vorinostat in the biochemical isoform assays; both compounds exhibit similar EC50 values in all but the HDAC8 assay." SIGNOR-257918 SMG1 protein Q96Q15 UNIPROT UPF1 protein Q92900 UNIPROT up-regulates phosphorylation Thr28 AELLGADtQGSEFEF 9606 23356578 t lperfetto "Smg-1 directly phosphorylates upf1 helicase, another key component of nmd, upon recognition of ptc on postspliced mrna during the initial round of translation. Phosphorylated-upf1 recruits the smg-5/smg-7 complex to induce ribosome dissociation and decapping-mediated decay. T28 and s1096 are responsible for phospho-specific recruitment of smg-6 to the n-terminal conserved region, and the smg-5/smg-7 heterodimer complex to the c-terminal sq-rich region of upf1, respectively" SIGNOR-200793 AXL protein P30530 UNIPROT AXL protein P30530 UNIPROT "up-regulates activity" phosphorylation Tyr821 QEPDEILyVNMDEGG -1 9178760 t llicata "Our data showed that various receptor substrates are at least associated with the C-terminal tyrosine pY821. Two additional potential autophosphorylation sites (pY866 and pY779) may play a minor role in binding of e€ector proteins" SIGNOR-250592 "MSL acetyltransferase" complex SIGNOR-C344 SIGNOR H2BW1 protein Q7Z2G1 UNIPROT "down-regulates activity" monoubiquitination 9606 21726816 t miannu "MSL1/2 ubiquitylates histone H2B on K 34. Importantly, only mono-ubiquitylation of H2B by MSL1/2 was detected in cells (data not shown), suggesting that MSL1/2, like RNF20/RNF40, was mainly a mono-ubiquitylase under physiological conditions.the MOF-MSL complex functions to promote both H4 K16ac and H2B K34ub. H2B K34ub, in turn, promotes H2B K120ub, H3 K4me3 and K79me2 to facilitate transcription elongation." SIGNOR-271989 RFX1 protein P22670 UNIPROT MYC protein P01106 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 12032779 f miannu "Several different transcription factors have been implicated in the down-regulation of c-myc expression during differentiation, including C/EBPalpha, CTCF, BLIMP-1, and RFX1." SIGNOR-253829 PPP2CB protein P62714 UNIPROT MYC protein P01106 UNIPROT down-regulates dephosphorylation Ser62 LLPTPPLsPSRRSGL 9606 16987807 t esanto "Phosphorylation at ser-62 by pro-directed kinases (p-k) is a prerequisite for gsk3-dependent phosphorylation of thr-58. This triggers binding of pin1, subsequently protein phosphatase 2a (pp2a)-dependent dephosphorylation of ser-62, and then recruitment of scf-fbw7 to the thr-58-phosphorylated myc. Scf-fbw7 polyubiquitinylates myc (branching through lys-48), leading to its proteasomal degradation." SIGNOR-149726 PIM1 protein P11309 UNIPROT BAD protein Q92934 UNIPROT "down-regulates activity" phosphorylation Ser99 PFRGRSRsAPPNLWA 9606 BTO:0000007 16403219 t miannu "Pim kinases phosphorylate multiple sites on Bad and promote 14-3-3 binding and dissociation from Bcl-XL. pim kinases are constitutively active when expressed in HEK-293 cells and are able to phosphorylate the Bcl-2 family member Bad on three residues, Ser112, Ser136 and Ser155 in vitro and in cells." SIGNOR-250392 "C3 convertase complex" complex SIGNOR-C310 SIGNOR "C5 convertase complex" complex SIGNOR-C312 SIGNOR "form complex" binding 31331124 t lperfetto "C3b associates with C3 convertase to form C5 convertase and cleaves C5." SIGNOR-263447 CGA protein P01215 UNIPROT TSHR protein P16473 UNIPROT up-regulates binding 9606 12045258 t miannu "Human thyrotropin (tsh), follitropin (fsh), lutropin (lh), and chorionic gonadotropin (cg) are members of the glycoprotein hormone family derived from heterodimerization of a common ? Subunit with hormone-specific ? Subunits. These hormones were originally purified from the anterior pituitary (tsh, lh, and fsh) and placenta (human cg) and shown to activate specific g protein_coupled receptors in the thyroid (tsh receptor) and gonads (lh and fsh receptors), respectively" SIGNOR-88519 MAPK13 protein O15264 UNIPROT PRKD1 protein Q15139 UNIPROT down-regulates phosphorylation 9606 19135240 t gcesareni "P38delta catalyzes an inhibitory phosphorylation of pkd1, thereby attenuating stimulated insulin secretion." SIGNOR-183280 crizotinib chemical CHEBI:64310 ChEBI ALK protein Q9UM73 UNIPROT "down-regulates activity" "chemical inhibition" -1 22037378 t Luana "Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here." SIGNOR-258101 CDK4 protein P11802 UNIPROT RBL1 protein P28749 UNIPROT "up-regulates activity" phosphorylation Ser650 SVHERYSsPTAGSAK 9606 12006580 t llicata "Here we assessed the effects of alanine substitution at the individual or combined Cdk4(6)-specific sites in p130, compared with homologous sites in p107 (Thr(369)/Ser(650)/Ser(964)). In U-2-OS cells, the triple p107(DeltaCdk4)* mutant strongly inhibited E2F-4 activity and imposed a G(1) arrest resistant to cyclin D1 coexpression. " SIGNOR-250763 IKBKB protein O14920 UNIPROT DOK1 protein Q99704 UNIPROT up-regulates phosphorylation Ser446 SGIKSHNsALYSQVQ 9606 15574499 t amattioni "Ikkbeta phosphorylates dok1 s(439)s(443) and s(446)s(450) after tnf-alpha, il-1, or gamma-radiation. mutant dok1 a(439), a(443), a(446), and a(450) differed from wild-type dok1 in not inhibiting platelet-derived growth factor-induced extracellular signal-regulated kinase 1/2 phosphorylation or cell growth. Mutant dok1 a(439), a(443), a(446), and a(450) also did not promote cell motility whereas wild-type dok1 promoted cell motility." SIGNOR-131455 AMPK complex SIGNOR-C15 SIGNOR HDAC5 protein Q9UQL6 UNIPROT down-regulates phosphorylation Ser259 FPLRKTAsEPNLKVR 9606 21892142 t lperfetto "Another recently described set of transcriptional regulators targeted by ampk and its related family members across a range of eukaryotes are the class iia family of histone deacetylases (hdacs)" SIGNOR-216596 RBPJ protein Q06330 UNIPROT CDKN1A protein P38936 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 15866158 t "Induction of the p21WAF1/Cip1 gene by Notch 1 activation in differentiating keratinocytes is associated with direct targeting of the RBP-J_ protein to the p21 promoter." SIGNOR-252032 CTSD protein P07339 UNIPROT APP protein P05067 UNIPROT "up-regulates activity" cleavage Phe709 ENPTYKFfEQMQN -1 8943232 t lperfetto "FIG. 4. Schematic representation of the major cathepsin D cleavage sites in FLAG-bAPP156-bFGF and in bAPP100-FLAG. The amino acid sequences for the FLAG-bAPP156-bFGF and bAPP100-FLAG substrates are shown. Large arrows denote major cleavage sites. Unique cathepsin D cleavage sites in urea-denatured FLAG-bAPP156-bFGF are labeled (U). Small arrowheads denote minor bAPP100-FLAG cleavage sites determined by mass spectral analysis.|Taken together, these results indicate that in vitro, cathepsin D is unlikely to function as gamma-secretase; however, the ability of this enzyme to efficiently cleave betaAPP substrates at nonamyloidogenic sites within the molecule may reflect a role in betaAPP catabolism." SIGNOR-261777 SNCA protein P37840 UNIPROT "ER stress" stimulus SIGNOR-ST9 SIGNOR up-regulates 9606 12666095 f lperfetto "Furthermore, mutant isoforms of alpha-synuclein more readily oligomerize, and it has been suggested that its tendency to aggregate into misfolded structures may confer toxic properties to the protein." SIGNOR-249702 GHITM protein Q9H3K2 UNIPROT CYCS protein P99999 UNIPROT "down-regulates quantity" relocalization 9606 BTO:0000567 18417609 t Giulio "MICS1 was clearly coprecipitated with cytochrome c-3FLAG and the amount was DSP concentration-dependent (Figure 6A). Together with the finding that overexpression of exogenous MICS1 delayed the apoptotic release of cytochrome c in normal-serum level medium (Figure 4A), these results suggest that MICS1 helps to retain cytochrome c in the inner membrane, apart from the morphological changes." SIGNOR-260294 CD19 protein P15391 UNIPROT PIK3R1 protein P27986 UNIPROT "up-regulates activity" binding 10090 10201980 t lperfetto "Phosphorylation of CD19 Y484 and Y515, and linked activation of phosphatidylinositol 3-kinase, are required for B cell antigen receptor-mediated activation of Bruton's tyrosine kinase." SIGNOR-249608 PTPN1 protein P18031 UNIPROT PDGFRB protein P09619 UNIPROT down-regulates dephosphorylation Tyr771 ADIESSNyMAPYDNY 9606 18567737 t gcesareni "Ptp1b blocked pdgf-induced tyr716 and tyr751 phosphorylation of the pdgfr." SIGNOR-179080 KRAS protein P01116 UNIPROT PIK3CG protein P48736 UNIPROT up-regulates binding 9606 9727023 t gcesareni "Grb2 binds and activates sos, which then activates ras, and this activates p110 independently of p85./it was also described that ras interacts with pi3k in a direct manner." SIGNOR-59819 CDK9 protein P50750 UNIPROT POLR2A protein P24928 UNIPROT up-regulates phosphorylation Ser1714 SPTSPSYsPTSPSYS 9606 24385927 t lperfetto "Cyclin-dependent kinase 9 (cdk9) promotes elongation by rna polymerase ii (rnapii), mrna processing, and co-transcriptional histone modification. Cdk9 phosphorylates multiple targets, including the conserved rnapii elongation factor spt5 and rnapii itself" SIGNOR-203536 PARP1 protein P09874 UNIPROT KDM5B protein Q9UGL1 UNIPROT "up-regulates activity" relocalization 9606 33859667 t SaraGualdi "The mechanism of KDM5B recruitment is quite specific and requires the presence of nucleosomes containing histone variant MacroH2A1.1 and PARylation by PARP1." SIGNOR-271574 TNF protein P01375 UNIPROT TNFRSF1A protein P19438 UNIPROT "up-regulates activity" binding 9606 21133840 t "simone vumbaca" "TNF alpha and IFN gamma exhibit a cross-talk at the level of TNFR1 to induce activation of macrophages" SIGNOR-256025 CALM3 protein P0DP25 UNIPROT PPP3CB protein P16298 UNIPROT up-regulates binding 9606 11796223 t miannu "Calcium-bound calmodulin associates with calcineurin (cn), releasing the phosphatase from the repressive effects on an autoinhibitory domain." SIGNOR-266338 AKT2 protein P31751 UNIPROT BRAF protein P15056 UNIPROT down-regulates phosphorylation Ser428 GPQRERKsSSSSEDR 9606 10869359 t gcesareni "We show that phosphorylation of b-raf by akt occurs at multiple residues within its amino terminal regulatory domain, at both the conserved and unique phosphorylation sites. Akt phosphorylated b-raf on s364 and s428 to inactivate its kinase activity b-raf contains three akt consensus sites, table i. One site, ser364 is conserved with c-raf;however, two sites, ser428 and thr439, are unique to b-raf" SIGNOR-78685 CAMK2A protein Q9UQM7 UNIPROT CAMK2A protein Q9UQM7 UNIPROT down-regulates phosphorylation Ser314 MLATRNFsGGKSGGN 9606 1324926 t lperfetto "After removal of ca2+/calmodulin, the autonomous kinase undergoes a burst of inhibitory autophosphorylation at sites distinct from the autonomy site. Ca(2+)-independent autophosphorylation occurs within the calmodulin binding domain at thr305, thr306, and ser314" SIGNOR-17308 trametinib chemical CHEBI:75998 ChEBI MAP2K1 protein Q02750 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-192823 CCN2 protein P29279 UNIPROT LRP6 protein O75581 UNIPROT up-regulates binding 9606 18528331 t gcesareni "Igfbp-4 physically interacted with a wnt receptor, frizzled 8 (frz8), and a wnt co-receptor, low-density lipoprotein receptor-related protein 6 (lrp6), and inhibited the binding of wnt3a to frz8 and lrp6." SIGNOR-178875 VAV2 protein P52735 UNIPROT RAC1 protein P63000 UNIPROT "up-regulates activity" "guanine nucleotide exchange factor" 9606 32203420 t Luana "We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2)." SIGNOR-260583 FBXW11 protein Q9UKB1 UNIPROT ZNF281 protein Q9Y2X9 UNIPROT "down-regulates quantity by destabilization" ubiquitination 9606 BTO:0001615 phosphorylation:Ser638 PRVDLHTsGEHSELV 29179460 t lperfetto "E3 ligase the beta-transducin repeat-containing protein 2 (beta-TrCP2) governs the ubiquitination and degradation of ZNF281. In human CRC specimens, endogenous beta-TrCP2 were inversely correlated with ZNF281." SIGNOR-264897 MAPK1 protein P28482 UNIPROT PAK1 protein Q13153 UNIPROT "down-regulates activity" phosphorylation Thr212 VIEPLPVtPTRDVAT 10116 BTO:0001260 15542607 t lperfetto "We also show that ERK2 phosphorylates PAK1 on Thr(212) in vitro and that Thr(212) is phosphorylated in smooth muscle cells following PDGF-BB treatment in an adhesion- and MEK/ERK-dependent fashion. Expression of a phosphomimic variant, PAK-T212E, does not alter ERK association, but markedly attenuates downstream ERK signaling. Taken together, these data suggest that PAK1 may facilitate ERK signaling by serving as a scaffold to recruit Raf, MEK, and ERK to adhesion complexes, and that subsequent growth factor-stimulated phosphorylation of PAK-Thr(212) by ERK may serve to provide a negative feedback signal" SIGNOR-249432 PPP3CA protein Q08209 UNIPROT NFATC1 protein O95644 UNIPROT up-regulates dephosphorylation 9606 21880741 t gcesareni "Calcineurin directly dephosphorylates nfat resulting in the nuclear import of nfat." SIGNOR-176370 SH2B1 protein Q9NRF2 UNIPROT JAK2 protein O60674 UNIPROT "up-regulates activity" binding 27154742 t lperfetto "The SH2B adaptor protein 1 (SH2B1) is a key regulator of leptin, as it enhances leptin signalling by both stimulating Janus kinase 2 (JAK2) activity and assembling a JAK2/IRS1/2 signalling complex" SIGNOR-253078 CALU protein O43852 UNIPROT GGCX protein P38435 UNIPROT "down-regulates activity" binding 10116 BTO:0000759 15075329 t lperfetto "Results are presented that demonstrate that the endoplasmic reticulum chaperone protein calumenin is associated with gamma-carboxylase and inhibits its activity." SIGNOR-265910 NLK protein Q9UBE8 UNIPROT NOTCH1 protein P46531 UNIPROT down-regulates phosphorylation 9606 20118921 t gcesareni "Nlk-phosphorylated notch1icd is impaired in its ability to form a transcriptionally_ active_ ternary_ complex." SIGNOR-163697 PRKD1 protein Q15139 UNIPROT PTRH2 protein Q9Y3E5 UNIPROT up-regulates phosphorylation Ser87 GKVAAQCsHAAVSAY 9606 18703509 t lperfetto "Overexpression of constitutively active pkd or pkd activation by treatment with phorbol 12-myristate 13-acetate results in phosphorylation of two serine residues (ser5 and ser87) in a form of bit1 that is confined to the cytoplasm and concomitantly increases the apoptotic activity of cytoplasmic bit1" SIGNOR-180089 MAPK3 protein P27361 UNIPROT DUSP6 protein Q16828 UNIPROT down-regulates phosphorylation Ser159 DGSCSSSsPPLPVLG 9606 15632084 t amattioni "Phosphorylation of serines 159 and 197 by erk1/2 enhances proteasomal degradation of mkp-3" SIGNOR-132975 FYN protein P06241 UNIPROT SLAMF1 protein Q13291 UNIPROT "up-regulates activity" phosphorylation Tyr327 ETNSITVyASVTLPE 9534 BTO:0000298 11806999 t "All 3 tyrosines of CD150 (Tyr281, Tyr307, Tyr327) are phosphorylated by the src kinase Fyn. CD150 is unique among its homologues in the immunoglobulin superfamily in that it is able to bind SAP, a floating SH2 domain, in the absence of tyrosine phosphorylation. In this study, using a detailed mutagenesis mapping approach we have shown that SAP binding to CD150 is in fact bimodal. Prior to tyrosine phosphorylation, SAP binds the membrane-proximal motif surrounding Tyr281. Following tyrosine phosphorylation by tyrosine kinases such as Fyn, SAP binds additionally to the distal motif surrounding Tyr327." SIGNOR-251183 ADNP protein Q9H2P0 UNIPROT CTCF protein P49711 UNIPROT "down-regulates activity" relocalization 10090 BTO:0001086 SIGNOR-C407 31491387 t miannu "These results argue against the simultaneous binding of CTCF and ADNP to the same genomic loci. Instead, they support a model in which ADNP counteracts stable association of CTCF with DNA at over 15,000 binding sites in the mouse genome." SIGNOR-266755 AKT2 protein P31751 UNIPROT TSC2 protein P49815 UNIPROT down-regulates phosphorylation Thr1462 GLRPRGYtISDSAPS 9606 12172553 t gcesareni "We demonstrate here that tuberin is phosphorylated on s939 and t1462 in response to pi3k activation. Our results are consistent with akt being the pi3k-depen-dent tuberin kinase. The pi3k-akt-mediated phosphorylation of tuberin would inhibit the function of the tuberin-hamartin complex." SIGNOR-91392 HIRA protein P54198 UNIPROT "HIRA complex 2" complex SIGNOR-C462 SIGNOR "form complex" binding 9606 30285846 t miannu "H3.3 is an ancient and conserved H3 variant and plays essential roles in transcriptional regulation. HIRA complex, which is composed of HIRA, UBN1 or UBN2, and Cabin1, is a H3.3 specific chaperone complex. In this study, we demonstrate that the UBN1 or UBN2 subunit is mainly responsible for specific recognition and direct binding of H3.3 by the HIRA complex." SIGNOR-269437 CAMK2B protein Q13554 UNIPROT CYLD protein Q9NQC7 UNIPROT up-regulates phosphorylation Ser362 FYTLNGSsVDSQPQS 9606 24614225 t lperfetto "Purified camkii phosphorylates cyld on at least three residues (s-362, s-418, and s-772 on the human cyld protein q9nqc7-1) and promotes its deubiquitinase activity." SIGNOR-25334 mTORC1 complex SIGNOR-C3 SIGNOR Adipogenesis phenotype SIGNOR-PH26 SIGNOR up-regulates 10090 19593385 f lperfetto "Activation of mTORC1 causes a robust increase in the mRNA and protein expression of peroxisome proliferator-activated receptor gamma (PPARgamma), which is the master transcriptional regulator of adipocyte differentiation." SIGNOR-235349 BCL11A protein Q9H165 UNIPROT HBG2 protein P69892 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0004911 20395365 f Regulation miannu "BCL11A and SOX6 co-occupy the human beta-globin cluster along with GATA1, and cooperate in silencing gamma-globin transcription in adult human erythroid progenitors." SIGNOR-251800 "bis(2-ethylhexyl) phthalate" chemical CHEBI:17747 ChEBI SLC5A5 protein Q92911 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10116 BTO:0003800 16257484 f miannu "DIDP, BBP and DOP stimulate NIS mRNA expression. Here, hNIS promoter construct (N3) was up-regulated 2.5-fold by DIDP, 2.6-fold by BBP and 2.4-fold by DOP in the presence of TSH. Likewise, these phthalates also enhanced rNIS endogenous mRNA expression, which increased ca. 2-fold after 48 h of treatment compared with the expression level generated by TSH only. At 72 h, mRNA content was unchanged." SIGNOR-268744 GSK2126458 chemical CID:25167777 PUBCHEM PIK3CA protein P42336 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-192892 HDAC1 protein Q13547 UNIPROT "MBD2/NuRD complex" complex SIGNOR-C337 SIGNOR "form complex" binding 9606 27098840 t miannu "The NuRD complex is a multi-protein transcriptional corepressor that couples histone deacetylase and ATP-dependent chromatin remodelling activities.In humans, an assembly of proteins called the NuRD complex makes chromatin more compact by removing acetyl groups from nucleosomes. This complex is important for early development and for the stability and repair of our genes. Three proteins make up its core: HDAC1, which removes the acetyl group from the nucleosome; MTA1, which acts as a scaffold to hold the complex together; and RBBP4, which enables the complex to interact with nucleosomes. MBD2 and MBD3 are members of the methyl cytosine-guanosine (CpG)-binding domain (MBD) family of proteins42; 43. Of the five MBD members, only MBD2 and MBD3 associate with NuRD and are required for the complex formation and gene repression." SIGNOR-263839 RHOQ protein P17081 UNIPROT EXOC7 protein Q9UPT5 UNIPROT up-regulates binding 9606 12687004 t gcesareni "Here we show that tc10 interacts with one of the components of the exocyst complex, exo70." SIGNOR-100486 TP53BP2 protein Q13625 UNIPROT PPP1R14A protein Q96A00 UNIPROT down-regulates binding 9606 8549741 t gcesareni "The phosphorylase phosphatase activity of pp1 was inhibited by p53bp2 at nanomolar concentrations." SIGNOR-39666 SF3B6 protein Q9Y3B4 UNIPROT SF3b complex SIGNOR-C442 SIGNOR "form complex" binding 9606 32140746 t lperfetto "Characterization of the purified SF3b complex indicated that it consists of seven proteins with a molecular size ranging from 10 to 155 kDa [10–12] (Fig. 1a). Due to methodological differences in identifying SF3b components in human and yeast, a number of names have been designated for these proteins across different species. In this review, I will use SF3b1-7 for consistency and clarity (Fig. 1a)." SIGNOR-268408 CHEK1 protein O14757 UNIPROT "Histone H3" proteinfamily SIGNOR-PF69 SIGNOR "down-regulates activity" phosphorylation 9606 18243098 t gcesareni "We identify chk1 as the kinase responsible for h3-t11 phosphorylation. H3-t11 phosphorylation occurs throughout the cell cycle and is chk1 dependent in vivo.Phosphorylation at thr-12 (h3t11ph) by pkn1 is a specific tag for epigenetic transcriptional activation that promotes demethylation of lys-10 (h3k9me) by kdm4c/jmjd2c." SIGNOR-265326 GCG protein P01275 UNIPROT LATS1 protein O95835 UNIPROT up-regulates 9606 23075495 f gcesareni "On the other hand, galfas-coupled signals, such as epinephrine and glucagon, induce kinase activity of lats1/2, leading to phosphorylation and yap/taz." SIGNOR-199202 ARHGAP19 protein Q14CB8 UNIPROT RHOA protein P61586 UNIPROT "down-regulates activity" "gtpase-activating protein" 9606 BTO:0000007 32203420 t Luana "We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2)." SIGNOR-260471 NQO1 protein P15559 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 BTO:0003934 28599455 f irozzo "The results demonstrated that NQO1 siRNA-mediated knockdown effectively impaired colony formation capacity, induced cell cycle arrest at the G1 phase and suppressed migration of KKU-100 cells." SIGNOR-256265 SMURF1 protein Q9HCE7 UNIPROT IMPACT protein Q9P2X3 UNIPROT unknown ubiquitination -1 20804422 t miannu "Recombinant proteins were used to profile substrate ubiquitination by the Smurf1 ubiquitin ligase on a global scale using protein microarrays. T Proteins ubiquitinated on the protein microarray were confirmed as potential substrates of the Smurf1 activity using an off chip in vitro ubiquitination assay." SIGNOR-272686 CLOCK protein O15516 UNIPROT PER3 protein P56645 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 22750052 f "Mammalian clocks are primarily based on a transcription and translation feedback loop in which a heterodimeric complex of the transcription factors CLOCK (circadian locomotor output cycles kaput) and BMAL1 (brain and muscle Arnt-like protein 1) activates the expression of its own repressors, the period (PER1-3) and cryptochrome (CRY1,2) proteins." SIGNOR-253635 AKT proteinfamily SIGNOR-PF24 SIGNOR MDM2 protein Q00987 UNIPROT "up-regulates activity" phosphorylation Ser166 SSRRRAIsETEENSD 9606 15169778 t lperfetto "Stabilization of mdm2 via decreased ubiquitination is mediated by protein kinase b/akt-dependent phosphorylation." SIGNOR-244296 HES1 protein Q14469 UNIPROT FLT3 protein P36888 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 10090 25234168 t "We then found that Hes1 directly bound to the promoter region of the FMS-like tyrosine kinase 3 (FLT3) gene and downregulated the promoter activity." SIGNOR-261563 LRRC4 protein Q9HBW1 UNIPROT CCNE1 protein P24864 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0000142 25526788 f miannu "LRRC4/NGL-2 can delay the cell cycle in late G1 by increasing the expression of cell cycle inhibitory molecules (p21, p27) and reducing the expression of cell cycle regulatory proteins (CyclinD1, CDK2, CyclinE, CDK4) via the inhibition of K-Ras/c-Raf/ERK/MAPK, PI-3K/AKT/NF- κB, p70S6/PKC and STAT3, and the upregulation of the JNK2/c-Jun/mp53 signaling pathway." SIGNOR-264057 PRKCB protein P05771 UNIPROT NRGN protein Q92686 UNIPROT "up-regulates activity" phosphorylation Ser36 AAAKIQAsFRGHMAR -1 8080473 t lperfetto "Phosphorylation of RC3 by PKC alpha, beta, or gamma was stimulated by Ca2+, phospholipid, and diacylglycerol. A single site, Ser36, which is adjacent to the predicted calmodulin (CaM)-binding domain, was phosphorylated by these enzymes. Phosphorylation of RC3 by PKC or PKM, a protease-degraded PKC, was inhibited by CaM. The effect of CaM apparently targets at RC3, as phosphorylation of protamine sulfate by PKM was not inhibited by CaM." SIGNOR-248914 SOS1 protein Q07889 UNIPROT KRAS protein P01116 UNIPROT up-regulates "guanine nucleotide exchange factor" 9606 25624485 t "Ras proteins bind GDP/GTP and possess intrinsic GTPase activity." gcesareni "Because the KRAS-GDP to KRAS-GTP transition catalyzed by the GEF, son of sevenless 1 (SOS1), represents the rate-limiting step for nucleotide exchange, disrupting the activating SOS1/KRAS protein interaction has also been the focus of drug development efforts" SIGNOR-201703 PAK2 protein Q13177 UNIPROT CASP7 protein P55210 UNIPROT down-regulates phosphorylation Thr173 FRGDRCKtLLEKPKL 9606 BTO:0000150 21555521 t gcesareni "Pak2 can bind with caspase-7 and phosphorylate caspase-7 at the ser-30, thr-173, and ser-239 sites. Functionally, the phosphorylation of caspase-7 decreases its activity, thereby inhibiting cellular apoptosis." SIGNOR-173663 PRKCA protein P17252 UNIPROT NKX3-1 protein Q99801 UNIPROT up-regulates phosphorylation Ser48 RQGGRTSsQRQRDPE 9606 BTO:0001130 11980664 t llicata "Phosphorylation of wild-type nkx3.1 decreased the apparent binding affinity of the protein for the consensus sequence by 3-fold relative to the nonphosphorylated protein (fig. 3) _ ." SIGNOR-86723 SMO protein Q99835 UNIPROT GNB2 protein P62879 UNIPROT up-regulates binding 9606 16885213 t gcesareni "Consistent with its predicted topology, smo couples to a specific family of inhibitory g protein (gis) to regulate hh signaling." SIGNOR-148589 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR PBK protein Q96KB5 UNIPROT unknown phosphorylation Thr9 EGISNFKtPSKLSEK 9606 15541388 t lperfetto "Topk-thr-9 was phosphorylated by cdk1/cyclin b and topk significantly associates with mitotic spindles." SIGNOR-216896 STAT1 protein P42224 UNIPROT MUC4 protein Q99102 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0001861 19757157 t lperfetto "Through promoter screening, overexpressing methods and luciferase reporter studies, we found that transcription factors CREB, Ets-1, Elk-1 and STAT1 can positively regulate MUC4 expression at the promoter and mRNA level." SIGNOR-254099 CBL protein P22681 UNIPROT PDGFRB protein P09619 UNIPROT "down-regulates quantity by destabilization" polyubiquitination 10090 BTO:0000944 10347229 t miannu " Overexpression of wild type Cbl in NIH3T3 cells led to an enhancement of the ligand-dependent ubiquitination and subsequent degradation of the PDGFRbeta, as observed with PDGFRalpha." SIGNOR-272549 MDM2 protein Q00987 UNIPROT KAT5 protein Q92993 UNIPROT "down-regulates quantity by destabilization" polyubiquitination 9606 BTO:0001938 11927554 t miannu "Furthermore, we provide evidence that Mdm2, the ubiquitin ligase of the p53 tumour suppressor, interacts physically with Tip60 and induces its ubiquitylation and proteasome-dependent degradation." SIGNOR-272613 CDK2 protein P24941 UNIPROT PRDX1 protein Q06830 UNIPROT down-regulates phosphorylation Thr90 CHLAWVNtPKKQGGL 9606 BTO:0000567 11986303 t lperfetto "Peroxiredoxin (prx) i is a member of the peroxiredoxin family of peroxidases and contains a consensus site (thr(90)-pro-lys-lys) for phosphorylation by cyclin-dependent kinases (cdks). This protein has now been shown to be phosphorylated specifically on thr(90) by several cdks, including cdc2, in vitro. Phosphorylation of prx i on thr(90) reduced the peroxidase activity of this protein by 80%.Prx i was also phosphorylated, with an efficiency similar to that observed with cdc2, when incubated in vitro with cdk2, cdk4, or cdk6 that had been immunoprecipitated from hela cell lysates with specific antibodies (data not shown)." SIGNOR-87101 MARK1 protein Q9P0L2 UNIPROT MAP2 protein P11137 UNIPROT "down-regulates activity" phosphorylation Ser1679 NVKSKIGsTDNIKYQ -1 8631898 t miannu "Here we show that p110mark phosphorylates analogous KXGS sites in the microtubule binding domains of the neuronal MAP2 and the ubiquitous MAP4. Phosphorylation in vitro leads to the dissociation of MAP2 and MAP4 from microtubules and to a pronounced increase in dynamic instability." SIGNOR-250164 DAPK3 protein O43293 UNIPROT MYL9 protein P24844 UNIPROT up-regulates phosphorylation Thr19 KKRPQRAtSNVFAMF 9606 19851336 t lperfetto "More than a dozen kinases have been reported to phosphorylate the rlcs of nm ii (fig. 2), including myosin light chain kinase (mlck;also known as mylk), rho-associated, coiled coil-containing kinase (rock), citron kinase, leucine zipper interacting kinase (zipk;also known as dapk3) and myotonic dystrophy kinase-related cdc42-binding kinase (mrck;also known as cdc42bp)6,34,45,46. These kinases phosphorylate rlcs on ser19, thr18 or both, to relieve the inhibition imposed on the myosin molecule by unphosphorylated rlcs and the head_head interaction outlined above." SIGNOR-188793 STK4 protein Q13043 UNIPROT H2BC3 protein P33778 UNIPROT unknown phosphorylation Ser15 APAPKKGsKKAITKA 9606 21212262 t lperfetto "The mst1 is a serine/threonine kinase that is activated upon apoptotic stimulation, which in turn activates its downstream targets, jnk/p38, histone h2b and foxo. Mst1 induces apoptosis by phosphorylating histone h2b on a relatively conserved site, ser-14 in mammalian cells" SIGNOR-171009 TLN1 protein Q9Y490 UNIPROT ITGB3 protein P05106 UNIPROT "up-regulates activity" binding 10090 19118207 t miannu "Over the past 10 years, the binding of talin to the cytoplasmic tail of integrin-β subunits has been established to have a key role in integrin activation. Binding of the phosphotyrosinebinding (PTB)-domain-like subdomain of the protein 4.1, ezrin, radixin, moesin (FERM) domain of talin to the conserved WxxxNP(I/L)Y motif of the β-integrin tail permits additional weaker interactions between talin and the membrane-proximal region of the tail that trigger integrin activation, probably through the disruption of inhibitory interactions between α- and β-subunit cytoplasmic tails." SIGNOR-257625 SOX9 protein P48436 UNIPROT CDX2 protein Q99626 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 15240568 f "SOX9 represses the expression of the CDX2 transcription factor, known to be mostly active in villus cells." SIGNOR-253322 HK1 protein P19367 UNIPROT "alpha-D-glucose 6-phosphate(2-)" smallmolecule CHEBI:58225 ChEBI "up-regulates quantity" "chemical modification" 9606 16051738 t miannu "Hexokinase catalyzes the phosphorylation of glucose to G6P, using ATP as a phosphoryl donor." SIGNOR-266445 ERP44 protein Q9BS26 UNIPROT ITPR1 protein Q14643 UNIPROT "down-regulates activity" binding 9606 BTO:0000567 15652484 t Simone "In this study, we found that ERp44, an ER lumenal protein of the thioredoxin family, directly interacts with the third lumenal loop of IP(3)R type 1 (IP(3)R1) and that the interaction is dependent on pH, Ca(2+) concentration, and redox state. In this study we demonstrated that ERp44 directly interacts with the L3V domain of IP3R1, thereby inhibiting its channel activity." SIGNOR-261046 PSEN1 protein P49768 UNIPROT gamma-secretase complex SIGNOR-C98 SIGNOR up-regulates cleavage 9606 10497236 t "Gamma secretase subunit that leads a proteolitic cleavage through Asp257 and Asp385 after transport to cell surface." lperfetto "Presenilin-1 (ps1), a polytopic membrane protein primarily localized to the endoplasmic reticulum, is required for efficient proteolysis of both notch and beta-amyloid precursor protein (app) within their trans- membrane domains." SIGNOR-217746 PTPRC protein P08575 UNIPROT LYN protein P07948 UNIPROT "down-regulates activity" dephosphorylation Tyr508 YTATEGQyQQQP 10090 BTO:0000776 10415030 t "CD45 negatively regulates lyn activity by dephosphorylating both positive and negative regulatory tyrosine residues in immature B cells.| Phosphoamino acid analysis confirmed that Lyn is tyrosine phosphorylated with little serine or threonine phosphorylation. In CD45-negative cells, two bands at 8.2 and 4.1 kDa were phosphorylated in the absence of B cell Ag receptor (BCR) ligation. The 8.2-kDa band corresponded to a fragment containing the positive regulatory site (Tyr397), as assessed by its size and its phosphorylation in an in vitro kinase assay. The 4.1-kDa band was phosphorylated by COOH-terminal Src kinase, suggesting that it contains the COOH-terminal negative regulatory site (Tyr508)" SIGNOR-248354 CSNK2A1 protein P68400 UNIPROT PKD2 protein Q13563 UNIPROT up-regulates phosphorylation Ser812 FPRSLDDsEEDDDED 9606 14742446 t gcesareni "Ser(812) can be phosphorylated by ck2 in vitro and substitution s812a results in failure to incorporate phosphate in cultured epithelial cells." SIGNOR-121572 MAPK7 protein Q13164 UNIPROT PML protein P29590 UNIPROT down-regulates phosphorylation 9606 BTO:0001271 20832753 t gcesareni "We found that bmk1 interacted with promyelocytic leukemia protein (pml), and inhibited its tumor-suppressor function through phosphorylation." SIGNOR-167947 PDGFRB protein P09619 UNIPROT PDGFRB protein P09619 UNIPROT "up-regulates activity" phosphorylation Tyr740 TGESDGGyMDMSKDE -1 8195171 t miannu "Synthetic peptide analysis revealed that certain autophosphorylation sites in the PDGF beta-receptor (Tyr-579, Tyr-740, Tyr-751, and Tyr-771) were able to mediate the specific binding of the Shc SH2 domain as well as intact Shc proteins." SIGNOR-250257 C9orf72 protein Q96LT7 UNIPROT ULK1/Atg13/Fip200 complex SIGNOR-C100 SIGNOR "up-regulates activity" binding 9606 27334615 t lperfetto "C9orf72 interacts with the ULK1 initiation complex|C9orf72 regulates translocation of the ULK1 complex to the phagophore via Rab1a" SIGNOR-261281 ARHGEF4 protein Q9NR80 UNIPROT RHOA protein P61586 UNIPROT "up-regulates activity" "guanine nucleotide exchange factor" 9606 BTO:0000007 32203420 t Luana "We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2)." SIGNOR-260531 873837-23-1 chemical CID:46930994 PUBCHEM ERBB2 protein P04626 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-190470 APOA5 protein Q6Q788 UNIPROT LPL protein P06858 UNIPROT "up-regulates activity" binding 9606 21773006 t Regulation miannu "Apo A5 binds to and enhances the activity of lipoprotein lipase (LPL) enzyme" SIGNOR-251845 HOXA7 protein P31268 UNIPROT TGM1 protein P22735 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0000667 11435435 f miannu "Antisense HOXA7 expression activated transglutaminase 1, involucrin, and keratin 10 message and protein levels, demonstrating that endogenous HOXA7 down-regulates multiple differentiation-specific keratinocyte genes." SIGNOR-254474 RAD23B protein P54727 UNIPROT Protein_degradation phenotype SIGNOR-PH96 SIGNOR up-regulates 9606 16401726 f miannu "The XPCB domain of Rad23 binds Png1, which in turn facilitates the substrate recognition of Rad23. Through interactions with Ub chains and the proteasome mediated by the UBA and UBL domains in Rad23, Rad23 facilitates substrate transfer to the proteasome." SIGNOR-261062 "A4/b7 integrin" complex SIGNOR-C187 SIGNOR Cell_adhesion phenotype SIGNOR-PH7 SIGNOR up-regulates 9606 25388208 f miannu "Integrin-mediated cell adhesion is important for development, immune responses, hemostasis and wound healing." SIGNOR-269031 TRAF7 protein Q6Q0C0 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR up-regulates 9606 15001576 f miannu "Overexpression of traf7 induced caspase-dependent apoptosis." SIGNOR-123218 TRAF6 protein Q9Y4K3 UNIPROT TAB1 protein Q15750 UNIPROT "up-regulates activity" binding 9606 25290089 t lperfetto "The irak1/traf6 complex can also activate jnk and p38 signalling through assembly of a catalytically active tab2-tab3-tak1 complex." SIGNOR-205455 PRKCA protein P17252 UNIPROT GFAP protein P14136 UNIPROT "down-regulates activity" phosphorylation Ser13 ITSAARRsYVSSGEM -1 2155236 t lperfetto "Glial fibrillary acidic protein (GFAP), the intermediate filament component of astroglial cells, can serve as an excellent substrate for both cAMP-dependent protein kinase and protein kinase C, in vitro. GFAP phosphorylated by each protein kinase does not polymerize, and the filaments that do polymerize tend to depolymerize after phosphorylation. Dephosphorylation of phospho-GFAP by phosphatase led to a recovery of the polymerization competence of GFAP. Most of the phosphorylation sites for cAMP-dependent protein kinase and protein kinase C on GFAP are the same, Ser-8, Ser-13, and Ser-34. cAMP-dependent protein kinase has one additional phosphorylation site, Thr-7." SIGNOR-248860 GPR84 protein Q9NQS5 UNIPROT GNAI1 protein P63096 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-256704 RPIA protein P49247 UNIPROT "D-ribofuranose 5-phosphate(2-)" smallmolecule CHEBI:78346 ChEBI "up-regulates quantity" "chemical modification" 9606 34775382 t miannu "The reversible nonoxidative phase starts with Ru5P that is transformed into ribose-5-phosphate (R5P) by ribulose-5-phosphate isomerase. R5P is an essential component of purine and pyrimidine nucleotides biosynthesis. Ru5P may also be converted into xylulose-5-phosphate by ribulose-5-phosphate-3-epimerase, which was reported to enhance glycolytic flux." SIGNOR-267070 SLC27A2 protein O14975 UNIPROT "fatty acyl-CoA" smallmolecule CHEBI:37554 ChEBI "up-regulates quantity" "chemical modification" 9606 10198260 t lperfetto "Very-long-chain acyl-CoA synthetases (VLCS) activate very-long-chain fatty acids (VLCFA) containing 22 or more carbons to their CoA derivatives." SIGNOR-260415 TFAP2A protein P05549 UNIPROT DCC protein P43146 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 19745029 f miannu "Promoter analysis and transfection studies showed that the up-regulation of DCC in OA chondrocytes may be mediated by the transcription factors Sox9 and AP-2." SIGNOR-255189 SGK1 protein O00141 UNIPROT NEDD4L protein Q96PU5 UNIPROT up-regulates phosphorylation Ser342 SSRLRSCsVTDAVAE 9606 11742982 t lperfetto "Here we show by expression studies in xenopus laevis oocytes that the aldosterone-induced sgk1 kinase interacts with the ubiquitin protein ligase nedd4-2 in a py motif-dependent manner and phosphorylates nedd4-2 on ser444 and, to a lesser extent, ser338. Such phosphorylation reduces the interaction between nedd4-2 and enac, leading to elevated enac cell surface expression." SIGNOR-113052 GLIS1 protein Q8NBF1 UNIPROT WNT5A protein P41221 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 32047936 t miannu "GLIS1, a novel hypoxia-inducible transcription factor, promotes breast cancer cell motility via activation of WNT5A" SIGNOR-269040 STOM protein P27105 UNIPROT SLC2A1 protein P11166 UNIPROT "down-regulates activity" binding 9606 10562431 t Giulio "Similar to the results obtained in the RBC, Glut1 and stomatin immunoprecipitated with each other in lysates of Clone 9 cells. The above results suggest that stomatin is closely associated with Glut1 in the plasma membrane and that overexpression of stomatin results in a depression in the basal rate of glucose transport." SIGNOR-261278 KMT2A protein Q03164 UNIPROT RUNX1 protein Q01196 UNIPROT "up-regulates quantity by stabilization" binding 9606 BTO:0002181 22012064 t irozzo "Similar to CBFβ, we show that MLL binds to AML1 abrogating its proteasome-dependent degradation.Furthermore, we demonstrate that MLL binds to a region of AML1 (that is conserved in AML2 and AML3) and increases AML1 (AML2 and AML3) protein levels" SIGNOR-255707 MTHFD1L protein Q6UB35 UNIPROT formate smallmolecule CHEBI:15740 ChEBI "up-regulates quantity" "chemical modification" 9606 16171773 t lperfetto "A human mitochondrial isozyme of C1-tetrahydrofolate (THF) synthase was previously identified by its similarity to the human cytoplasmic C1-THF synthase. All C1-THF synthases characterized to date, from yeast to human, are trifunctional, containing the activities of 5,10-methylene-THF dehydrogenase, 5,10-methenyl-THF cyclohydrolase, and 10-formyl-THF synthetase. Here we report on the enzymatic characterization of the recombinant human mitochondrial isozyme. Enzyme assays of purified human mitochondrial C1-THF synthase protein revealed only the presence of 10-formyl-THF synthetase activity." SIGNOR-268254 "vitamin K epoxide" smallmolecule CHEBI:28371 ChEBI VKORC1L1 protein Q8N0U8 UNIPROT "up-regulates activity" "chemical activation" 9606 31226734 t lperfetto "The epoxide form of vitamin K is reduced by epoxide reductase (vitamin K epoxide reductase complex 1; VKORC1 or vitamin K epoxide reductase complex 1-like 1; VKORC1L1) to a reduced form and then to the reduced hydroquinone form" SIGNOR-265914 oxandrolone chemical CHEBI:7820 ChEBI AR protein P10275 UNIPROT "up-regulates activity" "chemical activation" 9606 10077001 t miannu "The anabolic steroids, oxandrolone and fluoxymesterone, have high inhibition constants for binding, yet induce the N/C interaction and stabilize AR at relatively low ligand concentrations and are AR agonists in vivo." SIGNOR-259265 (S)-methylmalonyl-CoA(5-) smallmolecule CHEBI:57327 ChEBI succinyl-CoA(5-) smallmolecule CHEBI:57292 ChEBI "up-regulates quantity" "precursor of" 9606 1978672 t miannu "Methylmalonyl-CoA mutase (MCM) is an adenosylcobalamin-dependent enzyme that catalyses isomerization between methylmalonyl-CoA and succinyl-CoA (3-carboxypropionyl-CoA)." SIGNOR-269110 Immune_response phenotype SIGNOR-PH17 SIGNOR ARDS phenotype SIGNOR-PH128 SIGNOR up-regulates 9606 32446778 f miannu "The presence of SARS-CoV-2 in the lung induces an uncontrolled generalized immune response. Several immune cells (like T-lymphocytes, macrophages and dendritic cells) sustain the impressive secretion of cytokines and chemokines ultimately leading to acute respiratory distress syndrome. These data clearly indicate that, in SARS-CoV in-fection, ARDS is the ultimate result of a cytokine storm." SIGNOR-261035 CDK11B protein P21127 UNIPROT EIF3F protein O00303 UNIPROT "up-regulates activity" phosphorylation Ser46 PAAAPASsSDPAAAA 19245811 t lperfetto "EIF3f is phosphorylated by CDK11p46 at Ser46 during apoptosis.|Phosphorylation of eIF3f plays an important role in regulating its function in translation and apoptosis. Phosphorylation of eIF3f enhances the association of eIF3f with the core eIF3 subunits during apoptosis. " SIGNOR-273133 3-iodo-L-tyrosine smallmolecule CHEBI:27847 ChEBI 3,3',5'-triiodothyronine smallmolecule CHEBI:28774 ChEBI "up-regulates quantity" "precursor of" 9606 28153798 t scontino "The synthesis of T3 and T4 is achieved through the transfer of an iodophenoxyl group from a MIT or DIT residue called a ‚Äúdonor‚Äù onto a DIT residue called an ‚Äúacceptor‚Äù. TPO seems to be primarily responsible for catalyzing the oxidations of iodotyrosines." SIGNOR-268128 TNF protein P01375 UNIPROT SNAI2 protein O43623 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 20509143 f miannu "we show that TNFα treatment of human breast cancer cells up-regulates SLUG with a dependency on canonical NF-κB/HIF1α signaling, which is strongly enhanced by p53 inactivation." SIGNOR-255152 AKT proteinfamily SIGNOR-PF24 SIGNOR SH3RF1 protein Q7Z6J0 UNIPROT down-regulates phosphorylation Ser304 KNTKKRHsFTSLTMA 9606 17535800 t miannu "We report here that posh is a direct substrate for phosphorylation by akt in vivo and in vitro, and we identify a major site of akt phosphorylation as serine 304 of posh, which lies within the rac-binding domain. We further show that phosphorylation of posh results in a decreased ability to bind activated rac, as does phosphomimetic s304d and s304e mutation of posh." SIGNOR-155229 BTG2 protein P78543 UNIPROT NFE2L2 protein Q16236 UNIPROT "up-regulates activity" binding 9606 BTO:0000093 22493435 t miannu "BTG2 stimulation of antioxidant gene expression is also NFE2L2-dependent. We further demonstrate that BTG2 is a binding partner for NFE2L2 and increases its transcriptional activity." SIGNOR-254647 IQSEC2 protein Q5JU85 UNIPROT GRIA2 protein P42262 UNIPROT "up-regulates quantity" relocalization 9606 BTO:0000142 27009485 t miannu "BRAG1 increases the synaptic recycling pool of AMPARs.these data suggest that the BRAG1 enhancement of AMPAR transmission is mediated by the increased expression of the recycling pool of synaptic GluA2/3 receptors." SIGNOR-264913 CNR1 protein P21554 UNIPROT GNAI3 protein P08754 UNIPROT "up-regulates activity" binding 9606 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-256867 "3-phosphonato-D-glyceroyl phosphate(4-)" smallmolecule CHEBI:57604 ChEBI 3-phosphonato-D-glycerate(3-) smallmolecule CHEBI:58272 ChEBI "up-regulates quantity" "precursor of" 9606 16051738 t miannu "Phosphoglycerate kinase generates one molecule of ATP by catalyzing the reversible conversion of 1,3-bisphosphoglycerate to 3-phosphoglycerate. Two isozymes of PGK exist: PGK-1, ubiquitously expressed in all somatic cells, and PGK-2, expressed only in spermatozoa." SIGNOR-266500 LAMB1 protein P07942 UNIPROT Laminin-1 complex SIGNOR-C183 SIGNOR "form complex" binding 7496033 t lperfetto "Laminin-1 is an extracellular matrix protein composed of three polypeptide chains that are designated alpha 1, beta 1, and gamma 1." SIGNOR-253233 MAPK3 protein P27361 UNIPROT CEBPB protein P17676 UNIPROT up-regulates phosphorylation Thr235 SSSSPPGtPSPADAK 9606 19327116 t gcesareni "Thr235 phosphorylation occurs in nuclei of differentiated macrophages, but not in monocytes." SIGNOR-184917 CAMK2G protein Q13555 UNIPROT MYLK protein Q15746 UNIPROT "down-regulates activity" phosphorylation Ser1760 RAIGRLSsMAMISGL 2160950 t llicata "Phosphorylation of MLC kinase by CaM protein kinase II increased the dissociation constant of MLC kinase for calmodulin about 10 times without changing the Vmax. The location of the phosphorylation sites was identified by isolating and sequencing the tryptic phosphopeptides of MLC kinase. The preferred site was identified as serine 512 and the second site as serine 525. These sites are the same as the sites phosphorylated by cAMP-dependent protein kinase." SIGNOR-250700 Ub:E2 complex SIGNOR-C497 SIGNOR RNF26 protein Q9BY78 UNIPROT "up-regulates activity" ubiquitination 9606 34199813 t miannu "The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t" SIGNOR-271018 CSNK2A2 protein P19784 UNIPROT GTF2A1 protein P52655 UNIPROT "up-regulates activity" phosphorylation Ser316 VEEEPLNsEDDVSDE -1 11278496 t llicata "We now show that human TFIIA is phosphorylated in vivo on serine residues that are partially conserved between yeast and human TFIIA large subunits. Alanine substitution mutation of serine residues 316 and 321 in TFIIA alphabeta reduced TFIIA phosphorylation significantly in vivo. Additional alanine substitutions at serines 280 and 281 reduced phosphorylation to undetectable levels. Mutation of all four serine residues reduced the ability of TFIIA to stimulate transcription in transient transfection assays with various activators and promoters, indicating that TFIIA phosphorylation is required globally for optimal function." SIGNOR-250997 Ub:E2 complex SIGNOR-C497 SIGNOR RNF125 protein Q96EQ8 UNIPROT "up-regulates activity" ubiquitination 9606 34199813 t miannu "The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t" SIGNOR-271212 CCN4 protein O95388 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR "up-regulates activity" phosphorylation Ser473 RPHFPQFsYSASGTA 10116 11782444 t "Here it is shown that WISP-1 can activate the antiapoptotic Akt/PKB signaling pathway." SIGNOR-256269 AML1-ETO "fusion protein" SIGNOR-FP1 SIGNOR KIT protein P10721 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 29236325 f irozzo "We report here that AML1/ETO transactivates c-KIT expression through directly binding to and mediating the long-range interaction between the promoter and intronic enhancer regions of c-KIT." SIGNOR-255699 FST protein P19883 UNIPROT MSTN protein O14793 UNIPROT "down-regulates activity" binding 10090 11459935 t gcesareni "Binding of myostatin to Act RIIB could be inhibited by the activin-binding protein follistatin and, at higher concentrations, by the myostatin propeptide. T" SIGNOR-235150 SLBP protein Q14493 UNIPROT H2AB1 protein P0C5Y9 UNIPROT "up-regulates quantity by expression" "translation regulation" 9606 BTO:0001938 19155325 t lperfetto "Synthesis of mature histone mRNA requires only a single processing reaction: an endonucleolytic cleavage between a conserved stem-loop and a purine-rich downstream element to form the 3' end. The stem-loop binding protein (SLBP) is required for processing, and following processing, histone mRNA is transported to the cytoplasm, where SLBP participates in translation of the histone mRNA|We used radiolabeled probes generated by PCR targeting the open reading frame (ORF) to detect histones H2A, H2B, H3, H4, and H1 and used 7SK snRNA as a loading control (Fig. 2A). The abundance of histone H2A, H2B, H3, and H4 mRNAs is reduced to 37% to 70% of control levels in the SLBP knockdown cells when compared to the C2 control." SIGNOR-265411 PKN1 protein Q16512 UNIPROT PKN1 protein Q16512 UNIPROT "up-regulates activity" phosphorylation Ser374 GLYSRSGsLSGRSSL -1 10467162 t lperfetto "Autophosphorylation of wild-type PKN increased the protein kinase activity, however, substitution of Thr64, Ser374, or Thr531 in the regulatory region of PKN with alanine, abolished this effect." SIGNOR-249021 AURKB protein Q96GD4 UNIPROT H3C1 protein P68431 UNIPROT "down-regulates activity" phosphorylation Ser29 ATKAARKsAPATGGV 9606 21282660 t "Ser 27 (29) phosphorylation of H3 isinhibitory as induces transcription." gcesareni "Histone code pathway involving h3 s28 phosphorylation and k27 acetylation activates transcription and antagonizes polycomb silencingaurora-b phosphorylates histone h3 at serine28 with regard to the mitotic chromosome condensation" SIGNOR-171717 TRPC6 protein Q9Y210 UNIPROT calcium(2+) smallmolecule CHEBI:29108 ChEBI "up-regulates quantity" relocalization 9606 12032305 t "Members of the transient receptor potential channel (TRPC) family have been characterized as molecular substrates mediating receptor-activated cation influx" SIGNOR-253339 UBE4B protein O95155 UNIPROT ATXN3 protein P54252 UNIPROT "down-regulates quantity by destabilization" polyubiquitination 9606 BTO:0000007 14749733 t miannu "Mammalian E4B (UFD2a), a ubiquitin chain assembly factor (E4), copurified with the polyubiquitylation activity for ataxin-3. E4B interacted with, and thereby mediated polyubiquitylation of, ataxin-3.  Collectively, these data suggest that E4B promotes the degradation of ataxin-3, and that this effect surmounts the stabilization of ataxin-3 conferred by expansion of the polyglutamine tract." SIGNOR-271502 SIM1 protein P81133 UNIPROT ARNT protein P27540 UNIPROT "down-regulates activity" binding -1 SIGNOR-C125 9020169 t 2 miannu "SIM1 can inhibit AHR·ARNT binding to the XRE and can inhibit expression from an XRE-driven reporter gene indicates that SIM1 may act as negative regulator of transcription as well as a positive regulator. The above inhibitory effects may result from SIM1 competing with AHR for binding to ARNT, although we cannot exclude the possibility that SIM1 may also have other inhibitory effects of AHR·ARNT activity. In a similar fashion, SIM1 may act as a negative regulator of all ARNT-dependent genes." SIGNOR-240756 BMPR1B protein O00238 UNIPROT SMAD9 protein O15198 UNIPROT up-regulates phosphorylation 9606 19620713 t gcesareni "Two types of bmp-induced signaling pathways are known, the smad and p38 mapk pathways. In the former case, bmpr1 phosphorylates smad-1,-5,-8, which forms a complex with smad4 that translocates into the nucleus and regulates gene expression." SIGNOR-187196 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR PTTG1 protein O95997 UNIPROT up-regulates phosphorylation 9606 10906323 t "inferred from 70% family members" gcesareni "Pttg is phosphorylated in vitro on ser(162) by map kinase and this phosphorylation site plays an essential role in pttg transactivation function." SIGNOR-270155 carfilzomib chemical CHEBI:65347 ChEBI PSMB10 protein P40306 UNIPROT "down-regulates activity" "chemical inhibition" 9606 BTO:0000898 17591945 t miannu "Carfilzomib is a tetrapeptide epoxyketone related to epoxomicin (Figure 1A), the latter of which shows high specificity in vitro for the ChT-L proteasome activity. To evaluate the proteasomal inhibitory potential of carfilzomib in MM, extracts from ANBL-6 cells were exposed to increasing concentrations of carfilzomib. Extended exposure to carfilzomib for 5 hours saturated the β5 and β5i active sites in a dose-dependent manner and also led to increased binding to the β1, β1i, β2, and β2i subunits, with maximal binding observed at 50 nM." SIGNOR-259308 CIC protein Q96RK0 UNIPROT Sin3B_complex complex SIGNOR-C409 SIGNOR "up-regulates activity" binding 10090 BTO:0000142 32229723 t miannu "Mechanistically, we demonstrated that CIC represses VGF expression by tethering SIN3-HDAC to form a transcriptional corepressor complex. Mass spectrometry analysis of CIC-interacting proteins further identified the BRG1-containing mSWI/SNF complex whose function is necessary for transcriptional repression by CIC. CIC interacts with mSWI/SNF complex during neurogenesis. CIC tethers SIN3-HDAC corepressor complex and mSWI/SNF complex to VGF promoter during neurogenesis." SIGNOR-269206 PHLPP1 protein O60346 UNIPROT PRKCB protein P05771 UNIPROT "down-regulates quantity" dephosphorylation Ser661 QNEFAGFsYTNPEFV 9606 BTO:0000067 18162466 t gcesareni "Here we show that the two PHLPP isoforms, PHLPP1 and PHLPP2, also dephosphorylate the hydrophobic motif on PKC betaII, an event that shunts PKC to the detergent-insoluble fraction, effectively terminating its life cycle" SIGNOR-237047 MAPK9 protein P45984 UNIPROT CTNNB1 protein P35222 UNIPROT up-regulates phosphorylation Ser605 LFVQLLYsPIENIQR 9606 18423204 t amattioni "Beta-catenin, upon entering the nucleus, in turn activates transcription of downstream target genes. Jnk2 phosphorylates Beta-catenin on critical residues (ser191 and ser605). Jnk activity is required for Beta-catenin nuclear localization in response to wnt." SIGNOR-178262 CCNT1 protein O60563 UNIPROT P-TEFb complex SIGNOR-C238 SIGNOR "form complex" binding -1 34955012 t lperfetto "Cyclin-dependent-kinases (CDKs) are members of the serine/threonine kinase family and are highly regulated by cyclins, a family of regulatory subunits that bind to CDKs. CDK9 represents one of the most studied examples of these transcriptional CDKs. CDK9 forms a heterodimeric complex with its regulatory subunit cyclins T1, T2 and K to form the positive transcription elongation factor b (P-TEFb). " SIGNOR-267739 ROCK1 protein Q13464 UNIPROT ADD1 protein P35611 UNIPROT up-regulates phosphorylation Thr480 TKEDGHRtSTSAVPN 9606 BTO:0000671 10209029 t lperfetto "Rho-associated kinase (rho- kinase), which is activated by the small guanosine triphosphatase rho, phosphorylates alpha-adducin and thereby enhances the f-actin-binding activity of alpha-adducin in vitro. Here we identified the sites of phosphorylation of alpha-adducin by rho-kinase as thr445 and thr480" SIGNOR-66996 MAPK8IP1 protein Q9UQF2 UNIPROT MAPK8 protein P45983 UNIPROT down-regulates binding 9606 18486448 t gcesareni "The jip proteins function by aggregating components of a map kinase module (including mlk, mkk7, and jnk) and facilitate signal transmission by the protein kinase cascade. Overexpression of jip1 deactivates the jnk pathway selectively by cytoplasmic retention of jnk and thereby inhibits gene expression mediated by jnk, which occurs in the nucleus" SIGNOR-178655 Calcineurin complex SIGNOR-C155 SIGNOR NFATC2 protein Q13469 UNIPROT "up-regulates activity" dephosphorylation Ser168 YREPLCLsPASSGSS 9606 BTO:0000567 11030334 t "NFAT1 is phosphorylated on fourteen conserved phosphoserine residues in its regulatory domain, thirteen of which are dephosphorylated upon stimulation. Dephosphorylation of all thirteen residues is required to mask a nuclear export signal (NES), cause full exposure of a nuclear localization signal (NLS), and promote transcriptional activity" SIGNOR-252319 CSNK2B protein P67870 UNIPROT IKZF1 protein Q13422 UNIPROT down-regulates phosphorylation Ser13 GQDMSQVsGKESPPV 9606 BTO:0001271 21750978 t miannu "We identified four novelikarosphosphorylation sites that are phosphorylated by ck2 kinase. / ck2-mediated phosphorylation inhibits ikaros' localization to pc-hc / hyperphosphorylation of ikaros promotes its degradation by the ubiquitin/proteasome pathway" SIGNOR-174844 MAPK3 protein P27361 UNIPROT SMAD2 protein Q15796 UNIPROT up-regulates phosphorylation Ser250 TGSPAELsPTTLSPV 9606 BTO:0000763 12193595 t gcesareni "These results suggest that oncogenic ras, acting through mek1 and erk kinases, induces the phosphorylation of smad2 and smad3 .we show that phosphorylation of smad2, a mediator of the activin/transforming growth factor-beta signal, by activated extracellular signal-regulated kinase 1 (erk1) increases the amount of smad2 protein and leads to enhanced transcriptional activity" SIGNOR-91734 BTRC protein Q9Y297 UNIPROT SMAD4 protein Q13485 UNIPROT down-regulates ubiquitination 9606 14988407 t gcesareni "Here we show that beta-trcp1, a f-box protein in the scf e3 ligase complex, interacts with smad4 and induces the degradation of smad4" SIGNOR-123057 INSR protein P06213 UNIPROT GAB1 protein Q13480 UNIPROT "up-regulates activity" phosphorylation Tyr285 TEADGELyVFNTPSG 10090 10978177 t "HGab-1 was phosphorylated by IR at eight tyrosine residues (Y242, Y285, Y373, Y447, Y472, Y619, Y657, and Y689). t Gab-1 is the major binding partner of PI-3 kinase in 3T3L1 cells when stimulated with insulin" SIGNOR-251311 GRK5 protein P34947 UNIPROT LRP6 protein O75581 UNIPROT up-regulates phosphorylation 9606 2787365 t gcesareni "we found that g protein-coupled receptor kinases 5 and 6 (grk5/6), traditionally known to phosphorylate and desensitize 7tm g protein-coupled receptors, directly phosphorylate the pppsp motifs on single transmembrane lrp6 and regulate wnt/lrp6 signaling" SIGNOR-23330 F2RL3 protein Q96RI0 UNIPROT GNAS protein Q5JWF2 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-256772 VRK1 protein Q99986 UNIPROT ATF2 protein P15336 UNIPROT up-regulates phosphorylation Ser62 FGPARNDsVIVADQT 9606 15105425 t gcesareni "Vrk1 phosphorylates atf2 mainly on thr-73, stabilizing the atf2 protein and increasing its intracellular level." SIGNOR-124330 afimoxifene chemical CHEBI:44616 ChEBI ESR2 protein Q92731 UNIPROT "down-regulates activity" "chemical inhibition" -1 9048584 t miannu "In total 37 substances were tested for both ER subtypes (Fig. 3 and Table 1). In Fig. 3 several examples of typical competitor curves obtained are shown. In all cases monophasic curves were obtained for compounds with significant affinity. . The present study is the first in which the ligand binding properties of both ER subtypes are measured separately, and caution is needed when comparing RBAs from this study with the previous studies involving mixtures of ER subtypes." SIGNOR-258596 MAPK3 protein P27361 UNIPROT UBTF protein P17480 UNIPROT down-regulates phosphorylation Thr201 DIPEKPKtPQQLWYT 9606 11741541 t lperfetto "Erk1/2 was found to phosphorylate the architectural transcription factor ubf at amino acids 117 and 201 within hmg boxes 1 and 2, preventing their interaction with dna" SIGNOR-112817 MFGE8 protein Q08431 UNIPROT STAT3 protein P40763 UNIPROT "up-regulates activity" 9606 21901532 f miannu "In an attempt to clarify the direct anti-inflammatory role of MFG-E8, we revealed a distinct signaling pathway where MFG-E8 activates suppressor of cytokine signaling (SOCS) 3 gene expression via STAT3 mediated pathway, which in turn served as a negative regulator for LPS induced TLR4 signaling by targeting NF-κB p65 component, thereby attenuating the down-stream signaling for TNF-α production" SIGNOR-260654 MAP2K2 protein P36507 UNIPROT MAPK1 protein P28482 UNIPROT up-regulates phosphorylation Tyr187 HTGFLTEyVATRWYR 9606 11971971 t gcesareni "Mapk1 is phosphorylated by map2k1/mek1 and map2k2/mek2 on thr-185 and tyr-187 in response to external stimuli like insulin or ngf. Both phosphorylations are required for activity." SIGNOR-86713 AGRP protein O00253 UNIPROT MC4R protein P32245 UNIPROT "down-regulates activity" binding 9606 10318826 t miannu "AGRP is a potent antagonist of the melanocortin-3 receptor and the MC4R and has also been shown to have a lesser degree of inhibitory action at the melanocortin-5 receptor." SIGNOR-252379 HOXA9 protein P31269 UNIPROT IGF1 protein P05019 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 25252870 f miannu "Hoxa9bound directly to the putative promoter and a dnase-hypersensitive region in the first intron of the igf1 gene. Transcription rates of the igf1 gene paralleledhoxa9activity" SIGNOR-205308 IKBKE protein Q14164 UNIPROT REL/RELA complex SIGNOR-C68 SIGNOR up-regulates phosphorylation 9606 16888014 t lperfetto "The present results demonstrate that ikkepsilon- and tbk1-mediated phosphorylation of crel in the c-terminal td leads to cytoplasmic dissociation of a crel-ikb_ complex and nuclear accumulation of crel." SIGNOR-217664 PAK1 protein Q13153 UNIPROT PXN protein P49023 UNIPROT unknown phosphorylation Ser272 ELDELMAsLSDFKIQ 9606 16717130 t llicata "We show that p21-activated kinase (pak)-induced phosphorylation of serine 273 in paxillin is a critical regulator of this turnover." SIGNOR-146842 BCL2L1 protein Q07817 UNIPROT BAX protein Q07812 UNIPROT down-regulates binding 9606 9670005 t amattioni "The presence of an anti-apoptotic molecule such as bcl-2 or bcl-xl can inhibit the activation of bax following a death signal." SIGNOR-59141 PMPCB protein O75439 UNIPROT PINK1 protein Q9BXM7 UNIPROT "down-regulates quantity by destabilization" cleavage 9606 BTO:0000007 22354088 t miannu "Using an unbiased RNA-mediated interference (RNAi)-based screen, we identified four mitochondrial proteases, mitochondrial processing peptidase (MPP), presenilin-associated rhomboid-like protease (PARL), m-AAA and ClpXP, involved in PINK1 degradation. We find that PINK1 turnover is particularly sensitive to even modest reductions in MPP levels. Moreover, PINK1 cleavage by MPP is coupled to import such that reducing MPP activity induces PINK1 accumulation at the mitochondrial surface, leading to Parkin recruitment and mitophagy." SIGNOR-261363 PKI-587 chemical CID:44516953 PUBCHEM PIK3CA protein P42336 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-205989 PLCG1 protein P19174 UNIPROT SOS1 protein Q07889 UNIPROT up-regulates binding 9606 10913276 t gcesareni "We provide evidence that sos1, a p21ras-specific guanine nucleotide exchange factor, directly binds to the sh3 domain of plc-gamma1, and that the sh3 domain of plc-gamma1 is involved in sos1-mediated p21ras activation." SIGNOR-80024 GTF2B protein Q00403 UNIPROT TFIIF complex SIGNOR-C394 SIGNOR "up-regulates activity" relocalization 9606 27096372 t lperfetto "Our structures suggest that a primary function of TFIID during PIC assembly is the proper positioning of TBP on the upstream promoter, which ultimately determines the placement of Pol II relative to the TSS. The structures presented here offer a structural framework for understanding the complex mechanism underlying TFIID function, shedding new light into the overlapping roles of TFIID as both a coactivator and a general platform for PIC assembly in the coordination of transcription initiation." SIGNOR-266193 PRKG2 protein Q13237 UNIPROT CTH protein P32929 UNIPROT "down-regulates activity" phosphorylation Ser377 SDTLIRLsVGLEDEE 25900831 t lperfetto "CO stimulated protein kinase G (PKG)-dependent phosphorylation of Ser(377) of CSE, inhibiting the production of H2S." SIGNOR-275800 CDK13 protein Q14004 UNIPROT POLR2A protein P24928 UNIPROT "up-regulates activity" phosphorylation Ser1875 SPTSPKYsPTSPTYS 9606 BTO:0006413 32917631 t "Ser2 in CTD of PolII" lperfetto "Together, these studies demonstrate the important, yet largely redundant, role for CDK12 and CDK13 for the regulation of POLII CTD phosphorylation at multiple residues, as well as the global role for both of these kinases in regulating POLII occupancy across the genome.|CDK12 and CDK13 are thus evolutionarily related and structurally similar kinases, and biochemical assays have demonstrated that both have POLII C-terminal domain (CTD) kinase activity and the ability to phosphorylate the Ser2 residue of the repetitive CTD heptad sequence" SIGNOR-273039 DYRK3 protein O43781 UNIPROT mTORC1 complex SIGNOR-C3 SIGNOR down-regulates phosphorylation 9606 23415227 t lperfetto "When dyrk3 is active, it allows stress granule dissolution, releasing mtorc1 for signaling and promoting its activity by directly phosphorylating the mtorc1 inhibitor pras40" SIGNOR-217571 NEK6 protein Q9HC98 UNIPROT ACD protein Q96AP0 UNIPROT "up-regulates activity" phosphorylation Ser169 SNAGLSLsQLLDEMR 9606 BTO:0000007 27396482 t lperfetto "NEK6-mediated phosphorylation of human TPP1 regulates telomere length through telomerase recruitment|Shelterin component TPP1 plays critical roles in chromosome end protection and telomere length regulation. Specifically, TPP1 contains an OB-fold domain that provides an interface to recruit telomerase.|" SIGNOR-264424 ADRA2A protein P08913 UNIPROT GNAO1 protein P09471 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-256977 CDK1 protein P06493 UNIPROT NDUFA12 protein Q9UI09 UNIPROT "up-regulates activity" phosphorylation Thr142 QEWIPPStPYK 24746669 t lperfetto "Here, we show that a fraction of cyclin B1/Cdk1 proteins localizes to the matrix of mitochondria and phosphorylates a cluster of mitochondrial proteins, including the complex I (CI) subunits in the respiratory chain. Cyclin B1/Cdk1-mediated CI phosphorylation enhances CI activity, whereas deficiency of such phosphorylation in each of the relevant CI subunits results in impairment of CI function.|These results were confirmed by generating phosphorylation defective forms of the five CI subunits through substitutions of S/T residues with Alanine (A) on either Cdk1 optimal or minimal consensus motifs (T383 on NDUFV1, S105 on NDUFV3, S364 on NDUFS2, S55/S29/T5 on NDUFB6, and T142/T120 on NDUFA12). The mutation of Cdk1 consensus motifs severely diminished their phosphorylation" SIGNOR-275587 CDK1 protein P06493 UNIPROT NDUFA12 protein Q9UI09 UNIPROT "up-regulates activity" phosphorylation Thr120 HKFNVTGtPEQYVPY 24746669 t lperfetto "Here, we show that a fraction of cyclin B1/Cdk1 proteins localizes to the matrix of mitochondria and phosphorylates a cluster of mitochondrial proteins, including the complex I (CI) subunits in the respiratory chain. Cyclin B1/Cdk1-mediated CI phosphorylation enhances CI activity, whereas deficiency of such phosphorylation in each of the relevant CI subunits results in impairment of CI function.|These results were confirmed by generating phosphorylation defective forms of the five CI subunits through substitutions of S/T residues with Alanine (A) on either Cdk1 optimal or minimal consensus motifs (T383 on NDUFV1, S105 on NDUFV3, S364 on NDUFS2, S55/S29/T5 on NDUFB6, and T142/T120 on NDUFA12). The mutation of Cdk1 consensus motifs severely diminished their phosphorylation" SIGNOR-275588 CDK1 protein P06493 UNIPROT NDUFB6 protein O95139 UNIPROT "up-regulates activity" phosphorylation Thr5 tPDEKLRL 24746669 t lperfetto "Here, we show that a fraction of cyclin B1/Cdk1 proteins localizes to the matrix of mitochondria and phosphorylates a cluster of mitochondrial proteins, including the complex I (CI) subunits in the respiratory chain. Cyclin B1/Cdk1-mediated CI phosphorylation enhances CI activity, whereas deficiency of such phosphorylation in each of the relevant CI subunits results in impairment of CI function.|These results were confirmed by generating phosphorylation defective forms of the five CI subunits through substitutions of S/T residues with Alanine (A) on either Cdk1 optimal or minimal consensus motifs (T383 on NDUFV1, S105 on NDUFV3, S364 on NDUFS2, S55/S29/T5 on NDUFB6, and T142/T120 on NDUFA12). The mutation of Cdk1 consensus motifs severely diminished their phosphorylation" SIGNOR-275589 ACVR1 protein Q04771 UNIPROT SMAD1 protein Q15797 UNIPROT "up-regulates activity" phosphorylation Ser465 HNPISSVs 9534 9748228 t "ALK2 receptor specifically interacts with and phosphorylates Smad1 protein. ALK2 Activates Smad1 and Induces BMP-specific Signals. Biochemical analysis revealed that constitutively active ALK2 associated with and phosphorylated Smad1 on the COOH-terminal SSXS motif" SIGNOR-251439 CDK1 protein P06493 UNIPROT NDUFS2 protein O75306 UNIPROT "up-regulates activity" phosphorylation Ser364 KVDDAKVsPPKRAEM 24746669 t lperfetto "Here, we show that a fraction of cyclin B1/Cdk1 proteins localizes to the matrix of mitochondria and phosphorylates a cluster of mitochondrial proteins, including the complex I (CI) subunits in the respiratory chain. Cyclin B1/Cdk1-mediated CI phosphorylation enhances CI activity, whereas deficiency of such phosphorylation in each of the relevant CI subunits results in impairment of CI function.|These results were confirmed by generating phosphorylation defective forms of the five CI subunits through substitutions of S/T residues with Alanine (A) on either Cdk1 optimal or minimal consensus motifs (T383 on NDUFV1, S105 on NDUFV3, S364 on NDUFS2, S55/S29/T5 on NDUFB6, and T142/T120 on NDUFA12). The mutation of Cdk1 consensus motifs severely diminished their phosphorylation" SIGNOR-275592 CDK1 protein P06493 UNIPROT NDUFV3 protein P56181 UNIPROT "up-regulates activity" phosphorylation Ser105 QPSSGREsPRH 24746669 t lperfetto "Here, we show that a fraction of cyclin B1/Cdk1 proteins localizes to the matrix of mitochondria and phosphorylates a cluster of mitochondrial proteins, including the complex I (CI) subunits in the respiratory chain. Cyclin B1/Cdk1-mediated CI phosphorylation enhances CI activity, whereas deficiency of such phosphorylation in each of the relevant CI subunits results in impairment of CI function.|These results were confirmed by generating phosphorylation defective forms of the five CI subunits through substitutions of S/T residues with Alanine (A) on either Cdk1 optimal or minimal consensus motifs (T383 on NDUFV1, S105 on NDUFV3, S364 on NDUFS2, S55/S29/T5 on NDUFB6, and T142/T120 on NDUFA12). The mutation of Cdk1 consensus motifs severely diminished their phosphorylation" SIGNOR-275593 CEBPA protein P49715 UNIPROT GFI1 protein Q99684 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 20924107 f irozzo "We show here that C/EBPα interacts with a functional C/EBP binding site in the Gfi-1 5'-flanking region and enhances the promoter activity of Gfi-1." SIGNOR-256068 NDUFB4 protein O95168 UNIPROT "Mitochondrial respiratory chain complex I" complex SIGNOR-C277 SIGNOR "form complex" binding 30030361 t lperfetto "Thus, we now know the complete mammalian cI structure [22,23] and how the subunits are organized in six modules (N, Q, ND1, ND2, ND4 and |The main ND4-module intermediate binds NDUFB1, NDUFB4, NDUFB5, NDUFB6, NDUFB10, NDUFB11 and MT-ND4" SIGNOR-262167 ESR1 protein P03372 UNIPROT NR0B2 protein Q15466 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 10648597 f gcesareni "We demonstrate that shp variants, carrying either interaction-defective nr box mutations or a deletion of the repressor domain, have lost the capacity to inhibit agonist-dependent transcriptional estrogen receptor activation." SIGNOR-74288 AKT1 protein P31749 UNIPROT CREB1 protein P16220 UNIPROT "up-regulates activity" phosphorylation Ser119 EILSRRPsYRKILND 9606 BTO:0000007 9829964 t gcesareni "When overexpressed in serum-stimulated cells, Akt/PKB potently induced Ser-133 phosphorylation of CREB and promoted recruitment of CBP. Correspondingly, Akt/PKB stimulated target gene expression via CREB in a phospho(Ser-133)-dependent manner." SIGNOR-252549 MFNG protein O00587 UNIPROT NOTCH2 protein Q04721 UNIPROT up-regulates binding 9606 11346656 t gcesareni "These observations indicate that the fringe proteins directly modify notch2, which is consistent with the recent finding that fringe is a glycosyltransferase that directly modifies notch (30, 31). It was further indicated that lfng does this at a site from the n terminus through the 15th egf repeat of notch2, and mfng does so at a site from the 23rd through the 29th egf repeat of notch2." SIGNOR-107708 MAPK3 protein P27361 UNIPROT PTPN7 protein P35236 UNIPROT "up-regulates activity" phosphorylation Ser93 ALQRQPPsPKQLEEE -1 16226275 t lperfetto "First, Erk phosphorylates HePTP at residues Thr45 and Ser72. Second, HePTP dephosphorylates Erk at PTyr185.|" SIGNOR-249475 RNF6 protein Q9Y252 UNIPROT LIMK1 protein P53667 UNIPROT "down-regulates quantity by destabilization" polyubiquitination 9606 BTO:0000007 16204183 t miannu "Consistent with a role in axonal growth, we found that Rnf6 binds to, polyubiquitinates, and targets LIMK1 for proteasomal degradation in growth cones of primary hippocampal neurons. " SIGNOR-271481 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR NDUFB6 protein O95139 UNIPROT "up-regulates activity" phosphorylation Ser55 NKFLENKsPWRKMVH 24746669 t lperfetto "Here, we show that a fraction of cyclin B1/Cdk1 proteins localizes to the matrix of mitochondria and phosphorylates a cluster of mitochondrial proteins, including the complex I (CI) subunits in the respiratory chain. Cyclin B1/Cdk1-mediated CI phosphorylation enhances CI activity, whereas deficiency of such phosphorylation in each of the relevant CI subunits results in impairment of CI function.|These results were confirmed by generating phosphorylation defective forms of the five CI subunits through substitutions of S/T residues with Alanine (A) on either Cdk1 optimal or minimal consensus motifs (T383 on NDUFV1, S105 on NDUFV3, S364 on NDUFS2, S55/S29/T5 on NDUFB6, and T142/T120 on NDUFA12). The mutation of Cdk1 consensus motifs severely diminished their phosphorylation" SIGNOR-275598 GNAS protein P63092 UNIPROT Microtubule_polimerization phenotype SIGNOR-PH106 SIGNOR down-regulates -1 10224115 f miannu "G protein alpha subunits Gi1alpha, Gsalpha, and Goalpha are shown to activate the GTPase activity of tubulin, inhibit microtubule assembly, and accelerate microtubule dynamics." SIGNOR-256524 TTN protein Q8WZ42 UNIPROT OBSCN protein Q5VST9 UNIPROT "up-regulates quantity" relocalization 9606 BTO:0003324 19840192 t miannu "Ankyrin-B is targeted to the M-line via its interaction with the C-terminal domain of the large sarcomeric protein obscurin. Obscurin is targeted to the M-line via its N-terminal interactions with myomesin and titin. This population of ankyrin-B recruits B56α, a regulatory subunit of protein phosphatase 2A, to the M-line where the phosphatase may regulate the phosphorylation status of contractile and signalling proteins." SIGNOR-266728 ibuprofen chemical CHEBI:5855 ChEBI PTGS1 protein P23219 UNIPROT "down-regulates activity" "chemical inhibition" -1 9544212 t miannu "The IC50 values for two benchmark compounds were determined for comparison. The marketed NSAID ibuprofen was a modestly selective COX-1 inhibitor, while Searle's SC-5766614 was a highly selective (>100-fold) COX-2 inhibitor, results consistent with literature reports." SIGNOR-258883 PMS2 protein P54278 UNIPROT MLH1/PMS2 complex SIGNOR-C59 SIGNOR "form complex" binding 9606 10542278 t miannu "Hmlh1 and hpms2 function in postreplicative mismatch repair in the form of a heterodimer referred to as hmutl_" SIGNOR-71777 RALA protein P11233 UNIPROT FOXO4 protein P98177 UNIPROT "up-regulates activity" phosphorylation Thr451 PIPKALGtPVLTPPT 10090 11689711 t gcesareni "We conclude that Ral-mediated phosphorylation of threonines 447 and 451 is required for proper activity of AFX-WT." SIGNOR-248003 EIF3_complex complex SIGNOR-C401 SIGNOR "60S cytosolic large ribosomal subunit" complex SIGNOR-C287 SIGNOR "down-regulates activity" 9606 15703437 f lperfetto "EIF3 and, to some extent, eIF1A have been implicated in preventing reassociation of free 40S and 60S subunits and in dissociation of empty 80S ribosomes" SIGNOR-269149 PBX2 protein P40425 UNIPROT FGF8 protein P55075 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 10090 BTO:0003560 10026229 t miannu "Our results in ES cells suggest that Engrailed inhibits Fgf8 expression in the absence of Pbx1. We identified single Engrailed- and Pbx-binding sites in the Fgf8 intron that inhibit expression of Fgf8 in mouse ES cells, but that together can allow full Fgf8 expression. Our data support the model that Engrailed heterodimerized with Pbx might activate transcription, while Engrailed or Pbx proteins alone might repress transcription" SIGNOR-265778 CH5132799 chemical CID:49784945 PUBCHEM MTOR protein P42345 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-190937 NCKAP1 protein Q9Y2A7 UNIPROT "WAVE complex" complex SIGNOR-C271 SIGNOR "form complex" binding 9606 BTO:0000567 15070726 t lperfetto "Here we purify Wave-2 from HeLa cells. Five proteins, Sra, Nap, Wave-2, Abi, and Hspc, are copurified, indicating that they form a tight complex. " SIGNOR-261874 CLTB protein P09497 UNIPROT "AP-2/clathrin vescicle" complex SIGNOR-C249 SIGNOR "form complex" binding 9606 24789820 t lperfetto "AP2 adaptor complexes, associated at the membrane with PtdIns(4,5)P2 (PIP2), recruit clathin triskelions to initiate lattice assembly. " SIGNOR-260666 PPAT protein Q06203 UNIPROT "L-glutamine zwitterion" smallmolecule CHEBI:58359 ChEBI "down-regulates quantity" "chemical modification" 9606 8106516 t "Two Genes for de Novo Purine Nucleotide Synthesis on Human Chromosome 4 Are Closely Linked and Divergently Transcribed√¢‚Ǩ¬ù" SIGNOR-267187 F2 protein P00734 UNIPROT F2RL3 protein Q96RI0 UNIPROT up-regulates binding 9606 22318735 t gcesareni "Thrombin activates platelets by binding and cleaving protease-activated receptors 1 and 4 (par1 and par4)." SIGNOR-196003 TP53INP1 protein Q96A56 UNIPROT GABARAP protein O95166 UNIPROT up-regulates binding 9606 22421968 t gcesareni "Tp53inp1 is also able to interact with atg8-family proteins" SIGNOR-196664 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR NDUFV3 protein P56181 UNIPROT "up-regulates activity" phosphorylation Ser105 QPSSGREsPRH 24746669 t lperfetto "Here, we show that a fraction of cyclin B1/Cdk1 proteins localizes to the matrix of mitochondria and phosphorylates a cluster of mitochondrial proteins, including the complex I (CI) subunits in the respiratory chain. Cyclin B1/Cdk1-mediated CI phosphorylation enhances CI activity, whereas deficiency of such phosphorylation in each of the relevant CI subunits results in impairment of CI function.|These results were confirmed by generating phosphorylation defective forms of the five CI subunits through substitutions of S/T residues with Alanine (A) on either Cdk1 optimal or minimal consensus motifs (T383 on NDUFV1, S105 on NDUFV3, S364 on NDUFS2, S55/S29/T5 on NDUFB6, and T142/T120 on NDUFA12). The mutation of Cdk1 consensus motifs severely diminished their phosphorylation" SIGNOR-275601 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR NDUFV1 protein P49821 UNIPROT "up-regulates activity" phosphorylation Thr383 HESCGQCtPCREGVD 24746669 t lperfetto "Here, we show that a fraction of cyclin B1/Cdk1 proteins localizes to the matrix of mitochondria and phosphorylates a cluster of mitochondrial proteins, including the complex I (CI) subunits in the respiratory chain. Cyclin B1/Cdk1-mediated CI phosphorylation enhances CI activity, whereas deficiency of such phosphorylation in each of the relevant CI subunits results in impairment of CI function.|These results were confirmed by generating phosphorylation defective forms of the five CI subunits through substitutions of S/T residues with Alanine (A) on either Cdk1 optimal or minimal consensus motifs (T383 on NDUFV1, S105 on NDUFV3, S364 on NDUFS2, S55/S29/T5 on NDUFB6, and T142/T120 on NDUFA12). The mutation of Cdk1 consensus motifs severely diminished their phosphorylation" SIGNOR-275602 CDK1 protein P06493 UNIPROT USP24 protein Q9UPU5 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser2604 HLQQGSEsPMMIGEL 9606 BTO:0000018 27991932 t lperfetto "Epidermal growth factor (EGF) treatment, and the KrasG12D and EGFRL858R mutations decrease USP24 protein stability via EGF- or CDK1-mediated phosphorylation at Ser1616, Ser2047 and Ser2604." SIGNOR-275603 SREBF1 protein P36956 UNIPROT ELOVL6 protein Q9H5J4 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000599 18226595 t Luana "These data demonstrated that Elovl-6 is regulated directly and primarily by SREBP-1c." SIGNOR-267943 TLE1 protein Q04724 UNIPROT SIX3 protein O95343 UNIPROT "up-regulates activity" binding -1 12441302 t lperfetto "Biochemical and mutational analysis shows that the Six domain of both SIX3 and SIX6 strongly interact with the QD domain of TLE1 and AES. TLE1 over-expression induces an enlargement of the eye field and reinforcesSIX3/SIX6 capability of initiating retina formation" SIGNOR-234595 ADARB1 protein P78563 UNIPROT EIF2AK2 protein P19525 UNIPROT "up-regulates activity" binding 9606 BTO:0000661 19605474 t miannu "Both forms of ADAR1 show enhanced interactions with PKR at the peak of HIV infection, suggesting a role for this protein in the regulation of PKR activation." SIGNOR-266359 ARHGAP39 protein Q9C0H5 UNIPROT CDC42 protein P60953 UNIPROT "down-regulates activity" "gtpase-activating protein" 9606 BTO:0000007 32203420 t Luana "We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2)." SIGNOR-260495 CTNND1 protein O60716 UNIPROT RAC1 protein P63000 UNIPROT up-regulates binding 9606 22946057 t gcesareni "We demonstrate that p120-catenin participates in the stimulation of rac1 activity, binding directly to this protein. In addition we show that vav2 also binds to p120-catenin and is required for rac1 activation and for beta-catenin translocation to the nucleus.Vav2 And rac1 association with p120-catenin was modulated by phosphorylation of this protein, which was stimulated upon serine/threonine phosphorylation by ck1 and inhibited by tyrosine phosphorylation by src or fyn" SIGNOR-198938 D2HGDH protein Q8N465 UNIPROT 2-oxoglutarate(2-) smallmolecule CHEBI:16810 ChEBI "up-regulates quantity" 26178471 f lperfetto "Here we show that wild-type D2HGDH elevates α-KG levels" SIGNOR-253131 CDK1 protein P06493 UNIPROT USP9X protein Q93008 UNIPROT "up-regulates activity" phosphorylation Ser2547 YEGSEEVsPPQTKDQ 32152317 t "Phosphosites were derived from Figure S1" lperfetto "Here, we find that CDC14B antagonizes CDK1-mediated activating mitotic phosphorylation of the deubiquitinase USP9X at serine residue 2563, which we show to be essential for USP9X to mediate mitotic survival. Starting from an unbiased proteome-wide screening approach, we specify Wilms' tumor protein 1 (WT1) as the relevant substrate that becomes deubiquitylated and stabilized by serine 2563-phosphorylated USP9X in mitosis." SIGNOR-275608 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR USP24 protein Q9UPU5 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser2604 HLQQGSEsPMMIGEL 9606 BTO:0000018 27991932 t lperfetto "Epidermal growth factor (EGF) treatment, and the KrasG12D and EGFRL858R mutations decrease USP24 protein stability via EGF- or CDK1-mediated phosphorylation at Ser1616, Ser2047 and Ser2604." SIGNOR-275609 CDK2 protein P24941 UNIPROT SKP2 protein Q13309 UNIPROT "up-regulates quantity by stabilization" phosphorylation Ser64 SNLGHPEsPPRKRLK 18239684 t lperfetto "The activity of SCF(Skp2) is regulated by the Cyclin-dependent kinase (CDK)2-mediated phosphorylation of Skp2 on Ser64 allows its expression in mid-G1 phase, even in the presence of active APC(Cdh1). Reciprocally, dephosphorylation of Skp2 by the mitotic phosphatase Cdc14B at the M --> G1 transition promotes its degradation by APC(Cdh1)." SIGNOR-249173 ITGB1BP1 protein O14713 UNIPROT "Av/b5 integrin" complex SIGNOR-C178 SIGNOR "down-regulates activity" binding 9606 19118207 t miannu "Integrins also bind to many PTBdomain-containing proteins (Calderwood et al., 2003) – including Dok1 and integrincytoplasmic-domain-associated protein 1 (ICAP1) – and these can compete with talin for binding to integrin and so can impair activation" SIGNOR-257661 CREB3 protein O43889 UNIPROT HERPUD1 protein Q15011 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 16940180 f miannu "Luman/creb3 induces transcription of the endoplasmic reticulum (er) stress response protein herp through an er stress response element." SIGNOR-149268 HBB protein P68871 UNIPROT CYP2E1 protein P05181 UNIPROT "up-regulates activity" 9606 BTO:0000575 19325051 f Regulation miannu "Hemoglobin dramatically stimulated CYP 2E1 activity but not the protein expression in quercetin- and ethanol-cotreated hepatocytes." SIGNOR-251764 ATM protein Q13315 UNIPROT XPA protein P23025 UNIPROT unknown phosphorylation Ser196 RSLEVWGsQEALEEA -1 16540648 t llicata "Kinase phosphorylation assays were done with synthesized short peptides (20-mer) with the sequences at Ser173 and Ser196 of XPA, respectively. Both peptides seemed to be good substrates for DNA-PK, ATR ( Fig. 2D), and ATM (data not shown)." SIGNOR-250580 calcium(2+) smallmolecule CHEBI:29108 ChEBI CDH16 protein O75309 UNIPROT "up-regulates activity" "chemical activation" 9606 22535893 t miannu "Cadherins are Ca(2+)-dependent cell-cell adhesion molecules that play critical roles in animal morphogenesis." SIGNOR-265833 PKA proteinfamily SIGNOR-PF17 SIGNOR CHKB protein Q9Y259 UNIPROT "up-regulates activity" phosphorylation Ser39 TPKRRRAsSLSRDAE 27149373 t lperfetto "Choline kinase beta (CKbeta) is one of the CK isozymes involved in the biosynthesis of phosphatidylcholine. | This study provides evidence for CKβ phosphorylation by protein kinase A (PKA).|Phosphorylation sites were located on CKβ residues serine-39 and serine-40 as determined by mass spectrometry and site-directed mutagenesis. Phosphorylation increased the catalytic efficiencies for the substrates choline and ATP about 2-fold, without affecting ethanolamine phosphorylation, and the S39D/S40D CKβ phosphorylation mimic behaved kinetically very similar." SIGNOR-275632 choline smallmolecule CHEBI:15354 ChEBI "choline phosphate(1-)" smallmolecule CHEBI:295975 ChEBI "up-regulates quantity" "precursor of" 27149373 t lperfetto "Choline kinase (CK) phosphorylates choline in the cytidine diphosphate (CDP)-choline pathway for the biosynthesis of phosphatidylcholine (PC), the most abundant class of phospholipids in eukaryotic membranes" SIGNOR-275633 CHKB protein Q9Y259 UNIPROT "choline phosphate(1-)" smallmolecule CHEBI:295975 ChEBI "up-regulates quantity" "chemical modification" 27149373 t lperfetto "Choline kinase (CK) phosphorylates choline in the cytidine diphosphate (CDP)-choline pathway for the biosynthesis of phosphatidylcholine (PC), the most abundant class of phospholipids in eukaryotic membranes" SIGNOR-275634 CHKB protein Q9Y259 UNIPROT choline smallmolecule CHEBI:15354 ChEBI "down-regulates quantity" "chemical modification" 27149373 t lperfetto "Choline kinase (CK) phosphorylates choline in the cytidine diphosphate (CDP)-choline pathway for the biosynthesis of phosphatidylcholine (PC), the most abundant class of phospholipids in eukaryotic membranes" SIGNOR-275635 CHKA protein P35790 UNIPROT "choline phosphate(1-)" smallmolecule CHEBI:295975 ChEBI "up-regulates quantity" "chemical modification" 27149373 t lperfetto "Choline kinase (CK) phosphorylates choline in the cytidine diphosphate (CDP)-choline pathway for the biosynthesis of phosphatidylcholine (PC), the most abundant class of phospholipids in eukaryotic membranes" SIGNOR-275636 CHKA protein P35790 UNIPROT choline smallmolecule CHEBI:15354 ChEBI "down-regulates quantity" "chemical modification" 27149373 t lperfetto "Choline kinase (CK) phosphorylates choline in the cytidine diphosphate (CDP)-choline pathway for the biosynthesis of phosphatidylcholine (PC), the most abundant class of phospholipids in eukaryotic membranes" SIGNOR-275637 ERBB3 protein P21860 UNIPROT PIK3CD protein O00329 UNIPROT up-regulates binding 9606 16729043 t gcesareni "Pi3k is the sole binding partner to six tyrosines of erbb3 and one in erbb4." SIGNOR-146867 NFIX protein Q14938 UNIPROT ID3 protein Q02535 UNIPROT "down-regulates quantity" "transcriptional regulation" 10090 31838646 t Gianni "By integrating transcriptomic profiling (RNA-seq) of Nfia- and Nfix-deficient GNPs with epigenomic profiling (ChIP-seq against NFIA, NFIB and NFIX, and DNase I hypersensitivity assays), we reveal that these transcription factors share a large set of potential transcriptional targets, suggestive of complementary roles for these NFI family members in promoting neural development" SIGNOR-268885 FOXL2 protein P58012 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR up-regulates 9606 BTO:0000975 16153597 f miannu "We observed that foxl2 induces apoptosis in the ovarian cells unveiling a novel function of foxl2" SIGNOR-140391 CDK1 protein P06493 UNIPROT CUX1 protein P39880 UNIPROT down-regulates phosphorylation Ser1237 TEYSQGAsPQPQHQL 9606 11584018 t lperfetto "Phosphorylation of serines 1237 and 1270 caused inhibition of dna binding in vitro. In cotransfection studies, cyclin a-cdk1 inhibited cdp/cux stable dna binding and prevented repression of the p21(waf1) reporter." SIGNOR-110908 ethanolaminium(1+) smallmolecule CHEBI:57603 ChEBI O-phosphonatoethanaminium(1-) smallmolecule CHEBI:58190 ChEBI "up-regulates quantity" "precursor of" 29928787 t lperfetto "In this study, we investigated the roles of ethanolamine kinases (Etnk-1 and 2) and choline kinases (Chk-α and β) in contributing to increased PE in human breast and pancreatic cancer cells." SIGNOR-275638 CHKB protein Q9Y259 UNIPROT O-phosphonatoethanaminium(1-) smallmolecule CHEBI:58190 ChEBI "up-regulates quantity" "chemical modification" 29928787 t lperfetto "In this study, we investigated the roles of ethanolamine kinases (Etnk-1 and 2) and choline kinases (Chk-α and β) in contributing to increased PE in human breast and pancreatic cancer cells." SIGNOR-275639 CHKB protein Q9Y259 UNIPROT ethanolaminium(1+) smallmolecule CHEBI:57603 ChEBI "down-regulates quantity" "chemical modification" 29928787 t lperfetto "In this study, we investigated the roles of ethanolamine kinases (Etnk-1 and 2) and choline kinases (Chk-α and β) in contributing to increased PE in human breast and pancreatic cancer cells." SIGNOR-275640 RUNX1 protein Q01196 UNIPROT SPI1 protein P17947 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 23817177 f irozzo "RUNX1 wild-type protein first binds to the PU.1 URE region and recruits the MLL complex to open up part of the compact chromatin structure. The partially relaxed chromatin allows the binding of another RUNX1 at the PU.1 promoter region to further distort compact DNA structure. The relaxed form of chromatin facilitates the accumulation of transcription factors and cofactors to initiate transcriptional activity." SIGNOR-255709 TAB2 protein Q9NYJ8 UNIPROT MAP3K7 protein O43318 UNIPROT "up-regulates activity" binding 9606 14633987 t lperfetto "These results suggest that TAB2 and TAB3 function redundantly as mediators of TAK1 activation in IL-1 and TNF signal transduction." SIGNOR-119370 TRAF3 protein Q13114 UNIPROT MAP3K14 protein Q99558 UNIPROT "down-regulates quantity by destabilization" binding 10090 15084608 t lperfetto "Traf3 is physically associated with nik via a specific sequence motif located in the n-terminal region of nik; this molecular interaction appears to target nik for degradation by the proteasome." SIGNOR-124236 CFH protein P08603 UNIPROT CFB protein P00751 UNIPROT "down-regulates activity" binding 9606 19050261 t miannu "As a regulator of the alternative pathway, FH binds to C3b and inhibits the binding of factor B to C3b, acts as a cofactor for the factor I-mediated cleavage of C3b to iC3b (cofactor activity), and accelerates the decay of C3bBb, the alternative pathway C3 convertase (decay-accelerating activity)" SIGNOR-252142 CARM1 protein Q86X55 UNIPROT MDH1 protein P40925 UNIPROT "down-regulates activity" acetylation Arg230 FVTTVQQrGAAVIKA 9606 27840030 t lperfetto "Arginine Methylation of MDH1 by CARM1 Inhibits Glutamine Metabolism and Suppresses Pancreatic Cancer|Arginine methylation at R248 negatively regulates MDH1 activity|PRMT4/CARM1 methylates MDH1 at R248 and inhibits its dimerization" SIGNOR-267639 MAPK3 protein P27361 UNIPROT SOS1 protein Q07889 UNIPROT down-regulates phosphorylation Ser1167 ESAPAESsPSKIMSK 9606 8816480 t gcesareni "In this report, we describe the identification of five map kinase sites (s-1137, s-1167, s-1178, s-1193, and s-1197) on hsos1" SIGNOR-43943 ETNK1 protein Q9HBU6 UNIPROT O-phosphonatoethanaminium(1-) smallmolecule CHEBI:58190 ChEBI "up-regulates quantity" "chemical modification" 36583229 t lperfetto "ETNK1 encodes ethanolamine kinase 1, which is involved in the de novo biosynthesis of phosphatidylethanolamine and is responsible for the phosphorylation of ethanolamine to phosphoethanolamine" SIGNOR-275641 DDX5 protein P17844 UNIPROT "Microprocessor complex" complex SIGNOR-C356 SIGNOR "up-regulates activity" binding 34936874 t lperfetto "Both the phosphorylation and sumoylation of DDX5 enhance the formation of a DDX5/Drosha/DGCR8 complex, thus promoting microRNA-10b processing." SIGNOR-275659 DDX5 protein P17844 UNIPROT mir-10b mirna URS00004CAC40_9606 RNAcentral "up-regulates quantity" "post transcriptional regulation" 34936874 t lperfetto "Both the phosphorylation and sumoylation of DDX5 enhance the formation of a DDX5/Drosha/DGCR8 complex, thus promoting microRNA-10b processing." SIGNOR-275660 "Microprocessor complex" complex SIGNOR-C356 SIGNOR mir-10b mirna URS00004CAC40_9606 RNAcentral "up-regulates quantity" "post transcriptional regulation" 34936874 t lperfetto "Both the phosphorylation and sumoylation of DDX5 enhance the formation of a DDX5/Drosha/DGCR8 complex, thus promoting microRNA-10b processing." SIGNOR-275661 GSK3B protein P49841 UNIPROT PSEN1 protein P49768 UNIPROT "down-regulates activity" phosphorylation Ser353 SHLGPHRsTPESRAA 9606 BTO:0000007 SIGNOR-C110 17360711 t gcesareni "We demonstrate that phosphorylation of serines 353 and 357 by glycogen synthase kinase-3beta (gsk3beta) induces a structural change of the hydrophilic loop of ps1the structural change of ps1 reduces the interaction with beta-catenin leading to decreased phosphorylation and ubiquitination of beta-catenin." SIGNOR-153627 ARNTL protein O00327 UNIPROT MAGEL2 protein Q9UJ55 UNIPROT "down-regulates activity" binding 9606 BTO:0000007 22208286 t miannu "Magel2 represses the activity of the Clock:Bmal1 heterodimer in a Per2-luciferase assay. Magel2 interacts with Bmal1 and with Per2 as measured by co-immunoprecipitation in co-transfected cells, and exhibits a subcellular distribution consistent with these interactions when visualized by immunofluorescence. As well, Magel2 induces the redistribution of the subcellular localization of Clock towards the cytoplasm, in contrast to the nucleus-directed effect of Bmal1 on Clock subcellular localization." SIGNOR-253517 RBM42 protein Q9BTD8 UNIPROT "U4/U6.U5 snRNP complex" complex SIGNOR-C478 SIGNOR "form complex" binding 9606 30765414 t lperfetto "The major spliceosomal building blocks are the U1, U2, U4/U6, and U5 small nuclear ribonucleoproteins (snRNPs). Each consists of a small nuclear RNA (snRNA) (or two, in the case of U4/U6), seven Sm proteins that form a ring (or seven Lsm proteins in the case of U6), and a variable number of snRNP-specific proteins (Fig. 1F) (Will and Lührmann 2011). Under splicing conditions, the U4/U6 and U5 snRNPs form a 25S U4/U6.U5 tri-snRNP, in which the U4 and U6 snRNAs are base-paired, forming a three-way junction." SIGNOR-270645 MAPK1 protein P28482 UNIPROT ESR1 protein P03372 UNIPROT up-regulates phosphorylation Ser118 LHPPPQLsPFLQPHG 9606 12466266 t gcesareni "Phosphorylation at serines 104 and 106 by erk1/2 mapk is important for estrogen receptor-alpha activity;ser118 is phosphorylated by mitogen-activated protein kinase (mapk) in vitro and in cells treated with epidermal growth factor (egf) and insulin-like growth factor (igf) in vivo." SIGNOR-96072 HSD3B1 protein P14060 UNIPROT testosterone smallmolecule CHEBI:17347 ChEBI "up-regulates quantity" "chemical modification" 10116 BTO:0000534;BTO:0000056 1537836 t lperfetto "We have recently characterized two types of rat 3 beta-hydroxysteroid dehydrogenase/delta 5-delta 4 isomerase (3 beta-HSD) isoenzymes expressed in adrenals and gonads. | However, in the presence of NADH, type III isoenzyme, in common with the type I isoform, converts 5 alpha-androstane-3,17-dione (A-dione) and 5 alpha-dihydrotestosterone (DHT) to the corresponding 3 beta-hydroxysteroids." SIGNOR-268637 AKT1 protein P31749 UNIPROT DOCK6 protein Q96HP0 UNIPROT "up-regulates activity" phosphorylation Ser1194 GQRSRLAsMLDSDTE 23462102 t lperfetto "Akt and PP2A reciprocally regulate the guanine nucleotide exchange factor Dock6 to control axon growth of sensory neurons|At later developmental stages, the abundance of the kinase Akt increased, resulting in the binding of Akt to Dock6 and the phosphorylation of Dock6 at Ser(1194). | In dorsal root ganglion neurons from mice lacking Dock6, reintroduction of Dock6 with a nonphosphorylatable S1194A mutation rescued axon extension but not branch number, whereas reintroduction of Dock6 with a phosphomimetic S1194E mutation resulted in premature branching" SIGNOR-275666 MECP2 protein P51608 UNIPROT PTPN1 protein P18031 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 10090 BTO:0000478 26214522 f Luana " We demonstrated that the PTPN1 gene, which encodes PTP1B, was a target of MECP2 and that disruption of MECP2 function was associated with increased levels of PTP1B in RTT models." SIGNOR-264552 PPP2CA protein P67775 UNIPROT DOCK6 protein Q96HP0 UNIPROT "down-regulates activity" phosphorylation Ser1194 GQRSRLAsMLDSDTE 23462102 t lperfetto "Akt and PP2A reciprocally regulate the guanine nucleotide exchange factor Dock6 to control axon growth of sensory neurons|At later developmental stages, the abundance of the kinase Akt increased, resulting in the binding of Akt to Dock6 and the phosphorylation of Dock6 at Ser(1194). | In dorsal root ganglion neurons from mice lacking Dock6, reintroduction of Dock6 with a nonphosphorylatable S1194A mutation rescued axon extension but not branch number, whereas reintroduction of Dock6 with a phosphomimetic S1194E mutation resulted in premature branching" SIGNOR-275669 TAF1C protein Q15572 UNIPROT "SL1 complex" complex SIGNOR-C464 SIGNOR "form complex" binding 9606 30693017 t lperfetto "SL1 comprises TBP, TAF1A (also known as TAFI48), TAF1B (also known as TAFI63), TAF1C (also known as TAFI110), and TAF1D (also known as TAFI41) and recruits the RNAP1 complex to induce PIC formation." SIGNOR-269564 INTS3 protein Q68E01 UNIPROT "Integrator complex" complex SIGNOR-C265 SIGNOR "form complex" binding 7227 26220997 t lperfetto "Integrator is a metazoan-specific multisubunit, multifunctional protein complex composed of 14 subunits named Int1–Int14 (Integrator subunits) " SIGNOR-261485 vismodegib chemical CHEBI:66903 ChEBI SMO protein Q99835 UNIPROT down-regulates "chemical inhibition" 9606 21679342 t gcesareni "Cyclopamine with improved solubility (ipi-926), smo inhibitors that considerably differ in structure from cyclopamine (gdc-0499, lde225, bms-833923, xl-139, pf-0449913), inhibitors of the transformation of inactive smo into active smo (sant 74-75), and inhibitors of the transport of cytoplasmic inactive smo to cilia (sant 1-4) have been developed to date." SIGNOR-174417 CITED2 protein Q99967 UNIPROT MMP13 protein P45452 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0003859 12960175 f miannu "CITED2 plays a major role in shear-induced down-regulation of MMP-1 and MMP-13 via a transforming growth factor-beta-dependent pathway." SIGNOR-253777 HAUS1 protein Q96CS2 UNIPROT "HAUS complex" complex SIGNOR-C281 SIGNOR "form complex" binding 9606 BTO:0000567 19369198 t lperfetto "Here, by using mass spectrometry, we identified the full human augmin complex of 8 subunits and show that it interacts with the gamma-tubulin ring complex (gamma-TuRC)" SIGNOR-262319 PHKA1 protein P46020 UNIPROT PHKG2 protein P15735 UNIPROT "down-regulates activity" binding 9606 10487978 t "Phk is among the most complex of the protein kinases so far elucidated. It has one catalytic (gamma) subunit and three different regulatory (alpha, beta, and delta) subunits, a molecular mass of 1.3 X 106 daltons, and each holoenzyme molecule is presumed to contain four molecules of each subunit. The three regulatory subunits inhibit the phosphotransferase activity of the gamma subunit." SIGNOR-267407 TGFBR2 protein P37173 UNIPROT VPS39 protein Q96JC1 UNIPROT "up-regulates activity" binding 9534 12941698 t miannu "TLP interacts with TGF-β and activin receptors in vivo. Endogenous TLP associates with both active and kinase-deficient TGF-beta and activin type II receptors, but interacts with the common-mediator Smad4 only in the presence of TGF-beta/activin signaling." SIGNOR-261374 TRiC complex SIGNOR-C539 SIGNOR Tubulin proteinfamily SIGNOR-PF46 SIGNOR "up-regulates quantity by stabilization" binding 9606 36185250 t miannu "Mammalian cells contain an evolutionarily conserved type II chaperonin called chaperonin containing tailless complex polypeptide 1 (CCT) or tailless complex polypeptide 1 ring complex (TRiC). The CCT complex is composed of eight subunits [CCT1-8 (yeast) or CCTα-θ (mammals)] and folds substrates needed for cell invasion and proliferation, such as actin, tubulin, and cell division cycle protein 20 homolog (cdc20), as well as oncoproteins like signal transducer and activator of transcription 3 (STAT3), Kirsten rat sarcoma viral oncogene homolog (KRAS), and Myelocytomatosis (MYC)." SIGNOR-272868 miR-29a mirna URS00004E9304_9606 RNAcentral TET2 protein Q6N021 UNIPROT "down-regulates quantity by repression" "post transcriptional regulation" 10116 17994015 t Luana "Here, we show that MeCP2 levels are repressed by miR132, a brain-enriched microRNA (miRNA). We propose that the interaction of miR132 with its miRNA recognition element (MRE) in the MeCP2 3′ UTR prevents MeCP2 levels from becoming deleteriously high during neuronal maturation." SIGNOR-264703 HSP90AB1 protein P08238 UNIPROT CBLL1 protein Q75N03 UNIPROT "up-regulates quantity" binding 9606 BTO:0000007 31952268 t miannu "By immunoprecipitation, we present evidence that Hakai interacts with Hsp90 chaperone complex in several epithelial cells and demonstrate that is a novel Hsp90 client protein. Interestingly, by overexpressing and knocking-down experiments with Hakai, we identified Annexin A2 as a Hakai-regulated protein. Interestingly, geldanamycin-induced Hakai degradation is accompanied by an increased expression of E-cadherin and Annexin A2. Hsp90 participates in the correct folding of its client proteins, allowing them to maintain their stability and activity." SIGNOR-271475 FOXO3 protein O43524 UNIPROT NOTCH3 protein Q9UM47 UNIPROT "down-regulates quantity" "transcriptional regulation" 10090 24749067 f gcesareni "We demonstrate that FOXO3, perhaps by activating Notch signaling, promotes the quiescent state during SC self-renewal in adult muscle regeneration." SIGNOR-244079 PRKCA protein P17252 UNIPROT MBD4 protein O95243 UNIPROT "up-regulates activity" phosphorylation Ser165 CSMAALTsHLQNQSN 23195996 t lperfetto "Phosphorylation of MBD4 promotes 5-meC glycosylase activity Further evidence emerged to support the involvement of MBD4 in active demethylation. Protein-kinase C phosphorylation of MBD4 at two specific serine residues (165 and 262) following parathyroid hormone stimulation was shown to promote demethylation within the CYP27B1 gene promoter [12]" SIGNOR-275673 PKC proteinfamily SIGNOR-PF53 SIGNOR MBD4 protein O95243 UNIPROT "up-regulates activity" phosphorylation Ser262 SGFVQSDsKRESVCN 23195996 t lperfetto "Phosphorylation of MBD4 promotes 5-meC glycosylase activity Further evidence emerged to support the involvement of MBD4 in active demethylation. Protein-kinase C phosphorylation of MBD4 at two specific serine residues (165 and 262) following parathyroid hormone stimulation was shown to promote demethylation within the CYP27B1 gene promoter [12]" SIGNOR-275674 Merimepodib chemical CID:153241 PUBCHEM IMPDH2 protein P12268 UNIPROT "down-regulates activity" "chemical inhibition" 9606 11288107 t Federica "These studies demonstrate that VX-497 is a potent, specific, and reversible IMPDH inhibitor that selectively inhibits lymphocyte proliferation." SIGNOR-261106 PKC proteinfamily SIGNOR-PF53 SIGNOR MBD4 protein O95243 UNIPROT "up-regulates activity" phosphorylation Ser165 CSMAALTsHLQNQSN 23195996 t lperfetto "Phosphorylation of MBD4 promotes 5-meC glycosylase activity Further evidence emerged to support the involvement of MBD4 in active demethylation. Protein-kinase C phosphorylation of MBD4 at two specific serine residues (165 and 262) following parathyroid hormone stimulation was shown to promote demethylation within the CYP27B1 gene promoter [12]" SIGNOR-275675 UBE2I protein P63279 UNIPROT MBD4 protein O95243 UNIPROT "up-regulates activity" sumoylation Lys137 KNGETSLkPEDFDFT 31476572 t lperfetto "MBD4 is sumoylated at three main sites: K137, K215 and K377.|Sumoylation increases the G:T repair activity of MBD4 in cell extracts.|we conducted an in vitrosumoylation assay, employing recombinant activating E1 (Aos1-Uba2) and conjugating E2 (Ubc9) enzymes, along with recombinant YFP-SUMO1 and MBD4 or, as positive control for sumoylation, TDG (Fig. 2D). These results indicate that MBD4 is sumoylated in vivo and in vitro." SIGNOR-275676 KIF5C protein O60282 UNIPROT Organelle_transport phenotype SIGNOR-PH159 SIGNOR up-regulates 9606 BTO:0000938 9438838 f miannu "The kinesin superfamily of proteins plays a major role in this complex organelle transport. Kinesin is primarily associated with anterogradely transported membranous organelles in nerve axons. KIF5B and HsuKHC are expressed ubiquitously in many tissues, whereas KIF5A, KIF5C, and HsnKHC are specific to nerve tissue." SIGNOR-264066 TAB1 protein Q15750 UNIPROT MAP3K7 protein O43318 UNIPROT "up-regulates activity" binding 9606 8638164 t lperfetto "The yeast two-hybrid system has now revealed two human proteins, termed tab1 and tab2 (for tak1 binding protein), that interact with tak1. Overproduction of tab1 enhanced activity of the plasminogen activator inhibitor 1 gene promoter, which is regulated by tgf-beta, and increased the kinase activity of tak1. Tab1 activates the kinase activity of tak1 by directly binding to its catalytic domain. Tab1 overexpression increase the kinase activity of tak1 in mammalian cells." SIGNOR-41941 RAD1 protein O60671 UNIPROT TOPBP1 protein Q92547 UNIPROT up-regulates binding 9606 18594563 t gcesareni "The 9-1-1 complex functions as a clamp, encircling the dna, and recruits the brct domain-containing protein topbp1 in a phospho-dependent manner" SIGNOR-179379 UBE2I protein P63279 UNIPROT MBD4 protein O95243 UNIPROT "up-regulates activity" sumoylation Lys215 TSTHLLLkEDEGVDD 31476572 t lperfetto "MBD4 is sumoylated at three main sites: K137, K215 and K377.|Sumoylation increases the G:T repair activity of MBD4 in cell extracts.|we conducted an in vitrosumoylation assay, employing recombinant activating E1 (Aos1-Uba2) and conjugating E2 (Ubc9) enzymes, along with recombinant YFP-SUMO1 and MBD4 or, as positive control for sumoylation, TDG (Fig. 2D). These results indicate that MBD4 is sumoylated in vivo and in vitro." SIGNOR-275677 UBE2I protein P63279 UNIPROT MBD4 protein O95243 UNIPROT "up-regulates activity" sumoylation Lys377 HLHTDILkRGSEMDN 31476572 t lperfetto "MBD4 is sumoylated at three main sites: K137, K215 and K377.|Sumoylation increases the G:T repair activity of MBD4 in cell extracts.|we conducted an in vitrosumoylation assay, employing recombinant activating E1 (Aos1-Uba2) and conjugating E2 (Ubc9) enzymes, along with recombinant YFP-SUMO1 and MBD4 or, as positive control for sumoylation, TDG (Fig. 2D). These results indicate that MBD4 is sumoylated in vivo and in vitro." SIGNOR-275678 "SAE1/SAE2 complex" complex SIGNOR-C294 SIGNOR MBD4 protein O95243 UNIPROT "up-regulates activity" sumoylation Lys137 KNGETSLkPEDFDFT 31476572 t lperfetto "MBD4 is sumoylated at three main sites: K137, K215 and K377.|Sumoylation increases the G:T repair activity of MBD4 in cell extracts.|we conducted an in vitrosumoylation assay, employing recombinant activating E1 (Aos1-Uba2) and conjugating E2 (Ubc9) enzymes, along with recombinant YFP-SUMO1 and MBD4 or, as positive control for sumoylation, TDG (Fig. 2D). These results indicate that MBD4 is sumoylated in vivo and in vitro." SIGNOR-275679 MAPK3 protein P27361 UNIPROT LAT protein O43561 UNIPROT down-regulates phosphorylation Thr184 PSAPALStPGIRDSA 9606 15192708 t "The effect has been demonstrated using O43561-2" gcesareni "Lat, an adapter protein essential for t-cell signaling, is phosphorylated at its thr 155 by erk in response to t-cell receptor stimulation. Thr 155 phosphorylation reduces the ability of lat to recruit plcgamma1 and slp76, leading to attenuation of subsequent downstream events such as [ca2+]i mobilization and activation of the erk pathway." SIGNOR-125770 CIITA protein P33076 UNIPROT S100A4 protein P26447 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 17143014 f miannu "IFN-gamma represses S100A4 promoter activity through induction of the class II transactivator (CIITA)." SIGNOR-253776 ETFBKMT protein Q8IXQ9 UNIPROT ETFB protein P38117 UNIPROT "down-regulates activity" methylation Lys203 PNIMKAKkKKIEVIK -1 25416781 t miannu "Accordingly, we found that METTL20-mediated methylation of ETFβ in vitro reduced its ability to receive electrons from the medium chain acyl-CoA dehydrogenase and the glutaryl-CoA dehydrogenase. In conclusion, the present study establishes METTL20 as the first human KMT localized to mitochondria and suggests that it may regulate cellular metabolism through modulating the interaction between its substrate ETFβ and dehydrogenases." SIGNOR-269451 DNA_damage stimulus SIGNOR-ST1 SIGNOR RAD23A protein P54725 UNIPROT up-regulates 24086043 f lperfetto "GG-NER is initiated by the GG-NER specific factor XPC-RAD23B, in some cases with the help of UV-DDB (UV-damaged DNA-binding protein)." SIGNOR-275686 DDB1 protein Q16531 UNIPROT RAD23A protein P54725 UNIPROT up-regulates 24086044 f lperfetto "GG-NER is initiated by the GG-NER specific factor XPC-RAD23B, in some cases with the help of UV-DDB (UV-damaged DNA-binding protein)." SIGNOR-275687 DNA_damage stimulus SIGNOR-ST1 SIGNOR RAD23B protein P54727 UNIPROT up-regulates 24086043 f lperfetto "GG-NER is initiated by the GG-NER specific factor XPC-RAD23B, in some cases with the help of UV-DDB (UV-damaged DNA-binding protein)." SIGNOR-275688 DDB1 protein Q16531 UNIPROT RAD23B protein P54727 UNIPROT up-regulates 24086044 f lperfetto "GG-NER is initiated by the GG-NER specific factor XPC-RAD23B, in some cases with the help of UV-DDB (UV-damaged DNA-binding protein)." SIGNOR-275689 DNA_damage stimulus SIGNOR-ST1 SIGNOR ERCC8 protein Q13216 UNIPROT up-regulates 24086043 f lperfetto "TC-NER is initiated by RNA polymerase stalled at a lesion with the help of TC-NER specific factors CSA, CSB, and XAB2." SIGNOR-275690 DNA_damage stimulus SIGNOR-ST1 SIGNOR ERCC6 protein Q03468 UNIPROT up-regulates 24086043 f lperfetto "TC-NER is initiated by RNA polymerase stalled at a lesion with the help of TC-NER specific factors CSA, CSB, and XAB2." SIGNOR-275691 GSK3A protein P49840 UNIPROT MAFA protein Q8NHW3 UNIPROT "up-regulates activity" phosphorylation Thr53 PPGSLSStPLSTPCS 9606 18042454 t miannu "We also demonstrate that gsk-3 triggers mafa sequential phosphorylation on residues s61, t57, t53, and s49 /we demonstrated that phosphorylation by gsk-3 is conserved among the large maf proteins. It couples ubiquitination/degradation and transcriptional activation and modulates maf biological activity./ Taken together, these results suggest that, in contrast to what can be expected from ubiquitination/degradation, gsk-3-mediated mafa phosphorylation increases its transactivating ability, thereby controlling its biological activity." SIGNOR-159373 ANKRD28 protein O15084 UNIPROT PPP1CC protein P36873 UNIPROT "up-regulates activity" binding -1 17023142 t lperfetto "Phosphatase Interactor Targeting K protein (PITK) was previously identified as a novel PP1 targeting subunit implicated in modulating the phosphorylation of the transcriptional regulator heterogeneous nuclear ribonucleoprotein K (hnRNP K)" SIGNOR-264794 BACE1 protein P56817 UNIPROT APP protein P05067 UNIPROT "up-regulates activity" cleavage 28923680 t "Beta-secretase 1 (BACE1) cleaves the type-I transmembrane protein APP to form the N-terminus of Aβ." SIGNOR-255480 DNA_damage stimulus SIGNOR-ST1 SIGNOR XAB2 protein Q9HCS7 UNIPROT up-regulates 24086043 f lperfetto "TC-NER is initiated by RNA polymerase stalled at a lesion with the help of TC-NER specific factors CSA, CSB, and XAB2." SIGNOR-275692 ERCC8 protein Q13216 UNIPROT RAD23B protein P54727 UNIPROT "up-regulates activity" 24086043 f lperfetto "GG-NER is initiated by the GG-NER specific factor XPC-RAD23B, in some cases with the help of UV-DDB (UV-damaged DNA-binding protein). TC-NER is initiated by RNA polymerase stalled at a lesion with the help of TC-NER specific factors CSA, CSB, and XAB2. Both pathways require the core NER factors to complete the excision process|The core NER dual incision reaction has been reconstituted in vitro with purified factors using XPC-RAD23B, TFIIH, XPA, RPA, XPG, and ERCC1-XPF (Aboussekhra et al. 1995; Mu et al. 1995; Araujo et al. 2000).|The core NER dual incision reaction has been reconstituted in vitro with purified factors using XPC-RAD23B, TFIIH, XPA, RPA, XPG, and ERCC1-XPF (Aboussekhra et al. 1995; Mu et al. 1995; Araujo et al. 2000). Functional studies revealed that XPC-RAD23B is the initial damage recognition factor in this system, as the presence of XPC-RAD23B is required for assembly of the other core NER factors and progression through the NER pathway both in vitro and in vivo" SIGNOR-275693 EGLN3 protein Q9H6Z9 UNIPROT PK proteinfamily SIGNOR-PF80 SIGNOR "up-regulates activity" hydroxylation 9606 BTO:0000567 21620138 t "Interaction of PKM2 with prolyl hydroxylase 3 (PHD3) enhances PKM2 binding to HIF-1Œ± and PKM2 coactivator function. Mass spectrometry and anti-hydroxyproline antibody assays demonstrate PKM2 hydroxylation on proline-403/408. PHD3 knockdown inhibits PKM2 coactivator function, reduces glucose uptake and lactate production, and increases O(2) consumption in cancer cells." SIGNOR-268147 BMP2 protein P12643 UNIPROT BMPR1A/1B/2 complex SIGNOR-C29 SIGNOR up-regulates binding 9606 7791754 t lperfetto "Bmpr-ii is a transmembrane serine/threonine kinase that binds bmp-2 and bmp-7 in association with multiple type i receptors, including bmpr-ia/brk1, bmpr-ib, and actr-i, which is also an activin type i receptor." SIGNOR-217532 TSC22D3 protein Q99576 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR "down-regulates activity" relocalization 9606 BTO:0000738 20018851 t "inferred from 70% of family members" "GILZ inhibits FOXO1, FOXO3, and FOXO4 transcriptional activities measured with natural or synthetic FOXO-responsive promoters in HL-60 cells." SIGNOR-269854 BMP4 protein P12644 UNIPROT BMPR1A protein P36894 UNIPROT up-regulates binding 26330344 t fferrentino "BMP interacts with specific receptors on the cell surface, BMP receptor types 1 and 2 (BMPr1 and BMPr2)." SIGNOR-253548 XAB2 protein Q9HCS7 UNIPROT RAD23B protein P54727 UNIPROT "up-regulates activity" 24086043 f lperfetto "GG-NER is initiated by the GG-NER specific factor XPC-RAD23B, in some cases with the help of UV-DDB (UV-damaged DNA-binding protein). TC-NER is initiated by RNA polymerase stalled at a lesion with the help of TC-NER specific factors CSA, CSB, and XAB2. Both pathways require the core NER factors to complete the excision process|The core NER dual incision reaction has been reconstituted in vitro with purified factors using XPC-RAD23B, TFIIH, XPA, RPA, XPG, and ERCC1-XPF (Aboussekhra et al. 1995; Mu et al. 1995; Araujo et al. 2000).|The core NER dual incision reaction has been reconstituted in vitro with purified factors using XPC-RAD23B, TFIIH, XPA, RPA, XPG, and ERCC1-XPF (Aboussekhra et al. 1995; Mu et al. 1995; Araujo et al. 2000). Functional studies revealed that XPC-RAD23B is the initial damage recognition factor in this system, as the presence of XPC-RAD23B is required for assembly of the other core NER factors and progression through the NER pathway both in vitro and in vivo" SIGNOR-275695 RAD23B protein P54727 UNIPROT TFIIH complex SIGNOR-C457 SIGNOR "up-regulates activity" binding 24086043 t lperfetto "GG-NER is initiated by the GG-NER specific factor XPC-RAD23B, in some cases with the help of UV-DDB (UV-damaged DNA-binding protein). TC-NER is initiated by RNA polymerase stalled at a lesion with the help of TC-NER specific factors CSA, CSB, and XAB2. Both pathways require the core NER factors to complete the excision process|The core NER dual incision reaction has been reconstituted in vitro with purified factors using XPC-RAD23B, TFIIH, XPA, RPA, XPG, and ERCC1-XPF (Aboussekhra et al. 1995; Mu et al. 1995; Araujo et al. 2000).|The core NER dual incision reaction has been reconstituted in vitro with purified factors using XPC-RAD23B, TFIIH, XPA, RPA, XPG, and ERCC1-XPF (Aboussekhra et al. 1995; Mu et al. 1995; Araujo et al. 2000). Functional studies revealed that XPC-RAD23B is the initial damage recognition factor in this system, as the presence of XPC-RAD23B is required for assembly of the other core NER factors and progression through the NER pathway both in vitro and in vivo" SIGNOR-275696 RAD23B protein P54727 UNIPROT XPA protein P23025 UNIPROT "up-regulates activity" binding 24086043 t lperfetto "GG-NER is initiated by the GG-NER specific factor XPC-RAD23B, in some cases with the help of UV-DDB (UV-damaged DNA-binding protein). TC-NER is initiated by RNA polymerase stalled at a lesion with the help of TC-NER specific factors CSA, CSB, and XAB2. Both pathways require the core NER factors to complete the excision process|The core NER dual incision reaction has been reconstituted in vitro with purified factors using XPC-RAD23B, TFIIH, XPA, RPA, XPG, and ERCC1-XPF (Aboussekhra et al. 1995; Mu et al. 1995; Araujo et al. 2000).|The core NER dual incision reaction has been reconstituted in vitro with purified factors using XPC-RAD23B, TFIIH, XPA, RPA, XPG, and ERCC1-XPF (Aboussekhra et al. 1995; Mu et al. 1995; Araujo et al. 2000). Functional studies revealed that XPC-RAD23B is the initial damage recognition factor in this system, as the presence of XPC-RAD23B is required for assembly of the other core NER factors and progression through the NER pathway both in vitro and in vivo" SIGNOR-275697 RAD23B protein P54727 UNIPROT RPA1 protein P27694 UNIPROT "up-regulates activity" binding 24086043 t lperfetto "GG-NER is initiated by the GG-NER specific factor XPC-RAD23B, in some cases with the help of UV-DDB (UV-damaged DNA-binding protein). TC-NER is initiated by RNA polymerase stalled at a lesion with the help of TC-NER specific factors CSA, CSB, and XAB2. Both pathways require the core NER factors to complete the excision process|The core NER dual incision reaction has been reconstituted in vitro with purified factors using XPC-RAD23B, TFIIH, XPA, RPA, XPG, and ERCC1-XPF (Aboussekhra et al. 1995; Mu et al. 1995; Araujo et al. 2000).|The core NER dual incision reaction has been reconstituted in vitro with purified factors using XPC-RAD23B, TFIIH, XPA, RPA, XPG, and ERCC1-XPF (Aboussekhra et al. 1995; Mu et al. 1995; Araujo et al. 2000). Functional studies revealed that XPC-RAD23B is the initial damage recognition factor in this system, as the presence of XPC-RAD23B is required for assembly of the other core NER factors and progression through the NER pathway both in vitro and in vivo" SIGNOR-275698 PTPN2 protein P17706 UNIPROT STAT3 protein P40763 UNIPROT "down-regulates activity" dephosphorylation Tyr705 DPGSAAPyLKTKFIC 9606 15780598 t lperfetto "Upon ligand binding, IL-2R , IL-6R or LeptinR , IFN-_R , IFN-_R and PRLR or growth hormone (GH) receptor associated JAKs become activated. These JAKs mediate phosphorylation of specific tyrosine residues and recruit STATs. Activated STATs are released from the receptor and translocate to the nucleus. PTP1B dephosphorylates JAK2, TYK2 and STAT5 . The 45-kDa form of TC-PTP was shown to dephosphorylate JAK1 and JAK3 as well as STAT1, STAT3 and STAT5." SIGNOR-93998 RAD23B protein P54727 UNIPROT RPA2 protein P15927 UNIPROT "up-regulates activity" binding 24086043 t lperfetto "GG-NER is initiated by the GG-NER specific factor XPC-RAD23B, in some cases with the help of UV-DDB (UV-damaged DNA-binding protein). TC-NER is initiated by RNA polymerase stalled at a lesion with the help of TC-NER specific factors CSA, CSB, and XAB2. Both pathways require the core NER factors to complete the excision process|The core NER dual incision reaction has been reconstituted in vitro with purified factors using XPC-RAD23B, TFIIH, XPA, RPA, XPG, and ERCC1-XPF (Aboussekhra et al. 1995; Mu et al. 1995; Araujo et al. 2000).|The core NER dual incision reaction has been reconstituted in vitro with purified factors using XPC-RAD23B, TFIIH, XPA, RPA, XPG, and ERCC1-XPF (Aboussekhra et al. 1995; Mu et al. 1995; Araujo et al. 2000). Functional studies revealed that XPC-RAD23B is the initial damage recognition factor in this system, as the presence of XPC-RAD23B is required for assembly of the other core NER factors and progression through the NER pathway both in vitro and in vivo" SIGNOR-275699 RAD23B protein P54727 UNIPROT RPA3 protein P35244 UNIPROT "up-regulates activity" binding 24086043 t lperfetto "GG-NER is initiated by the GG-NER specific factor XPC-RAD23B, in some cases with the help of UV-DDB (UV-damaged DNA-binding protein). TC-NER is initiated by RNA polymerase stalled at a lesion with the help of TC-NER specific factors CSA, CSB, and XAB2. Both pathways require the core NER factors to complete the excision process|The core NER dual incision reaction has been reconstituted in vitro with purified factors using XPC-RAD23B, TFIIH, XPA, RPA, XPG, and ERCC1-XPF (Aboussekhra et al. 1995; Mu et al. 1995; Araujo et al. 2000).|The core NER dual incision reaction has been reconstituted in vitro with purified factors using XPC-RAD23B, TFIIH, XPA, RPA, XPG, and ERCC1-XPF (Aboussekhra et al. 1995; Mu et al. 1995; Araujo et al. 2000). Functional studies revealed that XPC-RAD23B is the initial damage recognition factor in this system, as the presence of XPC-RAD23B is required for assembly of the other core NER factors and progression through the NER pathway both in vitro and in vivo" SIGNOR-275700 RAD23B protein P54727 UNIPROT RPA4 protein Q13156 UNIPROT "up-regulates activity" binding 24086043 t lperfetto "GG-NER is initiated by the GG-NER specific factor XPC-RAD23B, in some cases with the help of UV-DDB (UV-damaged DNA-binding protein). TC-NER is initiated by RNA polymerase stalled at a lesion with the help of TC-NER specific factors CSA, CSB, and XAB2. Both pathways require the core NER factors to complete the excision process|The core NER dual incision reaction has been reconstituted in vitro with purified factors using XPC-RAD23B, TFIIH, XPA, RPA, XPG, and ERCC1-XPF (Aboussekhra et al. 1995; Mu et al. 1995; Araujo et al. 2000).|The core NER dual incision reaction has been reconstituted in vitro with purified factors using XPC-RAD23B, TFIIH, XPA, RPA, XPG, and ERCC1-XPF (Aboussekhra et al. 1995; Mu et al. 1995; Araujo et al. 2000). Functional studies revealed that XPC-RAD23B is the initial damage recognition factor in this system, as the presence of XPC-RAD23B is required for assembly of the other core NER factors and progression through the NER pathway both in vitro and in vivo" SIGNOR-275701 PIK3R1 protein P27986 UNIPROT PIK3CD protein O00329 UNIPROT "up-regulates activity" binding 9534 14665640 t lperfetto "Signal transduction pathways triggered by Tie2 have been extensively examined. Tyr-1101of Tie2 directly associates in a phosphotyrosine (pTyr)-dependent manner with the p85 regulatory subunit of phosphatidylinositol (PI) 3-kinase, which in turn activate PI 3-kinase, leading to cell motility and survival" SIGNOR-242643 "U1 snRNP complex" complex SIGNOR-C480 SIGNOR RNA_splicing phenotype SIGNOR-PH201 SIGNOR up-regulates 9606 30765414 f lperfetto "The major spliceosomal building blocks are the U1, U2, U4/U6, and U5 small nuclear ribonucleoproteins (snRNPs). Each consists of a small nuclear RNA (snRNA) (or two, in the case of U4/U6), seven Sm proteins that form a ring (or seven Lsm proteins in the case of U6), and a variable number of snRNP-specific proteins (Fig. 1F) (Will and Lührmann 2011). Under splicing conditions, the U4/U6 and U5 snRNPs form a 25S U4/U6.U5 tri-snRNP, in which the U4 and U6 snRNAs are base-paired, forming a three-way junction." SIGNOR-270687 SYP protein P08247 UNIPROT VAMP2 protein P63027 UNIPROT "up-regulates quantity" binding 9606 26903854 t miannu "Recent studies have revealed that sybII and synaptotagmin-1 interact with other SV cargoes to ensure a high fidelity of retrieval. These cargoes are synaptophysin (for sybII) and SV2A (for synaptotagmin-1). SV2A Acts as an iTRAP to Direct Synaptotagmin-1 Retrieval to SVs." SIGNOR-264117 SULT1E1 protein P49888 UNIPROT 17beta-estradiol smallmolecule CHEBI:16469 ChEBI "up-regulates quantity" "chemical modification" -1 7779757 t Luana "HEST-1 maximally sulfates β-estradiol and estrone at concentrations of 20 nM." SIGNOR-269749 RAD23B protein P54727 UNIPROT ERCC1 protein P07992 UNIPROT "up-regulates activity" binding 24086043 t lperfetto "GG-NER is initiated by the GG-NER specific factor XPC-RAD23B, in some cases with the help of UV-DDB (UV-damaged DNA-binding protein). TC-NER is initiated by RNA polymerase stalled at a lesion with the help of TC-NER specific factors CSA, CSB, and XAB2. Both pathways require the core NER factors to complete the excision process|The core NER dual incision reaction has been reconstituted in vitro with purified factors using XPC-RAD23B, TFIIH, XPA, RPA, XPG, and ERCC1-XPF (Aboussekhra et al. 1995; Mu et al. 1995; Araujo et al. 2000).|The core NER dual incision reaction has been reconstituted in vitro with purified factors using XPC-RAD23B, TFIIH, XPA, RPA, XPG, and ERCC1-XPF (Aboussekhra et al. 1995; Mu et al. 1995; Araujo et al. 2000). Functional studies revealed that XPC-RAD23B is the initial damage recognition factor in this system, as the presence of XPC-RAD23B is required for assembly of the other core NER factors and progression through the NER pathway both in vitro and in vivo" SIGNOR-275703 SCF-betaTRCP complex SIGNOR-C5 SIGNOR PER2 protein O15055 UNIPROT "down-regulates quantity by destabilization" ubiquitination 9606 17876059 t miannu "Here, the authors show that the F-box protein beta-transducin repeat containing protein 1 (beta-TrCP1) as part of the E3 ubiquitin ligase complex is an essential component of the mammalian circadian oscillator. Down-regulation of endogenous beta-TrCP1 as well as expression of a dominant-negative form both result in lengthening of the circadian period in oscillating fibroblasts. These phenotypes are due to an impaired degradation of PERIOD (PER) proteins, since expression of beta-TrCP interaction-deficient PER2 variants--but not wild-type PER2--results in a dramatic stabilization of PER2 protein as well as in the disruption of circadian rhythmicity." SIGNOR-268055 ERBB2 protein P04626 UNIPROT EGFR protein P00533 UNIPROT up-regulates binding 9606 8816440 t gcesareni "Although erbb-2 binds neither ligand, even in a heterodimeric receptor complex, it is the preferred heterodimer partner of the three other members, and it favors interaction with erbb-3." SIGNOR-147838 NFIX protein Q14938 UNIPROT ANOS1 protein P23352 UNIPROT "down-regulates quantity" "transcriptional regulation" 10090 31838646 t Gianni "By integrating transcriptomic profiling (RNA-seq) of Nfia- and Nfix-deficient GNPs with epigenomic profiling (ChIP-seq against NFIA, NFIB and NFIX, and DNase I hypersensitivity assays), we reveal that these transcription factors share a large set of potential transcriptional targets, suggestive of complementary roles for these NFI family members in promoting neural development" SIGNOR-268884 XPA protein P23025 UNIPROT Nucleotide-excision_repair phenotype SIGNOR-PH209 SIGNOR up-regulates 24086043 f lperfetto "The core NER dual incision reaction has been reconstituted in vitro with purified factors using XPC-RAD23B, TFIIH, XPA, RPA, XPG, and ERCC1-XPF (Aboussekhra et al. 1995; Mu et al. 1995; Araujo et al. 2000). Functional studies revealed that XPC-RAD23B is the initial damage recognition factor in this system, as the presence of XPC-RAD23B is required for assembly of the other core NER factors and progression through the NER pathway both in vitro and in vivo" SIGNOR-275704 RPA1 protein P27694 UNIPROT Nucleotide-excision_repair phenotype SIGNOR-PH209 SIGNOR up-regulates 24086043 f lperfetto "The core NER dual incision reaction has been reconstituted in vitro with purified factors using XPC-RAD23B, TFIIH, XPA, RPA, XPG, and ERCC1-XPF (Aboussekhra et al. 1995; Mu et al. 1995; Araujo et al. 2000). Functional studies revealed that XPC-RAD23B is the initial damage recognition factor in this system, as the presence of XPC-RAD23B is required for assembly of the other core NER factors and progression through the NER pathway both in vitro and in vivo" SIGNOR-275705 CASP8 protein Q14790 UNIPROT CASP3 protein P42574 UNIPROT "up-regulates activity" cleavage 9606 BTO:0000007 16964285 t amattioni "Casp8 induces apoptosis by directly activating casp3." SIGNOR-149420 CTNNB1 protein P35222 UNIPROT TCF4 protein P15884 UNIPROT "up-regulates activity" binding 9606 BTO:0000007 11713476 t amattioni "beta-catenin interacts with the TCF/Lef family transcription factors." SIGNOR-178042 ACLY protein P53396 UNIPROT ATP(4-) smallmolecule CHEBI:30616 ChEBI "down-regulates quantity by destabilization" "chemical modification" 9606 19286649 t miannu "ATP citrate lyase (ACL) is a cytosolic enzyme that catalyzes the synthesis of acetyl-CoA and oxaloacetate using citrate, CoA, and ATP as substrates and Mg(2+) as a necessary cofactor." SIGNOR-268082 STUB1 protein Q9UNE7 UNIPROT PRKN protein O60260 UNIPROT "up-regulates activity" binding -1 12150907 t miannu "In this study, we found that CHIP promotes Parkin-mediated Pael-R ubiquitination and subsequent degradation. In vitro ubiquitination assays suggested that only a combination of both Parkin and its cofactor CHIP function as a ubiquitin ligase, which is able to sufficiently ubiquitinate Pael-R in vivo (Figure 6). " SIGNOR-272888 RPA2 protein P15927 UNIPROT Nucleotide-excision_repair phenotype SIGNOR-PH209 SIGNOR up-regulates 24086043 f lperfetto "The core NER dual incision reaction has been reconstituted in vitro with purified factors using XPC-RAD23B, TFIIH, XPA, RPA, XPG, and ERCC1-XPF (Aboussekhra et al. 1995; Mu et al. 1995; Araujo et al. 2000). Functional studies revealed that XPC-RAD23B is the initial damage recognition factor in this system, as the presence of XPC-RAD23B is required for assembly of the other core NER factors and progression through the NER pathway both in vitro and in vivo" SIGNOR-275706 1-methyl-5-[[2-[5-(trifluoromethyl)-1H-imidazol-2-yl]-4-pyridinyl]oxy]-N-[4-(trifluoromethyl)phenyl]-2-benzimidazolamine chemical CHEBI:91451 ChEBI KDR protein P35968 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-206382 RPA4 protein Q13156 UNIPROT Nucleotide-excision_repair phenotype SIGNOR-PH209 SIGNOR up-regulates 24086043 f lperfetto "The core NER dual incision reaction has been reconstituted in vitro with purified factors using XPC-RAD23B, TFIIH, XPA, RPA, XPG, and ERCC1-XPF (Aboussekhra et al. 1995; Mu et al. 1995; Araujo et al. 2000). Functional studies revealed that XPC-RAD23B is the initial damage recognition factor in this system, as the presence of XPC-RAD23B is required for assembly of the other core NER factors and progression through the NER pathway both in vitro and in vivo" SIGNOR-275708 ERCC5 protein P28715 UNIPROT Nucleotide-excision_repair phenotype SIGNOR-PH209 SIGNOR up-regulates 24086043 f lperfetto "The core NER dual incision reaction has been reconstituted in vitro with purified factors using XPC-RAD23B, TFIIH, XPA, RPA, XPG, and ERCC1-XPF (Aboussekhra et al. 1995; Mu et al. 1995; Araujo et al. 2000). Functional studies revealed that XPC-RAD23B is the initial damage recognition factor in this system, as the presence of XPC-RAD23B is required for assembly of the other core NER factors and progression through the NER pathway both in vitro and in vivo" SIGNOR-275709 ERCC1 protein P07992 UNIPROT Nucleotide-excision_repair phenotype SIGNOR-PH209 SIGNOR up-regulates 24086043 f lperfetto "The core NER dual incision reaction has been reconstituted in vitro with purified factors using XPC-RAD23B, TFIIH, XPA, RPA, XPG, and ERCC1-XPF (Aboussekhra et al. 1995; Mu et al. 1995; Araujo et al. 2000). Functional studies revealed that XPC-RAD23B is the initial damage recognition factor in this system, as the presence of XPC-RAD23B is required for assembly of the other core NER factors and progression through the NER pathway both in vitro and in vivo" SIGNOR-275710 TDG protein Q13569 UNIPROT Base-excision_repair phenotype SIGNOR-PH222 SIGNOR up-regulates 23545420 f lperfetto "The BER pathway is initiated by one of at least 11 distinct DNA glycosylases, depending on the type of lesion (Table 1)." SIGNOR-275713 MBD4 protein O95243 UNIPROT Base-excision_repair phenotype SIGNOR-PH222 SIGNOR up-regulates 23545420 f lperfetto "The BER pathway is initiated by one of at least 11 distinct DNA glycosylases, depending on the type of lesion (Table 1)." SIGNOR-275714 OGG1 protein O15527 UNIPROT Base-excision_repair phenotype SIGNOR-PH222 SIGNOR up-regulates 23545420 f lperfetto "The BER pathway is initiated by one of at least 11 distinct DNA glycosylases, depending on the type of lesion (Table 1)." SIGNOR-275715 MUTYH protein Q9UIF7 UNIPROT Base-excision_repair phenotype SIGNOR-PH222 SIGNOR up-regulates 23545420 f lperfetto "The BER pathway is initiated by one of at least 11 distinct DNA glycosylases, depending on the type of lesion (Table 1)." SIGNOR-275716 NTHL1 protein P78549 UNIPROT Base-excision_repair phenotype SIGNOR-PH222 SIGNOR up-regulates 23545420 f lperfetto "The BER pathway is initiated by one of at least 11 distinct DNA glycosylases, depending on the type of lesion (Table 1)." SIGNOR-275717 NEIL1 protein Q96FI4 UNIPROT Base-excision_repair phenotype SIGNOR-PH222 SIGNOR up-regulates 23545420 f lperfetto "The BER pathway is initiated by one of at least 11 distinct DNA glycosylases, depending on the type of lesion (Table 1)." SIGNOR-275718 NEIL2 protein Q969S2 UNIPROT Base-excision_repair phenotype SIGNOR-PH222 SIGNOR up-regulates 23545420 f lperfetto "The BER pathway is initiated by one of at least 11 distinct DNA glycosylases, depending on the type of lesion (Table 1)." SIGNOR-275719 CTNND2 protein Q9UQB3 UNIPROT CDH5 protein P33151 UNIPROT "up-regulates quantity by stabilization" binding 9606 BTO:0001109 14610055 t miannu "To clarify the role of p120 in mammalian cells, we have knocked down p120 with siRNA in cells expressing epithelial (E-), placental (P-), neuronal (N-), and vascular endothelial (VE-) cadherins. We report that each of these cadherins, as well as α- and β-catenins, were rapidly degraded in the absence of p120, resulting in loss of cell–cell adhesion. The effect was clearly dose dependent, indicating that p120 expression levels may directly determine cadherin levels. Degradation of p120-uncoupled cadherin occurred after its arrival at the surface, indicating that p120 regulates cadherin turnover at the level of internalization or recycling. p120 homologues ARVCF and δ-catenin could substitute for p120, so at least one family member is likely required to maintain adhesion. Thus, cadherin complexes are rapidly turned over and degraded in mammalian cells in the absence of direct interaction with p120 or a p120 family member." SIGNOR-252132 DCTN2 protein Q13561 UNIPROT Cytoplasmic_Dynein proteinfamily SIGNOR-PF67 SIGNOR "up-regulates activity" relocalization 25364732 t lperfetto "ZW10 interacts with dynamitin, a subunit of the dynein-dynactin complex (Echeverri et al., 1996), thereby recruiting this motor to kinetochores" SIGNOR-265018 ARAP2 protein Q8WZ64 UNIPROT RAC1 protein P63000 UNIPROT "down-regulates activity" "gtpase-activating protein" 9606 BTO:0000007 32203420 t Luana "We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2)." SIGNOR-260454 FLT3 protein P36888 UNIPROT ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR "up-regulates activity" 9606 30552988 f miannu "Oncogenic, constitutively active mutants of FLT3 are known to be expressed in acute myeloid leukemia and to correlate with poor prognosis. Activation of the receptor mediates cell survival, cell proliferation and differentiation of cells. Several of the signal transduction pathways downstream of FLT3 have been shown to include various members of the SRC family of kinases (SFKs). They are involved in regulating the activity of RAS/ERK pathways through the scaffolding protein GAB2 and the adaptor protein SHC." SIGNOR-260132 PPARG protein P37231 UNIPROT Adipogenesis phenotype SIGNOR-PH26 SIGNOR up-regulates 10090 16150867 f lperfetto "Adipocyte differentiation is regulated largely through the actions of the peroxisome proliferator-activated receptor (PPAR) gamma nuclear receptor" SIGNOR-228622 MAF protein O75444 UNIPROT MYB protein P10242 UNIPROT down-regulates binding 9606 9566892 t miannu "Full-length c-maf binds to the c-myb and ets-1. / c-maf inhibits c-myb and ets-1 transcriptional activity." SIGNOR-56811 TCF4 protein P15884 UNIPROT SOX9 protein P48436 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 15240568 f "The β-catenin–TCF4 complex activity is required for SOX9 expression." SIGNOR-253323 HSD17B11 protein Q8NBQ5 UNIPROT estrone smallmolecule CHEBI:17263 ChEBI "up-regulates quantity" "chemical modification" 9606 BTO:0000056 16166196 t lperfetto "A novel 17beta-hydroxysteroid dehydrogenase (17beta-HSD) chronologically named type 12 17beta-HSD (17beta-HSD12), that transforms estrone (E1) into estradiol (E2) was identified by sequence similarity with type 3 17beta-HSD (17beta-HSD3) that catalyzes the formation of testosterone from androstenedione in the testis." SIGNOR-268663 CASP1 protein P29466 UNIPROT SPHK2 protein Q9NRA0 UNIPROT "up-regulates activity" binding 9606 BTO:0000007 20197547 t "Our data so far indicated colocalization of SphK2 with caspase-1 at the plasma membrane after induction of apoptosis.These observations supported caspase-1–dependent cleavage of SphK2 at its N-terminus as a prerequisite for its release." SIGNOR-268831 MMP14 protein P50281 UNIPROT FGG protein P02679 UNIPROT "down-regulates quantity by destabilization" cleavage Tyr27 LSSTCVAyVATRDNC -1 10930399 t lperfetto "Matrix metalloproteinases collagenase-2, macrophage elastase, collagenase-3, and membrane type 1-matrix metalloproteinase impair clotting by degradation of fibrinogen and factor XII| We have now investigated the role of collagenase-2 (MMP-8), macrophage elastase (MMP-12), collagenase-3 (MMP-13), and membrane type 1-matrix metalloproteinase (MT1-MMP, MMP-14) in the degradation of fibrinogen and Factor XII of the plasma clotting system.|MMP-14 27YVATRDN g-chain| 105XDAATLKSR g-chain | 92LTYNPDES g-chain |105LTTNIXEXL a-chain|433LVTSKGDKE a-chain| 117FXSANNRD a-chain" SIGNOR-263616 M1_polarization phenotype SIGNOR-PH54 SIGNOR IL1B protein P01584 UNIPROT up-regulates 9606 BTO:0000801 32454942 f miannu "Macrophages and microglia show a high plasticity and have been arbitrarily classified into “M1” (proinflammatory) and “M2” (prorepair, anti-inflammatory) phenotypes depending on their activation state, although it is now widely accepted that this classification is hugely oversimplified, particularly for microglia, and only partially reflects the real situation. According to the M1/M2 model, M1 polarized cells are characterized by the release of proinflammatory mediators, such as TNF, IL-1β, and IFNγ" SIGNOR-263825 AS-605240 chemical CID:5289247 PUBCHEM PIK3CG protein P48736 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-189921 E protein P59637 UNIPROT SDCBP protein O00560 UNIPROT "up-regulates activity" relocalization 9534 25122212 t Luana "Overall, these results support the hypothesis that the interaction of E protein PBM with syntenin facilitates the recruitment of syntenin in the cytosol and leads to p38 MAPK activation." SIGNOR-260752 ACO2 protein Q99798 UNIPROT citrate(3-) smallmolecule CHEBI:16947 ChEBI "down-regulates quantity" "chemical modification" 9606 24068518 t miannu "Citrate is converted to cis-aconitate. This is catalyzed by aconitase. Cis-aconitate is an intermediate and is further converted to isocitrate by aconitase. Aconitase is involved in both reactions. In which first dehydration and then rehydration occur and as a result final product isocitrate is obtained." SIGNOR-266244 PTPN1 protein P18031 UNIPROT TRPV6 protein Q9H1D0 UNIPROT down-regulates dephosphorylation 9606 BTO:0000007 17197020 t gcesareni "We conclude that phosphorylation/dephosphorylation of tyrosines in position 161 and 162 is essential for regulation of ca2+ influx through trpv6 ca2+ channels in hek293 cells. Co-transfection with src led to tyrosine phosphorylation of trpv6 which could be dephosphorylated by ptp1b. y161/162 are essential for tyrosine phosphorylation-dependent modulation of trpv6-mediated ca2+ entry." SIGNOR-151711 NRG1 protein Q02297 UNIPROT "ErbB receptor family" proteinfamily SIGNOR-PF36 SIGNOR up-regulates binding 9606 14967450 t "inferred from 70% of family members" gcesareni "The neuregulins (also called heregulins and neu differentiation factors) nrg-1 and nrg-2 bind erbb-3 and erbb-4;and nrg-3 and nrg-4 bind erbb-4." SIGNOR-269870 PP1 proteinfamily SIGNOR-PF54 SIGNOR GSK3B protein P49841 UNIPROT "up-regulates activity" dephosphorylation Ser9 SGRPRTTsFAESCKP 26088133 t lperfetto "Anchored PP1 may relieve PKA-mediated inhibition of GSK3beta by dephosphorylating Ser-9, providing bi-directional control of AKAP220 complex formation in response to cAMP." SIGNOR-264820 MAP2K7 protein O14733 UNIPROT MAPK10 protein P53779 UNIPROT up-regulates phosphorylation Thr221 AGTSFMMtPYVVTRY 9606 15911620 t lperfetto "Two mapkks, sek1 and mkk7, synergistically activate jnk. Sek1 prefers the tyr-185 residue, and mkk7 prefers the thr-183 residue (17, 19)." SIGNOR-137609 MAPK3 protein P27361 UNIPROT POLR2A protein P24928 UNIPROT down-regulates phosphorylation Ser1882 SPTSPTYsPTTPKYS 9606 14662762 t lperfetto "Erk1/2 are major ser-5 kinases after h2o2 treatment. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination." SIGNOR-120228 MARCHF9 protein Q86YJ5 UNIPROT HLA-DQB1 protein P01920 UNIPROT "down-regulates quantity by destabilization" ubiquitination 9606 BTO:0001522 19457934 t miannu "MARCH9, a member of the RING-CH family of transmembrane E3 ubiquitin ligases, down-regulates CD4, major histocompatibility complex-I (MHC), and ICAM-1 in lymphoid cells. To identify novel MARCH9 substrates, we used high throughput flow cytometry and quantitative mass spectrometry by stable isotope labeling by amino acids in cell culture (SILAC) to determine the differential expression of plasma membrane proteins in a MARCH9-expressing B cell line. This combined approach identified 13 potential new MARCH9 targets. " SIGNOR-271539 PDGFRB protein P09619 UNIPROT NCK1 protein P16333 UNIPROT up-regulates binding 9606 10026169 t esanto "Growth factor binding to receptor protein tyrosine kinases (r-ptks)1 induces their dimerization and trans-phosphorylation, creating docking sites for proteins containing sh2 and ptb protein interaction domains. Nck binds to the pdgf and egfr receptors (figure 3c)." SIGNOR-64737 SAV1 protein Q9H4B6 UNIPROT STK4 protein Q13043 UNIPROT up-regulates binding 9606 21084559 t "Sav1 interacts with Mst1/2 through the SARAH domains present in both Sav1 and Mst1/2." gcesareni "Mst is activated by binding of salvador (sav1, sav in drosophila), which is, in turn, also phosphorylated by mst." SIGNOR-169832 NEIL3 protein Q8TAT5 UNIPROT Base-excision_repair phenotype SIGNOR-PH222 SIGNOR up-regulates 23545420 f lperfetto "The BER pathway is initiated by one of at least 11 distinct DNA glycosylases, depending on the type of lesion (Table 1)." SIGNOR-275720 PRKG1 protein Q13976 UNIPROT VASP protein P50552 UNIPROT unknown phosphorylation Ser239 GAKLRKVsKQEEASG 9606 14679200 t lperfetto "Three phosphorylation sites have been identified in VASP: Ser157, Ser239, and Thr278, all of which can be phosphorylated by either PKA or PKG in vitro" SIGNOR-120351 CSNK2A1 protein P68400 UNIPROT SLK protein Q9H2G2 UNIPROT down-regulates phosphorylation Ser347 SSDLSIAsSEEDKLS 9606 16837460 t gcesareni "Slk down-regulation by v-src is indirect and is accompanied by slk hyperphosphorylation on serine residues. Deletion analysis revealed that casein kinase ii (ck2) sites at position 347/348 are critical for v-src-dependent modulation of slk activity." SIGNOR-147879 SYK protein P43405 UNIPROT MAP4K1 protein Q92918 UNIPROT "up-regulates activity" phosphorylation Tyr381 SESSDDDyDDVDIPT 9606 11514608 t lperfetto "BCR ligation induced rapid tyrosine-phosphorylation of HPK1 mainly by Syk and Lyn, resulting in its association with BASH and catalytic activation. BCR-mediated activation of HPK1 was impaired in Syk- or BASH-deficient B cells. The functional SH2 domain of BASH and Tyr-379 within HPK1 which we identified as a Syk-phosphorylation site were both necessary for interaction of both proteins and efficient HPK1 activation after BCR stimulation." SIGNOR-246567 MAPK1 protein P28482 UNIPROT SLC9A1 protein P19634 UNIPROT up-regulates phosphorylation Ser770 MMRSKETsSPGTDDV 9606 17209041 t miannu "We have demonstrated that the map kinases extracellular signal-regulated kinases 1 and 2 (erk1/2) are implicated in growth factor activation of nhe1. / our results suggest that amino acids ser770 and ser771 mediate erk-dependent activation of the na+/h+ exchanger in vivo." SIGNOR-151925 PIK3CB protein P42338 UNIPROT Survival phenotype SIGNOR-PH13 SIGNOR up-regulates 9534 BTO:0004055 14665640 f lperfetto "Signal transduction pathways triggered by Tie2 have been extensively examined. Tyr-1101of Tie2 directly associates in a phosphotyrosine (pTyr)-dependent manner with the p85 regulatory subunit of phosphatidylinositol (PI) 3-kinase, which in turn activate PI 3-kinase, leading to cell motility and survival" SIGNOR-242652 CSNK2A1 protein P68400 UNIPROT EIF4G2 protein P78344 UNIPROT "up-regulates activity" phosphorylation Ser902 ETAEEEEsEEEAD 9606 BTO:0000007 29530922 t miannu "DAP5(S902) is phosphorylated by CK2α. Phosphorylation of DAP5(S902) by CK2α is required for eIF2β binding." SIGNOR-266384 RNF5 protein Q99942 UNIPROT STING1 protein Q86WV6 UNIPROT "down-regulates quantity by destabilization" ubiquitination Lys150 EISAVCEkGNFNVAH 9606 BTO:0000007 19285439 t miannu "The ubiquitin ligase RNF5 regulates antiviral responses by mediating degradation of the adaptor protein MITA. RNF5 targeted MITA at Lys150 for ubiquitination and degradation after viral infection." SIGNOR-271484 UBAP2L protein Q14157 UNIPROT BMI1 protein P35226 UNIPROT "up-regulates activity" binding 9606 BTO:0000007 25185265 t Sara "We identified UBAP2L as a novel BMI1-interacting protein. UBAP2L, BMI1, RNF2, and PHC1 define a novel Polycomb subcomplex" SIGNOR-261315 PLCG1 protein P19174 UNIPROT 1,2-diacyl-sn-glycerol smallmolecule CHEBI:17815 ChEBI "up-regulates quantity" "chemical modification" 9606 23140367 t miannu "Phospholipase C (PLC) converts phosphatidylinositol 4,5-bisphosphate (PIP2) to inositol 1,4,5-trisphosphate (IP3) and diacylglycerol (DAG)." SIGNOR-251558 PPP2CA protein P67775 UNIPROT RACGAP1 protein Q9H0H5 UNIPROT down-regulates dephosphorylation Thr588 PEHQLLKtPSSSSLS 9606 18201571 t gcesareni "We report here that (i) mgcracgap is phosphorylated by aurora b and cdk1, (ii) pp2a dephosphorylates aurora b and cdk1 phosphorylated sites and (iii) inhibition of pp2a abrogates mgcracgap/ect2 interaction. Therefore, pp2a may regulate cytokinesis by dephosphorylating mgcracgap and its interacting partners." SIGNOR-160402 CCKAR protein P32238 UNIPROT GNA14 protein O95837 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257361 ZNF804A protein Q7Z570 UNIPROT PIK3AP1 protein Q6ZUJ8 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000007 23434502 t miannu "ZNF804A has been implicated in susceptibility to schizophrenia by several genome-wide association studies (GWAS), follow-up association studies and meta-analyses. ZNF804A was identified as a schizophrenia-associated gene by GWAS and was predicted to play a role in DNA binding and transcription To identify the genes that are affected by ZNF804A, we manipulated the expression of the ZNF804A protein in HEK293 human embryonic kidney cell lines and performed a cDNA microarray analysis followed by qPCR. We found that ZNF804A-overexpression up-regulated four genes (ANKRD1, INHBE, PIK3AP1, and DDIT3) and down-regulated three genes (CLIC2, MGAM, and BIRC3)." SIGNOR-269463 CSNK2A1 protein P68400 UNIPROT CD5 protein P06127 UNIPROT up-regulates phosphorylation Ser483 SMQPDNSsDSDYDLH 9606 9834084 t lperfetto "In this study, we use jurkat t cell transfectants of cd5 cytoplasmic tail mutants to reveal phosphorylation sites relevant to signal transduction. Our results show that casein kinase ii (ckii) is responsible for the constitutive phosphorylation of cd5 molecules at a cluster of three serine residues located at the extreme c terminus (s458, s459, and s461)" SIGNOR-62307 PRKCA protein P17252 UNIPROT RRAD protein P55042 UNIPROT unknown phosphorylation Ser214 LVRSREVsVDEGRAC -1 9677319 t lperfetto "Here we show that Rad serves as a substrate for phosphorylation by CaMKII, cAMP-dependent protein kinase (PKA), protein kinase C (PKC) and casein kinase II (CKII) with stoichiometries in vitro of 0.2-1.3 mol of phosphate/mol of Rad. | PKC and CKII phosphorylate multiple C-terminal serine residues, including Ser214, Ser257, Ser273, Ser290 and Ser299. | However, phosphorylation of Rad by PKC and CKII abolishes the interaction of Rad with calmodulin. These findings suggest that the binding of Rad to calmodulin, as well as its ability to bind GTP, might be regulated by the activation of several serine kinases." SIGNOR-249000 DIP2A protein Q14689 UNIPROT SOD1 protein P00441 UNIPROT "up-regulates activity" binding 10090 BTO:0000142 33781892 t miannu "DIP2a is associated with SOD in the mitochondria of mouse brain. DIP2a knockout inhibited SOD activity. In this paper, we analyzed the interacting proteins of DIP2A by mass spectrum analysis and found that DIP2A was correlated with superoxide dismutase (SOD), SOD1 and SOD2. Knockout of DIP2A decreased SOD activity and increased the level of ROS in the mouse brain." SIGNOR-266591 PKM protein P14618 UNIPROT STAT3 protein P40763 UNIPROT up-regulates phosphorylation Tyr705 DPGSAAPyLKTKFIC 9606 22306293 t llicata "Pkm2 activates transcription of mek5 by phosphorylating stat3 at y705. pkm2 regulates mek5 transcription via activation of stat3" SIGNOR-195766 PRKACA protein P17612 UNIPROT MIP protein P30301 UNIPROT "down-regulates activity" phosphorylation Ser229 LLFPRLKsISERLSV -1 2176601 t miannu "Phosphorylation at one of these sites (serine 243) could be increased by A kinase in vitro. phosphorylation of MIP reconstituted into single bilayers increased the voltage dependence and long-term closures of the channels observed." SIGNOR-250018 "Multiaminoacyl-tRNA synthetase" complex SIGNOR-C472 SIGNOR Ile-tRNA(Ile) smallmolecule CHEBI:29160 ChEBI "up-regulates quantity" "chemical modification" 9606 28271488 t miannu "Aminoacyl-tRNA synthetases (AARSs) are essential enzymes that specifically aminoacylate one tRNA molecule by the cognate amino acid. In mammals, nine synthetases, those specific for amino acids Arg, Asp, Gln, Glu, Ile, Leu, Lys, Met and Pro, associate into a multi-aminoacyl-tRNA synthetase complex, an association which is believed to play a key role in the cellular organization of translation, but also in the regulation of the translational and nontranslational functions of these enzymes." SIGNOR-270422 PTPN2 protein P17706 UNIPROT INSR protein P06213 UNIPROT down-regulates dephosphorylation Tyr1190 DIYETDYyRKGGKGL 9606 10734133 t flangone "Finally, we have tested the set of ptps for their ability to dephosphorylate a phosphopeptide corresponding to the irk autophosphorylation site. tc-ptp, sap-1, and ptp-1b all tested positive, but ptp-? Showed no activity, although the same gst-ptp preparation could efficiently convert pnpp (tablei). Interestingly, many other ptps showed activity, namely dep-1, glepp-1, lar, ptp-?, -?, -?, And shp-1." SIGNOR-75918 SMOC1 protein Q9H4F8 UNIPROT SPARC protein P09486 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 20359165 f lperfetto "The expression of several osteoblast differentiation markers (ALP, COL1, OPN, ON, BSP and OC) was higher in SMOC1-overexpressing cells than in emptyvector-expressing cells" SIGNOR-260401 MAPK1 protein P28482 UNIPROT NR4A2 protein P43354 UNIPROT up-regulates phosphorylation Ser126 SVYYKPSsPPTPTTP 9606 BTO:0000938 BTO:0000142 17681692 t llicata "We have shown that erk2 is a kinase to phosphorylate nurr1 on multiple sites. S126 and t132, which are located near af1 core of nurr1, are dominant sites phosphorylated by erk2. reporter gene assays show that nurr1delta124-133/t185a, an erk2 phospho-site mutant form, could not further increase its transcriptional activity on th promoter, suggesting that nurr1 phosphorylation by erk2 may regulate its transcriptional activity on th promoter." SIGNOR-157167 ATM protein Q13315 UNIPROT TP53 protein P04637 UNIPROT "up-regulates quantity by stabilization" phosphorylation Ser15 PSVEPPLsQETFSDL 9606 17967874 t lperfetto "In this study, we show that the increased interaction between B56gamma and p53 after DNA damage requires ATM-dependent phosphorylation of p53 at Ser15." SIGNOR-158632 FGF2 protein P09038 UNIPROT HBB protein P68871 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 8142649 f Regulation miannu "Basic fibroblast growth factor (bFGF) and transforming growth factor-beta 1 (TGF-beta) have both been shown to act on hematopoietic progenitor cells. bFGF antagonized the TGF-beta-mediated induction of hemoglobin in a dose-dependent manner, with 0.1 ng/mL bFGF inhibiting hemoglobin induction by 40% and 10 ng/mL bFGF completely abrogating hemoglobin production." SIGNOR-251795 E2F3 protein O00716 UNIPROT TFDP1 protein Q14186 UNIPROT "up-regulates activity" binding 10029 BTO:0000246 8832394 t 2 miannu "The transcriptionally active forms of E2F are heterodimers composed of one polypeptide encoded by the E2F gene family and one polypeptide encoded by the DP gene family.In transfected cells, DP-1 did not accumulate in the nucleus unless it was coexpressed with the heterodimeric partners E2F-1, E2F-2, or E2F-3." SIGNOR-240553 RPS6KA5 protein O75582 UNIPROT H3-3A protein P84243 UNIPROT "down-regulates activity" phosphorylation Ser11 TKQTARKsTGGKAPR 9606 10464286 t "Ser 11 phosphorylation of H3 is either activatory and inhibitory as promotes DNA condensation (activatory) and induce transcription (inhibitory)." gcesareni "Phosphorylation at ser-11 (h3s10ph) by rps6ka4 and rps6ka5 is important during interphase because it enables the transcription of genes following external stimulation, like mitogens, stress, growth factors or uv irradiation and result in the activation of genes, such as c-fos and c-jun." SIGNOR-70440 hydrogencarbonate smallmolecule CHEBI:17544 ChEBI "GABA-A (a4-b2-d) receptor" complex SIGNOR-C326 SIGNOR "up-regulates activity" "chemical activation" 9606 BTO:0000938 26136660 t miannu "The raise in the intracellular bicarbonate concentration may augment the depolarizing efflux of bicarbonate upon activation of GABAA receptors; however, both transporters also extrude chloride and thereby increase the gradient for a hyperpolarizing chloride current." SIGNOR-264924 CHEK2 protein O96017 UNIPROT RB1 protein P06400 UNIPROT "up-regulates activity" phosphorylation Ser612 MYLSPVRsPKKKGST 9606 BTO:0000093 17380128 t lperfetto "Phosphorylation of prb at ser612 by chk1/2 leads to a complex between prb and e2f-1 after dna damageprb inhibits cell cycle progression through interactions with the e2f family of transcription factors. Here, we report that dna damage induced not only the dephosphorylation of prb at cdk phosphorylation sites and the binding of prb to e2f-1, but also the phosphorylation of prb at ser612. Phosphorylation of prb at ser612 enhanced the formation of a complex between prb and e2f-1" SIGNOR-153908 "SMN complex" complex SIGNOR-C158 SIGNOR Spliceosomal_snRNP_assembly phenotype SIGNOR-PH79 SIGNOR up-regulates 9606 9323129 f lperfetto "These findings suggest a role for SMN and SIP1 in spliceosomal snRNP biogenesis and function and provide a likely molecular mechanism for the cause of SMA" SIGNOR-253123 ILK protein Q13418 UNIPROT MYL12B protein O14950 UNIPROT "up-regulates activity" phosphorylation Ser20 KRPQRATsNVFAMFD 9606 11278951 t lperfetto "Integrin-linked kinase cdna was cloned, sequenced, expressed in e. coli, and shown to phosphorylate myosin light chain in the absence of ca(2+) at ser(19) and thr(18). Smooth muscle contraction follows an increase in cytosolic Ca(2+) concentration, activation of myosin light chain kinase, and phosphorylation of the 20-kDa light chain of myosin at Ser(19)." SIGNOR-106423 AATK protein Q6ZMQ8 UNIPROT CDK5R1 protein Q15078 UNIPROT up-regulates binding 9606 BTO:0000007 BTO:0000142 14521924 t gcesareni "Apoptosis-associated tyrosine kinase is a cdk5 activator p35 binding protein." SIGNOR-118403 MAPK1 protein P28482 UNIPROT SMAD2 protein Q15796 UNIPROT up-regulates phosphorylation Ser250 TGSPAELsPTTLSPV 9606 BTO:0000763 12193595 t miannu "Phosphorylation of smad2 by erk increases its transcriptional activity /thr220 and ser245, ser250, and ser255 were possible phosphorylation sites. The phosphorylation of peak a peptide by erk1 is consistent with that prediction." SIGNOR-91718 DNA_damage stimulus SIGNOR-ST1 SIGNOR CHEK2 protein O96017 UNIPROT "up-regulates activity" 9606 19151762 f lperfetto "Cell cycle progression is monitored constantly to ensure faithful passage of genetic codes and genome stability. We have demonstrated previously that, upon DNA damage, TTK/hMps1 activates the checkpoint kinase CHK2 by phosphorylating CHK2 at Thr68" SIGNOR-242605 isoprenaline chemical CHEBI:64317 ChEBI ADRB1 protein P08588 UNIPROT "up-regulates activity" "chemical activation" 9534 BTO:0000298 8982677 t miannu "K i values of the agonists for [~25I]iodocyanopindolol binding to the COS-7 cell membranes are shown in Table 1. In the membranes expressing one of the 13-adrenoceptor subtypes, both isoproterenol and T-0509 caused monophasic dis- placement of [~25I]iodocyanopindolol, suggesting a single binding site of the agonists." SIGNOR-258578 MAPK3 protein P27361 UNIPROT IRS1 protein P35568 UNIPROT "down-regulates activity" phosphorylation Ser616 DDGYMPMsPGVAPVP 9606 15001544 t lperfetto "Rin beta-cells exposed to high glucose exhibited increased c-jun n-terminal kinase (jnk) and erk1/2 activity, which was associated with increased irs-1 phosphorylation at serine (ser)(307) and ser(612), respectively, that inhibits coupling of irs-1 to the insulin receptor and is upstream of the inhibition of irs-1 tyrosine phosphorylation." SIGNOR-123177 NFATC1 protein O95644 UNIPROT PTGS2 protein P35354 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 21871017 t miannu "NFAT induces the transcription of the COX2 (cyclo-oxygenase-2) gene incancer cells thereby enhancing invasive migration" SIGNOR-264026 ATF4 protein P18848 UNIPROT SIGMAR1 protein Q99720 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 22079628 f miannu "we have demonstrated that Sig-1Rs were transcriptionally upregulated by ATF4 in ER stress." SIGNOR-253750 FBXW11 protein Q9UKB1 UNIPROT AICDA protein Q9GZX7 UNIPROT "down-regulates quantity by destabilization" binding 9606 BTO:0000007 31092637 t miannu " Further analysis indicated that CUL7 mediated AID ubiquitination by forming a complex with FBXW11. In a CUL7 fl/fl CD19 cre+ mouse model, we demonstrated that CUL7 knockout significantly enhanced AID protein levels in B cells in the germinal center and increased both the IgG1 and IgA class switching. Collectively, our results reveal a subtle regulation mechanism for tightly controlling AID protein levels. F-box proteins are components of SCF ubiquitin-ligase complexes that contain Skp1, CUL1, or CUL7, and an F-box protein" SIGNOR-272024 DEK protein P35659 UNIPROT "B-WICH complex" complex SIGNOR-C447 SIGNOR "form complex" binding 9606 21559432 t miannu "The B-WICH complex is an extended form of WICH [26], and is involved in both RNA pol I and RNA pol III transcription [20], [21]. In addition to the three core proteins, WSTF, SNF2h, and nuclear myosin (NM1); the myb binding protein 1b, RNA helicase II/DXX21, and SAP155 all also associate via RNA species [21]. The subunit SNF2h is an ISWI ATPase, which slides nucleosomes in an ATP-dependent manner [27]. WSTF is a component of several complexes: two SNF2h complexes, B-WICH [21] and WICH [26], and one SWI/SNF type of chromatin remodelling complex, the WINAC complex, which is involved in vitamin D-mediated RNA pol II transcription" SIGNOR-268823 IL1A protein P01583 UNIPROT IL1R1 protein P14778 UNIPROT "up-regulates activity" binding 9606 BTO:0001573 9565970 t lperfetto "Il-1ri is responsible for il-1 signaling" SIGNOR-56718 EZH2 protein Q15910 UNIPROT "Polycomb repressive complex 2" complex SIGNOR-C130 SIGNOR "form complex" binding 9606 23110252 t lperfetto "The PRC2 core, conserved from Drosophila to humans, is composed of four proteins that add up to about 230 kDa (Figure 1A) (see Margueron and Reinberg, 2010 for a recent review): EED (present in different isoforms), either one of the two methyltranferases Ezh1 or Ezh2 (Ezh1/2), Suz12, and either RbAp46 or RbAp48 (RbAp46/48)." SIGNOR-241894 GSK3B protein P49841 UNIPROT MAPT protein P10636 UNIPROT "down-regulates activity" phosphorylation Ser519 SGYSSPGsPGTPGSR 9606 BTO:0000590 12387894 t lperfetto "We found that cdk5 phosphorylated tau(441) at Thr-181, Ser-199, Ser-202, Thr-205, Thr-212, Ser-214, Thr-217, Thr-231, Ser-235, Ser-396, and Ser-404, but not at Ser-262, Ser-400, Thr-403, Ser-409, Ser-413, or Ser-422. GSK-3beta phosphorylated all the cdk5-catalyzed sites above except Ser-235." SIGNOR-249343 APEX1 protein P27695 UNIPROT Base-excision_repair phenotype SIGNOR-PH222 SIGNOR up-regulates 23545420 f lperfetto "An essential role of BER has been documented by inactivating functions of proteins in the common steps of BER. Thus, the major AP-endonuclease in mammalian cells, APE1, is essential for survival, as shown using knockout mice (Friedberg and Meira 2006). APE1 (also called HAP1 and Apex) carries both an AP-endonuclease activity and a redox function required for activation of several transcription factors" SIGNOR-275721 "adenosine 5'-monophosphate" smallmolecule CHEBI:16027 ChEBI IMP smallmolecule CHEBI:17202 ChEBI "up-regulates quantity" "precursor of" 9606 BTO:0001103 1631143 t miannu "AMP deaminase (AMPD; EC 3.5.4.6) is encoded by a multigene family in mammals. The AMPD1 gene is expressed at high levels in skeletal muscle, where this enzyme is thought to play an important role in energy metabolism. AMP deaminase (AMPD; EC 3.5.4.6), an enzyme that catalyzes deamination of AMP to IMP, and the purine nucleotide cycle, of which AMPD is one component, play a central role in purine nucleotide interconversion in eukaryotic cells." SIGNOR-269774 EIF4A3 protein P38919 UNIPROT "Exon junction complex" complex SIGNOR-C369 SIGNOR "form complex" binding -1 16923391 t miannu "The EJC is deposited onto mRNA during splicing and is transported to the cytoplasm where it influences translation, surveillance, and localization of the spliced mRNA. The complex is formed by the association of four proteins (eIF4AIII, Barentsz [Btz], Mago, and Y14), mRNA, and ATP." SIGNOR-265240 PFKP protein Q01813 UNIPROT "beta-D-fructofuranose 1,6-bisphosphate(4-)" smallmolecule CHEBI:32966 ChEBI "up-regulates quantity" "chemical modification" 9606 16051738 t miannu "Phosphofructokinase catalyzes the rate-limiting, ATP-mediated phosphorylation of F6P to FBP. PFK is a homo- or heterotetramer with a molecular mass of approximately 380 kDa, and the enzyme is allosterically regulated, among other metabolites, by 2,3-DPG.35." SIGNOR-266473 RETREG3 protein Q86VR2 UNIPROT Neurite_outgrowth phenotype SIGNOR-PH134 SIGNOR up-regulates 9606 BTO:0000934 23939472 f lperfetto "We found that NRF-1 positively regulates FAM134C and ENOX1, but negatively regulates C3orf10 in human neuroblastoma IMR-32 cells and primary rat cortical neurons. In IMR-32 cells, FAM134C positively regulates and C3orf10 negatively regulates neurite outgrowth, but ENOX1 plays no role in neurite outgrowth regulation. " SIGNOR-261490 SREBF1 protein P36956 UNIPROT VLDL_assembly phenotype SIGNOR-PH62 SIGNOR up-regulates 9606 11111091 f miannu "SREBP1 increased the expression of MTP and increased the assembly and secretion of VLDL containing apo B100. SREBP1 induced the expression of the genes regulating the synthesis of all VLDL lipids" SIGNOR-252112 NPY protein P01303 UNIPROT NPY5R protein Q15761 UNIPROT up-regulates binding 9606 11825645 t gcesareni "Npy expression significantly increases whereas the gene expression of its receptors npy1r, npy2r, and npy5r initially decreases." SIGNOR-114746 RFX4 protein Q33E94 UNIPROT IFT172 protein Q9UG01 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 19887680 f miannu "We find that Ift172, which encodes an intraflagellar transport protein necessary for ciliogenesis, is a direct transcriptional target of Rfx4" SIGNOR-223319 CSNK1A1 protein P48729 UNIPROT FOXO3 protein O43524 UNIPROT down-regulates phosphorylation Ser318 SRTNSNAsTVSGRLS 9606 20110348 t lperfetto "Casein kinase (ck) 1 mediates the hierarchical phosphorylation of foxo3a at s318 and s321, which like foxo1 (rena et al., 2002 blue right-pointing triangle, 2004 blue right-pointing triangle), is probably to enhance its rate of nuclear export" SIGNOR-163672 CDK5 protein Q00535 UNIPROT TP53 protein P04637 UNIPROT up-regulates phosphorylation Ser33 LPENNVLsPLPSQAM 9606 17591690 t llicata "We show that cdk5 phosphorylates p53 on ser15, ser33 and ser46 cdk5-stabilized p53 protein is transcriptionally active" SIGNOR-156422 PRKACA protein P17612 UNIPROT RASGRF1 protein Q13972 UNIPROT up-regulates phosphorylation Ser927 KEKYRRMsLASAGFP 9606 BTO:0000938 10601308 t llicata "Phosphorylation of serine 916 of ras-grf1 contributes to the activation of exchange factor activity by muscarinic receptors." SIGNOR-73202 capecitabine chemical CHEBI:31348 ChEBI TYMS protein P04818 UNIPROT "down-regulates activity" "chemical inhibition" 9606 15866500 t miannu "These findings suggest that the mechanism of antiproliferative toxicity of capecitabine is at least partly due to TS inhibitory activity of its active metabolite 5-fluoro-2'-deoxyuridine monophosphate (FdUMP)." SIGNOR-259354 GSK3B protein P49841 UNIPROT HSF1 protein Q00613 UNIPROT "down-regulates activity" phosphorylation Ser303 RVKEEPPsPPQSPRV -1 8940068 t "Ser-303 is phosphorylated by glycogen synthase kinase 3 (GSK3) through a mechanism dependent on primary phosphorylation of Ser-307 by MAPK. Secondary phosphorylation of Ser-303 by GSK3 may thus repress the activity of HSF-1, and its requirement for priming by MAPK phosphorylation of Ser-307 provides a potential link between the MAPK cascade and HSF-1." SIGNOR-251216 masitinib chemical CHEBI:63450 ChEBI PDGFRA protein P16234 UNIPROT "down-regulates activity" "chemical inhibition" -1 22037378 t Luana "Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here." SIGNOR-258245 PLK1 protein P53350 UNIPROT RIOK2 protein Q9BVS4 UNIPROT "up-regulates activity" phosphorylation Ser335 TKEGSEFsFSDGEVA -1 21880710 t miannu "Here, we report that the atypical protein kinase Rio2 is a novel substrate of Plk1 and can be phosphorylated by Plk1 at Ser-335, Ser-380, and Ser-548. Overexpression of Rio2 causes a prolonged mitotic exit whereas knockdown of Rio2 accelerates mitotic progression, suggesting that Rio2 is required for the proper mitotic progression. F urthermore, time-lapse imaging data show that overexpression of Rio2 but not Rio2 S3A results in a slowed metaphase-anaphase transition. Collectively, these findings strongly indicate that the Plk1-mediated phosphorylation of Rio2 regulates metaphase-anaphase transition during mitotic progression." SIGNOR-262937 SUCLA2 protein Q9P2R7 UNIPROT "Succinyl-CoA ATP variant" complex SIGNOR-C398 SIGNOR "form complex" binding 9606 32627745 t miannu "Succinyl-CoA synthetase (SCS) catalyzes the only substrate-level phosphorylation in the tricarboxylic acid cycle.  In mammals, SCS is a mitochondrial enzyme and is an α,β-heterodimer with different isoforms: ATP-specific SCS (ATPSCS) and GTP-specific SCS (GTPSCS)." SIGNOR-266262 AR protein P10275 UNIPROT AR protein P10275 UNIPROT "up-regulates activity" binding 9606 15861399 t miannu "The unliganded AR resides predominately in the cytoplasm as a heteromeric complex with hsp90 and other chaperone proteins. These chaperone proteins maintain AR in a form that is receptive to ligand binding. Regulation of gene expression by androgen-activated AR occurs through receptor nuclear translocation, dimerization, and binding to androgen response elements (AREs) in the DNA of target genes." SIGNOR-251537 ADSS1 protein Q8N142 UNIPROT IMP smallmolecule CHEBI:17202 ChEBI "down-regulates quantity" "chemical modification" 9606 10496970 t miannu "Adenylosuccinate synthetase catalyzes the first committed step in the de novo biosynthesis of AMP, thermodynamically coupling the hydrolysis of GTP to the formation of adenylosuccinate from l-aspartate and IMP." SIGNOR-267344 GSK3A protein P49840 UNIPROT MITF protein O75030 UNIPROT up-regulates phosphorylation Ser405 QARAHGLsLIPSTGL 9606 10587587 t "The effect has been demonstrated using O75030-9" gcesareni "Glycogen synthase kinase 3 (gsk3) was found to phosphorylate ser298 in vitro, thereby enhancing the binding of mitf to the tyrosinase promoter" SIGNOR-72878 CACNA1G protein O43497 UNIPROT calcium(2+) smallmolecule CHEBI:29108 ChEBI "up-regulates quantity" relocalization 9606 30849329 t miannu "Voltage-gated calcium channels mediate the influx of calcium in response to membrane depolarization in excitable cells. In presynaptic nerve terminals, this calcium influx triggers transmitter release for synaptic transmission. Several neurological and cardiac disorders are caused by pathogenic variants in genes encoding α1-subunits of voltage-gated calcium channels, including CACNA1A (MIM: 601011) (familial hemiplegic migraine [MIM: 141500], episodic ataxia [MIM: 108500], and epilepsy [MIM: 617106]),3, 4, 5 CACNA1C (MIM: 114205) (Timothy syndrome [MIM: 601005]),6, 7 CACNA1D (MIM: 114206) (primary aldosteronism, neurodevelopmental disorders [MIM: 615474]),8, 9 and CACNA1G (MIM: 604065) (spinocerebellar ataxia [MIM: 616795])." SIGNOR-264324 RUNX2 protein Q13950 UNIPROT COL2A1 protein P02458 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 11331591 f gcesareni "In addition to osteocalcin, cbfa1 regulates expression of several other genes that are activated during osteoblast" SIGNOR-107169 CYP26A1 protein O43174 UNIPROT "all-trans-retinoic acid" smallmolecule CHEBI:15367 ChEBI "down-regulates quantity" "chemical modification" 9606 31963453 t lperfetto "Cytochrome P450 (CYP) subfamily 26 of enzymes degrade the excess of RA to avoid detrimental effects [17]. Among the three subtypes (CYP26A1, CYP26B1, and CYP26C1), CYP26A1 is particularly important during embryonic development" SIGNOR-265139 LYN protein P07948 UNIPROT PDIA3 protein P30101 UNIPROT unknown phosphorylation Tyr454 VRGFPTIyFSPANKK -1 8631326 t miannu "Lyn phosphorylates tyrosine residues Y444, Y453 and Y466 which are located in a highly acidic region of the protein at the C-terminus. Upon phosphorylation, p57 forms a complex with Lyn which can be immunoprecipitated with anti-Lyn IgG. The association which occurs between the phosphorylated substrate and the SH2 domain of the kinase is consistent with the suggested 'processive phosphorylation' model, which implies that a primary phosphorylation site of the substrate binds to the SH2 domain of the enzyme and triggers the phosphorylation at secondary site(s)." SIGNOR-262895 CLOCK/BMAL1 complex SIGNOR-C195 SIGNOR MTA1 protein Q13330 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 24089055 t lperfetto "Here we provide genetic and biochemical evidence that metastasis-associated protein 1 (MTA1), a widely upregulated gene product in human cancers, is an integral component of the circadian molecular machinery. | The CLOCK-BMAL1 heterodimer activates MTA1 transcription through a conserved E-box element at its promoter. MTA1, in turn, interacts with and recruits CLOCK-BMAL1 at its own and CRY1 promoters and promotes their transcription." SIGNOR-253718 SB-202190 chemical CHEBI:79090 ChEBI MAPK14 protein Q16539 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-206697 MAPK1 protein P28482 UNIPROT AHNAK protein Q09666 UNIPROT unknown phosphorylation Thr694 LPDMSVKtPKISMPD 10090 22028470 t miannu "We have optimized a chemical genetic system using analog-sensitive ERK2, a form of ERK2 engineered to use an analog of adenosine 5'-triphosphate (ATP), to tag and isolate ERK2 substrates in vitro. This approach identified 80 proteins phosphorylated by ERK2, 13 of which are known ERK2 substrates. With this improved methodology, we detected 98 sites directly phosphorylated by ERK2 on 80 proteins from NIH 3T3-L1 fibroblasts. Thirteen of these proteins are known substrates and the rest represent previously unknown kinase/substrate interactions. (table1)" SIGNOR-262768 CEBPA protein P49715 UNIPROT SPI1 protein P17947 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 14592841 t "Activation of C/EBPα induces PU.1 expression, cell cycle arrest, and differentiation in 32D cells expressing FLT3/ITD" SIGNOR-261531 PTK2B protein Q14289 UNIPROT ASAP1 protein Q9ULH1 UNIPROT "down-regulates activity" phosphorylation Tyr767 RDKQRLSyGAFTNQI 9606 BTO:0000007 12771146 t miannu "The tyrosine kinase Pyk2 regulates Arf1 activity by phosphorylation and inhibition of the Arf-GTPase-activating protein ASAP1. Pyk2 directly phosphorylates ASAP1 on tyrosine residues in vitro and increases ASAP1 tyrosine phosphorylation when co-expressed in HEK293T cells.Phosphorylation of tyrosine 308 and 782 affects the phosphoinositide binding profile of ASAP1, and fluorimetric Arf-GTPase assays with purified proteins revealed an inhibition of ASAP1 GTPase-activating protein activity by Pyk2-mediated tyrosine phosphorylation." SIGNOR-263187 STK3/4 proteinfamily SIGNOR-PF41 SIGNOR SAV1 protein Q9H4B6 UNIPROT "up-regulates activity" phosphorylation 9606 21084559 t miannu "Mst is activated by binding of salvador (sav1, sav in drosophila), which is, in turn, also phosphorylated by mst." SIGNOR-256184 VEGFD protein O43915 UNIPROT FLT4 protein P35916 UNIPROT up-regulates binding 9606 9435229 t gcesareni "Vegf-d is a ligand for both vegf receptors (vegfrs) vegfr-2 (flk1) and vegfr-3 (flt4) and can activate these receptors." SIGNOR-55065 CSNK1E protein P49674 UNIPROT TCF3 protein P15923 UNIPROT up-regulates phosphorylation 9606 11524435 t gcesareni "Tcf3 is a substrate for both glycogen synthase kinase (gsk) 3 and casein kinase (ck) 1epsilon, and phosphorylation of tcf3 by ckiepsilon stimulates its binding to beta-catenin, an effect reversed by gsk3." SIGNOR-110056 NHLH2 protein Q02577 UNIPROT MAOA protein P21397 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 BTO:0000142 22169038 f miannu "SIRT1 deacetylates the brain-specific helix-loop-helix transcription factor NHLH2 on lysine 49 to increase its activation of the MAO-A promoter" SIGNOR-254829 CDK1 protein P06493 UNIPROT ORC1 protein Q13415 UNIPROT up-regulates phosphorylation Thr375 AQNEATStPHRIRRK 9606 11931757 t lperfetto "Horc1p contains three (s/t)px(k/r) consensus sites for cdk phosphorylation (ser258, ser273, and thr375). These data combined strongly suggest that skp2 promotes horc1p turnover and that the n-terminal domain of horc1p, containing most of the phosphorylation sites and overlapping with one of the skp2-interacting domains, is a regulatory element for horc1p stability." SIGNOR-116329 MMP15 protein P51511 UNIPROT ECM_disassembly phenotype SIGNOR-PH80 SIGNOR up-regulates 17318226 f lperfetto "Historically, MMPs were thought to function mainly as enzymes that degrade structural components of the ECM." SIGNOR-272360 PRKCA protein P17252 UNIPROT PLD2 protein O14939 UNIPROT up-regulates phosphorylation Thr252 LLYMCLEtGAISFVQ 9606 15979581 t miannu "The phosphorylation sites in phospholipase d2 (pld2) induced by activation of protein kinase calpha (pkcalpha) in cos 7 cells were analyzed by mass spectrometry. Ser134, 146, and 243, and thr72, 99/100, and 252 were identified. These sites were mutated to ala and the double mutation of ser243 and thr252 eliminated the phosphorylation. / the s243/t252a mutant showed a partial decrease in pld2 activity" SIGNOR-138355 TNFAIP3 protein P21580 UNIPROT RIPK1 protein Q13546 UNIPROT "down-regulates quantity" ubiquitination 9606 15258597 t "A20The carboxy-terminal domain of A20, composed of seven C2/C2 zinc fingers, then functions as a ubiquitin ligase by polyubiquitinating RIP with K48-linked ubiquitin chains, thereby targeting RIP for proteasomal degradation." SIGNOR-259977 SRC protein P12931 UNIPROT EZR protein P15311 UNIPROT up-regulates phosphorylation Tyr478 PPPPPPVyEPVSYHV 9606 22397367 t lperfetto "Ezrin, a member of the erm family of proteins, is frequently over-expressed in human breast cancers, and is required for motility and invasion of epithelial cells. In particular, ezrin phosphorylation on y477 by src is specific to ezrin within the erm family, and is required for hgf-induced scattering of epithelial cells." SIGNOR-196443 PRKCA protein P17252 UNIPROT MBP protein P02686 UNIPROT unknown phosphorylation Ser249 GLSLSRFsWGAEGQR -1 2413024 t lperfetto "MBP was phosphorylated by either protein kinase A or C | Subsequent amino acid analysis and/or sequential Edman degradation of the purified phosphopeptides, together with the known primary sequence of this protein, revealed that Ser-46 and Ser-151 were specifically phosphorylated by protein kinase C, whereas Thr-34 and Ser-115 were phosphorylated preferentially by protein kinase A. Both kinases reacted with Ser-8, Ser-11, Ser-55, Ser-110, Ser-132, and Ser-161 at various reaction velocities." SIGNOR-248872 RSPO1 protein Q2MKA7 UNIPROT ZNRF3 protein Q9ULT6 UNIPROT down-regulates relocalization 9606 23151663 t gcesareni "This is counteracted by respondin 1, which induces znrf3 internalization" SIGNOR-199629 NEK9 protein Q8TD19 UNIPROT NEK7 protein Q8TDX7 UNIPROT "up-regulates activity" phosphorylation Ser195 SKTTAAHsLVGTPYY 9606 BTO:0000007 12840024 t lperfetto "Nercc1 catalyzes the phosphorylation of nek6 (ser206) and the equivalent site on nek7 (ser195), resulting in a 20-25-fold activation of nek6/7 kinase activity" SIGNOR-103030 PTK6 protein Q13882 UNIPROT PTK6 protein Q13882 UNIPROT "up-regulates activity" phosphorylation Tyr447 RLSSFTSyENPT 9606 12121988 t lperfetto "Mutation of a C-terminal tyrosine (Tyr-447) increases enzyme activity and SH2 domain accessibility, consistent with a role for this residue in autoinhibition. | These results suggest that the Y447F and W44A mutations disrupt the normal intramolecular regulation of Brk and increase the catalytic activity of Brk." SIGNOR-249152 ARHGEF6 protein Q15052 UNIPROT Cell_migration phenotype SIGNOR-PH38 SIGNOR up-regulates 9606 BTO:0000599 23776207 f lperfetto "Expression of the phospho-mimicking ACAP4 mutant promotes ARF6-dependent cell migration." SIGNOR-272237 6-{4-[(4-ethylpiperazin-1-yl)methyl]phenyl}-N-[(1R)-1-phenylethyl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine chemical CHEBI:40629 ChEBI ERBB2 protein P04626 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-189347 SRC protein P12931 UNIPROT EZR protein P15311 UNIPROT up-regulates phosphorylation Tyr146 KEVHKSGyLSSERLI 9606 15647376 t llicata "N this study we have demonstrated that ezrin y145 is a direct target for phosphorylation by the tyrosine kinase src evidence from this study suggests that a positive feedback loop exists whereby src-mediated ezrin y145 phosphorylation sustains src activity._" SIGNOR-133227 sunitinib chemical CHEBI:38940 ChEBI PDGFRA protein P16234 UNIPROT down-regulates "chemical inhibition" 9606 21423276 t gcesareni "The vegfr/pdgfr inhibitor sunitinib (selleck) was used at 35 mg/kg in citrate-buffered water and administered daily by oral gavage for 7 days." SIGNOR-172923 HJURP protein Q8NCD3 UNIPROT CENPA protein P49450 UNIPROT "up-regulates activity" binding 9606 BTO:0000567 19410544 t miannu "Here we demonstrate that prenucleosomal CENP-A is complexed with histone H4, nucleophosmin 1, and HJURP. Recruitment of new CENP-A into nucleosomes at replicated centromeres is dependent on HJURP. Recognition by HJURP is mediated through the centromere targeting domain (CATD) of CENP-A, a region that we demonstrated previously to induce a unique conformational rigidity to both the subnucleosomal CENP-A heterotetramer and the corresponding assembled nucleosome. We propose HJURP to be a cell-cycle-regulated CENP-A-specific histone chaperone required for centromeric chromatin assembly." SIGNOR-263707 RNF7 protein Q9UBF6 UNIPROT CDC34 protein P49427 UNIPROT "down-regulates activity" polyubiquitination 9606 10851089 t miannu "SAG was found to be the second family member of Rbx (RING box protein) or ROC (Regulator of cullins) or Hrt that is a component of SCF E3 ubiquitin ligase. Indeed, like ROC1/Rbx1/Hrt1, SAG binds to Cul1 and SAG-Cul1 complex has ubiquitin ligase activity to promote poly-ubiquitination of E2/Cdc34. " SIGNOR-271443 PPP3CB protein P16298 UNIPROT TFEB protein P19484 UNIPROT "up-regulates activity" dephosphorylation Ser211 LVGVTSSsCPADLTQ 9606 BTO:0000007 26000950 t "Lysosomal Ca2+ release via mucolipin 1 (MCOLN1) activates calcineurin, which binds and de-phosphorylates TFEB, thus promoting its nuclear translocation." SIGNOR-255306 BCR-ABL "fusion protein" SIGNOR-FP6 SIGNOR GRB2 protein P62993 UNIPROT down-regulates phosphorylation Tyr209 TGMFPRNyVTPVNRN 9606 BTO:0000017 11726515 t lperfetto "Phosphorylation of grb2 by bcr/abl or egf receptor reduced its sh3-dependent binding to sos in vivo, but not its sh2-dependent binding to bcr/abl. Tyr209 within the c-terminal sh3 domain of grb2 was identified as one of the tyrosine phosphorylation sites" SIGNOR-112354 ACACB protein O00763 UNIPROT acetyl-CoA smallmolecule CHEBI:15351 ChEBI "down-regulates quantity" "chemical modification" 9606 20952656 t miannu "ACC catalyzes the carboxylation of acetyl-CoA to malonyl-CoA, the rate-limiting and first committed step in de novo fatty acid biosynthesis. Two isoforms of ACC exist in mammals, ACC1 and ACC2, and both enzymes function to carboxylate acetyl-CoA to form malonyl-CoA" SIGNOR-267106 ZMIZ1 protein Q9ULJ6 UNIPROT AR protein P10275 UNIPROT "up-regulates activity" binding 9606 BTO:0001321 14609956 t miannu "Our results demonstrate that hZimp10 is a novel AR interacting protein that augments AR-mediated transcription. Moreover, hZimp10 co-localized with AR and SUMO-1 at replication foci throughout S phase, and it was capable of enhancing sumoylation of AR in vivo." SIGNOR-263935 PRKG1 protein Q13976 UNIPROT GTF2I protein P78347 UNIPROT up-regulates phosphorylation Ser412 GIPFRRPsTYGIPRL 9606 BTO:0000671 12082086 t lperfetto "G-kinase phosphorylated tfii-i in vitro and in vivo on ser(371) and ser(743) outside of the interaction domain. G-kinase strongly enhanced tfii-i transactivation of a serum-response element-containing promoter in cos7 cells" SIGNOR-89849 FERMT2 protein Q96AC1 UNIPROT SRC protein P12931 UNIPROT "up-regulates activity" binding 9606 BTO:0000007 26037143 t miannu "Here we report that Src binds to and phosphorylates Kindlin-2 at Y193. Reciprocally, Kindlin-2-Y193 phosphorylation activates and maintains Src kinase activity. Kindlin-2-Y193 phosphorylation is also involved in its binding capacity with Migfilin and the recruitment of Migfilin to the focal adhesions. Functionally, we demonstrate that Kindlin-2-Y193 phosphorylation regulates Kindlin-2-mediated cell spreading and migration." SIGNOR-266101 DUSP4 protein Q13115 UNIPROT MAPK1 protein P28482 UNIPROT "down-regulates activity" dephosphorylation Thr185 HDHTGFLtEYVATRW 10116 7535768 t "Dephosphorylation and Inactivation of ERKs|A single protein kinase, MEK, activates ERK2 by phosphorylating threonine 183 and tyrosine 185" SIGNOR-248717 17alpha-hydroxypregnenolone smallmolecule CHEBI:28750 ChEBI dehydroepiandrosterone chemical CHEBI:28689 ChEBI "up-regulates quantity" "precursor of" 9606 BTO:0001363;BTO:0000050;BTO:0000056 17192295 t lperfetto "THE MICROSOMAL ENZYME P450c17 catalyzes two reactions: the 17α-hydroxylation of progesterone and pregnenolone and the subsequent cleavage of the C17–20 carbon bond to produce dehydroepiandrosterone (DHEA) and androstenedione. Whereas only 17α-hydroxylase activity is necessary for the production of corticosteroids, both activities of P450c17 are required to synthesize sex hormones." SIGNOR-268647 LYPLA2 protein O95372 UNIPROT GAP43 protein P17677 UNIPROT "down-regulates quantity by destabilization" deacetylation Cys4 cMRRTKQV 9606 BTO:0000567 21152083 t miannu "Acyl-protein thioesterase 2 catalyzes the deacylation of peripheral membrane-associated GAP-43. In this work, we investigated the deacylation of growth-associated protein-43 (GAP-43), a dually acylated protein at cysteine residues 3 and 4. Thus, the results demonstrate that APT-2 is the protein thioesterase involved in the acylation/deacylation cycle operating in GAP-43 subcellular distribution.we demonstrated that the reduction in the protein level was abrogated when cells were also treated with proteasome inhibitors (chloroquine, MG132 and lactacystin) which strongly suggest that GAP-43 deacylation is an early and necessary step for its later ubiquitination and degradation by the proteasome. In addition, it also suggests that acyl-protein thioesterase levels not only regulate palmitate turnover but also global protein turnover of GAP-43." SIGNOR-266768 ABL1 protein P00519 UNIPROT WASL protein O00401 UNIPROT unknown phosphorylation Tyr175 EITTNRFyGPQVNNI 10090 16199863 t gcesareni "Mutation of both tyrosines 175 and 256 to phenylalanine was required to abolish Abl-mediated phosphorylation of N-WASP in the presence of Grb2 [€] suggesting that phosphorylation at tyrosine 175 is not critical for comet tail formation by Shigella" SIGNOR-247666 IKBKB protein O14920 UNIPROT IRS1 protein P35568 UNIPROT "down-regulates activity" phosphorylation Ser312 TESITATsPASMVGG -1 12351658 t "IRS-1 is a novel direct substrate for IKK and that phosphorylation of IRS-1 at Ser(312) (and other sites) by IKK may contribute to the insulin resistance mediated by activation of inflammatory pathways." SIGNOR-251293 AKT2 protein P31751 UNIPROT AKT1S1 protein Q96B36 UNIPROT down-regulates phosphorylation 9606 SIGNOR-C3 17386266 t gcesareni "Insulin-stimulated phosphorylation of pras40 by akt/pkb suppresses its mtorc1 inhibitory activity." SIGNOR-153931 ITGB4 protein P16144 UNIPROT PIK3CG protein P48736 UNIPROT up-regulates binding 9606 9428518 t gcesareni "Stable expression of alpha6beta4 increased carcinoma invasion in a pi3k-dependent manner, and transient expression of a constitutively active pi3k increased invasion in the absence of alpha6beta4. Ligation of alpha6beta4 stimulated significantly more pi3k activity than ligation of beta1 integrins, establishing specificity among integrins for pi3k activation." SIGNOR-54703 FBXW11 protein Q9UKB1 UNIPROT CTNNB1 protein P35222 UNIPROT down-regulates binding 9606 9784611 t gcesareni "we conclude that beta-trcp is a component of an e3 ubiquitin ligase that is responsible for the targeted degradation of phosphorylated beta-catenin.We Found that the binding of beta-trcp to beta-catenin was direct" SIGNOR-60751 MAPK3 protein P27361 UNIPROT ADAM17 protein P78536 UNIPROT up-regulates phosphorylation Thr735 KPFPAPQtPGRLQPA 9606 12058067 t gcesareni "Extracellular signal-regulated kinase phosphorylates tumor necrosis factor alpha-converting enzyme at threonine 735: a potential role in regulated sheddingwe show that extracellular signal-regulated kinase (erk) acts as an intermediate in protein kinase c-regulated trka cleavage. We report that the cytosolic tail of the tumor necrosis factor alpha-converting enzyme (tace) is phosphorylated by erk at threonine 735. In addition, we show that erk and tace associate. This association is favored by erk activation and by the presence of threonine 735. In contrast to the erk route, the p38 mapk was able to stimulate trka cleavage in cells devoid of tace activity, indicating that other proteases are also involved in trka shedding." SIGNOR-89625 MDM2 protein Q00987 UNIPROT TP73 protein O15350 UNIPROT "down-regulates activity" binding 9606 17700533 t miannu "Since HDM2, a key negative regulator of p53, also binds to and inhibits p73, we asked whether p73 could mediate Nutlin-3-induced apoptosis." SIGNOR-255470 PMP22 protein Q01453 UNIPROT ITGA6 protein P23229 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 21518455 f Regulation miannu "Peripheral myelin protein-22 (PMP22) modulates alpha 6 integrin expression in the human endometrium. Overexpression of PMP22 was sufficient to increase α6 integrin surface expression with a concominant increase in binding to the extracellular matrix laminin, while a reduction in PMP22 suppressed α6 integrin surface expression." SIGNOR-251897 MCU_MICU3_variant complex SIGNOR-C501 SIGNOR calcium(2+) smallmolecule CHEBI:29108 ChEBI "up-regulates quantity" relocalization 9606 32315830 t miannu "MCU is a Ca2+-selective channel that mediates mitochondrial Ca2+ influx. The human channel contains tetrameric pore-forming MCU, regulatory subunits MICU1/2, and EMRE that is required both for channel function and MICU1/2-mediated Ca2+ regulation." SIGNOR-270873 "SWI/SNF complex" complex SIGNOR-C92 SIGNOR TP53 protein P04637 UNIPROT "up-regulates activity" binding 9606 BTO:0002181 11950834 t irozzo "Using genetic and biochemical approaches, we show that several subunits of the human SWI/SNF complex bind to the tumor suppressor protein p53 in vivo and in vitro.Molecular connection between p53 and the SWI/SNF complex implicates that (i) the SWI/SNF complex is necessary for p53-driven transcriptional activation, and (ii) the SWI/SNF complex plays an important role in p53-mediated cell cycle control." SIGNOR-256285 GRIPAP1 protein Q4V328 UNIPROT MAP3K1 protein Q13233 UNIPROT "up-regulates activity" binding 9606 BTO:0002181;BTO:0000142 17761173 t Giorgia "To examine whether GRASP‐1 interacts with MEKK1 and JNK1 in neurons, co‐immunoprecipitation experiments were performed with detergent‐solubilized extracts from cultured cortical neurons. Both antiJNK1 and anti‐MEKK1 antibodies immunoprecipitated GRASP‐1 from neuronal lysates. These results suggest that GRASP‐1 interacts with MEKK1 and JNK1 in neurons." SIGNOR-260640 NUP88 protein Q99567 UNIPROT NPC complex SIGNOR-C263 SIGNOR "form complex" binding 27016207 t lperfetto "The protein inventory of the NPC has been studied for a very diverse set of eukaryotes, including trypanosomes, fungi, plants, animals, and humans [4], [5], [6], [7], [8], [9]. In all cases, about 30 different Nups were found (Fig. 2)." SIGNOR-262076 SGK1 protein O00141 UNIPROT NEDD4L protein Q96PU5 UNIPROT "down-regulates activity" phosphorylation 9606 15586017 t "Regulation of localization" miannu "The serum and glucocorticoid inducible kinase 1 (SGK1) is induced in the aldosterone sensitive distal nephron (ASDN) where it may stimulate Na reabsorption, partly by inhibiting ubiquitin ligase Nedd4-2-mediated retrieval of epithelial Na+ channel ENaC from the luminal membrane." SIGNOR-251949 DFFA protein O00273 UNIPROT DFFB protein O76075 UNIPROT down-regulates binding 9606 BTO:0000567 9108473 t amattioni "Dff is a heterodimer of 40 kda and 45 kda subunits." SIGNOR-29729 Laminin-10 complex SIGNOR-C182 SIGNOR "A6/b1 integrin" complex SIGNOR-C164 SIGNOR "up-regulates activity" binding 12123670 t lperfetto "We have developed a cell-free assay for binding of solubilized beta1 integrins to their physiologically relevant ligands using an electrochemiluminescent detection method|Binding was clearly optimal for the presumed physiological ligands, i.e., collagen IV for a1b1, collagen I for a2b1, VCAM-Ig for a4b1, fibronectin (the 120-kDa cell attachment fragment was used) for a5b1, and laminin for a6b1." SIGNOR-253222 PRKAA1 protein Q13131 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR "up-regulates activity" phosphorylation Thr179 SSPDKRLtLSQIYEW 9606 BTO:0000007 17711846 t gcesareni "Phosphorylation by AMPK leads to the activtion of FOXO3 transcriptional activity without affecting FOXO3 subcellular localization." SIGNOR-252980 Laminin-1 complex SIGNOR-C183 SIGNOR "A6/b1 integrin" complex SIGNOR-C164 SIGNOR "up-regulates activity" binding 12123670 t lperfetto "We have developed a cell-free assay for binding of solubilized beta1 integrins to their physiologically relevant ligands using an electrochemiluminescent detection method|Binding was clearly optimal for the presumed physiological ligands, i.e., collagen IV for a1b1, collagen I for a2b1, VCAM-Ig for a4b1, fibronectin (the 120-kDa cell attachment fragment was used) for a5b1, and laminin for a6b1." SIGNOR-253221 RPS6KA3 protein P51812 UNIPROT TH protein P07101 UNIPROT up-regulates phosphorylation Ser40 GQGAPGPsLTGSPWP 9606 12421349 t "The effect has been demonstrated using P07101-3" gcesareni "Mitogen-activated protein-kinase (map) kinase-activated protein kinases 1 and 2 (mapkap kinase-1, mapkap kinase-2), were found to phosphorylate bacterially expressed human tyrosine hydroxylaserecombinant human tyrosine hydroxylase (hth1) was found to be phosphorylated by mitogen and stress-activated protein kinase 1 (msk1) at ser40 and by p38 regulated/activated kinase (prak) on ser19. Phosphorylation by msk1 induced an increase in vmax" SIGNOR-95483 PABPC1 protein P11940 UNIPROT eIF4F_complex complex SIGNOR-C44 SIGNOR "up-regulates activity" binding 9606 30209168 t miannu "The binding of PABP to mRNA poly(A) tails is followed by interactions with eukaryotic initiation factor (eIF4G) and other translation factors, including eIF4E, to constitute a translation initiation complex, which mediates cellular mRNA circularization and enhances cap-dependent translation by facilitating ribosome recycling" SIGNOR-260943 KAT2B protein Q92831 UNIPROT NOTCH proteinfamily SIGNOR-PF30 SIGNOR up-regulates acetylation 9606 22120716 t gcesareni "In earlier studies, we demonstrated that maml1 enhanced p300 acetyltransferase activity, which increased the acetylation of notch by p300.Acetylation controls notch stability and function in t-cell leukemia." SIGNOR-254311 SMAD6 protein O43541 UNIPROT PELI1 protein Q96FA3 UNIPROT up-regulates binding 9606 19352540 t gcesareni "Mad6-pellino-1 interaction abrogated signaling mediated by a complex of irak1." SIGNOR-185128 6-bromo-3-(1-methyl-4-pyrazolyl)-5-(3-piperidinyl)-7-pyrazolo[1,5-a]pyrimidinamine chemical CHEBI:131165 ChEBI CHEK2 protein O96017 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-206841 MYOG protein P15173 UNIPROT Skeletal_muscle_differentiation phenotype SIGNOR-PH1 SIGNOR "up-regulates activity" BTO:0001103 7532173 f "Simone Vumbaca" "These results suggest that at least initially, the muscle-forming regions contained cells with myogenic potential, and that this potential is lost in the myogenin mutants as development proceeds." SIGNOR-255644 PRKCA protein P17252 UNIPROT KIT protein P10721 UNIPROT down-regulates phosphorylation Ser746 RRSVRIGsYIERDVT 9606 7539802 t miannu "Phosphorylation of kit/scfr by pkc-_ in vitro: identification of ser-741 and ser-746 as the major phosphorylation sites for pkc / pkc, which acts in an scf-stimulated feedback loop, that negatively controls kit/scfr kinase activity" SIGNOR-28605 TFDP1 protein Q14186 UNIPROT PCNA protein P12004 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000972 14618416 f miannu "To assess transactivating activity of E2F1/DP-1, we also analyzed expression of ten putative transcriptional targets of this complex in HCCs. Expression levels of TFDP1 and E2F1 correlated with those of seven transcriptional targets ( TYMS, DHFR, PCNA, RRM1, CCNE1, CDC2, and MYBL2) that play important roles in the G1/S transition, and down-regulation of TFDP1 inhibited growth of Hep3B cells." SIGNOR-253858 L-aspartate(1-) smallmolecule CHEBI:29991 ChEBI N-acetyl-L-aspartate(2-) smallmolecule CHEBI:16953 ChEBI "up-regulates quantity" "precursor of" 9606 19524112 t miannu "The biosynthetic enzyme, aspartate-N-acetyltransferase (Asp-NAT; EC 2.3.1.17) is a CNS specific enzyme that catalyzes the transfer of acetate from acetyl-CoA to L-aspartate forming NAA." SIGNOR-267519 CDK5/CDK5R1 complex SIGNOR-C144 SIGNOR MAPT protein P10636 UNIPROT "down-regulates activity" phosphorylation Thr548 KKVAVVRtPPKSPSS 9606 BTO:0000590 12387894 t lperfetto "We found that cdk5 phosphorylated tau(441) at Thr-181, Ser-199, Ser-202, Thr-205, Thr-212, Ser-214, Thr-217, Thr-231, Ser-235, Ser-396, and Ser-404, but not at Ser-262, Ser-400, Thr-403, Ser-409, Ser-413, or Ser-422. GSK-3beta phosphorylated all the cdk5-catalyzed sites above except Ser-235." SIGNOR-251596 SLC44A2 protein Q8IWA5 UNIPROT NfKb-p65/p50 complex SIGNOR-C13 SIGNOR up-regulates 9606 12761501 f Giorgia "Large-scale identification and characterization of human genes that activate NF-kappaB and MAPK signaling pathways" SIGNOR-260390 CAMK2G protein Q13555 UNIPROT EGFR protein P00533 UNIPROT "down-regulates activity" phosphorylation Ser1070 DSFLQRYsSDPTGAL BTO:0000017 1309762 t llicata "The mechanism of desensitization of kinase activity can be accounted for, in part, by the EGF-stimulated phosphorylation of the receptor at Ser1046/7, a substrate for the multifunctional calmodulin-dependent protein kinase II in vitro. Mutation of Ser1046/7 by replacement with Ala residues blocks desensitization of the EGF receptor protein-tyrosine kinase activity. " SIGNOR-250694 CyclinE/CDK2 complex SIGNOR-C16 SIGNOR NPM1 protein P06748 UNIPROT "down-regulates activity" phosphorylation Thr234 SFKKQEKtPKTPKGP 9606 11278991 t lperfetto "We have recently found that nucleophosmin (npm/b23), a phosphoprotein primarily found in nucleolus, associates with unduplicated centrosomes and is a direct substrate of cdk2-cyclin e in centrosome duplication." SIGNOR-216674 GSK3B protein P49841 UNIPROT GYS1 protein P13807 UNIPROT "down-regulates activity" phosphorylation Ser641 YRYPRPAsVPPSPSL 9606 BTO:0000887;BTO:0001103 14593110 t lperfetto "Glycogen synthase kinase-3 (gsk-3) phosphorylates four serine residues in the cooh terminus of glycogen synthase. Phosphorylation of one of these residues, ser640 (site 3a), causes strong inactivation of glycogen synthase" SIGNOR-235793 GSK3B protein P49841 UNIPROT MAPT protein P10636 UNIPROT down-regulates phosphorylation Thr548 KKVAVVRtPPKSPSS 9606 21215781 t "The effect has been demonstrated using P10636-8" lperfetto "Gsk3b phosphorylates tau at t231tau phosphorylation at t231, s235 and s262 also contributes to the dissociation of tau from microtubules" SIGNOR-171046 PPP2CA protein P67775 UNIPROT AKT1 protein P31749 UNIPROT "down-regulates activity" dephosphorylation Ser473 RPHFPQFsYSASGTA 10090 BTO:0000944 15367694 t "Protein phosphatase 2A negatively regulates insulin's metabolic signaling pathway by inhibiting Akt (protein kinase B) activity in 3T3-L1 adipocytes" SIGNOR-252606 Kindlin proteinfamily SIGNOR-PF48 SIGNOR "AE/b7 integrin" complex SIGNOR-C186 SIGNOR "up-regulates activity" binding 9606 29544897 t miannu "Kindlins bind with β-integrin cytoplasmic tails and execute broad biological functions including directed cell migration, proliferation, differentiation and survival." SIGNOR-259010 GABARAP protein O95166 UNIPROT TBC1D25 protein Q3MII6 UNIPROT up-regulates binding 9606 21383079 t gcesareni "In this study, we report evidence demonstrating that oatl1, a putative rab guanosine triphosphatase-activating protein (gap), is a novel binding partner of atg8 homologues in mammalian cells. Oatl1 is recruited to isolation membranes and autophagosomes through direct interaction with atg8 homologues and is involved in the fusion between autophagosomes and lysosomes through its gap activity." SIGNOR-172536 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR RUNX1 protein Q01196 UNIPROT up-regulates phosphorylation Ser249 DTRQIQPsPPWSYDQ 9606 BTO:0002181 16046550 t "The effect has been demonstrated using Q01196-8" lperfetto "We have identified four phosphorylation sites on aml1c that are necessary for transcriptional activity of aml1c in k562 and 293t cells (27).4 mutation of these four sites (serine 276, serine 293, serine 303, and threonine 300) to alanine abolishes transcriptional activation, whereas mutation of these sites to aspartic acid (which mimics phosphorylation) results in a hyperactive protein." SIGNOR-244703 PPP1R3C protein Q9UQK1 UNIPROT PP1 proteinfamily SIGNOR-PF54 SIGNOR up-regulates binding 9606 BTO:0000759 36551183 t miannu "In the liver, PTG and PPP1R3B(GL)are expressed at roughly equivalent levels [55], and they jointly promote hepatic glycogen mobilization and storage. PTG overexpression significantly increased glycogen content, mainly due to its ability to promote the redistribution of PP1 and glycogen synthase to glycogen granules, significantly increasing GS activity and glycogen synthesis (Figure 2)" SIGNOR-271735 BCR-ABL "fusion protein" SIGNOR-FP6 SIGNOR BCR protein P11274 UNIPROT "down-regulates activity" phosphorylation Tyr360 YSPRSFEdCGGGYTP 9606 9467953 t Manara "Thus, we propose that the phosphorylation of tyrosine 328 and 360 within Bcr by Bcr-Abl will drastically interfere with Bcr's kinase role in either signal transduction or some other cellular mechanism." SIGNOR-260828 WNT6 protein Q9Y6F9 UNIPROT MYOD1 protein P15172 UNIPROT up-regulates 9606 BTO:0000887;BTO:0001103 9753670 f gcesareni "In explant cultures of mouse paraxial mesoderm, wnt1 induced expression of the mrf myf5, whereas wnt7a or wnt6 preferentially activated the mrf myod. Wnt4, wnt5a and wnt6 exert an intermediate effect activating both myf5 and myod equivalently in paraxial mesoderm." SIGNOR-60418 STAT1 protein P42224 UNIPROT CIITA protein P33076 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000801 19029990 f lperfetto "STAT1 binds as a homodimer to cis elements known as gammaactivated sequences in the promoters of the genes encoding NOS2, the MHC class II transactivator (CIITA) and IL-12, among others." SIGNOR-249498 U0126 chemical CHEBI:90693 ChEBI MAP2K1 protein Q02750 UNIPROT down-regulates "chemical inhibition" 9606 11160424 t gcesareni "The mek1/2 inhibitors pd98059, sl327, and u0126 have been extensively used to implicate erk1/2 in neuroplasticity. u0126 was found to functionally antagonize ap-1 transcriptional activity via noncompetitive the dual specificity kinase mek with an ic50 of 0.07 microm for mek 1 and 0.06 microm for mek 2." SIGNOR-104939 CRK protein P46108 UNIPROT RAPGEF1 protein Q13905 UNIPROT up-regulates binding 9606 7806500 t gcesareni "The endogenous c3g could be coprecipitated with crk from cell lysates of cells expressing high levels of c-crk or v-crk, suggesting high binding affinity and a possible interaction in vivo." SIGNOR-33732 HDAC1 protein Q13547 UNIPROT CEBPA protein P49715 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 16431920 f fspada "These data suggest that c/ebp beta activates a single unified pathway of adipogenesis involving its stimulation of ppargamma expression, which then activates c/ebp alpha expression by dislodging hdac1 from the promoter for degradation in the proteasome" SIGNOR-143955 MAPK1 protein P28482 UNIPROT KHDRBS1 protein Q07666 UNIPROT up-regulates phosphorylation Ser58 SRGGARAsPATQPPP 9606 12478298 t lperfetto "In support of this assumption, purified gst_sam68 protein was phosphorylated by recombinant erk2we found that sam68 mutated in ser 58, thr 71 and thr 84 showed the same extent of impairment in induced exon inclusion as did sam68 mutated in all s/tp sites" SIGNOR-96410 doramapimod chemical CHEBI:40953 ChEBI MAPK14 protein Q16539 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-190332 PI-103 chemical CHEBI:90524 ChEBI PIK3CB protein P42338 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-206166 EIF3_complex complex SIGNOR-C401 SIGNOR EIF4G1 protein Q04637 UNIPROT "up-regulates activity" stabilization 9606 17581632 t lperfetto "EIF3 plays many functions in initiation complex formation. It interacts with eIF1, eIF5, eIF4B and eIF4G, and the direct interaction between eIF3 and eIF4G may serve as a bridge between the 40S ribosomal subunit and eIF4F-bound mRNA (Hershey and Merrick, 2000). eIF3 stabilizes the binding of the eIF2-GTP-Met-tRNAiMet ternary complex to the 40S subunit" SIGNOR-269155 CECR2 protein Q9BXF3 UNIPROT CERF complex SIGNOR-C340 SIGNOR "form complex" binding 9606 BTO:0000227 15640247 t miannu "Biochemical isolation of CECR2 revealed the presence of this protein as a component of a novel heterodimeric complex termed CECR2-containing remodeling factor (CERF). CERF comprises CECR2 and the ATP-dependent chromatin remodeler SNF2L, a mammalian ISWI ortholog expressed predominantly in the central nervous system. CERF is capable of remodeling chromatin in vitro and displays an ATP hydrolyzing activity that is stimulated by nucleosomes. Together, these data identify a novel chromatin remodeling complex with a critical role in neurulation." SIGNOR-263891 PPP2R5D protein Q14738 UNIPROT RAF1 protein P04049 UNIPROT "up-regulates activity" binding 9606 BTO:0000007 16239230 t gcesareni "... the PP2A holoenzymes ABC and ABC act downstream of Ras and upstream of MEK1 to promote activation of this MAPK signaling cascade. Furthermore both PP2A holoenzymes were found to associate with Raf1 and catalyze dephosphorylation of inhibitory phospho-Ser-259." SIGNOR-243420 PRKD1 protein Q15139 UNIPROT CTTN protein Q14247 UNIPROT down-regulates phosphorylation Ser348 EAVTSKTsNIRANFE 9606 BTO:0000150 19038333 t lperfetto "Here we have investigated the possible role of pkd as a cortactin kinase. Using a mass spectrometric approach, we found that pkd phosphorylates cortactin on ser 298 examination of cortactin phosphorylation kinetics revealed that ser 298 serves as a priming site for subsequent phosphorylation of ser 348" SIGNOR-182502 INSR protein P06213 UNIPROT CBL protein P22681 UNIPROT "up-regulates activity" phosphorylation Tyr774 SENEDDGyDVPKPPV 10090 BTO:0000944 11997497 t "Insulin receptor phosphorylates Cbl on tyrosines 371, 700, and 774 in the presence of APS. This phosphorylation event is required for the recruitment of Crk to the CAP/Cbl complex and for the subsequent activation of GLUT4 translocation." SIGNOR-251306 MIB1 protein Q86YT6 UNIPROT SMN1 protein Q16637 UNIPROT "down-regulates quantity by destabilization" polyubiquitination 9606 BTO:0000007 23615451 t miannu "In this study, we show that the E3 ubiquitin ligase, mind bomb 1 (Mib1), interacts with and ubiquitinates SMN and facilitates its degradation. Knocking down Mib1 levels increases SMN protein levels in cultured cells. " SIGNOR-272664 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR NUP50 protein Q9UKX7 UNIPROT "down-regulates activity" phosphorylation Ser315 TQSKPVSsPFPTKPL 9606 19767751 t llicata "Erk phosphorylates nup50 at ser221 and ser315 phosphorylation of nup50 reduces affinity for importin-beta" SIGNOR-263043 TRIM13 protein O60858 UNIPROT AKT2 protein P31751 UNIPROT "down-regulates quantity by destabilization" polyubiquitination 9606 BTO:0000007 21333377 t miannu "Here, we demonstrate that overexpression of RFP2 in cells induced apoptosis through proteasomal degradation of MDM2 and AKT.  We observed that RFP2 formed a complex with MDM2, a negative regulator of the p53 tumor suppressor, and AKT, a regulator of apoptosis inhibition at the cellular level. Additionally, we found that the interaction of RFP2 with MDM2 and AKT resulted in ubiquitination and proteasomal degradation of MDM2 and AKT in vivo and in vitro." SIGNOR-271853 SREBF1 protein P36956 UNIPROT PCSK9 protein Q8NBP7 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 17921436 t miannu "Expression of nuclear forms of sterol-regulatory element binding protein-1 (SREBP-1) and SREBP-2 dramatically increased the promoter activity of PCSK9." SIGNOR-255222 CH5132799 chemical CID:49784945 PUBCHEM PIK3C2B protein O00750 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-190940 GSK3B protein P49841 UNIPROT DPYSL3 protein Q14195 UNIPROT "up-regulates activity" phosphorylation Thr509 PVFDLTTtPKGGTPA 10116 16611631 t lperfetto "Together, these results suggest that crmp4 is able to increase neurite formation and elongation in neurons, although not as potently as crmp2, and that this process is regulated by ser522/ser518/thr514/thr509 phosphorylation in both cases. We demonstrate that cdk5 primes crmp2 and crmp4 for subsequent phosphorylation by gsk3, whereas dyrk2, phosphorylates and primes only crmp4 in vitro" SIGNOR-146011 TRIB3 protein Q96RU7 UNIPROT ACACB protein O00763 UNIPROT "down-regulates quantity by destabilization" binding 9606 BTO:0000007 16794074 t miannu "TRB3 appears to inhibit ACC activity by functioning as an adaptor for COP1.  Taken together, these results suggest that TRB3 may promote loss of fat by mediating the COP1-dependent ubiquitination and inactivation of ACC. Taking these results together, we propose that TRB3 may protect against diet-induced obesity by stimulating fatty acid oxidation in adipose during fasting through the COP1-mediated ubiquitination and degradation of ACC (Fig. 4D)." SIGNOR-271601 "AM/b2 integrin" complex SIGNOR-C170 SIGNOR PTK2 protein Q05397 UNIPROT "up-regulates activity" 9606 15688067 f miannu "Focal adhesion kinase (FAK) is activated by growth factors and integrins during migration, and functions as a receptor-proximal regulator of cell motility. At contacts between cells and the extracellular matrix, FAK functions as an adaptor protein to recruit other focal contact proteins or their regulators, which affects the assembly or disassembly of focal contacts. Whereas it was first hypothesized that FAK might bind directly to the cytoplasmic tails of integrins, accumulated evidence supports an indirect association of FAK with integrins through binding to integrin-associated proteins such as paxillin and talin." SIGNOR-257713 COX5A protein P20674 UNIPROT "Mitochondrial respiratory chain complex IV" complex SIGNOR-C280 SIGNOR "form complex" binding 30030361 t lperfetto "Complex IV (EC 1.9.31) or cytochrome c oxidase (COX) catalyses the oxidation of cytochrome c and the reduction of oxygen to water, coupled to proton translocation [108]. Mammalian cIV contains 13 or 14 subunits" SIGNOR-267751 SUFU protein Q9UMX1 UNIPROT GLI3 protein P10071 UNIPROT down-regulates relocalization 9606 BTO:0001130;BTO:0000848;BTO:0000527 10564661 t gcesareni "Su(fu) is a negative regulator of shh that interacts with all three gli proteins to retain them in the cytosol." SIGNOR-72308 MAML1 protein Q92585 UNIPROT CDK8 protein P49336 UNIPROT up-regulates relocalization 9606 15546612 t gcesareni "Cycc:cdk8 and cyct1:cdk9/p-tefb are recruited with notch and associated coactivators (mam, skip) to the hes1 promoter in signaling cells." SIGNOR-130718 GSK3B protein P49841 UNIPROT HDAC4 protein P56524 UNIPROT down-regulates phosphorylation Ser302 APGSGPSsPNNSSGS 9606 21118993 t lperfetto "The double mutation of serines 298/302 into alanines, but also the sole mutation of serine 302, abolishes hdac4 phosphorylation by gsk3_we have shown that cells lacking gsk3_ are unable to degrade hdac4 after serum starvation" SIGNOR-170148 PRKCA protein P17252 UNIPROT VCL protein P18206 UNIPROT unknown phosphorylation Ser1113 VREAEAAsIKIRTDA -1 11741957 t lperfetto "PKC Phosphorylates Serines 1033 and 1045 in Helix H5" SIGNOR-249129 RXRG protein P48443 UNIPROT MBP protein P02686 UNIPROT "up-regulates quantity" "transcriptional regulation" 31390799 f SimoneGraziosi "RXRγ gene silencing reduces the ability of the drugs to promote MBP expression." SIGNOR-269266 GNAI1 protein P63096 UNIPROT RAC1 protein P63000 UNIPROT "up-regulates activity" binding 10090 BTO:0000944 11099498 t "These findings indicate that both G alpha(i) and G beta gamma stimulate Rac and Cdc42 pathways with lysophosphatidic acid-induced cell spreading on fibronectin" SIGNOR-256530 PIP3 smallmolecule CHEBI:16618 ChEBI AKT proteinfamily SIGNOR-PF24 SIGNOR "up-regulates activity" relocalization 9606 23119004 t lperfetto "Binding of IGF to IGF-1R activates PI3K to generate PIP3 which in turn recruits and activates proteins that contain a pleckstrin homology ph) domain, including AKT and PDK1." SIGNOR-236509 KEL protein P23276 UNIPROT EDN3 protein P14138 UNIPROT "up-regulates activity" cleavage Trp117 YCHLDIIwINTPEQT -1 10438732 t miannu "These data demonstrate that the Kell blood group protein is a proteolytic enzyme that processes big ET-3, generating ET-3, a potent bioactive peptide with multiple biological roles." SIGNOR-256354 Dinaciclib chemical CID:46926350 PUBCHEM CDK2 protein P24941 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-191325 ITGA2B protein P08514 UNIPROT "AIIB/b3 integrin" complex SIGNOR-C173 SIGNOR "form complex" binding 16988024 t lperfetto "Integrins are one of the major families of cell adhesion receptors (Humphries, 2000; Hynes, 2002). All integrins are non-covalently-linked, heterodimeric molecules containing an α and a β subunit. Both subunits are type I transmembrane proteins, containing large extracellular domains and mostly short cytoplasmic domains (Springer and Wang, 2004; Arnaout et al., 2005). Mammalian genomes contain 18 α subunit and 8 β subunit genes, and to date 24 different α,β combinations have been identified at the protein level. Although some subunits only appear in a single heterodimer, twelve integrins contain the β1 subunit, and five contain αV." SIGNOR-253197 GSK3B protein P49841 UNIPROT MAFA protein Q8NHW3 UNIPROT "down-regulates quantity by destabilization" phosphorylation Thr57 LSSTPLStPCSSVPS 9606 18042454 t miannu "We also demonstrate that gsk-3 triggers mafa sequential phosphorylation on residues s61, t57, t53, and s49 /we demonstrated that phosphorylation by gsk-3 is conserved among the large maf proteins. It couples ubiquitination/degradation and transcriptional activation and modulates maf biological activity./ Taken together, these results suggest that, in contrast to what can be expected from ubiquitination/degradation, gsk-3-mediated mafa phosphorylation increases its transactivating ability, thereby controlling its biological activity." SIGNOR-159470 WT1 protein P19544 UNIPROT SOD1 protein P00441 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 9867871 t miannu "The human copper-zinc superoxide dismutase gene (SOD1) proximal promoter is regulated by Sp1, Egr-1, and WT1 via non-canonical binding sites. Egr-1 and two splicing variants of the Egr-related protein WT1 were able to transactivate the SOD1 promoter in co-transfection experiments." SIGNOR-253898 WNT10B protein O00744 UNIPROT FZD5 protein Q13467 UNIPROT up-regulates binding 9606 12055200 t fspada "Inhibition of adipogenesis by wnt10b is likely mediated by‚ wnt‚ receptors, frizzled 1, 2, and/or 5, and co-receptors low density lipoprotein receptor-related proteins 5 and 8" SIGNOR-210164 PRKACA protein P17612 UNIPROT BAD protein Q92934 UNIPROT down-regulates phosphorylation Ser99 PFRGRSRsAPPNLWA 9606 10949026 t gcesareni "Ser-155 is the major phosphoacceptor site for pka on bad, but that pka also phosphorylates ser-112 and ser-136. Phosphorylated bad appears to be the inactive moiety. These results implicate pkac as the candidate kinase for s112 phosphorylation in vivo." SIGNOR-81137 WNT7A protein O00755 UNIPROT LRP5 protein O75197 UNIPROT "up-regulates activity" binding 9606 15578921 t gcesareni "Wnt proteins bind to the frizzled receptors and lrp5/6 co-receptors, and through stabilizing the critical mediator betBeta-catenin, initiate a complex signaling cascade that plays an important role in regulating cell proliferation and differentiation." SIGNOR-131900 CAMK1 protein Q14012 UNIPROT HDAC5 protein Q9UQL6 UNIPROT down-regulates phosphorylation Ser259 FPLRKTAsEPNLKVR 9606 BTO:0000887 11114197 t gcesareni "Camk phosphorylates serines -259 and -498 in hdac5, which subsequently serve as docking sites for 14-3-3. Our studies suggest that 14-3-3 binding to hdac5 is required for camk-dependent disruption of mef2hdac complexes and nuclear export of hdac5, and implicate 14-3-3 as a signal-dependent regulator of muscle cell differentiation." SIGNOR-85018 PRKDC protein P78527 UNIPROT GOLPH3 protein Q9H4A6 UNIPROT "up-regulates activity" phosphorylation Thr148 KETQPPEtVQNWIEL -1 BTO:0000567 24485452 t "In response to DNA damage, DNA-PK phosphorylates GOLPH3, resulting in increased interaction with MYO18A, which applies a tensile force to the Golgi. Interference with the Golgi DNA damage response by depletion of DNA-PK, GOLPH3, or MYO18A reduces survival after DNA damage, whereas overexpression of GOLPH3, as is observed frequently in human cancers, confers resistance to killing by DNA-damaging agents" SIGNOR-253558 CSNK2A1 protein P68400 UNIPROT PTPN1 protein P18031 UNIPROT unknown phosphorylation -1 9600099 t llicata "In this study, we demonstrate that HPTP1B are multiple phosphorylated on threonine and tyrosine as well as serine near its N-terminus by CKII and p60c-src in vitro." SIGNOR-250941 SMAD5/SMAD4 complex SIGNOR-C205 SIGNOR RUNX2 protein Q13950 UNIPROT up-regulates "transcriptional regulation" 10090 BTO:0000165 11073979 f ggiuliani "As shown in Fig. 8A, overexpression of Smad5 by itself induced Runx2 expression even in the absence of BMP-2 (lane 5). Western blot analysis also confirmed the induced level of Runx2 protein in C2C12-Sm5 cells (Fig. 8B)" SIGNOR-255783 "(4S)-2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid O5-[3-(4,4-diphenyl-1-piperidinyl)propyl] ester O3-methyl ester" chemical CHEBI:103931 ChEBI ADRA1B protein P35368 UNIPROT "down-regulates activity" "chemical inhibition" 10029 BTO:0000246 7651358 t miannu "Membrane preparations from CHO cells stably transfected with the cloned human a1-AR genes showed saturable binding of [‘251]HEAT; Bm,,ı values were 1.3 ± 0.2, 5.5 ± 0.1, and 1.1 ± 0.1 pmol/mg of protein, with Kd values of 110 ± 21, 60 ± 1, and 300 ± 26 ıM (three experiments each), for the ala-, alb-, and ald-ARS, respectively. The potencies of a1-AR agonists and antagonists at the cloned human a1-ARs are shown in Table 1." SIGNOR-258465 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR SOS1 protein Q07889 UNIPROT "down-regulates activity" phosphorylation Ser1132 TLPHGPRsASVSSIS 9534 BTO:0004055 8816480 t lperfetto "In this report, we describe the identification of five map kinase sites (s-1137, s-1167, s-1178, s-1193, and s-1197) on hsos1Replacing the MAP kinase phosphorylation sites with alanine residues results in an increase in the binding affinity of Grb2 to hSos1" SIGNOR-244580 LTBP2 protein Q14767 UNIPROT FBN1 protein P35555 UNIPROT "up-regulates activity" binding 9606 BTO:0000452 19681046 t Regulation miannu "LTBP-2 interacts with fibrillin-1. The association of LTBP-2 with the ECM always coincided with that of fibrillin-1, and in fibroblast cultures the appearance of fibrillar fibrillin-1 structures preceded the assembly of LTBP-2 network." SIGNOR-251891 CYP11B2 protein P19099 UNIPROT cortisol smallmolecule CHEBI:17650 ChEBI "up-regulates quantity" "chemical modification" 9606 BTO:0000050 9814482 t lperfetto "Recombinant CYP11B genes encode enzymes that can catalyze conversion of 11-deoxycortisol to cortisol, 18-hydroxycortisol, and 18-oxocortisol." SIGNOR-268676 NR3C1 protein P04150 UNIPROT G6P proteinfamily SIGNOR-PF81 SIGNOR "up-regulates quantity" "transcriptional regulation" 9600 BTO:0000567 26652733 t "inferred from family member" "Further, CRTC2 is required for the glucocorticoid-associated cooperative mRNA expression of the glucose-6-phosphatase, a rate-limiting enzyme for hepatic gluconeogenesis, by facilitating the attraction of GR and itself to its promoter region already occupied by CREB" SIGNOR-270258 romidepsin chemical CHEBI:61080 ChEBI HDAC4 protein P56524 UNIPROT "down-regulates activity" "chemical inhibition" -1 20139990 t Luana "Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1)." SIGNOR-257991 torkinib chemical CHEBI:90679 ChEBI PIK3CA protein P42336 UNIPROT "down-regulates activity" "chemical inhibition" -1 22037378 t Luana "Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here." SIGNOR-258269 COLGALT2 protein Q8IYK4 UNIPROT COL3A1 protein P02461 UNIPROT "up-regulates activity" glycosylation -1 19075007 t "Recombinant GLT25D1 and GLT25D2 enzymes showed a strong galactosyltransferase activity toward various types of collagen and toward the serum mannose-binding lectin MBL, which contains a collagen domain. Amino acid analysis of the products of GLT25D1 and GLT25D2 reactions confirmed the transfer of galactose to hydroxylysine residues." SIGNOR-261158 "dasatinib (anhydrous)" chemical CHEBI:49375 ChEBI SRC protein P12931 UNIPROT "down-regulates activity" "chemical inhibition" -1 22037378 t Luana "Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here." SIGNOR-258103 HSPB1 protein P04792 UNIPROT DIABLO protein Q9NR28 UNIPROT down-regulates 9606 12855565 f gcesareni "These data demonstrate that hsp27 inhibits the release of smac" SIGNOR-103539 ELAVL4 protein P26378 UNIPROT ADAM10 protein O14672 UNIPROT "up-regulates quantity" "post transcriptional regulation" 9606 19221430 t miannu "Neuronal ELAV (nELAV) proteins are RNA-binding proteins which play a physiological role in controlling gene expression in memory formation, and their alteration may contribute to cognitive impairment associated with neurodegenerative pathologies such as Alzheimer's disease (AD). The experiments show for the first time that ADAM10mRNA represents a nELAV target and that these RNA-binding proteins can play a role in the post-transcriptional regulation of ADAM10 expression. nELAV proteins specifically bind the ADAM10 mRNA and this binding is disrupted following Aβ exposure" SIGNOR-266865 LCK protein P06239 UNIPROT ACP1 protein P24666 UNIPROT "up-regulates activity" phosphorylation Tyr132 QLIIEDPyYGNDSDF 9534 BTO:0004055 9038134 t "In co-transfected COS cells, Lck and Fyn caused phosphorylation of LMPTP. Most of the phosphate was located at Tyr-131, and some was also located at Tyr-132. Site-directed mutagenesis showed that Tyr-131 is important for the catalytic activity of LMPTP, and that thiophosphorylation of Tyr-131, and to a lesser degree Tyr-132, is responsible for the activation." SIGNOR-251366 EPHB2 protein P29323 UNIPROT SYNJ1 protein O43426 UNIPROT down-regulates phosphorylation 9606 BTO:0000938 15821731 t lperfetto "Ephb2 causes tyrosine phosphorylation in the proline-rich domain of synaptojanin 1, and inhibits both the interaction with endophilin and the 5'-phosphatase activity of synaptojanin 1" SIGNOR-135274 NHS protein Q6T4R5 UNIPROT "WRC complex" complex SIGNOR-C191 SIGNOR "up-regulates activity" relocalization 9606 20332100 t miannu "Excessive cell spreading and lamellipod extension as a result of NHS knockdown is likely to be a result of loss of WAVE complex regulation, leading to overactive WAVE activity or a dysregulation of nascent focal adhesions in lamellipodia.WAVE and NHS protein partners Abi1 and HSPC300, and the p34 subunit of the Arp2/3 complex, consistently localized at the edges of cells treated with NHS siRNA, independent of EGF stimulation and WAVE complex activation. These data show that localization of Abi1 and HSPC300 was altered in the absence of NHS." SIGNOR-253577 MAP2K6 protein P52564 UNIPROT MAPK13 protein O15264 UNIPROT up-regulates phosphorylation 9606 11242034 t gcesareni "Mapkk6 was shown to phosphorylate and specifically activate the p38/mpk2 sub of the mitogen-activated protein kinase superfamily." SIGNOR-105698 imatinib chemical CHEBI:45783 ChEBI ABL1 protein P00519 UNIPROT down-regulates "chemical inhibition" 9606 Other t "Selleck;VIRAL ABL" gcesareni SIGNOR-193372 STX10 protein O60499 UNIPROT "LE-TGN SNARE" complex SIGNOR-C157 SIGNOR "form complex" binding 9606 BTO:0000567 18195106 t lperfetto "We show in human cells that a soluble NSF attachment protein receptor (SNARE) complex comprised of syntaxin 10 (STX10), STX16, Vti1a, and VAMP3 is required for this MPR transport" SIGNOR-253080 AKT2 protein P31751 UNIPROT TSC complex SIGNOR-C101 SIGNOR "down-regulates activity" phosphorylation 10090 BTO:0000011 19593385 t lperfetto "In examining the requirements for different Akt-mediated phosphorylation sites on TSC2, we find that only TSC2 mutants lacking all five previously identified Akt sites fully block insulin-stimulated mTORC1 signaling in reconstituted Tsc2 null cells, and this mutant also inhibits adipogenesis" SIGNOR-235852 BACH2 protein Q9BYV9 UNIPROT XBP1 protein P17861 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0005014 24821775 f miannu "Expression and activity of the UPR downstream effector XBP1 is regulated positively by STAT5 and negatively by the B-cell-specific transcriptional repressors BACH2 and BCL6." SIGNOR-253756 BMP10 protein O95393 UNIPROT BMPR1A protein P36894 UNIPROT up-regulates binding 9606 BTO:0000938 BTO:0000562 16049014 t acerquone "We showed that three orphan ligands known to be important for joint and cartilage formation (gdf6) (10), interneuron, sensory neurons, and seminal vesicle formation (gdf7) (11_13), and heart development (bmp10) (14) used the type i receptors alk3 or alk6 and the type ii receptors bmprii or actriia to activate the smad1/5/8 proteins." SIGNOR-139052 dapagliflozin chemical CHEBI:85078 ChEBI SLC5A2 protein P31639 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-191289 CDK5 protein Q00535 UNIPROT EPRS1 protein P07814 UNIPROT down-regulates phosphorylation Ser886 LSQSSDSsPTRNSEP 9606 BTO:0000801 21220307 t lperfetto "Ser(886) phosphorylation is required for the interaction of nsap1, which blocks eprs binding to target mrnas. The same phosphorylation event induces subsequent binding of ribosomal protein l13a and gapdh and restores mrna binding. Ifn-_ activates cdk5 to phosphorylate ser(886) in the linker domain of glutamyl-prolyl trna synthetase (eprs), the initial event in assembly of the gait complex. Cdk5/p35 also induces, albeit indirectly via a distinct kinase, phosphorylation of ser(999), the second essential event in gait pathway activation" SIGNOR-171138 COL4A1 protein P02462 UNIPROT "A2/b1 integrin" complex SIGNOR-C160 SIGNOR "up-regulates activity" binding 9606 BTO:0000664 12123670 t lperfetto "We have developed a cell-free assay for binding of solubilized beta1 integrins to their physiologically relevant ligands using an electrochemiluminescent detection method|Binding was clearly optimal for the presumed physiological ligands, i.e., collagen IV for a1b1, collagen I for a2b1, VCAM-Ig for a4b1, fibronectin (the 120-kDa cell attachment fragment was used) for a5b1, and laminin for a6b1." SIGNOR-253242 AKT3 protein Q9Y243 UNIPROT FOXO3 protein O43524 UNIPROT down-regulates phosphorylation Ser253 APRRRAVsMDNSNKY 9606 19188143 t gcesareni "Akt-dependent phosphorylation of foxo3a (thr32, ser253, and ser315 for human foxo3) enhances foxo3a/14?3?3 Interaction and promotes foxo3a nuclear export to the cytoplasm, resulting in the repression of foxo3a transcriptional function" SIGNOR-183644 CXCL8 protein P10145 UNIPROT Angiogenesis phenotype SIGNOR-PH46 SIGNOR up-regulates 17326328 f lperfetto "More than a dozen different proteins have been identified as angiogenic activators, including vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), angiogenin, transforming growth factor (TGF)-α, TGF-β, tumor necrosis factor (TNF)-α, platelet-derived endothelial growth factor, granulocyte colony-stimulating factor, placental growth factor, interleukin-8, hepatocyte growth factor, and epidermal growth factor" SIGNOR-252288 F-actin_assembly phenotype SIGNOR-PH18 SIGNOR Dendritic_spine_morphogenesis phenotype SIGNOR-PH183 SIGNOR up-regulates 9606 14684878 f miannu "Dendritic spines are small protrusions found on dendrites of principal neurons of mammalian brain. Serving as postsynaptic compartments for individual excitatory inputs, spines show rapid movements and shape changes that are influenced by synaptic activity. The structural modifications of spines are believed to represent morphological correlates of synaptic plasticity. The form and motility of spines are determined mainly by the actin cytoskeleton" SIGNOR-266597 AREL1 protein O15033 UNIPROT DIABLO protein Q9NR28 UNIPROT "down-regulates quantity by destabilization" ubiquitination Lys62 CAVPIAQkSEPHSLS 9606 BTO:0002552 31732561 t lperfetto "AREL1 ubiquitinated SMAC, primarily on Lys62 and Lys191 |E701A substitution in the AREL1 HECT domain substantially increased its autopolyubiquitination and SMAC ubiquitination activity, whereas deletion of the last three amino acids at the C terminus completely abrogated AREL1 autoubiquitination and reduced SMAC ubiquitination." SIGNOR-267673 ABL1 protein P00519 UNIPROT EPHB2 protein P29323 UNIPROT down-regulates phosphorylation 9606 BTO:0000938 11494128 t lperfetto "Two-hybrid screens identified regions of abl and arg that bind to the ephb2 and epha4 receptors, suggesting a novel signaling connection involving the two kinase families.The connection between EphB2 and Abl/Arg appears to be reciprocal. Activated EphB2 causes tyrosine phosphorylation of Abl and Arg, and vice versa. Interestingly, treatment of COS cells and B35 neuronal-like cells with ephrin-B1 to activate endogenous EphB2 decreased the kinase activity of endogenous Abl." SIGNOR-109668 "2-cyclopentyl-4-(5-phenyl-1H-pyrrolo[2,3-b]pyridin-3-yl)benzoic acid" chemical CHEBI:95066 ChEBI SGK2 protein Q9HBY8 UNIPROT "down-regulates activity" "chemical inhibition" -1 18794135 t lperfetto "GSK650394 quantitatively inhibits the activity of SGK1 and SGK2 in a scintillation proximity assay." SIGNOR-262018 CHD4 protein Q14839 UNIPROT ChAHP complex SIGNOR-C407 SIGNOR "form complex" binding 10090 BTO:0002896 29795351 t miannu "Here we show that ADNP interacts with the chromatin remodeller CHD4 and the chromatin architectural protein HP1 to form a stable complex, which we refer to as ChAHP. Besides mediating complex assembly, ADNP recognizes DNA motifs that specify binding of ChAHP to euchromatin. In conclusion, CHD4, ADNP and HP1β/γ form a stable protein complex, which we refer to as ChAHP." SIGNOR-266752 RAD21 protein O60216 UNIPROT GATA2 protein P23769 UNIPROT "down-regulates activity" relocalization 9606 BTO:0001545 26607380 t miannu "Large-scale AML genome re-sequencing efforts have identified novel recurrently mutated genes, including the members of the cohesin complex (RAD21, SMC3, SMC1A, and STAG2), implicated in the pathogenesis of this disease.Using ATAC-seq, we determined that mutant cohesin lead to a state of elevated chromatin accessibility and higher predicted binding at transcription factor binding sites for ERG, GATA2, and RUNX1. Moreover, using ChIP-Seq, we formally demonstrated increased binding of GATA2 and RUNX1 to these sites. Finally, we demonstrated that knockdown of these three TFs in human HSPC can revert the differentiation block induced by mutant cohesin. These results support a model in which mutant cohesin impairs hematopoietic differentiation and enforces stem cell programs through the modulation of ERG, GATA2, and RUNX1 chromatin accessibility, expression, and activity." SIGNOR-261513 CEBPB protein P17676 UNIPROT SFTPD protein P35247 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0001910 11912209 t "Cotransfection of C/EBPalpha, C/EBPbeta, or C/EBPdelta cDNA in H441 lung adenocarcinoma cells significantly increased the luciferase activity of a wild-type SP-D promoter construct containing 698 bp of upstream sequence (SS698). Transfection of C/EBP also increased the level of endogenous SP-D mRNA in H441 cells| Thus, interactions among C/EBP elements in the near-distal promoter can modulate the promoter activity of SP-D." SIGNOR-254045 SMURF1 protein Q9HCE7 UNIPROT BMPR1A protein P36894 UNIPROT down-regulates ubiquitination 9606 17317136 t gcesareni "Smurf1 and smurf2 are e3 ubiquitin ligases known to suppress tgf-beta signaling through degradation of smads and receptors for tgf-beta and bmps." SIGNOR-153399 MED4 protein Q9NPJ6 UNIPROT "Core mediator complex" complex SIGNOR-C405 SIGNOR "form complex" binding 9606 28467824 t miannu "Mediator is a multiprotein co-activator that binds the transcription pre-initiation complex (PIC) and regulates RNA polymerase (Pol) II. The Mediator head and middle modules form the essential core Mediator (cMed), whereas the tail and kinase modules play regulatory roles." SIGNOR-266675 LATS2 protein Q9NRM7 UNIPROT SNAI1 protein O95863 UNIPROT "up-regulates quantity by stabilization" phosphorylation -1 24157836 t miannu "FBXL5 is located in the nucleus where it interacts with Snail1 promoting its polyubiquitination and affecting Snail1 protein stability and function by impairing DNA binding. Snail1 is ubiquitinated by the SCFFBXL5 complex. Snail1 downregulation by FBXL5 is prevented by Lats2, a protein kinase that phosphorylates Snail1 precluding its nuclear export but not its polyubiquitination." SIGNOR-272138 "Embryonic stem cell-specific SWI/SNF" complex SIGNOR-C484 SIGNOR Pluripotency phenotype SIGNOR-PH43 SIGNOR up-regulates 10090 BTO:0001086 19279220 f miannu "An embryonic stem cell chromatin remodeling complex, esBAF, is essential for embryonic stem cell self-renewal and pluripotency" SIGNOR-270728 CDK7 protein P50613 UNIPROT POLR2A protein P24928 UNIPROT down-regulates phosphorylation Ser1738 SPSYSPTsPSYSPTS 9606 14662762 t lperfetto "Although there is some inconsistency in the literature, it is generally thought that cdk7, a component of the transcription factor (tf) iih, is a major ser-5 kinase, whereas cdk9, a component of positive transcription elongation factor (p-tef) b, is a major ser-2 kinase within cells. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination." SIGNOR-120028 Ub:E2 complex SIGNOR-C497 SIGNOR RBX1 protein P62877 UNIPROT "up-regulates activity" ubiquitination 9606 34199813 t miannu "The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t" SIGNOR-270993 STK11 protein Q15831 UNIPROT SIK2 protein Q9H0K1 UNIPROT up-regulates phosphorylation Thr175 KSGELLAtWCGSPPY 9606 14976552 t llicata "A total of 12 human kinases (nuak1, nuak2, brsk1, brsk2, qik, qsk, sik, mark1, mark2, mark3, mark4 and melk) are related to ampk. Here we demonstrate that lkb1 can phosphorylate the t-loop of all the members of this subfamily, apart from melk, increasing their activity >50-fold." SIGNOR-122788 PTH1R protein Q03431 UNIPROT GNAS protein Q5JWF2 UNIPROT "up-regulates activity" binding 28363951 t lperfetto "This calciotropic hormone exerts its actions via binding to the PTH/PTH-related peptide receptor (PTH1R), which couples to multiple heterotrimeric G proteins, including Gs and Gq/11." SIGNOR-270551 TP53 protein P04637 UNIPROT TBXAS1 protein P24557 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 14586398 f miannu "We demonstrate that p53 and ets-1 coregulate TXSA in an antagonistic and inter-related manner, with ets-1 being a potent transcriptional activator and p53 inhibiting ets-1-dependent transcription." SIGNOR-254086 HTR4 protein Q13639 UNIPROT GNAI1 protein P63096 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257041 PRKCE protein Q02156 UNIPROT TICAM2 protein Q86XR7 UNIPROT up-regulates phosphorylation Ser16 NSCPLSLsWGKRHSV 9606 16757566 t llicata "Here we show that tram is transiently phosphorylated by pkcepsilon on serine-16 our study provides a possible target for these molecules in lps signaling. Dag may activate pkc?, Leading to the phosphorylation and activation of tram." SIGNOR-146991 DEAF1 protein O75398 UNIPROT HTR1A protein P08908 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 10090 BTO:0000142 29636529 t Gianni "The human 5-HT1A gene (HTR1A) rs6295 risk allele prevents Deaf1 binding to HTR1A, resulting in increased 5-HT1A autoreceptor transcription" SIGNOR-269064 PTPRG protein P23470 UNIPROT KIT protein P10721 UNIPROT "down-regulates activity" dephosphorylation Tyr703 DHAEAALyKNLLHSK -1 25624455 t miannu "PTPRG activation by the P1-WD peptide affected the tyrosine phosphorylation of several signaling molecules. Data analysis identified 31 molecules whose phosphorylation was modified in a statistically significant manner (Table I). inhibition of ABL1, BMX, BTK, DAB1, ITGB1, JAK2, KDR, KIT, LIMK1, MET, PDGFRB, SHC1, and VCL correlates with tyrosine dephosphorylation. In contrast, SRC inhibition correlates with hyperphosphorylation of the inhibitory Tyr530 residue and with dephosphorylation of the activatory Tyr419. Moreover, CDK2 and CTTN inhibition correlates with a hyperphosphorylation of the inhibitory Tyr15 and Tyr470, respectively. In contrast, a subgroup of 13 proteins, including BLNK, DOK2, ERBB2, GRIN2B, INSR, PDGFRA, PRKCD, PXN, STAT1, STAT2, STAT3, STAT5A, and ZAP70, appears to be activated by PTPRG activity." SIGNOR-254709 IL1B protein P01584 UNIPROT IL1R1 protein P14778 UNIPROT "up-regulates activity" binding 9606 BTO:0000801 24166242 t lperfetto "Pro-IL-1beta, mIL-1beta and mIL-beta all bind to IL-1RI, which recruits the IL-1 receptor accessory protein (IL-1RAcP) as a co-receptor." SIGNOR-249511 MAML1 protein Q92585 UNIPROT "Histone H3" proteinfamily SIGNOR-PF69 SIGNOR "down-regulates activity" acetylation 9606 17300219 t gcesareni "The n-terminal domain of maml1 directly interacts with both p300 and histones, and the p300-maml1 complex specifically acetylates histone h3 and h4 tails in chromatin." SIGNOR-265362 EIF2B3 protein Q9NR50 UNIPROT Ternary_GTP_eIF2_tRNA_complex complex SIGNOR-C452 SIGNOR "up-regulates activity" "guanine nucleotide exchange factor" 9606 15054402 t lperfetto "EIF2B converts the protein synthesis initiation factor 2 (eIF2) from an inactive GDP-bound form to an active eIF2-GTP complex owing to its guanine nucleotide exchange factor (GEF) activity." SIGNOR-269141 USP7 protein Q93009 UNIPROT MDM2 protein Q00987 UNIPROT up-regulates deubiquitination 9606 16082221 t gcesareni "Subsequently, hausp was shown to deubiquitinate mdm2 and mdmx, thereby stabilizing these proteins." SIGNOR-139450 MAPK8IP1 protein Q9UQF2 UNIPROT MAPK9 protein P45984 UNIPROT down-regulates binding 9606 10490659 t "JNK bound to an NH2-terminal reagion of JIP1 (residues 283 to 660)" gcesareni "These experiments demonstrated that 10 different jnk isoforms bound to both jip proteins." SIGNOR-70854 INTS4 protein Q96HW7 UNIPROT "Integrator complex" complex SIGNOR-C265 SIGNOR "form complex" binding 7227 26220997 t lperfetto "Integrator is a metazoan-specific multisubunit, multifunctional protein complex composed of 14 subunits named Int1–Int14 (Integrator subunits) " SIGNOR-261467 AXIN1 protein O15169 UNIPROT RNF111 protein Q6ZNA4 UNIPROT up-regulates binding 9606 14657019 t gcesareni "Here, we show that axin activates tgf-beta signaling by forming a multimeric complex consisting of smad7 and ubiquitin e3 ligase arkadia. Axin is a scaffold protein in tgf-beta signaling that promotes degradation of smad7 by arkadia." SIGNOR-119660 CDK9 protein P50750 UNIPROT SMAD1 protein Q15797 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser206 SSSTYPHsPTSSDPG 9606 19914161 t lpetrilli "Phosphorylation of the linker region of smad1, a receptor-activated smad (r-smad), at serine 206 (s206) and s214 induced by bmp and mediated by cdk8/9 is critical for binding of the e3 ubiquitin ligase smurf1. Binding of smurf1 leads to polyubiquitination of smad1 and its degradation by the proteasome;cdk8 and cyclint-cdk9 showed a preference for s206 and s214 but also phosphorylated s186 and s195 in the case of smad1;and t179, s208 and s213 in the case of smad3." SIGNOR-161573 CLN8 protein Q9UBY8 UNIPROT PPP2CA protein P67775 UNIPROT "up-regulates activity" binding 9606 BTO:0000007 30453012 t miannu "CLN8 interacts with ceramide binding proteins PP2A and I2PP2A. We showed that the phosphorylation levels of several substrates of PP2A, namely Akt, S6 kinase, and GSK3β, were decreased in CLN8 disease patient fibroblasts. This reduction can be reversed by inhibiting PP2A phosphatase activity with cantharidin, suggesting a higher PP2A activity in CLN8-deficient cells. The phosphorylation levels of PP2A substrates are decreased in the absence of CLN8." SIGNOR-265583 EPHA2 protein P29317 UNIPROT EPHA2 protein P29317 UNIPROT up-regulates phosphorylation Tyr588 QLKPLKTyVDPHTYE 9606 18387945 t lperfetto "The binding of ephrin ligands to eph receptors induces the transphosphorylation of the cytoplasmic domains and initiates kinase activity.Taken together, these results suggest that tyr587, tyr593, tyr771, and tyr734 are likely to be autophospho-rylated in vascular endothelial cells." SIGNOR-178169 anthra[1,9-cd]pyrazol-6(2H)-one chemical CHEBI:90695 ChEBI FLT3 protein P36888 UNIPROT down-regulates "chemical inhibition" 9606 21159646 t gcesareni "In comparison, in the same assay conditions, the previously reported mps1 inhibitor sp600125 (13) was 10-fold less potent than nms-p715 on mps1 and, in addition, it was highly unspecific, being more active on at least 12 kinases including mitotic kinases with ic50 values well below 1 ?mol/l" SIGNOR-170614 PBX1 protein P40424 UNIPROT "MYOD1/SWI/SNF complex" complex SIGNOR-C93 SIGNOR "form complex" binding 9606 BTO:0001103 17194702 t miannu "Myod targets brg1 to the myogenin promoter during the initiation of myogenesis in tissue culture models for skeletal muscle differentiation /initiation of myogenin transcription is dependent upon myod, the pbx homeodomain factor, and swi/snf chromatin-remodeling enzymes" SIGNOR-151700 succinyl-CoA(5-) smallmolecule CHEBI:57292 ChEBI succinate(2-) smallmolecule CHEBI:30031 ChEBI "up-regulates quantity" "precursor of" 9606 27487822 t miannu "In the citric acid cycle, succinyl-CoA synthetase (SCS) catalyzes the only step that provides substrate-level phosphorylation: succinyl-CoA + NDP + Pi = succinate + CoA + NTP, where N is adenosine or guanosine and the reaction requires magnesium ions." SIGNOR-266265 PAK4 protein O96013 UNIPROT PACSIN1 protein Q9BY11 UNIPROT "up-regulates activity" phosphorylation Ser346 SQAGDRGsVSSYDRG -1 22371566 t miannu "We identified two novel Pak5 substrates, Pacsin1 and Synaptojanin1, proteins that directly interact with one another to regulate synaptic vesicle endocytosis and recycling. Pacsin1 and Synaptojanin1 were phosphorylated by Pak5 and the other group II Paks in vitro, and Pak5 phosphorylation promoted Pacsin1-Synaptojanin1 binding both in vitro and in vivo." SIGNOR-263023 metaproterenol chemical CHEBI:6792 ChEBI ADRB1 protein P08588 UNIPROT "up-regulates activity" "chemical activation" 10030 BTO:0000457 20590599 t Luana "Of the agonists studied here, there was a general trend that those with highest intrinsic efficacy were so across all three receptor subtypes (i.e. at the top of Tables 3–5, e.g. fenoterol, terbutaline, metaproterenol and adrenaline)" SIGNOR-257873 TAOK proteinfamily SIGNOR-PF21 SIGNOR STK3 protein Q13188 UNIPROT up-regulates phosphorylation 9606 23431053 t milica "In addition, the thousand-and-one (tao) amino acids kinase or taok13 has been shown to directly phosphorylate and activate hpo or mst1/2." SIGNOR-230713 CREBBP protein Q92793 UNIPROT MYOD1 protein P15172 UNIPROT up-regulates acetylation 9606 BTO:0000887 SIGNOR-C6 10944526 t gcesareni "Our results provide direct evidence that myod acetylation functionally activates the protein and show that both pcaf and cbp/p300 are candidate enzymes for myod acetylation in vivo." SIGNOR-81050 VAV1 protein P15498 UNIPROT PRKCQ protein Q04759 UNIPROT up-regulates 9606 BTO:0000782 10725744 f lperfetto "Vav synergizes with protein kinase c theta to mediate il-4 gene expression in response to cd28 costimulation in t cells" SIGNOR-75827 ivacaftor chemical CHEBI:66901 ChEBI CFTR protein P13569 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck;potentiator gcesareni SIGNOR-193495 BCOR protein Q6W2J9 UNIPROT HDAC3 protein O15379 UNIPROT "up-regulates activity" binding 9606 10898795 t miannu "BCoR can interact w Because HDACs appear to be involved in repression by an increasing number of transcriptional repressors, we tested whether BCoR can associate with HDACs. BCoR can interact with HDAC1, HDAC3, and HDAC-B/5 more strongly than with HDAC-A/4, HDAC-C, HDAC-D, and HDAC-E." SIGNOR-252237 CDK1 protein P06493 UNIPROT CEP55 protein Q53EZ4 UNIPROT down-regulates phosphorylation Ser428 KVAASPKsPTAALNE 9606 16198290 t lperfetto "Upon mitotic entry, centrosome dissociation of cep55 is triggered by erk2/cdk1-dependent phosphorylation at s425 and s428. S425/428 phosphorylation is required for interaction with plk1, enabling phosphorylation of cep55 at s436. enabling it to relocate to the midbody to function in mitotic exit and cytokinesis." SIGNOR-140886 PRKCD protein Q05655 UNIPROT STAT1 protein P42224 UNIPROT up-regulates phosphorylation Ser727 TDNLLPMsPEEFDEV 9606 17502367 t gcesareni "All stats are phosphorylated on at least one serine residue in their tad specifically, ser727 in stats 1 and 3 and ser721 in stat4. Stat serine kinases have been identified through the use of inhibitors, dominant-negative alleles, and in vitro kinase assays. They include mapk (p38mapk: stats 1, 3, 4;erk: stat3, 5;jnk: stat3), pkc_ (stat1, stat3), mtor (stat3), nlk (stat3 (42)), and camkii and ikk_ (stat1 (39, 40, 43)).STAT Serine phosphorylation regulates transcriptional activity (see below)." SIGNOR-154791 PF-03814735 chemical CID:49830590 PUBCHEM AURKA protein O14965 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-205950 PCDHA10 protein Q9Y5I2 UNIPROT PCDHGA11 protein Q9Y5H2 UNIPROT "up-regulates activity" binding 9606 BTO:0000227 16697637 t miannu "The clustered protocadherins comprise the largest subfamily of the cadherin superfamily and are predominantly expressed in the nervous system. Pcdh-alpha proteins interact with beta1-integrin to promote cell adhesion. They also form oligomers with Pcdh-gamma proteins at the same membrane sites." SIGNOR-265712 F2R protein P25116 UNIPROT SDC4 protein P31431 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000007 21072196 f miannu "Both PAR2 and PAR1 activation resulted in up-regulated expression of several genes (CD44, FOSL1, TNFRSF12A, RAB3A, COPEB, CORO1C, THBS1, SDC4) known to be important in cancer." SIGNOR-254852 CLOCK protein O15516 UNIPROT NR3C1 protein P04150 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 21164265 t lperfetto "We recently reported that the basic helix-loop- helix transcription factor Clock, which is a histone acetyltransferase and a central component of the self-oscillating transcription factor loop that generates circadian rhythms, represses GR transcriptional activity by acetylating lysine residues within the 'lysine cluster' located in the hinge region of the receptor. This Clock-mediated repression of GR transcriptional activity oscillates in inverse phase to the HPA axis, acting as a target tissue counter-regulatory mechanism to the diurnally fluctuating circulating glucocorticoids." SIGNOR-253699 SLC24A5 protein Q71RS6 UNIPROT potassium(1+) smallmolecule CHEBI:29103 ChEBI "down-regulates quantity" relocalization 9606 30173760 t miannu "K+-dependent Na+-Ca2+ Exchangers (NCKX) are bi-directional plasma membrane Ca2+ transporters which belong to the Solute Carrier Family 24 A (SLC24 A) of membrane transporters. NCKXs operate via the alternating access model and mediate the extrusion of one Ca2+ ion coupled with one K+ ion in exchange for four Na+ ions (4Na+↔ 1Ca2+ + 1 K+)" SIGNOR-264398 6-(1,3-dioxo-2-benzo[de]isoquinolinyl)-N-hydroxyhexanamide chemical CHEBI:92401 ChEBI HDAC8 protein Q9BY41 UNIPROT "down-regulates activity" "chemical inhibition" -1 20139990 t Luana "Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1)." SIGNOR-258001 TICAM2 protein Q86XR7 UNIPROT TICAM1 protein Q8IUC6 UNIPROT "up-regulates activity" binding 9606 BTO:0000801 14519765 t lperfetto "Tram binds trif directly and recruits it to tlr4" SIGNOR-118367 BCL2L1 protein Q07817 UNIPROT BAK1 protein Q16611 UNIPROT down-regulates binding 9606 9463381 t amattioni "Bcl-xl bind to bax or five other pro-apoptotic relatives (bak, bad, bik, bid or bim)" SIGNOR-55549 BAG3 protein O95817 UNIPROT SIRT5 protein Q9NXA8 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 30910998 f Monia "Ectopic BAG3 expression decreases the interaction between GLS and SIRT5. we demonstrated that BAG3 overexpression decreased SIRT5 expression in HepG2 cells (Fig. 5d)." SIGNOR-261205 PRKACA protein P17612 UNIPROT CTNNB1 protein P35222 UNIPROT "up-regulates activity" phosphorylation Ser552 QDTQRRTsMGGTQQQ 9606 16476742 t lperfetto "In the present study, we have shown that (i) beta-catenin can be phosphorylated by protein kinase a (pka) in vitro and in intact cells at two novel sites, ser-552 and ser-675;(ii) phosphorylation by pka promotes the transcriptional activity (tcf/lef transactivation) of beta-catenin" SIGNOR-144478 NSMCE3 protein Q96MG7 UNIPROT NSMCE1 protein Q8WV22 UNIPROT "up-regulates activity" binding -1 20864041 t miannu "MAGE-G1 enhances NSE1 ubiquitin ligase activity in vitro." SIGNOR-265489 VAV1 protein P15498 UNIPROT GRB2 protein P62993 UNIPROT up-regulates binding 9606 BTO:0001271 9209406 t gcesareni "Recently, we have shown that the proto-oncogene vav product (vav) is also tyrosine-phosphorylated by treatment with gm-csf and epo and is constitutively associated with the sh3 domain of grb2/ash in ut-7." SIGNOR-49362 ARHGEF9 protein O43307 UNIPROT CDC42 protein P60953 UNIPROT "up-regulates activity" "guanine nucleotide exchange factor" 9606 BTO:0000007 32203420 t Luana "We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2)." SIGNOR-260534 ANO6 protein Q4KMQ2 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 10090 24663380 f miannu "Using a shRNA KD approach, we show that Ano6-KD C2C12 myoblasts exhibit reduced proliferation capacity. Our data demonstrate that Ano6 is required to maintain the proliferative status of myoblasts." SIGNOR-261213 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR BORA protein Q6PGQ7 UNIPROT "up-regulates activity" phosphorylation 9606 18521620 t gcesareni "Our data additionally identify the cdk1 site s252 as critical for the recruitment of plk1 to hbora. collectively, our findings lead us to propose that hbora contributes to integrate the functions of three major mitotic kinases, cdk1, plk1, and aurora a." SIGNOR-178799 "pazopanib hydrochloride" chemical CHEBI:71217 ChEBI FLT1 protein P17948 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-200030 CCL5 protein P13501 UNIPROT CCR3 protein P51677 UNIPROT up-regulates binding 9606 10734056 t "In addition to the CCR1 receptor, RANTES activates several members of the CC subfamily of chemokine receptors including CCR3, CCR4, and CCR5" SIGNOR-254370 ROBO proteinfamily SIGNOR-PF14 SIGNOR CDC25B protein P30305 UNIPROT down-regulates phosphorylation Ser375 ARVLRSKsLCHDEIE 9606 BTO:0000567;BTO:0000938 BTO:0000142 15150265 t lperfetto "P38 binds and phosphorylates cdc25-b and -c at serines 309 and 361 and at serine 216, respectively, and phosphorylation of these residues is required for binding to 14-3-3 proteinsphosphorylation of cdc25 triggers cell-cycle arrest by the sequestration of cdc25 by 14-3-3" SIGNOR-124847 HBA1 protein P69905 UNIPROT AHSP protein Q9NZD4 UNIPROT "down-regulates activity" 9606 2545495 f Regulation miannu "EDRF is rapidly inactivated by hemoglobin and superoxide." SIGNOR-251751 LRP6 protein O75581 UNIPROT LPR5/6 complex SIGNOR-C219 SIGNOR "form complex" binding 9606 27821587 t miannu "Low-density lipoprotein receptor-related proteins 5 and 6 (LRP5/6) are co-receptors for Wnt ligands." SIGNOR-256175 SSTR2 protein P30874 UNIPROT GNAI3 protein P08754 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-256827 MAPK1 protein P28482 UNIPROT LIMA1 protein Q9UHB6 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser362 PVHPKPLsPDSRASS 9606 BTO:0001033 23188829 t miannu "Mechanistic study revealed that EGF could activate the phosphorylation, ubiquitination, and degradation of EPLIN through an extracellular signal-regulated kinase 1/2 (ERK1/2)-dependent signaling cascade. Pharmacological inhibition of the ERK1/2 pathway effectively antagonized EGF-induced EPLIN degradation. Two serine residues, i.e. serine 362 and serine 604, were identified as putative ERK1/2 phosphorylation sites in human EPLIN, whose point mutation rendered resistance to EGF-induced protein turnover." SIGNOR-263054 TYSND1 protein Q2T9J0 UNIPROT SCP2 protein P22307 UNIPROT "up-regulates activity" cleavage -1 17255948 t miannu "Here, we demonstrate that Tysnd1, a previously uncharacterized protein, is responsible both for the removal of the leader peptide from PTS2 proteins and for the specific processing of PTS1 proteins. All of the identified Tysnd1 substrates catalyze peroxisomal β-oxidation. In vitro cleavage of Acox1, Scp2 and prethiolase by recombinant Tysnd1." SIGNOR-261055 ABL1 protein P00519 UNIPROT STK4 protein Q13043 UNIPROT "up-regulates activity" phosphorylation Tyr433 KIPQDGDyEFLKSWT 10116 21715626 t Manara "In the present study, we demonstrate that the protein kinase c-Abl phosphorylates MST1 at Y433, which triggers the stabilization and activation of MST1." SIGNOR-260927 GOT2 protein P00505 UNIPROT 2-oxoglutarate(2-) smallmolecule CHEBI:16810 ChEBI "up-regulates quantity" "chemical modification" 9606 31422819 t "Both isoforms [GOT! AND GOT2] catalyze the reversible interconversion of oxaloacetate and glutamate into aspartate and Œ±-ketoglutarate." SIGNOR-266922 PAK5 protein Q9P286 UNIPROT PACSIN1 protein Q9BY11 UNIPROT "up-regulates activity" phosphorylation Ser346 SQAGDRGsVSSYDRG -1 22371566 t miannu "We identified two novel Pak5 substrates, Pacsin1 and Synaptojanin1, proteins that directly interact with one another to regulate synaptic vesicle endocytosis and recycling. Pacsin1 and Synaptojanin1 were phosphorylated by Pak5 and the other group II Paks in vitro, and Pak5 phosphorylation promoted Pacsin1-Synaptojanin1 binding both in vitro and in vivo." SIGNOR-263025 MKNK1 protein Q9BUB5 UNIPROT EIF4E protein P06730 UNIPROT up-regulates phosphorylation Ser209 DTATKSGsTTKNRFV 9606 17724079 t lperfetto "Inhibition of mammalian target of rapamycin induces phosphatidylinositol 3-kinase-dependent and mnk-mediated eukaryotic translation initiation factor 4e phosphorylation.Therefore, eif4e is considered a survival protein involved in cell cycle progression, cell transformation, and apoptotic resistance. Phosphorylation of eif4e (usually at ser209) increases its binding affinity for the cap of mrna and may also favor its entry into initiation complexes." SIGNOR-157533 CAMK2A protein Q9UQM7 UNIPROT Chemoattraction_of_axon phenotype SIGNOR-PH197 SIGNOR up-regulates 9606 15363394 f miannu "In this study, we have identified CaMKII and CaN-PP1 as the downstream effectors of localized Ca2+ signals in mediating attractive and repulsive turning responses of growth cones, respectively. Local Ca2+ elevation activates CaMKII and CaN-PP1 for attraction and repulsion, respectively." SIGNOR-268385 DOK1 protein Q99704 UNIPROT ITGB1 protein P05556 UNIPROT "down-regulates activity" binding 9606 19118207 t miannu "Integrins also bind to many PTBdomain-containing proteins (Calderwood et al., 2003) – including Dok1 and integrincytoplasmic-domain-associated protein 1 (ICAP1) – and these can compete with talin for binding to integrin and so can impair activation" SIGNOR-257669 PRKCA protein P17252 UNIPROT ANXA2 protein P07355 UNIPROT unknown phosphorylation Ser26 TPPSAYGsVKAYTNF 9606 BTO:0000452 2946940 t lperfetto "The protein-tyrosine kinase substrate p36 is also a substrate for protein kinase C in vitro and in vivo. | We present evidence suggesting that protein kinase C mediates phosphorylation of serine 25." SIGNOR-248892 CAMK4 protein Q16566 UNIPROT STMN1 protein P16949 UNIPROT down-regulates phosphorylation Ser16 KELEKRAsGQAFELI 9606 7925472 t gcesareni "Serine 16 of oncoprotein 18 is a major cytosolic target for the ca2+/calmodulin-dependent kinase-gr." SIGNOR-34743 "Cullin 1-RBX1-Skp1" complex SIGNOR-C529 SIGNOR AURKB protein Q96GD4 UNIPROT "down-regulates quantity by destabilization" polyubiquitination 10090 BTO:0002268 23370391 t miannu "The SCF complex contains a catalytic core consisting of Skp1, Cullin1, and the E2 ubiquitin-conjugating (Ubc) enzyme and a F box component that acts as a receptor targeting numerous substrates via phosphodegron elicited interactions. our screening studies suggested that FBXL2 also targets Aurora B protein for ubiquitination and degradation." SIGNOR-272098 AMPK complex SIGNOR-C15 SIGNOR CPS1 protein P31327 UNIPROT "down-regulates quantity" "transcriptional regulation" 9606 BTO:0002553 28538732 f Luana "In KL cells, pharmacological activation of AMPK or expression of constitutively active AMPK reduced CPS1 mRNA and protein, and silencing AMPK increased CPS1 expression even in the presence of LKB1" SIGNOR-267920 EGFR protein P00533 UNIPROT CBL protein P22681 UNIPROT up-regulates relocalization 9606 11823423 t "Cbl binds directly to Tyr1045 receptors" gcesareni "Consistent with a negative role for c-Cbl, here we report that defective Tyr1045 of EGFR, an inducible c-Cbl docking site, enhances the mitogenic response to EGF" SIGNOR-114701 3-[(2-Bromo-4,5-dimethoxyphenyl)methyl]-2-butyl-1,3-diazaspiro[4.4]non-1-en-4-one chemical CID:44436444 PUBCHEM ACHE protein P22303 UNIPROT "down-regulates activity" "chemical inhibition" 9606 BTO:0001239 17888667 t Luana "AChE inhibitory activity study was carried out by using Ellman colorimetric assay with neostigmine as a reference standard against targets from different species, such as pure electric eel AChE, human serum AChE, and rat brain AChE. Among the compounds synthesized, compounds 5a, 5b, 5j showed good inhibition against AChE." SIGNOR-257760 "RNA Polymerase III" complex SIGNOR-C389 SIGNOR tRNA(Ala) smallmolecule CHEBI:29170 ChEBI "up-regulates quantity" "chemical modification" 9606 27911719 t lperfetto "RNAPIII is specialized for transcription of short, abundant nonprotein-coding RNA transcripts. In addition to all tRNAs, RNAPIII transcribes the 5S rRNA and other essential RNAs, including the U6 small nuclear RNA (snRNA), the snR52 small nucleolar RNA and the RNA components of the signal recognition particle (SRP1) and RNase P (RPR1)" SIGNOR-269480 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR STAT5A protein P42229 UNIPROT up-regulates phosphorylation 9606 BTO:0000975 10194762 t "inferred from 70% family members" gcesareni "Serine 780 is the only substrate in full-length stat5a for active erk" SIGNOR-270136 WNT3A protein P56704 UNIPROT LRP6 protein O75581 UNIPROT "up-regulates activity" binding 9606 BTO:0000568 16890161 t gcesareni "Here, we present evidence that lrp6 is internalized with caveolin and that the components of this endocytic pathway are required not only for wnt-3a-induced internalization of lrp6 but also for accumulation of beta-catenin." SIGNOR-148671 CAMK2A protein Q9UQM7 UNIPROT CREB1 protein P16220 UNIPROT down-regulates phosphorylation Ser142 RKILNDLsSDAPGVP 9606 BTO:0000938 11970864 t gcesareni "Phosphorylation of creb1 at ser142 and ser143 is selectively activated by ca(2+) influx;phosphorylation of ser142 and ser143, disrupts the interaction of creb with its cofactor cbp. Phosphorylation of serine 142 in creb by camkii leads to dissociation of the creb dimer." SIGNOR-117344 PRKG1 protein Q13976 UNIPROT CFTR protein P13569 UNIPROT up-regulates phosphorylation Ser813 DIYSRRLsQETGLEI 9606 10581361 t lperfetto "Direct amino acid sequencing and peptide mapping of cf-2 revealed that serines 660, 700, 737, and 813 as well as serine 768, serine 795, or both were phosphorylated by pka and pkgcftr possesses a large cluster of strict dibasic consensus sites for phosphorylation by protein kinase a (pka) in the r-domain and an obligatory dependence on phosphorylation is a hallmark of cftr cl(-) channel function" SIGNOR-72728 WNT10A protein Q9GZT5 UNIPROT CTNNB1 protein P35222 UNIPROT up-regulates 9606 21872687 f fspada "We show that knockdown of Beta-catenin completely prevents the inhibition of adipogenesis and stimulation of osteoblast differentiation by wnt6, wnt10a or wnt10b" SIGNOR-176187 G3BP1 protein Q13283 UNIPROT Stress_granules phenotype SIGNOR-PH124 SIGNOR up-regulates 9606 25520508 f miannu "Ras-GTPase-activating protein (SH3 domain) binding protein 1 (G3BP1) is a stress granule-resident protein that nucleates stress granule assembly and is also inactivated or coopted by many viruses to promote productive infection" SIGNOR-260747 ACO1 protein P21399 UNIPROT D-threo-isocitrate(3-) smallmolecule CHEBI:15562 ChEBI "up-regulates quantity" "chemical modification" 9606 24068518 t miannu "Citrate is converted to cis-aconitate. This is catalyzed by aconitase. Cis-aconitate is an intermediate and is further converted to isocitrate by aconitase. Aconitase is involved in both reactions. In which first dehydration and then rehydration occur and as a result final product isocitrate is obtained." SIGNOR-266245 TFDP1 protein Q14186 UNIPROT CCNE1 protein P24864 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000972 14618416 f miannu "To assess transactivating activity of E2F1/DP-1, we also analyzed expression of ten putative transcriptional targets of this complex in HCCs. Expression levels of TFDP1 and E2F1 correlated with those of seven transcriptional targets ( TYMS, DHFR, PCNA, RRM1, CCNE1, CDC2, and MYBL2) that play important roles in the G1/S transition, and down-regulation of TFDP1 inhibited growth of Hep3B cells." SIGNOR-253857 GFI1 protein Q99684 UNIPROT BAX protein Q07812 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0002181 17213822 f miannu "Our results suggest that the interaction between ETS1 and GFI1 facilitates their binding to specific sites on the Bax promoter and represses Bax expression in vivo." SIGNOR-254203 "125-L-serine-2-133-interleukin 2 (human reduced)" smallmolecule SID:46508054 ChEBI IL2RG protein P31785 UNIPROT "up-regulates activity" "chemical activation" 9606 18031103 t miannu "Aldesleukin (recombinant IL-2) has similar pharmacodynamic properties to endogenous IL-2 and, when administered to patients with cancer, stimulates the antitumour immune response." SIGNOR-259390 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR LATS1 protein O95835 UNIPROT up-regulates phosphorylation Ser613 EKKQITTsPITVRKN 9606 12372621 t lperfetto "Warts is a serine/threonine kinase and a dynamic component of the mitotic apparatus. We have found that cdc2/cyclin b forms a complex with a fraction of warts in the centrosome and phosphorylates the ser613 site of warts during mitosisit can be speculated that phosphorylation of warts by cdc2/cyclin b promotes a protein complex formation on the mitotic apparatus at early mitosis, which may be required for subsequent activation of warts kinase at the metaphase-anaphase transition." SIGNOR-216757 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR PCYT1A protein P49585 UNIPROT down-regulates phosphorylation 9606 BTO:0000763 15788406 t "inferred from 70% family members" gcesareni "Oxysterols inhibit phosphatidylcholine synthesis via erk docking and phosphorylation of ctp:phosphocholine cytidylyltransferase. Mutagenesis of ser315 within cctalpha was both required and sufficient to confer significant resistance to 22-hc/9-cis-ra inhibition of ptdcho synthesis." SIGNOR-270151 MAPK8 protein P45983 UNIPROT BCL2L11 protein O43521 UNIPROT up-regulates phosphorylation Thr116 SCDKSTQtPSPPCQA 9606 12591950 t "The effect has been demonstrated using O43521-2" gcesareni "Here, we demonstrate that jnk phosphorylates two members of the bh3-only subgroup of bcl2-related proteins (bim and bmf) that are normally sequestered by binding to dynein and myosin v motor complexes. Phosphorylation by jnk causes release from the motor complexes" SIGNOR-98396 PI-103 chemical CHEBI:90524 ChEBI PRKDC protein P78527 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-206175 ATE1 protein O95260 UNIPROT HSPA5 protein P11021 UNIPROT "down-regulates quantity by destabilization" "post transcriptional regulation" 9606 BTO:0000567 29295953 t miannu "We showed that the molecular chaperone BiP (also known as GRP78) was short-lived under basal conditions and ER stress. The turnover of BiP was in part driven by its amino-terminal arginylation (Nt-arginylation) by the arginyltransferase ATE1, which generated an autophagic N-degron of the N-end rule pathway." SIGNOR-261345 RUNX2 protein Q13950 UNIPROT BGLAP protein P02818 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 "BTO:0004958; BTO:0002648" 9182762 f "Giulio Giuliani" "Indeed, we identified Osf2/Cbfa1 binding sites in the promoter of four genes expressed only (the Osteocalcin genes) or highly (Œ±1(I) collagen, Bsp, and Osteopontin) in osteoblasts. Each of these elements was able to bind Osf2/Cbfa1." SIGNOR-255408 SCF-SKP2 complex SIGNOR-C136 SIGNOR CDKN1B protein P46527 UNIPROT "down-regulates quantity by destabilization" polyubiquitination -1 phosphorylation:Thr187 NAGSVEQtPKKPGLR 10375532 t miannu "Isolated SCF(Skp2) contained an E3 ubiquitin ligase activity towards p27. Our data thus suggest that SCF(Skp2) specifically targets p27 for degradation during cell-cycle progression.Immunodepletion of components of the complex - Cul-1, Skp1, or Skp2 - from the extract abolished p27 degradation, while addition of purified SCF(Skp2) to Skp2- depleted extract restored the capacity to degrade p27. " SIGNOR-272933 HIC1 protein Q14526 UNIPROT SIRT1 protein Q96EB6 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 21277938 f miannu "HIC1, via its BTB/POZ domain, forms a transcriptional repressor complex with Sirt1 [8] that binds directly to Sirt1 promoter itself, repressing its transcription." SIGNOR-254419 PIK-90 chemical CID:6857685 PUBCHEM PIK3CD protein O00329 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-206229 CIITA protein P33076 UNIPROT HLA-DMB protein P28068 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000776 11889043 f "Promoter-specific functions of CIITA and the MHC class II enhanceosome in transcriptional activation|We compared four genes co-regulated by RFX and CIITA (HLA-DRA, HLA-DPB, HLA-DMB and Ii) and found that the enhanceosome and CIITA make variable, promoter-dependent contributions to histone acetylation and transcription apparatus recruitment." SIGNOR-254010 RGCC protein Q9H4X1 UNIPROT CDK1 protein P06493 UNIPROT "up-regulates activity" binding 9606 BTO:0001685 11687586 t miannu "RGC-32 was physically associated with cyclin-dependent kinase p34CDC2 and increased the kinase activity in vivo and in vitro. In addition, RGC-32 was phosphorylated by p34CDC2-cyclin B1 in vitro. Mutation of RGC-32 protein at Thr-91 prevented the p34CDC2-mediated phosphorylation and resulted in loss of p34CDC2 kinase enhancing activity." SIGNOR-262726 SPOP protein O43791 UNIPROT GLI3 protein P10071 UNIPROT "down-regulates quantity" ubiquitination 9606 BTO:0000007 20463034 t Gianni "RNAi knockdown of Spop (a substrate-binding adaptor for the cullin3-based ubiquitin E3 ligase) in Sufu mutant mouse embryonic fibroblasts (MEFs) can restore the levels of Gli2 and Gli3 full-length proteins" SIGNOR-268861 CDK2 protein P24941 UNIPROT RBL2 protein Q08999 UNIPROT unknown phosphorylation Ser1068 HKNETMLsPREKIFY 9606 11157749 t llicata "We now identify 22 in vivo phosphorylation sites of p130, targeted by diverse kinases, and present evidence for three cyclin-dependent kinase 4(6) [cdk4(6)] specific phosphorylations, which appear critical for controlling the growth-restraining activity of p130." SIGNOR-104667 CDK5R1 protein Q15078 UNIPROT CDK5 protein Q00535 UNIPROT up-regulates binding 9606 15013773 t miannu "In brain, p35 or p25 exists with and activates cdk5" SIGNOR-123387 TRIM32 protein Q13049 UNIPROT DBNDD1 protein Q9H9R9 UNIPROT "down-regulates quantity by destabilization" ubiquitination 9534 BTO:0000298 19349376 t miannu "TRIM32 is an E3 ubiquitin ligase for dysbindin. TRIM32 targets dysbindin for degradation." SIGNOR-271422 ATM protein Q13315 UNIPROT BRCA1 protein P38398 UNIPROT up-regulates phosphorylation Ser1497 EPGVERSsPSKCPSL 9606 BTO:0000150 10550055 t gcesareni "However, shrna-mediated depletion of cdk1 alone or small molecule cdk1 inhibition abrogated s phase cell-cycle arrest and the phosphorylation of a subset of atr/atm targets after dna damage. Loss of dna damage-induced checkpoint control was caused by a reduction in formation of brca1-containing foci. Mutation of brca1 at s1497 and s1189/s1191 resulted in loss of cdk1-mediated phosphorylation and also compromised formation of brca1-containing foci." SIGNOR-72064 JAK2 protein O60674 UNIPROT EPOR protein P19235 UNIPROT "up-regulates activity" phosphorylation Tyr489 DGPYSNPyENSLIPA 12441334 t "JAK2 in turn phosphorylates several tyrosine residues on the EpoR-cytosolic domain and probably on JAK2 itself that serve as docking sites for SH2 or protein tyrosine binding domains of downstream signal transduction proteins such as STAT5, phosphatidylinositol 3-kinase, Shc, and tyrosine phosphatases SHP1 and SHP2" SIGNOR-251354 PRKACA protein P17612 UNIPROT GJB1 protein P08034 UNIPROT unknown phosphorylation Ser233 NPPSRKGsGFGHRLS -1 8390988 t miannu "connexin- 32 is proteolyzed by pcalpain and mcalpain. phosphorylation of connexin-32 by protein kinase C, but not by protein kinase A, efficiently prevents its proteolysis by both calpain isoforms. major phosphorylation sites: Ser233(for protein kinase A). Phosphorylation of connexin-32 by protein kinase C,but not by protein kinase A, prevents the proteolytic attack of p-calpain and m-calpain. Phosphorylation of connexin-32 by protein kinase A and protein kinase C does not prevent its proteolysis by papain, a-chymotrypsin, proteinase K, and trypsin" SIGNOR-249715 ERBB4 protein Q15303 UNIPROT PIK3CD protein O00329 UNIPROT up-regulates binding 9606 16729043 t gcesareni "Pi3k is the sole binding partner to six tyrosines of erbb3 and one in erbb4." SIGNOR-146885 UHRF2 protein Q96PU4 UNIPROT CCND1 protein P24385 UNIPROT "down-regulates quantity by destabilization" ubiquitination 9534 BTO:0000298 21952639 t miannu "We found that NIRF directly ubiquitinated cyclins D1 and E1, as evidenced by the appearance of the tail (Fig. 4B). In summary, the above findings suggest that NIRF tightly cooperates with the core cell cycle machinery and induces G1 arrest, which is accompanied by ubiquitination of cyclins D1 and E1." SIGNOR-271885 KLHL22 protein Q53GT1 UNIPROT "Cullin 3-RBX1-Skp1" complex SIGNOR-C526 SIGNOR "up-regulates activity" binding -1 23455478 t miannu "Here, we identify PLK1 as a target of the cullin 3 (CUL3)-based E3 ubiquitin ligase, containing the BTB adaptor KLHL22, which regulates chromosome alignment and PLK1 kinetochore localization but not PLK1 stability. In the absence of KLHL22, PLK1 accumulates on kinetochores, resulting in activation of the spindle assembly checkpoint (SAC). CUL3-KLHL22 ubiquitylates Lys 492, located within the PBD, leading to PLK1 dissociation from kinetochore phosphoreceptors. " SIGNOR-272109 OSM protein P13725 UNIPROT LIFR protein P42702 UNIPROT up-regulates binding 9606 BTO:0000801;BTO:0001271 1536831 t gcesareni "Oncostatin m binds the high-affinity leukemia inhibitory factor receptor" SIGNOR-19873 ST6GAL1 protein P15907 UNIPROT CD22 protein P20273 UNIPROT "down-regulates activity" glycosylation Asn101 FLGDKNKnCTLSIHP -1 8702538 t lperfetto "CD22-ligand interaction is regulated by the activity of a b-galactoside a2,6- sialyltransferase that can inactivate CD22-mediated binding by sialylating the CD22 receptor itself. These observations suggest that N-linked glycosylation sites on the CD22 molecule may play a role in the regulation of CD22-mediated adhesion." SIGNOR-261741 AKT1 protein P31749 UNIPROT PRKAA1 protein Q13131 UNIPROT "down-regulates activity" phosphorylation -1 16340011 t gcesareni "It is proposed that the effect of insulin to antagonize AMP-activated protein kinase activation involves a hierarchical mechanism whereby Ser 485/Ser 491 phosphorylation by protein kinase B reduces subsequent phosphorylation of Thr 172 by LKB1 and the resulting activation of AMP-activated protein kinase." SIGNOR-252739 HPS5 protein Q9UPZ3 UNIPROT BLOC-2 complex SIGNOR-C252 SIGNOR "form complex" binding 9606 15030569 t lperfetto "Characterization of BLOC-2, a complex containing the Hermansky-Pudlak syndrome proteins HPS3, HPS5 and HPS7" SIGNOR-260689 "CoREST-HDAC complex" complex SIGNOR-C105 SIGNOR Chromatine_condensation phenotype SIGNOR-PH21 SIGNOR up-regulates 9606 32101746 f miannu "The CoREST complex is one of seven families of class I histone deacetylase complexes that have specialized physiological functions but are all thought to act as repressors of gene expression. CoREST is unique within these complexes in that it removes both acetyl and methyl modifications through the activity of its demethylase (LSD1) and deacetylase (HDAC1) enzymes." SIGNOR-263861 THOC2 protein Q8NI27 UNIPROT "TREX complex" complex SIGNOR-C444 SIGNOR "form complex" binding 9606 33191911 t miannu "The TREX complex is found in all eukaryotes and contains the multi-subunit THO complex, the DEXD-box RNA helicase UAP56/DDX39B (yeast Sub2), and an RNA export adapter such as ALYREF (yeast Yra1). The human THO complex comprises six subunits, THOC1, −2, –3, −5, –6, and −7, of which four have known counterparts in the yeast Saccharomyces cerevisiae (Sc): THOC1 (yeast Hpr1), −2 (yeast Tho2), −3 (yeast Tex3), and −7 (yeast Mft1) . In this study we focus on the conserved TREX complex (Heath et al., 2016; Xie and Ren, 2019): THO–UAP56/DDX39B–ALYREF, and hereafter refer to UAP56/DDX39B as UAP56." SIGNOR-268509 TRPV4 protein Q9HBA0 UNIPROT UCP1 protein P25874 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 10090 BTO:0000443 23021218 f lperfetto "TRPV4 negatively regulated the expression of PGC1α, UCP1, and cellular respiration. Additionally, it potently controlled the expression of multiple proinflammatory genes involved in the development of insulin resistance." SIGNOR-253096 MAPK3 protein P27361 UNIPROT HDAC6 protein Q9UBN7 UNIPROT up-regulates phosphorylation Thr1031 ASSTDHQtPPTSPVQ 9606 24089523 t lperfetto "Histone deacetylase 6 (hdac6) is well known for its ability to promote cell migrationextracellular signal-regulated kinase (erk) phosphorylates histone deacetylase 6 (hdac6) at serine 1035 to stimulate cell migrationwe have identified two novel erk-mediated phosphorylation sites: threonine 1031 and serine 1035 in hdac6. Both sites were phosphorylated by erk1" SIGNOR-202702 RARG protein P13631 UNIPROT THRA protein P10827 UNIPROT up-regulates binding 9606 15650024 t lperfetto "We report that the retinoic acid receptors (rars), a distinct class of nuclear receptors, are also efficient heterodimer partners for trs" SIGNOR-133237 E2F1 protein Q01094 UNIPROT CCNE1 protein P24864 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 8649818 f lperfetto "We have found that cell cycle regulation of cyclin E transcription is mediated by E2F binding sites present in the promoter. The activity of this promoter can be regulated negatively by pRB." SIGNOR-245474 LRFN5 protein Q96NI6 UNIPROT Neurite_outgrowth phenotype SIGNOR-PH134 SIGNOR up-regulates 9606 BTO:0000938 21736948 f miannu "This study finds that all SALMs (SALMs 1–5) possess the abilityto promote neurite outgrowth and branching, as demonstrated byoverexpression and knockdown experiments." SIGNOR-264098 AKT proteinfamily SIGNOR-PF24 SIGNOR EZH2 protein Q15910 UNIPROT "down-regulates activity" phosphorylation Ser21 CWRKRVKsEYMRLRQ 9606 16224021 t lperfetto "Enhancer of zeste homolog 2 (ezh2) is a methyltransferase that plays an important role in many biological processes through its ability to trimethylate lysine 27 in histone h3. Here, we show that akt phosphorylates ezh2 at serine 21 and suppresses its methyltransferase activity by impeding ezh2 binding to histone h3" SIGNOR-244259 GABBR2 protein O75899 UNIPROT "GABA-B receptor" complex SIGNOR-C336 SIGNOR "form complex" binding 9606 BTO:0000007 9872316 t brain lperfetto "Heterodimerization is required for the formation of a functional GABA(B) receptor.|These results indicate that, in vivo, functional brain GABA(B) receptors may be heterodimers composed of GABA(B)R1 and GABA(B)R2." SIGNOR-263743 Cullin4-RBX1-DDB1 complex SIGNOR-C119 SIGNOR ST7 protein Q9NRC1 UNIPROT "down-regulates quantity by destabilization" polyubiquitination 9606 BTO:0004297 30945288 t miannu "We found that both CUL4A and CUL4B can form an E3 complex with DNA damage-binding protein 1 (DDB1) and DDB1-CUL4-associated factor 4 (DCAF4). In vitro and in vivo ubiquitination analyses indicate that CRL4DCAF4 E3 ligase specifically directs degradation of ST7 (suppression of tumorigenicity 7)." SIGNOR-272309 PRKCZ protein Q05513 UNIPROT MYH10 protein P35580 UNIPROT down-regulates phosphorylation Ser1937 RGGPISFsSSRSGRR 9606 16611744 t lperfetto "After egf stimulation, apkc_ translocates from the nucleus to the cytoplasm (figure 3) and is therefore able to interact with myosin ii-b. apkc_ phosphorylates nmhc ii-b on ser1937, which is located on the nonhelical tailpiece, leading to filament disassembly at certain sites of the cell" SIGNOR-146100 PKA proteinfamily SIGNOR-PF17 SIGNOR KCNA1 protein Q09470 UNIPROT "down-regulates quantity" phosphorylation Ser446 SDLSRRSsSTMSKSE 9606 BTO:0002178 23774215 t done miannu "Phosphorylation of KCNA1 at Ser446 by PKA is involved on its cytoplasmic retention" SIGNOR-273777 ABL1 protein P00519 UNIPROT LGALS3 protein P17931 UNIPROT unknown phosphorylation Tyr118 AGPLIVPyNLPLPGG 9606 20600357 t llicata "In this report we have identified novel tyrosine phosphorylation sites in galectin-3 as well as the kinase responsible for its phosphorylation. Our results demonstrate that tyrosines at positions 79, 107 and 118 can be phosphorylated in vitro and in vivo by c-abl kinase. our results demonstrate that cells expressing galectin-3 y107f variant showed reduced migration in wound healing assay ( fig. 5). This result confirms the role of galectin-3 tyrosine phosphorylation in cell motility." SIGNOR-166497 LRRC4 protein Q9HBW1 UNIPROT CDK2 protein P24941 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0000142 25526788 f miannu "LRRC4/NGL-2 can delay the cell cycle in late G1 by increasing the expression of cell cycle inhibitory molecules (p21, p27) and reducing the expression of cell cycle regulatory proteins (CyclinD1, CDK2, CyclinE, CDK4) via the inhibition of K-Ras/c-Raf/ERK/MAPK, PI-3K/AKT/NF- κB, p70S6/PKC and STAT3, and the upregulation of the JNK2/c-Jun/mp53 signaling pathway." SIGNOR-264058 KCNC1 protein P48547 UNIPROT potassium(1+) smallmolecule CHEBI:29103 ChEBI "down-regulates quantity" relocalization 9606 11506885 t miannu "Kv3 currents are activated specifically during action potential repolarization. Analysis of the Kv3 subfamily of K+ channel subunits has lead to the discovery of a new class of neuronal voltage-gated K+ channels characterized by positively shifted voltage dependencies and very fast deactivation rates. These properties are adaptations that allow these channels to produce currents that can specifically enable fast repolarization of action potentials without compromising spike initiation or height" SIGNOR-265586 INPP5D protein Q92835 UNIPROT "phosphatidylinositol bisphosphate" smallmolecule CHEBI:37328 ChEBI "up-regulates quantity" "chemical modification" 9606 23650141 t gcesareni "PtdIns(3,4)P2 is commonly reported as a product of the SH2 domain-containing inositol 5-phosphatases 1/2 (SHIP1 and SHIP2) that dephosphorylate PtdIns(3,4,5)P3 at the 5-position" SIGNOR-252427 SKI protein P12755 UNIPROT SMAD2 protein Q15796 UNIPROT "down-regulates activity" binding 9606 10575014 t lperfetto "Smad2/3 interacts with c-ski through its c-terminal mh2 domain in a tgf-beta-dependent mannerc-ski is incorporated in the smad dna binding complex, interferes with the interaction of smad3 with a transcriptional co-activator, p300, and in turn recruits hdac. c-ski is thus a transcriptional co-repressor that links smads to hdac in tgf-beta signaling." SIGNOR-217658 BMP7 protein P18075 UNIPROT ACTR2 protein P61160 UNIPROT up-regulates binding 9606 16446785 t acerquone "The two ligands induce the formation of two ligand-receptor complexes, cbmp7 (blue) and ctgf-b (red), that share the type i receptor alk2" SIGNOR-144144 "A4/b1 integrin" complex SIGNOR-C162 SIGNOR DLL1 protein O00548 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 25786978 f lperfetto "First, EPCs incorporated into the neovascular region recognize the TGFBIp secreted by cells in the environment via binding to integrins a4 and a5. Second, binding of TGFBIp to integrins in EPCs induces phosphorylation of intracellular signaling molecules in a pathway necessary for TGFBIp-mediated angiogenic activity of EPCs. In addition, binding of TGFBIp to integrins activates the NF-kappaB signaling pathway that induces expression of DLL1 and JAG1 in EPCs." SIGNOR-253285 ROR2 protein Q01974 UNIPROT MAPK8 protein P45983 UNIPROT up-regulates binding 9606 18667433 t gcesareni "Wnt5a stimulation induces activation of the c-jun n-terminal kinase jnk at the wound edge in a ror2-dependent manner, and inhibiting jnk activity abrogates wnt5a-induced lamellipodia formation and mtoc reorientation" SIGNOR-179671 STK11 protein Q15831 UNIPROT STK11 protein Q15831 UNIPROT "up-regulates activity" phosphorylation Thr402 TEAAQLStKSRAEGR 9606 BTO:0000007;BTO:0000567 12805220 t lperfetto "It was shown that thr336 and thr366 are the major autophosphorylation sites of mouse lkb1 (sapkota et al., 2002). We confirmed these data on the human orthologues thr336 and thr363. Moreover, the enhanced stoichiometry of lkb1 autophosphorylation by strad enabled us to identify two novel sites: thr185 and thr402. We show that increased lkb1 autophosphorylation of all sites correlates with the activation of its catalytic activity." SIGNOR-101852 ITGA10 protein O75578 UNIPROT "A10/b1 integrin" complex SIGNOR-C167 SIGNOR "form complex" binding 16988024 t lperfetto "Integrins are one of the major families of cell adhesion receptors (Humphries, 2000; Hynes, 2002). All integrins are non-covalently-linked, heterodimeric molecules containing an α and a β subunit. Both subunits are type I transmembrane proteins, containing large extracellular domains and mostly short cytoplasmic domains (Springer and Wang, 2004; Arnaout et al., 2005). Mammalian genomes contain 18 α subunit and 8 β subunit genes, and to date 24 different α,β combinations have been identified at the protein level. Although some subunits only appear in a single heterodimer, twelve integrins contain the β1 subunit, and five contain αV." SIGNOR-253185 asparagine smallmolecule CHEBI:22653 ChEBI AminoAcids stimulus SIGNOR-ST5 SIGNOR "up-regulates quantity" 29259120 t lperfetto "All extant life employs the same 20 amino acids for protein biosynthesis" SIGNOR-264753 2-[1-ethylsulfonyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1-pyrazolyl]-3-azetidinyl]acetonitrile chemical CHEBI:95341 ChEBI JAK1 protein P23458 UNIPROT "down-regulates activity" "chemical inhibition" 9606 20363976 t Luana "INCB028050 is a selective orally bioavailable JAK1/JAK2 inhibitor with nanomolar potency against JAK1 (5.9 nM) and JAK2 (5.7 nM)." SIGNOR-257833 HRAS protein P01112 UNIPROT BRAF protein P15056 UNIPROT up-regulates binding 9606 18098337 t lperfetto "BRAF kinase is a downstream target of KRAS and activates the MAPK pathway." SIGNOR-160043 FYN protein P06241 UNIPROT CDK5 protein Q00535 UNIPROT "up-regulates activity" phosphorylation Tyr15 EKIGEGTyGTVFKAK 9606 14757045 t "Constitutively active Fyn phosphorylated Tyr15 of Cdk5. Fyn Facilitates Kinase Activity of Cdk5 Via Tyr15 Phosphorylation" SIGNOR-251156 CDK1 protein P06493 UNIPROT ORC1 protein Q13415 UNIPROT up-regulates phosphorylation Ser273 VAFSEITsPSKRSQP 9606 11931757 t lperfetto "Horc1p contains three (s/t)px(k/r) consensus sites for cdk phosphorylation (ser258, ser273, and thr375). These data combined strongly suggest that skp2 promotes horc1p turnover and that the n-terminal domain of horc1p, containing most of the phosphorylation sites and overlapping with one of the skp2-interacting domains, is a regulatory element for horc1p stability." SIGNOR-116325 CSNK2A2 protein P19784 UNIPROT MS4A1 protein P11836 UNIPROT unknown phosphorylation Ser289 PPQDQESsPIENDSS 9606 BTO:0000776 7678037 t llicata "These data suggest taht CKII can phosphorylate more than one site on CD20 molecule. | Taken together, this data shown that insulin can increase serine/ threonine phosphorylation and may stimulate CKII activity in B cells." SIGNOR-251012 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 19819937 f "In addition to the JAK2–STAT5 pathway, the Ras GTPase–extracellular signal-regulated kinase (Ras–ERK) pathway has also been implicated in signaling of IL-5 and is important for IL-5-dependent cell survival, proliferation and differentiation of eosinophils." SIGNOR-254354 INSR protein P06213 UNIPROT PIK3R3 protein Q92569 UNIPROT unknown phosphorylation Tyr341 NEDADENyFINEEDE 9606 BTO:0000142;BTO:0000671 7542745 t llicata "This pattern of 32p-tyr release unambiguously identified tyr-341 in p55pik as a major in vitro phosphorylation site." SIGNOR-28791 STAT3 protein P40763 UNIPROT VEGFA protein P15692 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 12545153 t luana "Stat3 directly regulated the promoter of the VEGF gene. Blockade of activated Stat3 by ectopic expression of dominant-negative Stat3 significantly inhibited VEGF expression, and the growth and metastasis of human pancreatic cancer cells. " SIGNOR-259456 PPP3CB protein P16298 UNIPROT NFATC2 protein Q13469 UNIPROT "up-regulates activity" dephosphorylation Ser268 VALPPGAsPQRSRSP 9606 BTO:0000567 11030334 t "NFAT1 is phosphorylated on fourteen conserved phosphoserine residues in its regulatory domain, thirteen of which are dephosphorylated upon stimulation. Dephosphorylation of all thirteen residues is required to mask a nuclear export signal (NES), cause full exposure of a nuclear localization signal (NLS), and promote transcriptional activity" SIGNOR-248374 EPO protein P01588 UNIPROT EPOR protein P19235 UNIPROT up-regulates binding -1 9774108 t gcesareni "Human erythropoietin is a haematopoietic cytokine required for the differentiation and proliferation of precursor cells into red blood cells. It activates cells by binding and orientating two cell-surface erythropoietin receptors (EPORs) which trigger an intracellular phosphorylation cascade." SIGNOR-60663 PRKCA protein P17252 UNIPROT CD163 protein Q86VB7 UNIPROT unknown phosphorylation Ser1084 QRQRLAVsSRGENLV 9606 BTO:0000801 11298324 t lperfetto "Furthermore, we demonstrated that the cytoplasmic domains of CD163 variants are phosphorylated by PKC-alpha in vitro. Inhibition studies using specific kinase inhibitors reveal that both CKII and PKC are involved in the CD163 signaling mechanism resulting in the secretion of proinflammatory cytokines." SIGNOR-249082 ATM protein Q13315 UNIPROT FANCD2 protein Q9BXW9 UNIPROT up-regulates phosphorylation Ser1407 KSQNSQEsTADESED 9606 12086603 t lperfetto "These results suggest that s222 and either s1401, s1404, or s1408 are sites of atm-dependent phosphorylation in vitro.Phosphorylation Of fancd2 is required for activation of an s phase checkpoint" SIGNOR-90117 "8-Hydroxy-7-(6-sulfo-naphthalen-2-ylazo)-quinoline-5-sulfonic acid" chemical CID:92577 PUBCHEM DUSP26 protein Q9BV47 UNIPROT "down-regulates activity" "chemical inhibition" -1 19233143 t lperfetto "Phosphatase activity of dual-specificity protein phosphatase 26 (DUSP26) was decreased by the inhibitor in a dose-dependent manner. Kinetic studies with NSC-87877 and DUSP26 revealed a competitive inhibition." SIGNOR-261979 JNK proteinfamily SIGNOR-PF15 SIGNOR SFN protein P31947 UNIPROT down-regulates phosphorylation 9606 15071501 t "Ser residues in the reagion between alpha-helices 7 and 8, JNK3 is essential for apoptosis of hippocampal neurons" gcesareni "Here we demonstrate that activated jnk promotes bax translocation to mitochondria through phosphorylation of 14-3-3, a cytoplasmic anchor of bax. Phosphorylation of 14-3-3 led to dissociation of bax from this protein.Jnk phosphorylates 14-3-3zeta_ at ser-184 and 14-3-3sigma_ at ser-191" SIGNOR-269979 NR3C1 protein P04150 UNIPROT NR3C1/STAT5A complex SIGNOR-C84 SIGNOR "form complex" binding 9606 8878484 t fspada "We show here that the glucocorticoid receptor can act as a transcriptional co-activator for stat5 and enhance stat5-dependent transcription. Stat5 forms a complex with the gluco-corticoid receptor which binds to dna independently of the gre. This complex formation between stat5 and the glucocorticoid receptor diminishes the glucocorticoid response of a gre-con-taining promoter." SIGNOR-44373 levomethadone chemical CHEBI:136003 ChEBI OPRM1 protein P35372 UNIPROT "up-regulates activity" "chemical activation" 10029 BTO:0000246 9686407 t miannu "Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors." SIGNOR-258808 SMAD5 protein Q99717 UNIPROT SMAD6 protein O43541 UNIPROT "up-regulates quantity" "transcriptional regulation" 10090 22219353 t Gianni "Chromatin immunoprecipitation (ChIP) revealed a subset of the BIG (BMP4 induced genes) signature, including Satb2, Smad6, Hand1, Gadd45γ and Gata3, that was bound by Smad1/5 in the developing mandible, revealing direct Smad-mediated regulation" SIGNOR-268940 GNRHR protein P30968 UNIPROT GNAS protein Q5JWF2 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-256792 NFATC3 protein Q12968 UNIPROT PTGS2 protein P35354 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 21871017 t miannu "NFAT induces the transcription of the COX2 (cyclo-oxygenase-2) gene incancer cells thereby enhancing invasive migration" SIGNOR-264028 RBPJ protein Q06330 UNIPROT CDKN1A protein P38936 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 11432830 f gcesareni "The rbp-jkappa protein binds directly to the endogenous p21 promoter and p21 expression is induced specifically by activated notch1 through rbp-jkappa-dependent transcription." SIGNOR-109042 GNB1 protein P62873 UNIPROT GNG2 protein P59768 UNIPROT "up-regulates activity" binding 10696571 t "GNB1 dissociates from the receptor, bound with GNG2 as stable dimer" SIGNOR-251105 SMURF2 protein Q9HAU4 UNIPROT SMAD5 protein Q99717 UNIPROT "down-regulates quantity by destabilization" ubiquitination 9606 BTO:0001593 BTO:0000140 22298955 t lperfetto "Smurf1 and smurf2 are e3 ubiquitin ligases known to suppress tgf-beta signaling through degra-dation of smads and receptors for tgf-beta and bmps" SIGNOR-153420 F9 protein P00740 UNIPROT "Factor VIIIa-IXa" complex SIGNOR-C320 SIGNOR "form complex" binding 10090 BTO:0000131 25769543 t lperfetto "The present data point to key roles of FVIII and FIX in FX activation at the site of a platelet thrombus by supporting: (i) thrombin generation, (ii) thrombus growth and platelet phosphatidylserine exposure, and (iii) fibrin formation at the platelet surface. The likely mechanism is that tenase activity via FVIIIa and FIXa, which is confined to the sites of platelet thrombi, generates FXa that directly catalyzes the conversion of prothrombin into thrombin." SIGNOR-263552 AKT2 protein P31751 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR "down-regulates activity" phosphorylation Thr32 QSRPRSCtWPLPRPE 10090 BTO:0000944 11313479 t "Phosphorylation of AFX by PKB occurs in the nucleus. Phosphorylation of S193 reduces the rate of nuclear import. PKB-mediated phosphorylation of AFX, therefore, attenuates the import of the transcription factor, which shifts the localization of the protein from the nucleus to the cytoplasm and results in the inhibition of AFX transcriptional activity." SIGNOR-252873 spironolactone chemical CHEBI:9241 ChEBI NR3C2 protein P08235 UNIPROT "down-regulates activity" "chemical inhibition" -1 18038968 t Luana "Results of the RALES trial (Randomized Aldactone Evaluation Study) demonstrated that the published MR antagonist spironolactone, added to standard therapy, reduced mortality due to all causes by 30% as well as reduced hospitalizations and improved cardiac function in patients with severe heart failure.2" SIGNOR-257762 RPS6K proteinfamily SIGNOR-PF26 SIGNOR FOS protein P01100 UNIPROT "up-regulates activity" phosphorylation Ser362 AAAHRKGsSSNEPSS 9606 8248197 t gcesareni "We now provide evidence that two growth-regulated, nucleus- and cytoplasm-localized protein kinases, 90-kda ribosomal s6 kinase (rsk) and mitogen-activated protein kinase (map kinase), contribute to the serum-induced phosphorylation of c-fos. The major phosphopeptides derived from biosynthetically labeled c-fos correspond to phosphopeptides generated after phosphorylation of c-fos in vitro with both rsk and map kinase. The phosphorylation sites identified for rsk (ser-362) and map kinase (ser-374) are in the transrepression domain. Cooperative phosphorylation at these sites by both enzymes was observed in vitro and reflected in vivo by the predominance of the peptide phosphorylated on both sites, as opposed to singly phosphorylated peptides. This study suggests a role for nuclear rsk and map kinase in modulating newly synthesized c-fos phosphorylation and downstream signaling." SIGNOR-252789 TP53 protein P04637 UNIPROT BAX protein Q07812 UNIPROT up-regulates binding 9606 14963330 t gcesareni "Tp53 directly activated the proapoptotic bcl-2 protein bax in the absence of other proteins to permeabilize mitochondria and engage the apoptotic program" SIGNOR-121895 PEX1 protein O43933 UNIPROT PEX5 protein P50542 UNIPROT "up-regulates activity" binding 10029 16314507 t "Pex1, Pex6, and Pex26 are involved in Pex5 export from peroxisomes., we found that Pex1 and Pex6 bind to Pex5 (Fig. ​(Fig.6). Therefore, it is conceivable that Pex1 and Pex6 pull out Pex5 from peroxisome membranes in an ATP-dependent manner." SIGNOR-253618 DDR2 protein Q16832 UNIPROT SHC1 protein P29353 UNIPROT up-regulates binding 9606 16186108 t gcesareni "Collectively, our findings are consistent with the following mechanism for src-dependent ddr2 activation and signaling: 1) ligand binding promotes phosphorylation of tyr-740 in the ddr2 activation loop by src;2) tyr-740 phosphorylation stimulates intramolecular autophosphorylation of ddr2;3) ddr2 autophosphorylation generates cytosolic domain phosphotyrosines that promote the formation of ddr2 cytosolic domain-shc signaling complexes." SIGNOR-140724 ROCK1 protein Q13464 UNIPROT ARHGAP24 protein Q8N264 UNIPROT "up-regulates activity" phosphorylation Ser391 RSSMNNGsPTALSGS 9606 BTO:0000007 16862148 t lperfetto "ROCK phosphorylates FilGAP, and this phosphorylation stimulates its RacGAP activity and is a requirement for FilGAP-mediated bleb formation. | As shown in Fig. 5b, ROCK stimulated the incorporation of phosphate into FilGAP. We identified seven potential phosphorylation sites in FilGAP that was isolated by preparative SDS€“PAGE and subjected to trypsin digestion and mass spectrometry: Ser 391, Ser 402, Ser 413, Ser 415, Ser 437, Thr 452, and a cluster of serine and threonine residues (SSTTT) at position 573€“577 (see Supplementary Information, Table S2)." SIGNOR-249309 TLR2 protein O60603 UNIPROT TICAM2 protein Q86XR7 UNIPROT "up-regulates activity" binding 10090 22664090 t scontino "To initiate the innate immune response, Toll-like receptors (TLRs) associate with cytoplasmic adaptor proteins through TIR (Toll/interleukin-1 receptor) domain interactions. The four principal signaling adaptor proteins include MyD88, MAL, TRIF and TRAM, and the fifth protein SARM, involved in negative regulation of TLR pathways, is usually considered a part of the TIR domain-containing adaptor protein group" SIGNOR-266747 FUS protein P35637 UNIPROT AGRN protein O00468 UNIPROT "down-regulates quantity by repression" "post transcriptional regulation" 10090 28515487 f "This conclusion is also supported by the analysis of alternative splicing events in hFUS+/+; Smn+/− mice. As shown in Fig. 6b, the splicing of Dusp22, Mphosph9, Adarb1, hnRNP A2/B1, Gria4, Vps16, Atxn2 and Agrin, which are significantly affected in hFUS+/+ mice, is not further modified by SMN decrease" SIGNOR-262807 DRD2 protein P14416 UNIPROT GNAI1 protein P63096 UNIPROT "up-regulates activity" binding 9606 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-256701 USF1 protein P22415 UNIPROT Hexokinase proteinfamily SIGNOR-PF76 SIGNOR "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000599 9677331 f "inferred from family member" miannu "Cotransfection of an expression plasmid encoding USF1 into HepG2 hepatoma cells resulted in the activation of the glucokinase promoter, dependent on the integrity of the P2 element" SIGNOR-270263 PRKCH protein P24723 UNIPROT GSK3B protein P49841 UNIPROT down-regulates phosphorylation Ser9 SGRPRTTsFAESCKP 9606 19836308 t lperfetto "Gsk3 is different from most kinases in that it is constitutively partially active and the most common regulatory mechanism is inhibition by phosphorylation of ser21 in gsk3_ or ser9 in gsk3_. This inhibitory phosphorylation can be mediated by several kinases, such as akt/protein kinase b (pkb), protein kinase c (pkc) and protein kinase a (pka)." SIGNOR-188585 romidepsin chemical CHEBI:61080 ChEBI HDAC2 protein Q92769 UNIPROT "down-regulates activity" "chemical inhibition" -1 20139990 t Luana "Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1)." SIGNOR-257997 DVL2 protein O14641 UNIPROT DVL2 protein O14641 UNIPROT "up-regulates activity" binding 9606 17529994 t amattioni "Dix domain of dvl2 mediates dynamic polymerization, which is essential for the signaling activity of dvl2." SIGNOR-155224 ABL2 protein P42684 UNIPROT GPX1 protein P07203 UNIPROT "up-regulates activity" phosphorylation Tyr98 EILNSLKyVRPGGGF 9606 12893824 t lperfetto "GPx1 also functions as a substrate for c-Abl- and Arg-mediated phosphorylation on Tyr-96. The results further show that c-Abl and Arg stimulate GPx activity and that these kinases contribute to GPx-mediated protection of cells against oxidative stress." SIGNOR-104328 STAT5A protein P42229 UNIPROT HBA1 protein P69905 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 BTO:0000574 9168989 f Regulation miannu "We describe the roles of Stat5 and of these tyrosine residues in the EPOR in the erythroid differentiation of murine hematopoietic cell line SKT6 which produces hemoglobin in response to EPO. Chimeric receptors carrying the extracellular domain of the EGF receptor and the intracellular domain of the EPOR were introduced into SKT6 cells. Like EPO, EGF equally activated Stat5 and induced hemoglobin." SIGNOR-251787 CHUK protein O15111 UNIPROT NFKB2 protein Q00653 UNIPROT "up-regulates activity" phosphorylation Ser866 TAEVKEDsAYGSQSV 10090 BTO:0000785 15084608 t lperfetto "Ikkalfa phosphorylates p100, leading to its proteasomal processing to p52." SIGNOR-124226 CBX3 protein Q13185 UNIPROT H3-3A protein P84243 UNIPROT "up-regulates activity" binding 9606 methylation:Lys10 RTKQTARkSTGGKAP 19111658 t miannu "A core characteristic of heterochromatin is its association with heterochromatin protein 1 (HP1) proteins, a highly conserved family of chromosomal proteins that bind to di- and trimethylated H3K9 via a conserved N-terminal domain called the chromodomain (CD) HP1 proteins are a highly conserved family of eukaryotic proteins that bind to methylated histone H3 lysine 9 (H3K9) and are required for heterochromatic gene silencing." SIGNOR-264494 CDK1 protein P06493 UNIPROT ECT2 protein Q9H8V3 UNIPROT up-regulates phosphorylation Thr846 RAFSFSKtPKRALRR 9606 SIGNOR-C17 16247472 t lperfetto "Thr-814 to ala greatly diminished the ability of p34cdk1/cyclin b to phosphorylate recombinant ect2-c protein (figure 1b, left panel). These data suggest that thr-814 is a major cdk1 phosphorylation site in ect2-c in vitrothe sequence thr-pro-lys-arg (tpkr) starting at amino acid 814we found that the t814a mutation slightly reduces the exchange activity of ect2 on rac1" SIGNOR-141179 ABL1 protein P00519 UNIPROT PRKD1 protein Q15139 UNIPROT "up-regulates activity" phosphorylation Tyr463 NDTGSRYyKEIPLSE 9606 12637538 t Manara "We show that Abl directly phosphorylates PKD at Tyr(463) in vitro, and in cells phosphorylation of this site is sufficient to mediate full activation of PKD" SIGNOR-260791 WNT5A protein P41221 UNIPROT FZD6 protein O60353 UNIPROT "up-regulates activity" binding 9606 BTO:0000551;BTO:0000848 16273260 t gcesareni "Human wnt5a, wnt5b and wnt11 are non-canonical wnt ligands transducing pcp signals through fzd3 or fzd6 receptors." SIGNOR-141437 SHANK1 protein Q9Y566 UNIPROT "Postsynaptic density assembly" phenotype SIGNOR-PH163 SIGNOR up-regulates 9606 BTO:0000938 28179641 f miannu "SHANK proteins are ‘master’ scaffolding proteins that tether and organize intermediate scaffolding proteins. They are located at excitatory synapses, where they are crucial for proper synaptic development and function." SIGNOR-264605 ABL1 protein P00519 UNIPROT TOP1 protein P11387 UNIPROT "up-regulates activity" phosphorylation Tyr268 AKMLDHEyTTKEIFR 9606 15448168 t Manara "This study demonstrates that ABL1-dependent phosphorylation up-regulates topo I activity. The ABL1 SH3 domain bound directly to the N-terminal region of topo I. The results demonstrate that ABL1 phosphorylated topo I at Tyr268 in core subdomain II." SIGNOR-260775 PTPRJ protein Q12913 UNIPROT MAPK1 protein P28482 UNIPROT down-regulates dephosphorylation 9606 12771128 t gcesareni "A dominant-negative mutant of high cell density-enhanced ptp 1 (dep-1)//cd148 as well as reduction of its expression by rna interference partially restore vegfr-2 phosphorylation and map kinase activation." SIGNOR-101279 Ub:E2 complex SIGNOR-C497 SIGNOR RNF150 protein Q9ULK6 UNIPROT "up-regulates activity" ubiquitination 9606 34199813 t miannu "The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t" SIGNOR-271070 WNT8B protein Q93098 UNIPROT FZD3 protein Q9NPG1 UNIPROT up-regulates binding 9606 15578921 t gcesareni "Wnt proteins bind to the frizzled receptors and lrp5/6 co-receptors, and through stabilizing the critical mediator betBeta-catenin, initiate a complex signaling cascade that plays an important role in regulating cell proliferation and differentiation." SIGNOR-132024 HSPA9 protein P38646 UNIPROT "TIM23 complex" complex SIGNOR-C423 SIGNOR "form complex" binding 32074073 t lperfetto "The human TIM23 complex is formed by the core components TIM50 (50), TIM23 (23) and TIM17A/B (17A/B). The sorting elements are TIM21 (21) and ROMO1, and the motor elements include TIM44 (44), PAM18 (18; DNAJC15 and DNAJC19), PAM16 (16; MAGMAS), mtHSP70 (Mortalin) and GrpE." SIGNOR-267693 RIPK1 protein Q13546 UNIPROT DAB2IP protein Q5VWQ8 UNIPROT "up-regulates activity" phosphorylation Ser728 PSPARSSsYSEANEP 9606 27858941 t miannu "Upon TNF stimulation, RIP1 phosphorylates DAB2IP on Serine 604, inducing a conformational switch that allows formation of the complex." SIGNOR-254763 PTPRF protein P10586 UNIPROT INSR protein P06213 UNIPROT down-regulates dephosphorylation Tyr1189 RDIYETDyYRKGGKG 9606 1303753 t gcesareni "Lar ptpase shows strong preference for dephosphorylation first at py5 (at tri-, di-, and monophosphotyrosyl levels). Initially this regioselectivity gives the y5(py9)(py10) diphospho regioisomer, followed by equal dephosphorylation at py9 or py10 to give the corresponding monophosphoryl species on the way to fully dephosphorylated product." SIGNOR-16239 DDOST protein A0A024RAD5 UNIPROT "OST-A complex" complex SIGNOR-C535 SIGNOR "form complex" binding 9606 31831667 t miannu "Oligosaccharyltransferase (OST) catalyzes the transfer of a high-mannose glycan onto secretory proteins in the endoplasmic reticulum. Mammals express two distinct OST complexes that act in a cotranslational (OST-A) or posttranslocational (OST-B) manner. Here, we present high-resolution cryo-electron microscopy structures of human OST-A and OST-B. Although they have similar overall architectures, structural differences in the catalytic subunits STT3A and STT3B facilitate contacts to distinct OST subunits, DC2 in OST-A and MAGT1 in OST-B. In OST-A, interactions with TMEM258 and STT3A allow ribophorin-I to form a four-helix bundle that can bind to a translating ribosome, whereas the equivalent region is disordered in OST-B. " SIGNOR-272062 PAX3 protein P23760 UNIPROT TBX2 protein Q13207 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0002267 25211658 t lperfetto "We have recently found that a T-box gene family member, TBX2, is highly overexpressed in both ERMS and ARMS cells (Zhu et al, 2014). The regulation of TBX2 is uncharacterised in RMS cells, but is likely to link TBX2 expression to the known deregulation of signalling pathways in RMS. In melanoma cells, TBX2 is regulated by PAX3" SIGNOR-249596 BRD4 protein O60885 UNIPROT P-TEFb complex SIGNOR-C238 SIGNOR "up-regulates activity" binding 9606 16109377 t miannu "Binding of Brd4 to Core P-TEFb Is Essential for Transcription." SIGNOR-266411 IRS1 protein P35568 UNIPROT PIK3CB protein P42338 UNIPROT "up-regulates activity" binding 10090 BTO:0000887 14623899 t lperfetto "As shown previously, IRS-1 was required for insulin-stimulated phosphorylation of Akt in 32D cells, which is consistent with the binding and activation of PI3K by IRS-1 during insulin stimulation" SIGNOR-236618 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR T-reg_differentiation phenotype SIGNOR-PH91 SIGNOR down-regulates 9606 23620016 f "In the current study, addition of ERK inhibitors suppressed IL-6-induced RORgammat expression and promoted TGF-beta-induced Foxp3 expression." SIGNOR-254686 NVP-AEW541 chemical CID:11476171 PUBCHEM IGF1R protein P08069 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-194892 AKT1 protein P31749 UNIPROT IMPDH2 protein P12268 UNIPROT "up-regulates activity" phosphorylation 9534 BTO:0004055 10930578 t Federica "Further, we have demonstrated an in vivo association of IMPDH and PKB/Akt by co‐immunoprecipitation from COS cells expressing a constitutively active form of PKB/Akt. Finally, we were able to show that this constitutively active PKB/Akt could phosphorylate IMPDH in vitro. Thus, the interplay between PKB/Akt and IMPDH reported here could suggest that PKB/Akt activation leads to IMPDH type II activation which in turn prepares the cell for entry into S phase." SIGNOR-261262 ATM protein Q13315 UNIPROT IKBKG protein Q9Y6K9 UNIPROT "down-regulates activity" phosphorylation Ser85 ELLHFQAsQREEKEF 9606 SIGNOR-C14 16497931 t lperfetto "Atm phosphorylates serine-85 of nemo to promote its ubiquitin-dependent nuclear export." SIGNOR-144813 RHOBTB1 protein O94844 UNIPROT "Cullin 3-RBX1-Skp1" complex SIGNOR-C526 SIGNOR "up-regulates activity" binding 9606 BTO:0000007 30896450 t miannu "RhoBTB1 augmented the cGMP response to nitric oxide by restraining the activity of phosphodiesterase 5 (PDE5) by acting as a substrate adaptor delivering PDE5 to the Cullin-3 E3 Ring ubiquitin ligase complex for ubiquitination inhibiting PDE5." SIGNOR-272313 "vincaleukoblastine sulfate" chemical CHEBI:9984 ChEBI Tubulin proteinfamily SIGNOR-PF46 SIGNOR "down-regulates activity" "chemical inhibition" 9606 15579115 t miannu "Tubulin binding molecules have generated considerable interest after the successful introduction of the taxanes into clinical oncology and the widespread use of the vinca alkaloids vincristine and vinblastine. These compounds inhibit cell mitosis by binding to the protein tubulin in the mitotic spindle and preventing polymerization into the MTs." SIGNOR-259260 CASP1 protein P29466 UNIPROT "Pyrin inflammasome" complex SIGNOR-C226 SIGNOR "form complex" binding 30288079 t lperfetto "Canonical inflammasomes form activation platforms for caspase-1. Their assembly depends on some dedicated cytosolic PRRs from the nucleotide-binding domain leucin-rich repeat (NLR) family including NLR and pyrin domain containing receptor 1 (NLRP1), NLRP3, and NLR and caspase recruitment domain containing receptor 4 (NLRC4); the AIM2-like receptors (ALR) family including absent in melanoma 2 (AIM2); or the tripartite motif (TRIM) family including pyrin." SIGNOR-256412 IKBKG protein Q9Y6K9 UNIPROT NfKb-p65/p50 complex SIGNOR-C13 SIGNOR up-regulates phosphorylation 9606 SIGNOR-C14 15489227 t lperfetto "Chromatographic fractionation of cell extracts allowed the identification of two distinct enzymatic activities phosphorylating ser-536. Peak 1 represents an unknown kinase, whereas peak 2 contained ikkalpha, ikkbeta, ikkepsilon, and tbk1. collectively, our results provide evidence for at least five kinases that converge on ser-536 of p65 and a novel function for this phosphorylation site in the recruitment of components of the basal transcriptional machinery to the interleukin-8 promoter." SIGNOR-217382 MAPK1 protein P28482 UNIPROT JUN protein P05412 UNIPROT "up-regulates activity" phosphorylation 9606 23616010 t lperfetto "Erk also undergoes rapid translocation into the nucleus, where it phosphorylates and activates a variety of transcription factor targets, including sp1, e2f, elk-1, and ap1." SIGNOR-201943 FOXO proteinfamily SIGNOR-PF27 SIGNOR GK protein P32189 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 18805788 f gcesareni "In the gk gene regulation, foxo1 represses hnf-4-potentiated transcription of the gene, whereas it synergizes with hnf-4 in activating the g6pase gene transcription foxo1 localizes to the nucleus, where it represses hnf-4-dependent activity of the gk promoter as a corepressor." SIGNOR-252919 NUAK1 protein O60285 UNIPROT PPP1R12A protein O14974 UNIPROT down-regulates phosphorylation Ser445 LGLRKTGsYGALAEI 9606 20354225 t gcesareni "Phosphorylation of ser(445), ser(472), and ser(910) of mypt1 by nuak1 promoted the interaction of mypt1 with 14-3-3 adaptor proteins, thereby suppressing phosphatase activity." SIGNOR-164747 GPER1 protein Q99527 UNIPROT EGFR protein P00533 UNIPROT up-regulates binding 9606 BTO:0000150 11897506 t gcesareni "Gpcr-mediated transactivation of egfrs by estrogen provides a previously unappreciated mechanism of cross-talk between estrogen and serum growth factors, and explains prior data reporting the egf-like effects of estrogen" SIGNOR-115988 NRXN1 protein Q9ULB1 UNIPROT DAG1 protein Q14118 UNIPROT "up-regulates activity" binding 9606 BTO:0000142 22626542 t miannu "The DGC is potentially recruited to the postsynaptic membrane though a direct neurexin–dystroglycan interaction and an indirect interaction with NL2 via the synaptic scaffolding protein S-SCAM." SIGNOR-265458 PRKACA protein P17612 UNIPROT RAP1GAP protein P47736 UNIPROT unknown phosphorylation Ser490 KSPTRKKsGPFGSRR -1 1406653 t miannu "We have localized two of the sites of phosphorylation in vitro by cAMP-dependent kinase to serine residues 490 and 499. raplGAP undergoes phosphorylation at specific sites in vivo, the effects of phosphorylation on raplGAP have remained elusive." SIGNOR-250043 PRKCD protein Q05655 UNIPROT NFE2L2 protein Q16236 UNIPROT "up-regulates activity" phosphorylation Ser40 SREVFDFsQRRKEYE -1 12198130 t lperfetto "Phosphorylation of Nrf2 at Ser-40 by protein kinase C regulates antioxidant response element-mediated transcription." SIGNOR-249161 RALY protein Q9UKM9 UNIPROT PRMT1 protein Q99873 UNIPROT "up-regulates quantity" "post transcriptional regulation" 9606 BTO:0000567 30354839 t lperfetto "RALY binds poly-U rich elements within several RNAs and regulates the expression as well as the stability of specific transcripts. Here we show that RALY binds PRMT1 mRNA and regulates its expression.|We demonstrate that RALY down-regulation decreases protein arginine N-methyltransferase 1 levels" SIGNOR-262273 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR CAPN2 protein P17655 UNIPROT up-regulates phosphorylation 9606 14993287 t "inferred from 70% family members" lperfetto "Epidermal growth factor activates m-calpain (calpain ii), at least in part, by extracellular signal-regulated kinase-mediated phosphorylation.We now show that erk directly phosphorylates and activates m-calpain both in vitro and in vivo. We identified serine 50 as required for epidermal growth factor (egf)-induced calpain activation in vitro and in vivo." SIGNOR-270179 SLC34A2 protein O95436 UNIPROT EGF protein P01133 UNIPROT down-regulates 9606 BTO:0000195 BTO:0000763 11171583 f miannu "In vivo and in vitro studies showed that egf treatment decreased intestinal napi-iib mrna abundance by _50%, suggesting possible transcriptional regulation." SIGNOR-105161 CHUK protein O15111 UNIPROT FOXO3 protein O43524 UNIPROT down-regulates phosphorylation Ser644 GLDFNFDsLISTQNV 9606 SIGNOR-C14 15084260 t gcesareni "Ikappab kinase promotes tumorigenesis through inhibition of forkhead foxo3a. The tnf treatment of ht-29 cells increased ikk-dependent foxo3 ser644 phosphorylation." SIGNOR-124203 APEX1 protein P27695 UNIPROT CYP11B2 protein P19099 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 22652909 f miannu "We conclude that APEX1 is a novel transcriptional repressor of CYP11B2 and that differential APEX1 binding at -1651 of CYP11B2 results in altered gene expression." SIGNOR-253736 RXRA protein P19793 UNIPROT NR1H2 protein P55055 UNIPROT up-regulates binding 9606 14993927 t lperfetto "We provide genetic and molecular evidence that cholesterol homeostasis in scs does not require pparalpha and beta, but depends upon the tif2 coactivator and rxrbeta/lxrbeta heterodimers, in which rxrbeta af-2 is transcriptionally active." SIGNOR-123091 PTPN5 protein P54829 UNIPROT BAK1 protein Q16611 UNIPROT "up-regulates activity" dephosphorylation Tyr108 QPTAENAyEYFTKIA 9606 20959805 t "In this study, we report that on apoptotic stimulation Bak undergoes dephosphorylation at tyrosine residue 108 (Y108), a critical event that is necessary but not sufficient for Bak activation, but is required both for early exposure of the occluded N-terminal domain and multimerisation." SIGNOR-248542 DCC protein P43146 UNIPROT MYO10 protein Q9HD67 UNIPROT "up-regulates activity" binding 10090 BTO:0000938 17237772 t miannu "Here, we provide evidence for the involvement of the unconventional myosin X (Myo X) in netrin-1 function. We find that Myo X interacts with the netrin receptor deleted in colorectal cancer (DCC) and neogenin, a DCC-related protein. Expression of Myo X redistributes DCC to the cell periphery or to the tips of neurites, whereas its silencing prevents DCC distribution in neurites. Moreover, expression of DCC, but not neogenin, stimulates Myo X-mediated formation and elongation of filopodia, suggesting that Myo X function may be differentially regulated by DCC and neogenin." SIGNOR-268281 RAF1 protein P04049 UNIPROT MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR "up-regulates activity" phosphorylation 9606 BTO:0000975 11018021 t lperfetto "The best characterized Raf substrates are MEK1 and MEK2. The activation of MEK1/2 by Raf is required to mediate many of the cellular responses to Raf activation, suggesting that MEK1/2 are the dominant Raf effector proteins." SIGNOR-244945 SMAD3 protein P84022 UNIPROT SMAD3/JUN complex SIGNOR-C86 SIGNOR "form complex" binding 9606 9732876 t gcesareni "These results show a ligand-dependent association of smad3 with c-jun" SIGNOR-59873 SEPTIN4 protein O43236 UNIPROT XIAP protein P98170 UNIPROT "down-regulates quantity" binding 9534 BTO:0004055 15029247 t lperfetto "The mitochondrial ARTS protein promotes apoptosis through targeting XIAP.|Binding of ARTS to XIAP is direct, as recombinant ARTS and XIAP proteins can bind to each other in vitro. ARTS binding to XIAP is specific and related to its pro-apoptotic function, as mutant forms of ARTS (or related septins) that fail to bind XIAP failed to induce apoptosis. ARTS leads to decreased XIAP protein levels and caspase activation. Our data suggest that ARTS induces apoptosis by antagonizing IAPs." SIGNOR-267671 MAPK1 protein P28482 UNIPROT CDC42EP1 protein Q00587 UNIPROT unknown phosphorylation Ser113 SPAPPAIsPIIKNAI 10090 BTO:0000944 22028470 t miannu "We have optimized a chemical genetic system using analog-sensitive ERK2, a form of ERK2 engineered to use an analog of adenosine 5'-triphosphate (ATP), to tag and isolate ERK2 substrates in vitro. This approach identified 80 proteins phosphorylated by ERK2, 13 of which are known ERK2 substrates. With this improved methodology, we detected 98 sites directly phosphorylated by ERK2 on 80 proteins from NIH 3T3-L1 fibroblasts. Thirteen of these proteins are known substrates and the rest represent previously unknown kinase/substrate interactions. (table1)" SIGNOR-262765 PDPK1 protein O15530 UNIPROT RPS6KB2 protein Q9UBS0 UNIPROT "up-regulates activity" phosphorylation Thr228 HEGAVTHtFCGTIEY -1 11733037 t miannu " Mutational analysis revealed that the phosphorylation of Thr241 and Thr401 in p70beta1 was indispensable for the kinase activity. In contrast, a p70beta1 mutant in which Ser383 was substituted with Gly (S383G) still retained nearly the half maximal activity. Sequential phosphorylation of wild-type and S383G mutant of p70beta1 with mTOR and 3-phosphoinositide-dependent protein kinase 1 (PDK1) in vitro synergistically activated their kinase activities." SIGNOR-250273 PI3K complex SIGNOR-C156 SIGNOR AKT1 protein P31749 UNIPROT "up-regulates activity" 9606 BTO:0000150 12167717 f lperfetto "PKB induction requires phosphorylation of two critical residues, threonine 308 in the activation loop and serine 473 near the carboxyl terminus. Membrane localization of PKB was found to be a primary determinant of serine 473 phosphorylation. PI3K activity was equally important for promoting phosphorylation of serine 473," SIGNOR-252710 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR TOB1 protein P50616 UNIPROT down-regulates phosphorylation 9606 12050114 t "inferred from 70% family members" gcesareni "Tob is rapidly phosphorylated at Ser 152, Ser 154, and Ser 164 by Erk1 and Erk2 upon growth-factor stimulation." SIGNOR-270210 SIRT1 protein Q96EB6 UNIPROT PPARGC1A protein Q9UBK2 UNIPROT "up-regulates quantity" "transcriptional regulation" 9606 19553684 f gcesareni "Collectively, these data indicate that SIRT1 controls PGC-1alpha gene expression in skeletal muscle and that MyoD is a key mediator of this action" SIGNOR-238790 GGCX protein P38435 UNIPROT TGFB1 protein P01137 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10116 31539109 f miannu "GGCX can regulate osteoporosis via promoting the TGFβ/smad signaling pathway, facilitating BMSCs osteogenic differentiation, and inhibiting BMSCs adipogenic differentiation. The transfection of pcDNA-GGCX plasmid significantly promoted BMSC cell proliferation, increased calcified nodule formation, inhibited adipogenic differentiation, enhanced ALP activity, elevated RUNX2, and OPN mRNA expressions, and upregulated TGFβ1, Smad2, and Smad7 expressions (p < 0.05)." SIGNOR-261231 HSD17B11 protein Q8NBQ5 UNIPROT testosterone smallmolecule CHEBI:17347 ChEBI "up-regulates quantity" "chemical modification" 9606 BTO:0000056 16166196 t lperfetto "A novel 17beta-hydroxysteroid dehydrogenase (17beta-HSD) chronologically named type 12 17beta-HSD (17beta-HSD12), that transforms estrone (E1) into estradiol (E2) was identified by sequence similarity with type 3 17beta-HSD (17beta-HSD3) that catalyzes the formation of testosterone from androstenedione in the testis." SIGNOR-268666 hydrogencarbonate smallmolecule CHEBI:17544 ChEBI "GABA-A (a4-b1-g2) receptor" complex SIGNOR-C333 SIGNOR "up-regulates activity" "chemical activation" 9606 BTO:0000938 26136660 t miannu "The raise in the intracellular bicarbonate concentration may augment the depolarizing efflux of bicarbonate upon activation of GABAA receptors; however, both transporters also extrude chloride and thereby increase the gradient for a hyperpolarizing chloride current." SIGNOR-264923 BRAF protein P15056 UNIPROT MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR "up-regulates activity" phosphorylation 9606 21900390 t miannu "BRAFV600E has been shown to initiate thyroid follicular cell transformation. The BRAFV600E mutation disrupts the hydrophobic interaction, enabling the BRAF kinase to fold into a catalytically active formation, resulting in an almost 500-fold increase in kinase activity. Mutant BRAF can dimerize and activate MEK without Ras activation." SIGNOR-251988 PJA2 protein O43164 UNIPROT PRKAR2A protein P13861 UNIPROT "down-regulates quantity by destabilization" polyubiquitination 9606 BTO:0000007 21423175 t miannu "Praja2 controls the stability of PKA regulatory subunits. Praja2 ubiquitylates RIIα/β subunits. Subunits" SIGNOR-271856 "SAM complex" complex SIGNOR-C422 SIGNOR "Insertion into mitochondrial membrane" phenotype SIGNOR-PH193 SIGNOR up-regulates 33408415 f lperfetto "The mitochondrial outer membrane contains so-called β-barrel proteins, which allow communication between the cytosol and the mitochondrial interior1-3. Insertion of β-barrel proteins into the outer membrane is mediated by the multisubunit mitochondrial sorting and assembly machinery (SAM, also known as TOB)" SIGNOR-267687 MYCT1 protein Q8N699 UNIPROT CCND1 protein P24385 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 30283340 f miannu "MYCT1 overexpression significantly inhibited cell proliferation, arrested cell cycle at G0/G1 phase, and downregulated the expression of cyclins D and E. Moreover, MYCT1 overexpression triggered apoptosis in AML cells, which was accompanied by enhanced cleavage of caspase-3 and -9, upregulated expression of B-cell lymphoma 2 (Bcl-2)-associated X protein (Bax), and downregulated Bcl-2." SIGNOR-261730 PRKCD protein Q05655 UNIPROT IRS1 protein P35568 UNIPROT down-regulates phosphorylation Ser323 MVGGKPGsFRVRASS 9606 BTO:0000671 15069075 t gcesareni "Here we show in various cell models that the adipose hormone leptin, a putative mediator in obesity-related insulin resistance, promotes phosphorylation of ser-318 in irs1 by a janus kinase 2, irs2, and pkc-dependent pathway. we observed that insulin stimulates phosphorylation of ser(318) in irs-1, which is mediated, at least partially, by pkc-zeta." SIGNOR-123734 NfKb-p65/p50 complex SIGNOR-C13 SIGNOR Cell_death phenotype SIGNOR-PH109 SIGNOR down-regulates 9606 22021368 f apalma "Once genetic mutation of AML1 occurs in hematopoietic cells, aberrant activation of NF-κB signaling exerts antiapoptotic and proliferation-promoting effects via activation of BCL-XL or JUNB." SIGNOR-256654 PRKCE protein Q02156 UNIPROT PRKD2 protein Q9BZL6 UNIPROT up-regulates phosphorylation Ser710 GEKSFRRsVVGTPAY 9606 12058027 t miannu "In cells transfected with pkc? Or pkc? The phosphorylation of ser876 was markedly more pronounced than the phosphorylation of ser706/ser710 / the phosphorylation of ser706/ser710 in pkd2 reflects the activation of the kinase." SIGNOR-89415 "vincaleukoblastine sulfate" chemical CHEBI:9984 ChEBI TUBE1 protein Q9UJT0 UNIPROT "down-regulates activity" "chemical inhibition" 9606 15579115 t miannu "Tubulin binding molecules have generated considerable interest after the successful introduction of the taxanes into clinical oncology and the widespread use of the vinca alkaloids vincristine and vinblastine. These compounds inhibit cell mitosis by binding to the protein tubulin in the mitotic spindle and preventing polymerization into the MTs." SIGNOR-259258 RAB38 protein P57729 UNIPROT "AP-3 complex" complex SIGNOR-C247 SIGNOR "up-regulates activity" relocalization 9606 23247405 t lperfetto "Rab32 and Rab38 interact physically and colocalize with BLOC-2, AP-1 and AP-3|These results indicate that Rab32 and Rab38 operate in the same pathways previously defined for AP-1, AP-3 and BLOC-2 and suggest they are the specific proteins that divert AP-1, AP-3 and BLOC-2-dependent cargoes to maturing melanosomes and away from lysosomes." SIGNOR-260699 DOK1 protein Q99704 UNIPROT "AL/b2 integrin" complex SIGNOR-C169 SIGNOR "down-regulates activity" binding 9606 19118207 t miannu "Integrins also bind to many PTBdomain-containing proteins (Calderwood et al., 2003) – including Dok1 and integrincytoplasmic-domain-associated protein 1 (ICAP1) – and these can compete with talin for binding to integrin and so can impair activation" SIGNOR-257681 CDK1 protein P06493 UNIPROT SQSTM1 protein Q13501 UNIPROT up-regulates phosphorylation Ser272 RSRLTPVsPESSSTE 9606 SIGNOR-C17 20974803 t gcesareni "Here we show that cdk1 phosphorylates p62 in vitro and in vivo at t269 and s272, which is necessary for the maintenance of appropriate cyclin b1 levels and the levels of cdk1 activity necessary to allow cells to properly enter and exit mitosis." SIGNOR-169012 CREBBP protein Q92793 UNIPROT TP53 protein P04637 UNIPROT "up-regulates activity" acetylation 9606 25545885 t miannu "C-terminal acetylation of p53 by p300/CBP and PCAF promotes an open conformation of p53 by preventing the occlusion of the DNA binding domain by the C-terminal tail. This enhances p53 transcriptional activity, leading to growth arrest and/or apoptosis" SIGNOR-261495 PLK1 protein P53350 UNIPROT DVL2 protein O14641 UNIPROT up-regulates phosphorylation Thr206 MTSELEStSLGDSDE 9606 20823832 t lperfetto "Dvl2 bound to and was phosphorylated at thr206 by a mitotic kinase, polo-like kinase 1 (plk1), and this phosphorylation was required for spindle orientation and stable microtubule (mt)-kt attachment" SIGNOR-167858 LRFN1 protein Q9P244 UNIPROT Neurite_outgrowth phenotype SIGNOR-PH134 SIGNOR up-regulates 9606 BTO:0000938 21736948 f miannu "This study finds that all SALMs (SALMs 1–5) possess the abilityto promote neurite outgrowth and branching, as demonstrated byoverexpression and knockdown experiments." SIGNOR-264100 PEX6 protein Q13608 UNIPROT PEX1 protein O43933 UNIPROT "up-regulates activity" binding 10029 12717447 t "Pex26 recruits Pex6–Pex1 complexes to peroxisomes. Pex26 anchors Pex6 and Pex1 through Pex26–Pex6 and Pex6–Pex1 interactions." SIGNOR-253615 PCDHA13 protein Q9Y5I0 UNIPROT ITGB1 protein P05556 UNIPROT "up-regulates activity" binding 9606 BTO:0000227 16697637 t miannu "The clustered protocadherins comprise the largest subfamily of the cadherin superfamily and are predominantly expressed in the nervous system. Pcdh-alpha proteins interact with beta1-integrin to promote cell adhesion." SIGNOR-265672 SLC2A4 protein P14672 UNIPROT α-D-glucose smallmolecule CHEBI:17925 ChEBI "up-regulates quantity" relocalization 9606 17403369 t "Skeletal muscle both stores glucose as glycogen and oxidizes it to produce energy following the transport step. The principal glucose transporter protein that mediates this uptake is GLUT4, which plays a key role in regulating whole body glucose homeostasis" SIGNOR-267291 GATA1 protein P15976 UNIPROT GATA2 protein P23769 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 12432220 f irozzo "Closer examination revealed a cross-regulatory mechanism by which GATA-1 can control the expression of GATA-2 and vice versa, possibly via essential GATA binding sites in their cis-acting elements.In this model, GATA-2 activates GATA-1 gene expression, while GATA-1 represses GATA-2 gene expression." SIGNOR-256058 AURKB protein Q96GD4 UNIPROT YY1 protein P25490 UNIPROT up-regulates phosphorylation Ser180 KKGGGKKsGKKSYLS 9606 23226345 t lperfetto "Aurora b kinase phosphorylates yy1 on serine 184 and to a lesser extent serine 180 at the g2/m stage of the cell cycle (fig. 7). We show that yy1 is rapidly dephosphorylated as the cells exit mitosis, likely by pp1. Also, our data indicates that phosphorylation at serine 180 and serine 184 can affect the dna binding activity of yy1" SIGNOR-200075 IL1B protein P01584 UNIPROT ENPP1 protein P22413 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 7479785 f miannu "Interleukin 1 beta suppresses transforming growth factor-induced inorganic pyrophosphate (PPi) production and expression of the PPi-generating enzyme PC-1 in human chondrocytes. IL-1 beta may be an important regulator of mineralization in chondrocytes by inhibiting TGF beta-induced PPi production and PC-1 expression." SIGNOR-252199 OSM protein P13725 UNIPROT OSMR protein Q99650 UNIPROT up-regulates binding 9606 16286453 t gcesareni "The oncostatin m receptor (osmr) is part of receptor complexes for oncostatin m and interleukin-31." SIGNOR-141588 HAUS8 protein Q9BT25 UNIPROT "HAUS complex" complex SIGNOR-C281 SIGNOR "form complex" binding 9606 BTO:0000567 19369198 t lperfetto "Here, by using mass spectrometry, we identified the full human augmin complex of 8 subunits and show that it interacts with the gamma-tubulin ring complex (gamma-TuRC)" SIGNOR-262321 STAT1 protein P42224 UNIPROT IL12B protein P29460 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000801 19029990 f lperfetto "STAT1 binds as a homodimer to cis elements known as gammaactivated sequences in the promoters of the genes encoding NOS2, the MHC class II transactivator (CIITA) and IL-12, among others." SIGNOR-249500 ROCK1 protein Q13464 UNIPROT DPYSL2 protein Q16555 UNIPROT unknown phosphorylation Thr555 DNIPRRTtQRIVAPP 9534 10818093 t lperfetto "We produced an antibody that specifically recognizes CRMP-2 phosphorylated at Thr-555. Using this antibody, we found that Rho-kinase phosphorylated CRMP-2 downstream of Rho in COS7 cells. " SIGNOR-249042 CSNK2A1 protein P68400 UNIPROT MYCN protein P04198 UNIPROT unknown phosphorylation Ser261 TSGEDTLsDSDDEDD -1 1425701 t llicata "Analysis of phosphorylation sites in synthetic peptides of this acidic region identified the major sites phosphorylated by CKII as Ser261 and Ser263." SIGNOR-250920 PYG proteinfamily SIGNOR-PF96 SIGNOR glycogen smallmolecule CHEBI:28087 ChEBI "down-regulates quantity" "chemical modification" 9606 3346228 t "Mammalian glycogen phosphorylases are found in at least three isozymic forms that can be distinguished by functional and structural properties as well as by the tissues in which they are preferentially expressed [√¢‚Ǩ¬¶] Each phosphorylase isozyme fulfills different physiological requirements even though all forms of the enzyme catalyze the same reaction, the phosphorolysis of glycogen to yield glucose 1-phosphate." SIGNOR-267953 "U4/U6.U5 snRNP complex" complex SIGNOR-C478 SIGNOR RNA_splicing phenotype SIGNOR-PH201 SIGNOR up-regulates 9606 30765414 f lperfetto "The major spliceosomal building blocks are the U1, U2, U4/U6, and U5 small nuclear ribonucleoproteins (snRNPs). Each consists of a small nuclear RNA (snRNA) (or two, in the case of U4/U6), seven Sm proteins that form a ring (or seven Lsm proteins in the case of U6), and a variable number of snRNP-specific proteins (Fig. 1F) (Will and Lührmann 2011). Under splicing conditions, the U4/U6 and U5 snRNPs form a 25S U4/U6.U5 tri-snRNP, in which the U4 and U6 snRNAs are base-paired, forming a three-way junction." SIGNOR-270651 RXRB protein P28702 UNIPROT NRIP1 protein P48552 UNIPROT up-regulates binding 9606 12403842 t gcesareni "Receptor interacting protein 140 (rip140) is a coregulator for a large number of transcription factors. Rip140 interacts with retinoic acid receptor (rar) and retinoid x receptor (rxr) with or without ligands" SIGNOR-95160 ZBTB7A protein O95365 UNIPROT CDKN2A protein Q8N726 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 15662416 f miannu "Pokemon can specifically repress the transcription of the tumour suppressor gene ARF through direct binding." SIGNOR-225900 SMO protein Q99835 UNIPROT GATA2 protein P23769 UNIPROT "up-regulates activity" 10090 BTO:0000011 16399502 f fferrentino "In mammalian models [...] Hh signaling also inhibits mammalian adipogenesis. Hh signals elicit this function early in adipogenesis, upstream of PPARγ, potentially diverting preadipocytes as well as multipotent mesenchymal prescursors away from adipogenesis and toward osteogenesis. Hh may elicit these effects by inducing the expression of antiadipogenic transcription factors such as Gata2." SIGNOR-251656 "IL17R complex" complex SIGNOR-C260 SIGNOR NfKb-p65/p50 complex SIGNOR-C13 SIGNOR "up-regulates activity" 10090 BTO:0000944 8777726 f lperfetto "3T3 cells were preincubated with an IL-17Rspecific antiserum and then assayed for NF-KB activation by HVS13. Preincubation with the IL-1 7R antiserum dramatically decreased the NF-KB activity induced by HVSl3 as compared with cells preincubated with an irrelevant rat antiserum (Figure 5C). This result indicated that the engagement of the IL-17R by its ligands induced NF-KB activity." SIGNOR-261338 5-amino-1-(5-phosphonato-beta-D-ribosyl)imidazol-3-ium smallmolecule CHEBI:137981 ChEBI 5-amino-1-(5-phosphonato-D-ribosyl)imidazolium-4-carboxylate(2-) smallmolecule CHEBI:77657 ChEBI "up-regulates quantity" "precursor of" 9606 33179964 t miannu "The next two reactions (steps 6 and 7) involve carb oxylation of AIR to 4-carboxy-5-aminoimidazole ribonu cleotide (CAIR) and ligation of the carboxy group of CAIR with an amide group derived from Asp in an ATP dependent reaction forming 4-(N-succinylcarboxamide)- 5-aminoimidazole ribonucleotide (SAICAR). These reac tions are catalyzed by the bifunctional enzyme phosphoribosylaminoimidazole carboxylase/phosphori bosylaminoimidazole succinocarboxamide synthetase (PAICS)." SIGNOR-267316 FYN protein P06241 UNIPROT LCP2 protein Q13094 UNIPROT down-regulates phosphorylation 9606 9047237 t lperfetto "P59fyn_phosphorylated slp-76 at intermediate levels but, significantly, this phosphorylation failed to induce vav?SLP-76 complex formation" SIGNOR-46851 RPS3A protein P61247 UNIPROT "40S cytosolic small ribosomal subunit" complex SIGNOR-C286 SIGNOR "form complex" binding -1 25901680 t lperfetto "Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins." SIGNOR-262420 ABCC8 protein Q09428 UNIPROT "KATP channel" complex SIGNOR-C274 SIGNOR "form complex" binding 9606 28842488 t lperfetto "ATP-sensitive K+ (KATP) channels, found throughout the body, are generated as octameric complexes consisting of four pore-forming Kir6.1 or Kir6.2 subunits with four regulatory sulfonylurea receptor (SUR1 or SUR2) subunits." SIGNOR-262056 EGR1 protein P18146 UNIPROT SF1 protein Q15637 UNIPROT "up-regulates activity" binding 10090 19106114 t miannu "GNRH1 induces expression of early growth response 1 (EGR1), which interacts with steroidogenic factor 1 (SF1) and paired-like homeodomain transcription factor 1 (PITX1) to regulate Lhb promoter activity." SIGNOR-254914 KAT2A protein Q92830 UNIPROT H3-4 protein Q16695 UNIPROT "down-regulates activity" acetylation Lys10 RTKQTARkSTGGKAP 9606 SIGNOR-C465 34811519 t "Acetlyation of H3 causes transcriptional activation, thus has an inhibitory role on H3" lperfetto "The HAT module within the SAGA and ADA complexes acetylates histone H3, mainly on residues K9 and K14." SIGNOR-269596 MAPK3 protein P27361 UNIPROT NFATC4 protein Q14934 UNIPROT up-regulates phosphorylation Ser676 SNGRRKRsPTQSFRF 9606 15657420 t lperfetto "The formation of rsk-nfatc4-dna transcription complex is also apparent upon adipogenesis. Bound rsk phosphorylates ser(676) and potentiates nfatc4 dna binding by escalating nfat-dna association. Ser(676) is also targeted by the erk map kinase, which interacts with nfat at a distinct region than rsk. Thus, integration of the erk/rsk signaling pathway provides a mechanism to modulate nfatc4 transcription activity." SIGNOR-133276 "MYOD1/SWI/SNF complex" complex SIGNOR-C93 SIGNOR ATP2A1 protein O14983 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 15870273 f miannu "Swi/snf enzymes are necessary for myod to activate muscle gene transcription / myod increased the expression of 94 genes and decreased that of 70 genes /these 94 genes (represented by 96 array features) were analyzed for their dependence on a functional brg1-based swi/snf complex. In the presence of dominant-negative brg1, 29 genes did not achieve full activation by myod, as determined by statistical criteria (q 0.05) and a twofold or more decrease in expression level (table 1; see also table s1 in the supplemental material)" SIGNOR-136300 PRKACA protein P17612 UNIPROT ARFGEF1 protein Q9Y6D6 UNIPROT "up-regulates activity" phosphorylation Ser883 EIAGKKIsMKETKEL 9606 BTO:0000599 16467138 t lperfetto "Within 20 min after addition of 8-Br-cAMP, BIG1 accumulated in nuclei, and this effect was blocked by protein kinase A (PKA) inhibitors H-89 and PKI, suggesting a dependence on PKA-catalyzed phosphorylation. |Mutant BIG1 (S883A) in which Ala replaced Ser-883, a putative PKA phosphorylation site, did not move to the nucleus with cAMP addition, whereas replacement with Asp (S883D) resulted in nuclear accumulation of BIG1 without or with cAMP exposure, consistent with the mechanistic importance of a negative charge at that site" SIGNOR-272146 SH2B1 protein Q9NRF2 UNIPROT BLNK protein Q8WV28 UNIPROT "down-regulates activity" dephosphorylation 9606 BTO:0000776 32323266 t scontino "SHP-1 is recruited by the phosphorylated ITIM-bearing receptors such as CD22 and it dephosphorylates proximal BCR signaling molecules such as CD79, SYK, BLNK." SIGNOR-268446 CSNK2A2 protein P19784 UNIPROT SPIB protein Q01892 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser37 KHSSYPDsEGAPDSL 9606 BTO:0000567 10618498 t llicata "Phosphorylation of the Spi-B transcription factor reduces its intrinsic stability. | Serine residues 37 in the transactivation domain and 129, 144 and 146 in the PEST domain of Spi-B are phosphorylated by CKII in vitro | The CKII phosphorylation sites mapped in vitro are phosphorylated in vivo" SIGNOR-251042 STK39 protein Q9UEW8 UNIPROT CFTR protein P13569 UNIPROT "down-regulates activity" phosphorylation 9606 BTO:0000007 21317537 t miannu "SPAK phosphorylates the transporters to reduce their surface expression and thus their activity and consequently inhibits ductal secretion to stabilize the resting state. PP1 reverses the effect of SPAK. Molecular analysis revealed that the WNK kinases acted as scaffolds to recruit SPAK, which phosphorylated CFTR and NBCe1-B, reducing their cell surface expression." SIGNOR-263134 palmitoyl-CoA smallmolecule CHEBI:15525 ChEBI 3-hydroxyoctadecanoyl-CoA smallmolecule CHEBI:50583 ChEBI "up-regulates quantity" "precursor of" 9606 31616255 t miannu "The ELOVL family of enzymes in mammals is comprised of seven members that all reside in the endoplasmic reticulum (ER) and are thought to form a multimeric complex. Together, the ELOVL family is responsible for the elongation of saturated and unsaturated fatty acids.Fatty acid elongation occurs by cycling through a four step process (condensation, reduction, dehydration, and reduction), with two carbon atoms added through each cycle." SIGNOR-267884 MAP3K5 protein Q99683 UNIPROT MAP3K5 protein Q99683 UNIPROT "up-regulates activity" phosphorylation Thr838 GINPCTEtFTGTLQY 9606 17937911 t lperfetto "Reporter gene assays showed that all three identified in vitro autophosphorylation sites (thr813, thr838, thr842) regulate ask1 signalingmutation of thr838 drastically reduced reporter gene activity when compared to unstimulated control levels. Interestingly, mutation of the other two sites also provided a significant reduction in ask1 function (figure 6a), suggesting that autophosphorylation at the residues thr842 and thr813 regulates ask1 signaling." SIGNOR-158427 CSNK2B protein P67870 UNIPROT BID protein P55957 UNIPROT "up-regulates activity" phosphorylation Ser64 LQTDGNRsSHSRLGR 9606 BTO:0000567 11583622 t llicata "Here we report that Bid is phosphorylated by casein kinase I (CKI) and casein kinase II (CKII). Inhibition of CKI and CKII accelerated Fas-mediated apoptosis and Bid cleavage, whereas hyperactivity of the kinases delayed apoptosis. | These results suggest that residues S61, S64, and to a much lesser extent T58 are sites of phosphorylation of Bid." SIGNOR-251053 MAP2K5 protein Q13163 UNIPROT MAPK7 protein Q13164 UNIPROT up-regulates phosphorylation 9606 11782488 t gcesareni "Kato et al. reported that mek5 specifically activates bmk1 but not other mammalian map kinasesin vivo." SIGNOR-113770 NLGN2 protein Q8NFZ4 UNIPROT DLG4 protein P78352 UNIPROT "up-regulates activity" relocalization 9606 BTO:0000938 18923512 t brain lperfetto "Like NRXNs, NLGNs bind to intracellular PDZ-domain proteins, but in contrast to NRXNs, NLGNs bind to class I PDZ domains such as those contained in PSD95, a postsynaptic MAGUK protein65. PSD95 and its homologues are centrally involved in recruiting glutamate receptors at postsynaptic sites66. Similarly to CASK, PSD95 binds to intracellular adaptor proteins, and especially to GKAP (a protein that binds to the guanylate-kinase domain of PSD95), which, in turn, binds to SHANK proteins (Fig. 1b). A possible role of these interactions is to recruit postsynaptic adaptor proteins to the site of synaptic junctions." SIGNOR-264193 PRKACA protein P17612 UNIPROT TFAM protein Q00059 UNIPROT up-regulates phosphorylation Ser55 SCPKKPVsSYLRFSK 9606 23201127 t llicata "Here, we demonstrate that tfam is phosphorylated within its hmg box 1 (hmg1) by camp-dependent protein kinase in mitochondria. Hmg1 phosphorylation impairs the ability of tfam to bind dna and to activate transcription." SIGNOR-199934 PIK3R1 protein P27986 UNIPROT PIK3CA protein P42336 UNIPROT "up-regulates activity" binding 9534 BTO:0004055 14665640 t lperfetto "Signal transduction pathways triggered by Tie2 have been extensively examined. Tyr-1101of Tie2 directly associates in a phosphotyrosine (pTyr)-dependent manner with the p85 regulatory subunit of phosphatidylinositol (PI) 3-kinase, which in turn activate PI 3-kinase, leading to cell motility and survival" SIGNOR-242637 CSNK2A1 protein P68400 UNIPROT WAS protein P42768 UNIPROT up-regulates phosphorylation Ser483 KRSRAIHsSDEGEDQ 9606 12769847 t gcesareni "Here we identify two phosphorylation sites in the vca domain of wasp at serines 483 and 484. S483 and s484 are substrates for casein kinase 2 in vitro and in vivo. Phosphorylation of these residues increases the affinity of the vca domain for the arp2/3 complex 7-fold and is required for efficient in vitro actin polymerization by the full-length wasp molecule." SIGNOR-101264 PRKACA protein P17612 UNIPROT ARHGAP17 protein Q68EM7 UNIPROT "down-regulates activity" phosphorylation Ser702 LSAPRRYsSSLSPIQ 9606 BTO:0000132 26507661 t lperfetto "Screening for potential mediators of this effect resulted in the identification of the Rac1-specific GTPase-activating protein ARHGAP17 and the guanine nucleotide exchange factor ARHGEF6 as new PKA and PKG substrates in platelets. We mapped the PKA/PKG phosphorylation sites to serine 702 on ARHGAP17 using Phos-tag gels and to serine 684 on ARHGEF6. |ARHGAP17 is a Rho GTPase-activating protein of Rac1 and is bound to the SH3 domain of CIP4 via its SH3 binding region in resting platelets. Endothelial PGI2 stimulates the activation of PKA and leads to the phosphorylation of Ser-702 in ARHGAP17, which results in the dissociation of the ARHGAP17-CIP4 complex." SIGNOR-272155 CDK8 protein P49336 UNIPROT SMAD3 protein P84022 UNIPROT down-regulates phosphorylation Ser213 NLSPNPMsPAHNNLD 9606 19914168 t lpetrilli "Similarly, tgf-?-Induced and cdk8/9-mediated phosphorylation of smad3 at threonine 179 (t179) is important for binding of the nedd4l e3 ubiquitin ligase, which accelerates smad3 turnover;cdk8 and cyclint-cdk9 showed a preference for s206 and s214 but also phosphorylated s186 and s195 in the case of smad1;and t179, s208 and s213 in the case of smad3." SIGNOR-161646 STAT3 protein P40763 UNIPROT MYOD1 protein P15172 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 25194572 f miannu "Here we show that IL-6-activated Stat3 signaling regulates satellite cell behavior, promoting myogenic lineage progression through myogenic differentiation 1 (Myod1) regulation. IL-6 stimulation promoted an increase in the mRNA levels of both Stat3 and Myod1. Stat3 mediated this effect, as IL-6‚Äìdependent Myod1 upregulation was impaired after infection with the shStat3 lentivirus." SIGNOR-255416 RPS6K proteinfamily SIGNOR-PF26 SIGNOR STK11 protein Q15831 UNIPROT "down-regulates activity" phosphorylation Ser428 SSKIRRLsACKQQ 9606 BTO:0001271 25846811 t lperfetto "Negative regulation of the LKB1/AMPK pathway by ERK in human acute myeloid leukemia cellsBRAFV600E activates downstream molecules, including ERK and p90 ribosomal S6 kinase (RSK), and leads to the phosphorylation of LKB-1 at Ser428 by these kinases. This cascade results in the dissociation of LKB1 from AMPK." SIGNOR-252805 MAPKAPK2 protein P49137 UNIPROT ZFP36L1 protein Q07352 UNIPROT down-regulates phosphorylation Ser54 GGFPRRHsVTLPSSK 9606 18326031 t lperfetto "Mk2-mediated inhibition of brf1 requires phosphorylation at s54, s92, and s203. Phosphorylation of brf1 by mk2 does not appear to alter its ability to interact with ares or to associate with mrna decay enzymes. Thus, mk2 inhibits brf1-dependent amd through direct phosphorylation." SIGNOR-161274 3-(1-methyl-3-indolyl)-4-[1-[1-(2-pyridinylmethyl)-4-piperidinyl]-3-indolyl]pyrrole-2,5-dione chemical CHEBI:91368 ChEBI PRKCG protein P05129 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-191499 5-[6-[(4-methyl-1-piperazinyl)methyl]-1-benzimidazolyl]-3-[(1R)-1-[2-(trifluoromethyl)phenyl]ethoxy]-2-thiophenecarboxamide chemical CHEBI:91333 ChEBI PLK1 protein P53350 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-192991 "CID 132010322" chemical CID:132010322 PUBCHEM BRD4 protein O60885 UNIPROT "down-regulates activity" "chemical inhibition" 9606 31969702 t Monia "ABBV-744 potently inhibited the BD2 domain of BET family proteins with more than 290× selectivity relative to the BD1 domains of BRD2, BRD3 and BRD4" SIGNOR-261102 LMO2 protein P25791 UNIPROT ERG protein P11308 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0001106 21536859 f miannu "We further demonstrate that ERG expression in primary human T-ALL cells is mediated by the binding of other T-cell oncogenes SCL/TAL1, LMO2, and LYL1 in concert with ERG, FLI1, and GATA3 to the ERG +85 enhancer." SIGNOR-253922 PTPN6 protein P29350 UNIPROT CD72 protein P21854 UNIPROT down-regulates dephosphorylation 9606 BTO:0000776 9740800 t gcesareni "Our work clearly identifies cd72 as both an shp-1 binding protein (figure 1,figure 2) and a direct substrate for shp-1 in vivo (figure 3). As tyrosine phosphorylation of cd72 strongly correlates with the ability of the bcr to deliver growth-inhibitory/apoptosis-inducing signals (figure 4), our results suggest that shp-1-catalyzed dephosphorylation of cd72 may antagonize these signals." SIGNOR-60155 VHL protein P40337 UNIPROT CDKN1C protein P49918 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000037 15824735 f miannu "three of the nine targets had been identified previously as candidate TSGs (DOC-2/DAB2, CDKN1C and SPARC) and all were upregulated by wild-type pVHL." SIGNOR-255601 FGFR1 protein P11362 UNIPROT BCAR1 protein P56945 UNIPROT up-regulates phosphorylation Tyr327 PLLREETyDVPPAFA 9606 12601080 t lperfetto "Five tyrosine phosphorylation sites were identified in p130cas on tyr-128, tyr-249, tyr-306, tyr-327, and tyr-410. These tyrosine residues are all located in the substrate domain of p130cas that mediates binding to the sh2 domain of the adaptor molecule crk. Fgf-1-transduced fibroblasts demonstrated a > 10-fold increase in migration, an observation correlated with increased tyrosine phosphorylation of p125fak and p130cas." SIGNOR-98500 DEAF1 protein O75398 UNIPROT EN1 protein Q05925 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000375 31145909 t Gianni "Deaf1 is the first transcription factor implicated in the regulation of En1, a critical determinant of eccrine fate, within keratinocytes." SIGNOR-269062 RPAP2 protein Q8IXW5 UNIPROT POLR2A protein P24928 UNIPROT "up-regulates activity" dephosphorylation Ser1714 SPTSPSYsPTSPSYS 9606 BTO:0000567 22137580 t "In addition, we show that RPAP2 is a CTD Ser5 phosphatase. Taken together, our results indicate that during transcription of snRNA genes, Ser7 phosphorylation facilitates recruitment of RPAP2, which in turn both recruits Integrator and dephosphorylates Ser5.|The Pol II CTD is first phosphorylated on Ser5 and then on Ser7 by CDK7. RPAP2 associates with the Pol II CTD after Ser7 phosphorylation and tethers a subcomplex of Integrator to snRNA genes. RPAP2 dephosphorylates Ser5P of the CTD, facilitating transcription and the subsequent recruitment of the Int11 catalytic subunit of Integrator" SIGNOR-248753 ANKRD11 protein Q6UB99 UNIPROT NTRK2 protein Q16620 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 BTO:0000142 29274743 t miannu "Ankrd11 knockdown decreases the levels of bdnf and Trkb mRNAs. Next, we examine whether ANKRD11 accesses the Trkb promoter in cortical neurons. We performed the chromatin immunoprecipitation assay (ChIP) using an ANKRD11 antibody followed by PCR to amplify the Trkb promoter region. We found that ANKRD11 binds to the Trkb promoter (Fig. 6E). As expected, the level of ANKRD11 binding was decreased in the Ankrd11 knockdown condition." SIGNOR-266731 N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridinyl)cyclohexanecarboxamide chemical CHEBI:125619 ChEBI HTR1A protein P08908 UNIPROT "down-regulates activity" "chemical inhibition" 10029 BTO:0000246 9760039 t miannu "Marked differences were observed between the actions of ‘antagonists’ (Table 2; Fig. 2D ). methiothepin and butaclamol, as well asspiperone, exhibited negative efficacy by concentration-dependently inhibiting S GTPgS binding below basal levels, indicating that they act as inverse agonists in this system.WAY 100,135, yUH 301 and the 5-HTreceptor1A and b-adrenergic receptor antagonist ,ytertatolol, acted as ‘neutral’ antagonists, exhibiting antagonist activity without any detectable agonist or inverse agonist effects." SIGNOR-258844 TOP2B protein Q02880 UNIPROT PBX3 protein P40426 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 24463367 f lperfetto "While Top2a is essential in proliferating cells and has been linked to DNA replication and chromosome condensation/segregation, Top2b has been clearly indicated in regulating gene expression (e.g. Reln, Dab1, Catna2, Cdh13, Sst, Pbx3, and Epha7) during brain development" SIGNOR-242308 CHN1 protein P15882 UNIPROT CDK5R1 protein Q15078 UNIPROT up-regulates binding 9606 15013773 t miannu "_-chimaerin was identified to interact with the p35 activator of cdk5. The complex of _-chimaerin, cdk5 and p35 is enzymatically functional" SIGNOR-123439 GNA13 protein Q14344 UNIPROT ARHGEF1 protein Q92888 UNIPROT "up-regulates activity" binding 9606 14607242 t "It turned out that RGS domain of p115RhoGEF is specific for Gα12 and Gα13, and does not bind Gαi, Gαs and Gαq (Kozasa et al., 1998). The binding of Gα13 but not Gα12 stimulated GEF activity for Rho" SIGNOR-256521 NBEA protein Q8NFP9 UNIPROT DLG3 protein Q92796 UNIPROT "up-regulates activity" binding BTO:0000227 23277425 t lperfetto "Interestingly, a recent proteomic analysis (Lauks et al., 2012) revealed that Nbea binds SAP102, which interacts with glutamate receptors early in the biosynthetic route and regulates their targeting. This finding, along with the interaction of Nbea with the glycine receptor beta subunit (del Pino et al., 2011), further strengthens the notion that Nbea targets neurotransmitter receptors to synapses." SIGNOR-266004 MECP2 protein P51608 UNIPROT ALOX5 protein P09917 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0001412 19781662 f "Human 5-lipoxygenase (5-LO) is the key enzyme in the formation of inflammatory leukotrienes. 5-LO gene expression is mainly restricted to B cells and cells of myeloid origin. It is known that basal 5-lipoxygenase promoter activity is regulated by DNA methylation.|Using ChIP assays, we found that the methyl-DNA binding proteins MBD1, MBD2 and MeCP2 bind to the methylated 5-LO core promoter in U937 cells. Knock down of each of the MBDs upregulates 5-LO mRNA expression in U937 cells indicating that these proteins are involved in silencing of the 5-LO gene." SIGNOR-254062 RAPGEF3 protein O95398 UNIPROT RAP1A protein P62834 UNIPROT "up-regulates activity" "guanine nucleotide exchange factor" 9534 BTO:0000298 10777494 t miannu "Epac1 (cAMP-GEFI) and Epac2 (cAMP-GEFII) are closely related guanine nucleotide exchange factors (GEFs) for the small GTPase Rap1, which are directly regulated by cAMP. Here we show that both GEFs efficiently activate Rap2 as well." SIGNOR-263956 SP1 protein P08047 UNIPROT GGH protein Q92820 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 31739835 t miannu "Overexpression of Sp1 led to enhanced GGH promoter activity and GGH mRNA expression in allele-specific manners. These findings suggested that Sp1 acted as a positive regulator of human GGH transcription through the rs3758149 polymorphism in CEM/C1 cells." SIGNOR-261350 GART protein P22102 UNIPROT N(1)-(5-phospho-beta-D-ribosyl)glycinamide(1-) smallmolecule CHEBI:143788 ChEBI "up-regulates quantity" "chemical modification" 9606 34283828 t miannu "In humans, GART [phosphoribosylglycinamide formyltransferase (EC 2.1.2.2) / phosphoribosylglycinamide synthetase (EC 6.3.4.13) / phosphoribosylaminoimidazole synthetase (EC 6.3.3.1)] is a trifunctional protein which catalyzes the second, third, and fifth reactions of the ten step de novo purine synthesis (DNPS) pathway. The second step of DNPS is conversion of phosphoribosylamine (5-PRA) to glycineamide ribonucleotide (GAR)." SIGNOR-267300 "RNA Polymerase III" complex SIGNOR-C389 SIGNOR tRNA(Pyl) smallmolecule CHEBI:15185 ChEBI "up-regulates quantity" "chemical modification" 9606 27911719 t lperfetto "RNAPIII is specialized for transcription of short, abundant nonprotein-coding RNA transcripts. In addition to all tRNAs, RNAPIII transcribes the 5S rRNA and other essential RNAs, including the U6 small nuclear RNA (snRNA), the snR52 small nucleolar RNA and the RNA components of the signal recognition particle (SRP1) and RNase P (RPR1)" SIGNOR-269494 CCKBR protein P32239 UNIPROT GNAS protein Q5JWF2 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-256765 NDUFA2 protein O43678 UNIPROT "Mitochondrial respiratory chain complex I" complex SIGNOR-C277 SIGNOR "form complex" binding 30030361 t lperfetto "Thus, we now know the complete mammalian cI structure [22,23] and how the subunits are organized in six modules (N, Q, ND1, ND2, ND4 and ND5)The N-module, which is the tip of the hydrophilic arm and the last one to be incorporated [30,35], results from the assembly of NDUFV1, NDUFV2, NDUFS1 and NDUFA2 [34], to which NDUFA6, NDUFA7, NDUFA12, NDUFS4, NDUFS6 and NDUFV3 must be further associated with to complete the module [24]." SIGNOR-262154 Gbeta proteinfamily SIGNOR-PF4 SIGNOR RXRA protein P19793 UNIPROT "down-regulates activity" phosphorylation 9606 17604322 t "inferred from 70% family members" lperfetto "In colon cancer cells, the Ras/mitogen‚Äêactivated protein kinase (MAPK) pathway phosphorylates RXRalpha, which impairs its function as a heterodimeric partner for PPARgamma|A point‚Äêmutated RXRalpha T82A/S260A, which mimics the unphosphorylated form of RXRalpha, can form a heterodimer with PPARgamma and thereby activate target gene expression by binding to the PPRE" SIGNOR-269995 FBXW7 protein Q969H0 UNIPROT JUN protein P05412 UNIPROT "down-regulates quantity by destabilization" binding 9606 BTO:0000007 14739463 t miannu " We report that in neurons the stability of c-Jun is regulated by the E3 ligase SCF(Fbw7), which ubiquitinates phosphorylated c-Jun and facilitates c-Jun degradation. " SIGNOR-272950 ABL1 protein P00519 UNIPROT VAV1 protein P15498 UNIPROT up-regulates phosphorylation 9606 BTO:0001271 11790798 t gcesareni "Thus, the c-terminal tail of vav serves as a direct substrate of bcr-abl in vitro." SIGNOR-114091 PRKACA protein P17612 UNIPROT BAD protein Q92934 UNIPROT "down-regulates activity" phosphorylation Ser75 EIRSRHSsYPAGTED 9606 10230394 t gcesareni "Phosphorylation and inactivation of BAD by mitochondria-anchored protein kinase A|Collectively, these results implicate PKA as the principal mitochondria-based S112 kinase." SIGNOR-67383 ketanserin chemical CHEBI:6123 ChEBI SLC18A2 protein Q05940 UNIPROT "down-regulates activity" "chemical inhibition" 9606 BTO:0000318 8643547 t miannu "Reserpine and ketanserin are slightly more potent inhibitors of VMAT2-mediated transport than of VMAT1-mediated transport, whereas tetrabenazine binds to and inhibits only VMAT2." SIGNOR-258494 MAPK1 protein P28482 UNIPROT SOS1 protein Q07889 UNIPROT "down-regulates activity" phosphorylation Ser1197 KAYSPRYsISDRTSI 9534 8816480 t lperfetto "In this report, we describe the identification of five map kinase sites (s-1137, s-1167, s-1178, s-1193, and s-1197) on hsos1Replacing the MAP kinase phosphorylation sites with alanine residues results in an increase in the binding affinity of Grb2 to hSos1" SIGNOR-235929 INSR protein P06213 UNIPROT IRS4 protein O14654 UNIPROT "up-regulates activity" phosphorylation 10090 25905389 t lperfetto "The binding of insulin to the subunit of IR not only concentrates insulin at its site of action, but also induces conformational changes in the receptor, which in turn stimulates the tyrosine kinase activity intrinsic to the _ subunit of the IR and triggers the signaling cascades (Fig. 3). Insulin receptors trans phosphorylate several immediate substrates (on Tyr residues) including IRS1-4, Shc, and Gab 1, Cbl, APS, and P60dok." SIGNOR-217897 RBL2 protein Q08999 UNIPROT Cell_cycle_progress phenotype SIGNOR-PH42 SIGNOR down-regulates 10090 BTO:0000165 10801445 f gcesareni "Although forced expression of either p130 or pRb in mouse C2 myoblasts efficiently blocked cell cycle progression, only p130 inhibited the differentiation program." SIGNOR-241946 PRKAA1 protein Q13131 UNIPROT FOXO1 protein Q12778 UNIPROT up-regulates phosphorylation 9606 SIGNOR-C15 17900900 t gcesareni "The energy sensor amp-activated protein kinase (ampk) has been shown to directly phosphorylate foxo factors at six regulatory sites that are distinct from the akt." SIGNOR-157941 BCR-ABL "fusion protein" SIGNOR-FP6 SIGNOR BCR protein P11274 UNIPROT down-regulates phosphorylation Tyr360 VSPSPTTyRMFRDKS 9606 BTO:0001271 8622703 t lperfetto "We have previously demonstrated that the bcr protein is tyrosine phosphorylated within first-exon sequences by the bcr-abl oncoprotein. Here we report that in addition to tyrose 177 (y-177), y-360 and y283 are phosphorylated in bcr-abl proteins in vitro. Tyrosine-phosphorylated bcr, phosphorylated in vitro by bcr-abl, was greatly inhibited in its serine/threonine kinase activity, impairing both auto- and transkinase activities of bcr." SIGNOR-40619 FOXO3 protein O43524 UNIPROT FBXO32 protein Q969P5 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 BTO:0000165 15109499 f miannu "Constitutively active Foxo3 acts on the atrogin-1 promoter to cause atrogin-1 transcription and dramatic atrophy of myotubes and muscle fibers" SIGNOR-252070 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR SOS1 protein Q07889 UNIPROT down-regulates phosphorylation Ser1178 IMSKHLDsPPAIPPR 9606 20724475 t lperfetto "ERK activation was sufficient for the SOS1 phosphorylation and resulting inhibition of EGF-induced Ras activation. This result also showed that SOS1 could be phosphorylated by ERK in the absence of association with EGFR at the plasma membrane, which is a phosphotyrosine-dependent process." SIGNOR-244743 GSK3A protein P49840 UNIPROT AKT1 protein P31749 UNIPROT "down-regulates activity" phosphorylation Thr312 TMKTFCGtPEYLAPE 10090 BTO:0005655 23142783 t gcesareni "GSK3_ negatively regulates AKT activation by phosphorylating AKT at T312 in the substrate binding site, which inhibited IL-1-induced AKT activation and function." SIGNOR-252434 JNK proteinfamily SIGNOR-PF15 SIGNOR BCL2L11 protein O43521 UNIPROT up-regulates phosphorylation Ser118 DKSTQTPsPPCQAFN 9606 12591950 t lperfetto "Biml (bim long) was induced and phosphorylated parallel to jnk activitythese data demonstrate that biml is phosphorylated in vivo on thr-56 and that jnk also phosphorylates biml on at least one serine residue (ser-44 and/or ser-58)" SIGNOR-98388 "enalaprilat (anhydrous)" chemical CHEBI:4786 ChEBI ACE protein P12821 UNIPROT "down-regulates activity" "chemical inhibition" 10116 7527095 t miannu "The effects of 14-day trandolapril or enalapril treatment of spontaneously hypertensive rats (SHRs) were studied on blood pressure and angiotensin-converting enzyme (ACE) activity measured ex vivo in various organs. Both ACE inhibitors caused dose-dependent decreases in blood pressure and ACE activity, trandolapril being 30- and 400- to 1,000-fold more active than enalapril on blood pressure and ACE activity, respectively." SIGNOR-258429 PLAUR protein Q03405 UNIPROT ITGB3 protein P05106 UNIPROT "up-regulates activity" binding 9606 27383564 t "Recent evidence suggests that the activation of b3 integrin in podocytes mediates uPAR-induced cellular events leading to proteinuria" SIGNOR-253333 NRF1 protein Q16656 UNIPROT SLC46A1 protein Q96NT5 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 20724482 f miannu "Overexpression of NRF-1 or a constitutively active NRF-1 VP-16 construct resulted in increased reporter activity and PCFT mRNA levels. These novel findings identify NRF-1 as a major inducible transcriptional regulator of PCFT gene expression." SIGNOR-254884 HES1 protein Q14469 UNIPROT NEUROG1 protein Q92886 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 10090 BTO:0000938 30030829 f lperfetto "The basic-helixloop-helix factors HES1 and HES5 repress the expression of the proneural genes (Ascl1, Atoh1, Neurog1 and Neurog2) and thereby inhibit NSCs differentiation and neuron production" SIGNOR-265140 CDKN1A protein P38936 UNIPROT Cell_cycle_exit phenotype SIGNOR-PH41 SIGNOR up-regulates 10090 BTO:0000222 9388774 f gcesareni "The upregulation of the cyclin-dependent kinase inhibitor p21 and the dephosphorylation of retinoblastoma protein (pRb) appear to be critical regulatory events for the establishment ,,, the postmitotic ... states [in myoblasts differentiating into mature myotubes]" SIGNOR-241956 SMCR8 protein Q8TEV9 UNIPROT ULK1 protein O75385 UNIPROT "down-regulates quantity" "transcriptional regulation" 9606 BTO:0000007 28195531 t "While focusing on the role of SMCR8 during autophagy initiation, we found that kinase activity and gene expression of ULK1 are increased upon SMCR8 depletion. The latter phenotype involved association of SMCR8 with the ULK1 gene locus." SIGNOR-252030 "lysophosphatidic acids" smallmolecule CHEBI:32957 ChEBI LPAR3 protein Q9UBY5 UNIPROT up-regulates "chemical activation" 9606 16014605 t gcesareni "Lpa exerts its downstream signaling by binding to the lpa(1), lpa(2), and lpa(3) (formerly edg-2, -4, and -7) family of seven-transmembrane, segmented, heterotrimeric guanine nucleotide-binding protein (g protein)-coupled receptors." SIGNOR-138585 APBA1 protein Q02410 UNIPROT STXBP1 protein P61764 UNIPROT "up-regulates activity" binding 10116 9395480 t miannu "Munc18-1 is a neuronal protein that interacts with syntaxin 1 and is required for synaptic vesicle exocytosis. We have now identified two Munc18-1-interacting proteins called Mint1 and Mint2 that may mediate the function of Munc18-1." SIGNOR-264035 F2 protein P00734 UNIPROT F8 protein P00451 UNIPROT "up-regulates activity" cleavage Arg759 KNNAIEPrSFSQNSR -1 10350471 t lperfetto "Activation of factor VIII by thrombin occurs via limited proteolysis at R372, R740, and R1689." SIGNOR-263641 MAP2K6 protein P52564 UNIPROT MAPK11 protein Q15759 UNIPROT up-regulates phosphorylation 9606 9430721 t gcesareni "The p38 mapkinasekinasemkk6 is identified as a common activator of p38 alpha, p38 beta 2, and p38 gamma mapkinaseisoforms." SIGNOR-54947 HOXD12 protein P35452 UNIPROT MAFK protein O60675 UNIPROT "down-regulates activity" binding -1 11036080 t miannu "Hoxd12 and MHox, that interact with v-/c-Maf, using the phage display method. The Hox proteins also could associate with the other Maf protein family members, MafB, MafK, MafF, and MafG, but not with Jun and Fos. The Hox proteins negatively regulated the DNA binding, transactivation and cell-transforming abilities of Maf." SIGNOR-221929 ITGAV protein P06756 UNIPROT "Av/b3 integrin" complex SIGNOR-C177 SIGNOR "form complex" binding 16988024 t lperfetto "Integrins are one of the major families of cell adhesion receptors (Humphries, 2000; Hynes, 2002). All integrins are non-covalently-linked, heterodimeric molecules containing an α and a β subunit. Both subunits are type I transmembrane proteins, containing large extracellular domains and mostly short cytoplasmic domains (Springer and Wang, 2004; Arnaout et al., 2005). Mammalian genomes contain 18 α subunit and 8 β subunit genes, and to date 24 different α,β combinations have been identified at the protein level. Although some subunits only appear in a single heterodimer, twelve integrins contain the β1 subunit, and five contain αV." SIGNOR-253205 4-[[5-amino-1-[(2,6-difluorophenyl)-oxomethyl]-1,2,4-triazol-3-yl]amino]benzenesulfonamide chemical CHEBI:94506 ChEBI CCNA2 protein P20248 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-193537 HRH2 protein P25021 UNIPROT GNA14 protein O95837 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257424 mTORC2 complex SIGNOR-C2 SIGNOR AKT proteinfamily SIGNOR-PF24 SIGNOR "up-regulates activity" phosphorylation Thr479 FSYSASGtA 9606 BTO:0000093 24670654 t gcesareni "Phosphorylation of S477 and T479 at the Akt extreme carboxy terminus by cyclin-dependent kinase 2 (Cdk2)/cyclin A or mTORC2, under distinct physiological conditions, promotes Akt activation through facilitating, or functionally compensating for, S473 phosphorylation" SIGNOR-252454 DIO2 protein Q92813 UNIPROT iodide smallmolecule CHEBI:16382 ChEBI "up-regulates quantity" "chemical modification" 9606 34674502 t scontino "Three different deiodinases have been described: iodothyronine deiodinase 1 (DIO1), DIO2, and DIO3. Deiodination is the first step in the activation/inactivation process of THs and involves the removal of removes one iodine atom from the outer tyrosyl ring of T4 to produce T3." SIGNOR-266953 CDK2 protein P24941 UNIPROT RBL2 protein Q08999 UNIPROT unknown phosphorylation Ser413 VRYIKENsPCVTPVS 9606 11157749 t llicata "We now identify 22 in vivo phosphorylation sites of p130, targeted by diverse kinases, and present evidence for three cyclin-dependent kinase 4(6) [cdk4(6)] specific phosphorylations, which appear critical for controlling the growth-restraining activity of p130." SIGNOR-104675 TG101209 chemical CHEBI:90304 ChEBI RET protein P07949 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-207269 ERBB3 protein P21860 UNIPROT PIK3CG protein P48736 UNIPROT up-regulates binding 9606 16729043 t gcesareni "Pi3k is the sole binding partner to six tyrosines of erbb3 and one in erbb4." SIGNOR-146870 TEAD1 protein P28347 UNIPROT FOXM1 protein Q08050 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 22286761 f gcesareni "Yap directly induced the transcription of ccnd1 and foxm1, in cooperation with tead transcription factor." SIGNOR-194371 HK3 protein P52790 UNIPROT "alpha-D-glucose 6-phosphate(2-)" smallmolecule CHEBI:58225 ChEBI "up-regulates quantity" "chemical modification" 9606 16051738 t miannu "Hexokinase catalyzes the phosphorylation of glucose to G6P, using ATP as a phosphoryl donor." SIGNOR-266447 GSK3B protein P49841 UNIPROT GRB14 protein Q14449 UNIPROT "down-regulates activity" phosphorylation Ser366 GCSSQSIsPMRSISE -1 28130417 t lperfetto "Phosphorylation of clustered serine residues in the N-terminus of BPS domain negatively regulates formation of the complex between human Grb14 and insulin receptor| In vitro kinase assay using the motif-derived peptides showed that the serine residues located in N-terminal (Ser358, Ser362 and Ser366) and C-terminal (Ser419 and Ser423) regions of the BPS domain were phosphorylated by GSK-3." SIGNOR-264869 ESRRA protein P11474 UNIPROT NR2F1 protein P10589 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0000155 15955695 f miannu "In cancer tissue, the expression levels of EAR-2, COUP-TF1, EARgamma, Snail, and Slug decrease, and aromatase expression is then up-regulated through the binding of ERRalpha to S1 and the binding of CREB1 or related factors to CREaro." SIGNOR-253795 AKT proteinfamily SIGNOR-PF24 SIGNOR TWIST1 protein Q15672 UNIPROT up-regulates phosphorylation Ser42 GGRKRRSsRRSAGGG 9606 20400976 t lperfetto "Moreover, phosphorylation of twist-1 at ser42 was shown in vivo in various human cancer tissues, suggesting that this post-translational modification ensures functional activation of twist-1 after promotion of survival during carcinogenesis." SIGNOR-244373 FLT3 protein P36888 UNIPROT FLT3 protein P36888 UNIPROT "up-regulates activity" phosphorylation Tyr842 DIMSDSNyVVRGNAR 10090 BTO:0001516 16627759 t lperfetto "In vitro mapping of FLT3 autophosphorylation sites|Tryptic peptides covering more than 80% of the FLT3 kinase domain were recovered, and 5 tyrosine residues (Y591, Y726, Y842, Y955, and Y969) within this region were phosphorylated." SIGNOR-271925 Kindlin proteinfamily SIGNOR-PF48 SIGNOR "Av/b2 integrin" complex SIGNOR-C176 SIGNOR "up-regulates activity" binding 9606 29544897 t miannu "Kindlins bind with β-integrin cytoplasmic tails and execute broad biological functions including directed cell migration, proliferation, differentiation and survival." SIGNOR-259027 PRKCA protein P17252 UNIPROT CREBBP protein Q92793 UNIPROT down-regulates phosphorylation 9606 20577053 t gcesareni "The action of metformin was shown to be mediated through activation of apkc?/?, Which phosphorylates cbp at ser436, and disrupts the transcriptionally active creb-cbp-crtc2 complex," SIGNOR-166368 PRKAA1 protein Q13131 UNIPROT RPTOR protein Q8N122 UNIPROT "down-regulates activity" phosphorylation Ser792 DKMRRASsYSSLNSL 10090 BTO:0002572 SIGNOR-C15 SIGNOR-C3 18439900 t lperfetto "The phosphorylation of raptor by ampk is required for the inhibition of mtorc1 and cell-cycle arrest induced by energy stress." SIGNOR-161375 1-[4-[[2-(2-amino-5-pyrimidinyl)-7-methyl-4-(4-morpholinyl)-6-thieno[3,2-d]pyrimidinyl]methyl]-1-piperazinyl]-2-hydroxy-1-propanone chemical CHEBI:93753 ChEBI PIK3CD protein O00329 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-192617 Corticotropin protein P01189-PRO_0000024969 UNIPROT HSD3B1 protein P14060 UNIPROT "up-regulates quantity" 9606 24631756 f lperfetto "CTH signaling promotes the single steroidogenic rate limiting step, which is the conversion of cholesterol to pregnenolone by Cholesterol Side-Chain Cleavage Enzyme (P450scc), encoded in the CYP11A1 gene. This is conferred by a direct stimulating effect of ACTH on the promoter of CYP11A1 (Chung et al., 1997, Liu and Simpson, 1997, Hu et al., 2001). Further, it stimulates conversion of pregnenolone to 17-hydroxypregnenolone by upregulating the expression of 3β hydroxysteroid dehydrogenase enzyme (3β-HSD)" SIGNOR-268720 mTORC1 complex SIGNOR-C3 SIGNOR RPS6KB1 protein P23443 UNIPROT "up-regulates activity" phosphorylation Thr390 DSKFTRQtPVDSPDD 9606 11914378 t "Thr229 phosphorylation requires prior phosphorylation of the Ser/Thr-Pro sites in the autoinhibitory domain and Thr389 in the linker domain,[…] Moreover, in vitro mTOR directly phosphorylates Ser371, and this event modulates Thr389phosphorylation by mTOR, compatible with earlier in vivo findings." SIGNOR-255840 DRD2 protein P14416 UNIPROT GNAO1 protein P09471 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-256980 PTMS protein P20962 UNIPROT EP300 protein Q09472 UNIPROT "up-regulates activity" binding 9606 BTO:0000567 16150697 t miannu "Macromolecular translocation inhibitor II (MTI-II), which was first identified as an in vitro inhibitor of binding between the highly purified glucocorticoid receptor (GR) and isolated nuclei, is an 11.5-kDa Zn2+-binding protein that is also known as ZnBP or parathymosin. MTI-II Enhances GR-dependent Transcription through Its Acidic Domain. MTI-II Enhances GR-dependent Transcription in Cooperation with SRC-1 and p300 in Vivo. CBP and p300 Coprecipitate with MTI-II in a Glucocorticoid Hormone-dependent Manner. Immunoprecipitation analysis showed that in the presence of glucocorticoid hormone, p300 and CREB-binding protein are coprecipitated with MTI-II. Furthermore, the knockdown of endogenous MTI-II by RNAi reduces the transcriptional activity of GR in cells." SIGNOR-268461 NOTCH proteinfamily SIGNOR-PF30 SIGNOR BMPR1A/1B/2 complex SIGNOR-C29 SIGNOR up-regulates 9606 22298955 f gcesareni "Similar synergy is found in notch and bmp crosstalk: activating notch signaling enhanced bmp-induced alp activity and formation of calcified nodules in vitro." SIGNOR-254335 WNT5A protein P41221 UNIPROT RYK protein P34925 UNIPROT up-regulates binding 9606 22773843 t areggio "Purified human RYK binds to mouse Wnt1, 3a and 5a expressed in HEK293 cells. Separate experiments show that human RYK also immunopreciptitates human VANGL2 when the proteins are co-expressed in HEK293 cells." SIGNOR-258970 TTC5 protein Q8N0Z6 UNIPROT EP300 protein Q09472 UNIPROT "up-regulates activity" binding 9606 BTO:0001938 15448695 t miannu "DNA damage activates ATM kinase which then phosphorylates Strap at Ser 203 (red circles). Phosphorylated Strap is stabilized and undergoes nuclear accumulation where it assembles into a co-activator complex, which includes p300 and cofactors such as JMY" SIGNOR-262646 RPS6KB1 protein P23443 UNIPROT CCT2 protein P78371 UNIPROT unknown phosphorylation Ser260 GSRVRVDsTAKVAEI 9606 19332537 t llicata "Mass spectrometry and mutagenesis analysis revealed that rsk and s6k1 phosphorylate cct_ ser-260 in vitro and in intact cells" SIGNOR-184926 2-oxoglutarate(2-) smallmolecule CHEBI:16810 ChEBI Citric_Acid_Cycle phenotype SIGNOR-PH191 SIGNOR up-regulates 9606 15953811 f miannu "A branch-point metabolite α-ketoglutarate is generated in the TCA cycle during the oxidation of carbohydrates and fatty acids and by glutamate dehydrogenase during the oxidative deamination of glutamate. The enzymes that form the mitochondrial α-ketoglutarate– dehydrogenase complex (KGDHC), a key and arguably rate-limiting enzyme system of the tricarboxylic acid cycle, might mediate the interaction of these processes." SIGNOR-267821 MECP2 protein P51608 UNIPROT PTPN1 protein P18031 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0000452 26214522 t Luana "In this study, we have demonstrated that the PTPN1 gene, which encodes PTP1B, was a direct target of MECP2 and that PTP1B protein levels were dramatically increased in Mecp2-mutant mice and in fibroblasts derived from patients with RTT." SIGNOR-264546 SFPQ protein P23246 UNIPROT TH protein P07101 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 20938049 t lperfetto "It has been reported that DJ-1 is a neuroprotective transcriptional co-activator that sequesters a transcriptional co-repressor polypyrimidine tract-binding protein-associated splicing factor (PSF) from the TH gene promoter." SIGNOR-271697 GSK3A protein P49840 UNIPROT JUN protein P05412 UNIPROT down-regulates phosphorylation Ser243 PGETPPLsPIDMESQ 9606 1846781 t lperfetto "Phosphorylation of recombinant human c-jun proteins in vitro by gsk-3 decreases their dna-binding activity." SIGNOR-21776 FYN protein P06241 UNIPROT PRKCQ protein Q04759 UNIPROT up-regulates phosphorylation 9606 BTO:0000782 10383400 t miannu "Further indications of direct interaction are that p59fyn potentiates ?PKC Catalytic activity and that ?PKC Is a substrate for tyrosine phosphorylation by p59fyn." SIGNOR-68798 4-(2,6-dichlorobenzamido)-N-(piperidin-4-yl)-pyrazole-3-carboxamide chemical CHEBI:91326 ChEBI CDK4 protein P11802 UNIPROT "down-regulates activity" "chemical inhibition" -1 29901072 t miannu "AT7519, a pyrazole 3-carboxyamide compound, was developed by Astex and acts as an inhibitor of CDK1, CDK2, CDK4, CDK6 and CDK9." SIGNOR-262220 XL765 chemical CHEBI:71958 ChEBI PIK3CG protein P48736 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-207881 PRKCA protein P17252 UNIPROT HAND1 protein O96004 UNIPROT unknown phosphorylation Ser98 RLGRRKGsGPKKERR 9606 14636580 t lperfetto "In vitro and in vivo phosphorylation studies show that both PKA and PKC can phosphorylate HAND1 and -2. In addition, phosphopeptide mapping analysis of wild-type and mutant forms of HAND1 shows that three of these conserved residues, T107; S109 within helix I and S98 within the basic domain, are the phosphorylated residues. " SIGNOR-249243 MAP2K4 protein P45985 UNIPROT p38 proteinfamily SIGNOR-PF16 SIGNOR "up-regulates activity" phosphorylation 9534 BTO:0000298 7839144 t Luana "Two human MAP kinase kinases (MKK3 and MKK4) were cloned that phosphorylate and activate p38 MAP kinase." SIGNOR-260722 INHA protein P05111 UNIPROT TGFBR3 protein Q03167 UNIPROT down-regulates binding 9606 10746731 t gcesareni "Type iii tgf-beta receptor, betaglycan, can function as an inhibin co-receptor with actrii. Betaglycan binds inhibin with high affinity and enhances binding in cells co-expressing actrii and betaglycan. ability of betaglycan to facilitate inhibin antagonism of activin" SIGNOR-76470 PRKCB protein P05771 UNIPROT GAP43 protein P17677 UNIPROT unknown phosphorylation Ser41 AATKIQAsFRGHITR -1 2140056 t lperfetto "We conclude that serine-41 is the protein kinase C phosphorylation site of neuromodulin and that phosphorylation of this amino acid residue blocks binding of calmodulin to neuromodulin." SIGNOR-248859 CSNK2A1 protein P68400 UNIPROT SRF protein P11831 UNIPROT "up-regulates activity" phosphorylation Ser83 YSGSEGDsESGEEEE -1 2046671 t llicata "Casein kinase II (CKII) phosphorylates the mammalian transcription factor serum response factor (SRF) on a serine residue(s) located within a region of the protein spanning amino acids 70 to 92, thereby enhancing its DNA-binding activity in vitro. We report here that serine 83 appears to be the residue phosphorylated by CKII but that three other serines in this region can also be involved in phosphorylation and the enhancement of DNA-binding activity." SIGNOR-250958 ERG protein P11308 UNIPROT SPP1 protein P10451 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 21669963 f miannu "Using in vitro and in vivo molecular assays, we showed that ERG increases OPN expression and binds to an EBS (nt -115 to -118) in the OPN promoter." SIGNOR-254066 "SAGA complex" complex SIGNOR-C465 SIGNOR H3-5 protein Q6NXT2 UNIPROT "down-regulates activity" acetylation Lys15 ARKSTGGkAPRKQLA 9606 34811519 t "Acetlyation of H3 causes transcriptional activation, thus has an inhibitory role on H3" lperfetto "The HAT module within the SAGA and ADA complexes acetylates histone H3, mainly on residues K9 and K14." SIGNOR-269642 FGD3 protein Q5JSP0 UNIPROT CDC42 protein P60953 UNIPROT "up-regulates activity" "guanine nucleotide exchange factor" 9606 BTO:0000007 32203420 t Luana "We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2)." SIGNOR-260553 PLK1 protein P53350 UNIPROT BRCA2 protein P51587 UNIPROT unknown phosphorylation Thr203 SSLATPPtLSSTVLI 9606 BTO:0001938 12815053 t lperfetto "Plk1 interacts with BRCA2 in vivo, and mutation of Ser193, Ser205/206, and Thr203/207 to Ala in BR-N1 abolished Plk1 phosphorylation, suggesting that BRCA2 is the substrate of Plk1. Furthermore, both the hyperphosphorylated and hypophosphorylated forms of BRCA2 bind to RAD51, whereas the M phase hyperphosphorylated form of BRCA2 no longer associates with the P/CAF, suggesting that the dissociation of P/CAF-BRCA2 complex is regulated by phosphorylation." SIGNOR-249220 MRPS12 protein O15235 UNIPROT "28S mitochondrial small ribosomal subunit" complex SIGNOR-C266 SIGNOR "form complex" binding 9606 25838379 t miannu "The mammalian mitochondrial ribosome (mitoribosome) has a highly protein-rich composition with a small sedimentation coefficient of 55 S, consisting of 39 S large and 28 S small subunits. . We report here the identification of 28 S small subunit proteins." SIGNOR-261457 CYP21A2 protein P08686 UNIPROT 17alpha-hydroxyprogesterone smallmolecule CHEBI:17252 ChEBI "up-regulates quantity" "chemical modification" 9606 BTO:0000050 25855791 t lperfetto "Cytochrome P450 (P450)4 21A2 is the major steroid 21-hydroxylase, which catalyzes the 21-hydroxylation of progesterone and 17alpha-hydroxyprogesterone (17alpha-OH-progesterone) to form 11-deoxycorticosterone and 11-deoxycortisol, respectively" SIGNOR-268643 AKT1 protein P31749 UNIPROT CLK2 protein P49760 UNIPROT up-regulates phosphorylation Ser34 HKRRRSRsWSSSSDR 9606 BTO:0000567 20682768 t lperfetto "Akt directly binds to and phosphorylates clk2 on serine 34 and threonine 127, in vitro and in vivo.Our results suggest that akt activation controls cell survival to ionizing radiation by phosphorylating clk2, revealing an important regulatory mechanism required for promoting cell surviva" SIGNOR-167336 PDK3 protein Q15120 UNIPROT PDHA2 protein P29803 UNIPROT down-regulates phosphorylation Ser291 TYRYHGHsMSDPGVS 9606 16436377 t miannu "Pdh2 was found to be very similar to pdh1 / in the mechanism of inactivation by phosphorylation of three sites;and (iv) in the phosphorylation of sites 1 and 2 by pdk3 / (ser-264 (site 1), ser-271 (site 2), and ser-203 (site 3)" SIGNOR-143974 MAPK3 protein P27361 UNIPROT SMAD2 protein Q15796 UNIPROT up-regulates phosphorylation Thr220 QSNYIPEtPPPGYIS 9606 19115199 t gcesareni "These results suggest that oncogenic ras, acting through mek1 and erk kinases, induces the phosphorylation of smad2 and smad3 .we show that phosphorylation of smad2, a mediator of the activin/transforming growth factor-beta signal, by activated extracellular signal-regulated kinase 1 (erk1) increases the amount of smad2 protein and leads to enhanced transcriptional activity" SIGNOR-183000 CDKN1B protein P46527 UNIPROT CDK2 protein P24941 UNIPROT down-regulates binding 9606 SIGNOR-C16 17409098 t gcesareni "P27, an important cell cycle regulator, blocks the g(1)/s transition in cells by binding and inhibiting cdk2/cyclin a and cdk2/cyclin e complexes (cdk2/e)." SIGNOR-154191 CSNK2A1 protein P68400 UNIPROT VAMP4 protein O75379 UNIPROT up-regulates phosphorylation Ser30 RNLLEDDsDEEEDFF 9606 14608369 t gcesareni "The r-snare vamp4, which contains a dileucine motif, binds to the ap-1 or the ggas. Serine 20 and leucines 25,26 are essential for this binding. Ap-1 association with vamp4 is enhanced when serine 30 is phosphorylated by casein kinase 2. This phosphorylation-dependent modulation of ap-1 binding is mediated by pacs-1 (phosphofurin acidic cluster sorting protein). Ablation of both the dileucine motif and serine 30 results in a dramatic mislocalization of vamp4 in the regulated secretory pathway." SIGNOR-119090 F7 protein P08709 UNIPROT F10 protein P00742 UNIPROT "up-regulates activity" binding 9606 BTO:0000131 SIGNOR-C319 29880919 t lperfetto "TF has a high affinity for FVII and enables the trace levels (∼1% of the total FVII) of activated FVII (FVIIa) in the blood to cleave specific sites in the serine proteases FIX and FX, activating them into FIXa and FXa, respectively." SIGNOR-263545 PTTG1 protein O95997 UNIPROT TIMP2 protein P16035 UNIPROT "down-regulates quantity" 9606 19351864 f miannu "Suppressing PTTG expression by siRNA decreased cell motility in both PTTG-HA/EC9706 and KYSE150 cells. By using mass spectrometric analysis, we identified that PTTG up-regulated S100A4 and galectin-1 secretion and down-regulated tissue inhibitor of metalloproteinase-2 secretion to the culture media." SIGNOR-255069 PRKACA protein P17612 UNIPROT LIPE protein Q05469 UNIPROT "up-regulates activity" phosphorylation Ser950 EGFHPRRsSQGATQM 10090 BTO:0000944 11581251 t lperfetto "HSL activity is known to be regulated by phosphorylation (3). PKA increases HSL activity via phosphorylation at Ser563, Ser659, and Ser660 (14,15), although phosphorylation at Ser565 by glycogen synthase kinase, AMP-dependent protein kinase, or Ca2+/calmodulin-dependent protein kinase II has been reported to prevent activation of the enzyme" SIGNOR-249203 APBA2 protein Q99767 UNIPROT STXBP1 protein P61764 UNIPROT "up-regulates activity" binding 10116 BTO:0000142 9395480 t miannu "Munc18-1 is a neuronal protein that interacts with syntaxin 1 and is required for synaptic vesicle exocytosis. We have now identified two Munc18-1-interacting proteins called Mint1 and Mint2 that may mediate the function of Munc18-1." SIGNOR-264037 BCL3 protein P20749 UNIPROT NFKB2 protein Q00653 UNIPROT up-regulates binding 9606 16713561 t gcesareni "The cyclin d1 elevation is caused not by increased p65/p50 action but rather by increased nuclear activity of bcl-3-associated nf-kappab p50 and p52." SIGNOR-146768 JNK proteinfamily SIGNOR-PF15 SIGNOR AP1 complex SIGNOR-C154 SIGNOR "up-regulates activity" binding 9606 24315690 t miannu "In addition to the possible regulation of the transcription factor c-Jun by phosphorylation via the c-Jun N-terminal kinase (JNK) or the kinases ERK1, ERK2 and GSK3β, further signaling pathways lead to an up-regulation of c-Jun protein and thus AP-1 activity" SIGNOR-253340 AKT proteinfamily SIGNOR-PF24 SIGNOR CLK2 protein P49760 UNIPROT up-regulates phosphorylation Ser34 HKRRRSRsWSSSSDR 9606 BTO:0000567 20682768 t lperfetto "Akt directly binds to and phosphorylates clk2 on serine 34 and threonine 127, in vitro and in vivo.Our results suggest that akt activation controls cell survival to ionizing radiation by phosphorylating clk2, revealing an important regulatory mechanism required for promoting cell surviva" SIGNOR-244214 POU5F1 protein Q01860 UNIPROT DNMT1 protein P26358 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 22795133 t lperfetto "Oct4 and Nanog upregulate Dnmt1 through direct binding to its promoter, thereby leading to the repressed expression of p16 and p21 and genes associated with development and lineage differentiation" SIGNOR-253158 GRK5 protein P34947 UNIPROT TP53 protein P04637 UNIPROT down-regulates phosphorylation Thr55 DDIEQWFtEDPGPDE 9606 20124405 t llicata "Grk5, but not grk2 or grk6, phosphorylates p53 at thr-55, which promotes the degradation of p53, leading to inhibition of p53-dependent apoptotic response to genotoxic damage." SIGNOR-163707 PRKACA protein P17612 UNIPROT GMFB protein P60983 UNIPROT "up-regulates activity" phosphorylation Ser83 QHDDGRVsYPLCFIF -1 9030586 t miannu "Protein kinase A (PKA)-phosphorylated GMF is a potent inhibitor of extracellular signal-regulated kinase (ERK) and enhancer of p38; both are subfamilies of mitogen-activated protein (MAP) kinase, suggesting GMF as a bifunctional regulator of the MAP kinase cascades. PKA is capable of phosphorylating threonine 26 and serine 82." SIGNOR-249983 DYRK1B protein Q9Y463 UNIPROT DYRK1B protein Q9Y463 UNIPROT up-regulates phosphorylation Tyr273 LGQRIYQyIQSRFYR 9606 10910078 t lperfetto "Mirk kinase is activated by autophosphorylation on tyrosine at the y271/y273 site" SIGNOR-79810 VKORC1L1 protein Q8N0U8 UNIPROT "vitamin K" smallmolecule CHEBI:28384 ChEBI "up-regulates quantity" "chemical modification" 9606 31226734 t lperfetto "The epoxide form of vitamin K is reduced by epoxide reductase (vitamin K epoxide reductase complex 1; VKORC1 or vitamin K epoxide reductase complex 1-like 1; VKORC1L1) to a reduced form and then to the reduced hydroquinone form" SIGNOR-265903 DHCR7 protein Q9UBM7 UNIPROT cholesterol smallmolecule CHEBI:16113 ChEBI "up-regulates quantity" "chemical modification" 9606 9634533 t miannu "In cholesterol biosynthesis, 7-DHC is converted to cholesterol by the enzyme sterol D7 -reductase. This NADPH-dependent enzyme catalyzes the reduction of the D7 -diene bond in 7-DHC, to form cholesterol." SIGNOR-267252 TMIGD2 protein Q96BF3 UNIPROT AMPK complex SIGNOR-C15 SIGNOR "up-regulates activity" phosphorylation 9606 BTO:0000007 32978258 t miannu " Upon activation by autophagy stimuli, IGPR-1 is phosphorylated at Ser220 via IKKβ. IGPR-1 acts as a pro-autophagy signaling receptor leading to activation of AMPK. " SIGNOR-273665 TNF protein P01375 UNIPROT MPO-ANCA complex SIGNOR-C474 SIGNOR up-regulates 10090 BTO:0000133 15972951 f lperfetto "Second, LPS-mediated aggravation of anti-MPO IgG-induced glomerulonephritis was attenuated, but not prevented, by pretreatment with neutralizing anti-TNF-α antibodies." SIGNOR-270588 MAPK1 protein P28482 UNIPROT AHNAK protein Q09666 UNIPROT unknown phosphorylation Ser5099 DVEFDIKsPKFKAEA 10090 BTO:0000944 22028470 t miannu "We have optimized a chemical genetic system using analog-sensitive ERK2, a form of ERK2 engineered to use an analog of adenosine 5'-triphosphate (ATP), to tag and isolate ERK2 substrates in vitro. This approach identified 80 proteins phosphorylated by ERK2, 13 of which are known ERK2 substrates. With this improved methodology, we detected 98 sites directly phosphorylated by ERK2 on 80 proteins from NIH 3T3-L1 fibroblasts. Thirteen of these proteins are known substrates and the rest represent previously unknown kinase/substrate interactions. (table1)" SIGNOR-262763 PAMPs stimulus SIGNOR-ST11 SIGNOR FCN2 protein Q15485 UNIPROT "up-regulates activity" binding -1 11907111 t lperfetto "H-ficolin binds to PSA, a polysaccharide produced by Aerococcus viridans. C4 was activated by H-ficolin preparations bound to PSA which had been coated on ELISA plates." SIGNOR-263407 MAPK1 protein P28482 UNIPROT RPS6KB1 protein P23443 UNIPROT up-regulates phosphorylation Thr444 RFIGSPRtPVSPVKF 9606 BTO:0000887;BTO:0001103 11705993 t gcesareni "The principal target of rapamycin-induced p70s6k inactivation is a novel phosphorylation site within a conserved hydrophobic domain." SIGNOR-111511 CYSLTR2 protein Q9NS75 UNIPROT GNA14 protein O95837 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257140 PAMPs stimulus SIGNOR-ST11 SIGNOR "AIM2 inflammasome" complex SIGNOR-C222 SIGNOR "up-regulates activity" 16037825 f miannu "Among these sensors, members of the evolutionary conserved NLRs, together with AIM2 and pyrin, can assemble into a multimeric protein complex that is called the inflammasome (see poster).| An inflammasome assembles in response to a diverse range of pathogen-associated or danger-associated molecular patterns (PAMPs or DAMPs). The inflammasome platform leads to activation of caspase-1 through proximity-induced self-cleavage" SIGNOR-263126 Gbeta proteinfamily SIGNOR-PF4 SIGNOR BAD protein Q92934 UNIPROT down-regulates phosphorylation 9606 BTO:0000567 19777442 t "inferred from 70% family members" gcesareni "Erk-1 map kinase prevents tnf-induced apoptosis through bad phosphorylation and inhibition of bax translocation in hela cells." SIGNOR-270037 SRC protein P12931 UNIPROT ARAF protein P10398 UNIPROT up-regulates phosphorylation Tyr301 LGYRDSGyYWEVPPS 9534 BTO:0004055 9020159 t lperfetto "A-raf behaves like raf-1, being weakly activated by oncogenic ras more strongly activated by oncogenic src, and these signals synergize to give maximal activation. Activation of Raf-1 and A-Raf by Src requires tyrosine phosphorylation at residues 340 and 341 in Raf-1 and 301 and 302 in A-Raf." SIGNOR-236037 SP3 protein Q02447 UNIPROT ASNS protein P08243 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000599 11867623 t Luana "Sp1 and Sp3 Activate Transcription Driven by the AS Promoter" SIGNOR-268020 PRKACA protein P17612 UNIPROT RET protein P07949 UNIPROT down-regulates phosphorylation Ser696 SSGARRPsLDSMENQ 9606 BTO:0000938 20682772 t llicata "Furthermore, we find that activation of protein kinase a (pka) by forskolin reduces the recruitment of shp2 to ret and negatively affects ligand-mediated neurite outgrowth. In agreement with this, mutation of ser(696), a known pka phosphorylation site in ret, enhances shp2 binding to the receptor and eliminates the effect of forskolin on ligand-induced outgrowth." SIGNOR-167349 Ub:E2 complex SIGNOR-C497 SIGNOR IRF2BP1 protein Q8IU81 UNIPROT "up-regulates activity" ubiquitination 9606 34199813 t miannu "The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t" SIGNOR-271057 LSM-1231 chemical CHEBI:91471 ChEBI NTRK3 protein Q16288 UNIPROT "down-regulates activity" "chemical inhibition" -1 22037378 t Luana "Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here." SIGNOR-258240 SMARCC1 protein Q92922 UNIPROT "Embryonic stem cell-specific SWI/SNF" complex SIGNOR-C484 SIGNOR "form complex" binding 10090 BTO:0001086 19279220 t miannu "An embryonic stem cell chromatin remodeling complex, esBAF, is essential for embryonic stem cell self-renewal and pluripotency" SIGNOR-270724 MAPK14 protein Q16539 UNIPROT PLA2G4A protein P47712 UNIPROT "up-regulates activity" phosphorylation Ser505 LNTSYPLsPLSDFAT 9606 BTO:0000132 8910365 t lperfetto "These results provide the first direct evidence that p38 kinase is responsible for cpla2 phosphorylation in sfllrn-stimulated platelets and is involved in the early phosphorylation of cpla2 in thrombin-stimulated platelets" SIGNOR-44673 "Calprotectin complex" complex SIGNOR-C293 SIGNOR AGER protein Q15109 UNIPROT "up-regulates activity" binding 9606 28137827 t miannu "RAGE and TLR4 are well-characterized S100A8 and S100A9 receptors and expressed in AML cells Once secreted, S100A8 and S100A9 induce immune and inflammatory responses9 through interaction with receptors such as Toll-like receptor 4 (TLR4), receptor for advanced glycation end-product (RAGE), and CD33" SIGNOR-262825 PRKCZ protein Q05513 UNIPROT ATP1A1 protein P05023 UNIPROT "up-regulates activity" phosphorylation Ser16 KYEPAAVsEQGDKKG 9606 BTO:0000018 12671055 t miannu "Na,K-ATPase alpha(1) subunit was phosphorylated by PKC in hypoxia-treated AEC. In AEC treated with a PKC-zeta antagonist peptide or with the Na,K-ATPase alpha(1) subunit lacking the PKC phosphorylation site (Ser-18), hypoxia failed to decrease Na,K-ATPase abundance and function." SIGNOR-263181 ARAF protein P10398 UNIPROT MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR up-regulates phosphorylation 9606 21779497 t lperfetto "Active raf phosphorylates mek." SIGNOR-244809 GRK7 protein Q8WTQ7 UNIPROT GRK7 protein Q8WTQ7 UNIPROT unknown phosphorylation Ser490 YAKDIAEiDDFSEVR 9606 15946941 t Manara "In the absence of PKA, GRK1 and GRK7 are autophosphorylated | The mutants, S490A-GRK7 and S490E-GRK7, do not undergo autophosphorylation, indicating that Ser490 is the only autophosphorylation site in GRK7" SIGNOR-260838 CLTB protein P09497 UNIPROT "AP-1/clathrin vescicle" complex SIGNOR-C251 SIGNOR "form complex" binding 9606 23103167 t lperfetto "Clathrin-coated pits and vesicles are diffraction-limited objects with typical diameters ranging between 75 and 130 nm. The smaller ∼75 nm coats contain at least 36 copies of clathrin, a heterohexameric protein of three heavy chains and three light chains, and about half that number of copies of the heterotetrameric AP adaptor complex | Intracellular clathrin-coated vesicles contain AP1 or AP3 adaptors" SIGNOR-260677 MAP4K5 protein Q9Y4K4 UNIPROT GSK3B/Axin/APC complex SIGNOR-C110 SIGNOR "down-regulates activity" phosphorylation 9606 16914735 t lperfetto "Gckr can phosphorylate an n-terminal recombinant fusion protein of gsk3beta and enhance the in vivo phosphorylation of gsk3beta on serine 9reduction of gckr expression inhibits wnt3a-induced phosphorylation of gsk3beta at serine 9 and decreases the accumulation of cytosolic _-catenin." SIGNOR-228006 PCK2 protein Q16822 UNIPROT phosphonatoenolpyruvate smallmolecule CHEBI:58702 ChEBI "up-regulates quantity" "chemical modification" 9606 24632615 t miannu "Phosphoenolpyruvate carboxykinase (PEPCK, EC 4.1.1.32) is a key enzyme of gluconeogenesis. Two isoforms exist, a cytoplasmic form (PCK1, PEPCK-C) and a mitochondrial isoform (PCK2, PEPCK-M). PEPCK activity is present at significant levels in the liver, but also in the kidney and in brown and white adipose tissue. PEPCK, which converts oxaloacetate (OAA) to PEP, has an important role in glucose formation, but also for the generation of glycerol and serine." SIGNOR-266557 PRKCA protein P17252 UNIPROT KIT protein P10721 UNIPROT down-regulates phosphorylation Ser741 TKADKRRsVRIGSYI 9606 7539802 t miannu "Phosphorylation of kit/scfr by pkc-_ in vitro: identification of ser-741 and ser-746 as the major phosphorylation sites for pkc / pkc, which acts in an scf-stimulated feedback loop, that negatively controls kit/scfr kinase activity" SIGNOR-28601 TUFM protein P49411 UNIPROT ATG5 protein Q9H1Y0 UNIPROT "down-regulates activity" binding 9606 33113344 t miannu "PINK1 interacts with the autophagy effector TUFm and phosphorylates TUFm at Ser222. These results indicated that p222-hTUFm sequestered more monomer Atg5 and reduced the conjugated Atg5-Atg12 complex to subdue mitophagy." SIGNOR-266383 IMPDH2 protein P12268 UNIPROT MKI67 protein P46013 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 30518405 f miannu "We further demonstrated that IMPDH2 overexpression accelerated G1/S phase cell cycle transition by inducing increased expression of cyclin D1 and Ki-67 and downregulation of p21Cip1 and p27Kip1. More importantly, G1/S phase cell cycle transition was triggered by IMPDH2 through activation of AKT activity, downregulation of mTOR and FOXO1 transcriptional activity." SIGNOR-260958 CSNK2A1 protein P68400 UNIPROT TP53 protein P04637 UNIPROT "up-regulates activity" phosphorylation Ser392 FKTEGPDsD 9606 BTO:0000568 10747897 t llicata "Furthermore, we demonstrate that anisomycin- and tumor necrosis factor-alpha-induced phosphorylation of p53 at Ser-392, which is important for the transcriptional activity of this growth suppressor protein, requires p38 MAP kinase and CK2 activities." SIGNOR-250967 GSK3B protein P49841 UNIPROT MAPT protein P10636 UNIPROT "down-regulates activity" phosphorylation Thr498 KTPPAPKtPPSSGEP 9606 BTO:0000590 12387894 t lperfetto "We found that cdk5 phosphorylated tau(441) at Thr-181, Ser-199, Ser-202, Thr-205, Thr-212, Ser-214, Thr-217, Thr-231, Ser-235, Ser-396, and Ser-404, but not at Ser-262, Ser-400, Thr-403, Ser-409, Ser-413, or Ser-422. GSK-3beta phosphorylated all the cdk5-catalyzed sites above except Ser-235." SIGNOR-249351 RPS6KB1 protein P23443 UNIPROT EIF4B protein P23588 UNIPROT up-regulates phosphorylation Ser422 RERSRTGsESSQTGT 9606 15071500 t gcesareni "S6k1/s6k2 specifically phosphorylate ser422 in vitro. Substitution of ser422 with ala results in a loss of activity in an in vivo translation assay, indicating that phosphorylation of this site plays an important role in eif4b function." SIGNOR-123997 Ub:E2 complex SIGNOR-C497 SIGNOR NFX1 protein Q12986 UNIPROT "up-regulates activity" ubiquitination 9606 34199813 t miannu "The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t" SIGNOR-271015 GSK3B protein P49841 UNIPROT MAFB protein Q9Y5Q3 UNIPROT down-regulates phosphorylation 9606 18042454 t miannu "We showed that c-maf and mafb, like mafa, are indeed phosphorylated by gsk-3/ we demonstrated that phosphorylation by gsk-3 is conserved among the large maf proteins. It couples ubiquitination/degradation and transcriptional activation and modulates maf biological activity." SIGNOR-159476 MAPK13 protein O15264 UNIPROT TP53 protein P04637 UNIPROT up-regulates phosphorylation Ser46 AMDDLMLsPDDIEQW 9606 10581258 t gcesareni "In mcf-7 cells, p38 kinase activated p53 more effectively than other members of the ras pathway. p53 and p38 kinase exist in the same physical complex, and co-expression of p38 stabilized p53 protein. In vitro, p38 kinase phosphorylated p53 at ser33 and ser46, a newly identified site." SIGNOR-72691 PP2B proteinfamily SIGNOR-PF18 SIGNOR PPP1R1A protein Q13522 UNIPROT unknown dephosphorylation 10116 11278334 t "inferred from 70% family members" "In vitro and in vivo studies indicated that phospho-Ser-67 inhibitor-1 was dephosphorylated by protein phosphatases-2A and -2B. | However, inhibitor-1 phosphorylated at Ser-67 was a less efficient substrate for cAMP-dependent protein kinase. These results demonstrate regulation of a Cdk5-dependent phosphorylation site in inhibitor-1 and suggest a role for this site in modulating the amplitude of signal transduction events that involve cAMP-dependent protein kinase activation." SIGNOR-269991 TPO protein P07202 UNIPROT 3,3',5'-triiodothyronine smallmolecule CHEBI:28774 ChEBI "up-regulates quantity" "chemical modification" 9606 28153798 t scontino "The synthesis of T3 and T4 is achieved through the transfer of an iodophenoxyl group from a MIT or DIT residue called a ‚Äúdonor‚Äù onto a DIT residue called an ‚Äúacceptor‚Äù. TPO seems to be primarily responsible for catalyzing the oxidations of iodotyrosines." SIGNOR-267039 EEF1A2 protein Q05639 UNIPROT Ile-tRNA(Ile) smallmolecule CHEBI:29160 ChEBI up-regulates relocalization 9606 23699257 t lperfetto "During protein synthesis, eEF1A binds to and delivers aminoacylated tRNAs (aa-tRNAs) to the elongating ribosome (Fig. 1). GTP bound to eEF1A is hydrolyzed upon codon-anticodon match between an aa-tRNA in the A site of the ribosome and mRNA bound to the ribosome." SIGNOR-269532 SARS1 protein P49591 UNIPROT tRNA(Ser) smallmolecule CHEBI:29179 ChEBI "down-regulates quantity" "chemical modification" 9606 24095058 t miannu "As a member of the aminoacyl-tRNA synthetase family, seryl-tRNA synthetase (SerRS) catalyzes the aminoacylation reaction that charges serine onto its cognate tRNA for protein synthesis" SIGNOR-270493 CASP3 protein P42574 UNIPROT PARP1 protein P09874 UNIPROT "down-regulates activity" cleavage 10090 BTO:0000331 11907276 t amattioni "Caspase-3 cleaves parp-1. During cd95-mediated apoptosis proteolytic inactivation of parp-1 by caspases prevents atp depletion and thereby ensures the execution of the apoptotic process" SIGNOR-116178 CSNK2A2 protein P19784 UNIPROT BID protein P55957 UNIPROT "up-regulates activity" phosphorylation Thr59 EGYDELQtDGNRSSH 9606 BTO:0000567 11583622 t llicata "Here we report that Bid is phosphorylated by casein kinase I (CKI) and casein kinase II (CKII). Inhibition of CKI and CKII accelerated Fas-mediated apoptosis and Bid cleavage, whereas hyperactivity of the kinases delayed apoptosis. | These results suggest that residues S61, S64, and to a much lesser extent T58 are sites of phosphorylation of Bid." SIGNOR-250979 PRKAA1 protein Q13131 UNIPROT TP53 protein P04637 UNIPROT up-regulates phosphorylation Ser15 PSVEPPLsQETFSDL 9606 SIGNOR-C15 15866171 t gcesareni "Ampk activation induces phosphorylation of p53 on serine 15, and this phosphorylation is required to initiate ampk-dependent cell-cycle arrest" SIGNOR-135960 GFI1 protein Q99684 UNIPROT CYP27B1 protein O15528 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 15947108 f miannu "Identification of growth factor independent-1 (GFI1) as a repressor of 25-hydroxyvitamin D 1-alpha hydroxylase (CYP27B1) gene expression in human prostate cancer cells." SIGNOR-254205 UMPS protein P11172 UNIPROT "orotic acid" smallmolecule CHEBI:16742 ChEBI "down-regulates quantity" "chemical modification" 9606 18020427 t miannu "Orotate phosphoribosyltransferase (OPRTase, EC 2.4.2.10) catalyzes the Mg2+-dependent condensation of orotic acid (OA) with PRPP (5-alpha-d-phosphorylribose 1-diphosphate) to yield diphosphate (PPi) and the nucleotide OMP (orotidine 5'-monophosphate)." SIGNOR-253580 "5-benzoyl-2,3-dihydro-1H-pyrrolizine-1-carboxylic acid" chemical CHEBI:76223 ChEBI PTGS2 protein P35354 UNIPROT "down-regulates activity" "chemical inhibition" -1 22091869 t Luana " Here we report the application of STD-NMR to characterize the binding of the anti-inflammatory drugs ibuprofen, diclofenac, and ketorolac to COX-1 and COX-2. " SIGNOR-258324 PHKG1 protein Q16816 UNIPROT MAPT protein P10636 UNIPROT "down-regulates activity" phosphorylation Ser554 RTPPKSPsSAKSRLQ -1 8999860 t miannu "Muscle phosphorylase kinase phosphorylates Ser237, Ser262, Ser285, Ser305, and Ser352 of human tau. in vitro phosphorylation of tau on Ser262 alone strongly reduced the ability of tau to bind microtubules whereas the phosphorylation of many Ser/Thr-Pro motif sites of tau showed moderate effects on the binding of tau to microtubules" SIGNOR-250283 MBTPS1 protein Q14703 UNIPROT CREB3L1 protein Q96BA8 UNIPROT up-regulates cleavage 9606 16417584 t miannu "Cleavage of oasis by site-1 and site-2 proteases / oasis is cleaved at the membrane under er stress conditions and that its cleaved n-terminal domain translocates into the nucleus;and then activates transcription of target genes" SIGNOR-143785 SMURF1 protein Q9HCE7 UNIPROT CUEDC1 protein Q9NWM3 UNIPROT unknown ubiquitination -1 20804422 t miannu "Recombinant proteins were used to profile substrate ubiquitination by the Smurf1 ubiquitin ligase on a global scale using protein microarrays. T Proteins ubiquitinated on the protein microarray were confirmed as potential substrates of the Smurf1 activity using an off chip in vitro ubiquitination assay." SIGNOR-272682 TLRs proteinfamily SIGNOR-PF20 SIGNOR Immune_response phenotype SIGNOR-PH17 SIGNOR up-regulates 9606 20404851 f lperfetto "The negative regulation of TLR-induced responses is important for sup- pressing inflammation and deleterious immune responses." SIGNOR-216304 GNRH1 protein P01148 UNIPROT EGR1 protein P18146 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 19106114 f miannu "GNRH1 induces expression of early growth response 1 (EGR1), which interacts with steroidogenic factor 1 (SF1) and paired-like homeodomain transcription factor 1 (PITX1) to regulate Lhb promoter activity." SIGNOR-254917 MAP4K1 protein Q92918 UNIPROT MAP3K7 protein O43318 UNIPROT up-regulates 9606 10224067 f gcesareni "These studies establish that hpk1 acts as an upstream activator for the tak1-sek-jnk1 module in relaying the tgf-_ signal into the nuclei in 293t cells." SIGNOR-67321 MAPK13 protein O15264 UNIPROT EEF2K protein O00418 UNIPROT "down-regulates activity" phosphorylation Ser359 GTEEKCGsPQVRTLS 9606 BTO:0000887;BTO:0001103 11500363 t lperfetto "Sapk4/p38delta phosphorylated eef2k at ser359 in vitro, causing its inactivation." SIGNOR-109703 NCOR2 protein Q9Y618 UNIPROT BCL6 protein P41182 UNIPROT "up-regulates activity" binding 9606 BTO:0000007 10898795 t miannu "The POZ domains of BCL-6 and several other POZ proteins interact with corepressors N-CoR and SMRT." SIGNOR-252240 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR "down-regulates activity" phosphorylation 9606 BTO:0000007 10567369 t lperfetto "An ERK2-binding site at the N terminus of MEK1 was reported to mediate their stable association. We examined the importance of this binding site in the feedback phosphorylation of mek1 on thr(292) and thr(386) by erk2" SIGNOR-244858 Gbeta proteinfamily SIGNOR-PF4 SIGNOR PPP2R5C protein Q13362 UNIPROT down-regulates phosphorylation 9606 16456541 t "inferred from 70% family members" gcesareni "Iex-1 binds to b56 subunits and perk independently, enhances b56 phosphorylation by erk at a conserved ser/pro site in this complex and triggers dissociation from the catalytic subunit." SIGNOR-270101 SMAD7 protein O15105 UNIPROT TAB2 protein Q9NYJ8 UNIPROT up-regulates binding 9606 BTO:0001253 17384642 t lperfetto "The formation of smad7-tab2 and smad7-tab3 complexes resulted in the suppression of tnf signaling" SIGNOR-153917 "AIIB/b3 integrin" complex SIGNOR-C173 SIGNOR FGA protein P02671 UNIPROT "up-regulates activity" binding 9606 BTO:0000132 16418530 t lperfetto "In response to agonist stimulation, the αIIbβ3 integrin on platelets is converted to an active conformation that binds fibrinogen and mediates platelet aggregation." SIGNOR-253359 midostaurin chemical CHEBI:63452 ChEBI FLT3 protein P36888 UNIPROT "down-regulates activity" "chemical inhibition" -1 12124173 t "PKC412 is a potent inhibitor of mutant FLT3 and is a candidate for testing as an antileukemia agent in AML patients with mutant FLT3 receptors." SIGNOR-256308 LRRFIP1 protein Q32MZ4 UNIPROT EGFR protein P00533 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 10090 BTO:0000944 14522076 t Luana "GC-binding factor 2 (GCF2) is a transcriptional repressor that decreases activity of the epidermal growth factor receptor (EGFR) and other genes. |Deletion mutants of GCF2 revealed that amino acids 429–528 are required for both DNA binding and repression of the EGFR promoter." SIGNOR-266057 SYNE3 protein Q6ZMZ3 UNIPROT "LINC complex" complex SIGNOR-C303 SIGNOR "form complex" binding 24481844 t lperfetto "LINC complex couples the nuclear lamina to the cytoskeleton. SUN domain proteins, SUN1 and SUN2, located at the inner nuclear membrane (INM) interact with the nuclear lamins, Lamin A/C, B1, and B2, that line the nucleoplasmic face of the INM. SUN domain proteins interact with Nesprins in the perinuclear space (PNS). Nesprins protrude from the outer nuclear membrane (ONM) and interact with the cytoskeleton, often through an intermediate binding partner. Nesprin 1 giant (g) and Nesprin 2g potentially link the NE directly to the Z-disc (Z), whereas Nesprin 1alpha and 2alpha may connect via an unknown intermediate protein. In addition, the shorter isoforms of Nesprin 1 and Nesprin 2 may localize to the INM." SIGNOR-263284 MAML1 protein Q92585 UNIPROT MEF2C protein Q06413 UNIPROT up-regulates binding 9606 16510869 t gcesareni "Unexpectedly, however, emerging evidence implicate maml proteins as exciting key transcriptional co-activators in other signal transduction pathways including: muscle differentiation and myopathies (mef2c), tumor suppressor pathway (p53) and colon carcinoma survival (beta-catenin)." SIGNOR-144913 SH3RF1 protein Q7Z6J0 UNIPROT RAC2 protein P15153 UNIPROT up-regulates binding 9606 9482736 t gcesareni "Posh interacts with the gtp form of rac but not the gdp form" SIGNOR-55811 PF-5274857 chemical CID:56956240 PUBCHEM SMO protein Q99835 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-206058 PRKCA protein P17252 UNIPROT NOX5 protein Q96PH1 UNIPROT up-regulates phosphorylation Thr540 KRLSRSVtMRKSQRS 9606 24505490 t llicata "A constitutively active form of pkc? Robustly increased basal and pma-stimulated nox5 activity and promoted the phosphorylation of nox5 on ser490, thr494, and ser498." SIGNOR-204554 SUFU protein Q9UMX1 UNIPROT SAP18 protein O00422 UNIPROT up-regulates binding 9606 11960000 t gcesareni "Here we report that the mouse homolog of su(fu) [msu(fu)] specifically interacts with sap18, a component of the msin3 and histone deacetylase complex. In addition, we demonstrate that msu(fu) functionally cooperates with sap18 to repress transcription by recruiting the sap18-msin3 complex to promoters containing the gli-binding element." SIGNOR-117311 NPTX1 protein Q15818 UNIPROT BAD protein Q92934 UNIPROT "up-regulates quantity" 9606 BTO:0004168;BTO:0003227 31113871 f lperfetto "We found that the protein levels of BCL2-associated agonist of cell death (BAD) and BCL2-associated X protein (BAX) were increased in NPTX1-overexpressing SMMC-7721 and MHCC-97h cells relative to control cells. In contrast, decreased levels of myeloid cell leukemia sequence 1 (Mcl-1) and B-cell lymphoma-2 (Bcl-2) were found in NPTX1-overexpressing SMMC-7721 and MHCC-97h cells relative to control" SIGNOR-260410 PPAT protein Q06203 UNIPROT "Purine biosynthesis" phenotype SIGNOR-PH186 SIGNOR "up-regulates activity" 9606 28029518 f "The first reaction in the de novo purine biosynthetic pathway is the conversion of PRPP to 5-phosphoribosylamine (PRA) by PRPP amidotransferase (PPAT) and is presumed to be rate-limiting." SIGNOR-267188 MST1 protein P26927 UNIPROT MST1R protein Q04912 UNIPROT up-regulates binding 9606 8062829 t gcesareni "P185ron is a tyrosine kinase activated by msp" SIGNOR-31107 TRIM24 protein O15164 UNIPROT TP53 protein P04637 UNIPROT down-regulates ubiquitination 9606 19844164 t miannu "New ring-domain e3-ubiquitin ligase trim24 that targets p53 for degradation" SIGNOR-188726 MAPKAPK5 protein Q8IW41 UNIPROT TP53 protein P04637 UNIPROT up-regulates phosphorylation Ser37 NVLSPLPsQAMDDLM 9606 BTO:0001286 17254968 t llicata "Furthermore, we show that prak activates p53 by direct phosphorylation. prak phosphorylates p53 at ser37" SIGNOR-152847 TULP3 protein O75386 UNIPROT GPR161 protein Q8N6U8 UNIPROT "up-regulates activity" relocalization 10090 23332756 t "Upon knockdown of Tulp3 using siRNA in IMCD3 cells, ciliary localization of Gpr161 was severely reduced" SIGNOR-259938 BMPR1A protein P36894 UNIPROT SMAD1 protein Q15797 UNIPROT up-regulates phosphorylation Ser465 HNPISSVs 9606 9136927 t fspada "Here, we report that bmp receptors phosphorylate and activate smad1 directly. Phosphorylation of smad1 in vivo involves serines in the carboxy-terminal motif ssxs. These residues are phosphorylated directly by a bmp type i receptor in vitro" SIGNOR-249649 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR FOXM1 protein Q08050 UNIPROT up-regulates phosphorylation Thr611 ETLPISStPSKSVLP 9606 19737929 t lperfetto "A conserved phosphorylation site within the forkhead domain of foxm1b is required for its activation by cyclin-cdk1further analysis reveals that the leu-641 residue within an lxl motif is required for the recruitment of the cyclin-cdk complex, and the thr-596 residue is a critical cdk1 phosphorylation site within the activation domain of foxm1b. Cdk-dependent phosphorylation stimulates the foxm1b transcriptional activity" SIGNOR-216837 SNRPF protein P62306 UNIPROT "U1 snRNP complex" complex SIGNOR-C480 SIGNOR "form complex" binding 9606 30765414 t lperfetto "The major spliceosomal building blocks are the U1, U2, U4/U6, and U5 small nuclear ribonucleoproteins (snRNPs). Each consists of a small nuclear RNA (snRNA) (or two, in the case of U4/U6), seven Sm proteins that form a ring (or seven Lsm proteins in the case of U6), and a variable number of snRNP-specific proteins (Fig. 1F) (Will and Lührmann 2011). Under splicing conditions, the U4/U6 and U5 snRNPs form a 25S U4/U6.U5 tri-snRNP, in which the U4 and U6 snRNAs are base-paired, forming a three-way junction." SIGNOR-270682 4-(2-methyl-3-propan-2-yl-4-imidazolyl)-N-(4-methylsulfonylphenyl)-2-pyrimidinamine chemical CHEBI:91419 ChEBI CDK1 protein P06493 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-190176 TNF protein P01375 UNIPROT SCN10A protein Q9Y5Y9 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 BTO:0004102 26112872 f miannu "TNF-α increases Na(+) currents by accelerating the channel activation as well as increasing the expression of VGSCs in a mechanism dependent upon NF-κB and p38 MAPK signal pathways in CNS neurons. TNF-α increased Na(+) currents by accelerating the activation of VGSCs. The threshold for action potential (AP) was decreased and firing rate were increased. VGSCs were up-regulated at both the mRNA and protein levels." SIGNOR-253484 WIF1 protein Q9Y5W5 UNIPROT WNT8A protein Q9H1J5 UNIPROT down-regulates binding 9606 10201374 t gcesareni "Here we describe wnt-inhibitory factor-1 (wif-1), a secreted protein that binds to wnt proteins and inhibits their activities." SIGNOR-66892 SELENOS protein Q9BQE4 UNIPROT DERL1 protein Q9BUN8 UNIPROT "up-regulates activity" binding 9606 BTO:0000567 15215856 t miannu "VIMP mediates p97 binding to hDerlin-1. these data suggest that Derlin-1 and VIMP form a membrane protein complex that serves as a receptor for p97." SIGNOR-261370 CDK13 protein Q14004 UNIPROT CyclinK/CDK13 complex SIGNOR-C38 SIGNOR "form complex" binding 9606 22012619 t miannu "We identified a 70-kda cyclin k (cyck) that binds cdk12 and cdk13 to form two different complexes (cyck/cdk12 or cyck/cdk13) in human cells" SIGNOR-176844 CSNK1D protein P48730 UNIPROT DVL2 protein O14641 UNIPROT up-regulates phosphorylation Ser143 FHPNVSSsHENLEPE 9606 22609948 t lperfetto "Ck1_/__dependent phosphorylation of dvl2 at s143 and t224and that this event is critical to interact with plk1 in early stages of the cell cycle" SIGNOR-197547 PDK1 protein Q15118 UNIPROT PDHA1 protein P08559 UNIPROT down-regulates phosphorylation Ser232 NRYGMGTsVERAAAS -1 7782287 t gcesareni "Sites 1, 2, and 3 in the E1 mutants were phosphorylated either individually or in the presence of the other sites by the dihydrolipoamide acetyltransferase-protein X-E1 kinase indicating a site-independent mechanism of phosphorylation." SIGNOR-32977 CLTA protein P09496 UNIPROT "AP-2/clathrin vescicle" complex SIGNOR-C249 SIGNOR "form complex" binding 9606 24789820 t lperfetto "AP2 adaptor complexes, associated at the membrane with PtdIns(4,5)P2 (PIP2), recruit clathin triskelions to initiate lattice assembly. " SIGNOR-260667 LCK protein P06239 UNIPROT LAT protein O43561 UNIPROT up-regulates phosphorylation Tyr200 SMESIDDyVNVPESG 9606 BTO:0000782 16938345 t gcesareni "Evidence of lat as a dual substrate for lck and syk in t lymphocytes.Lat is a linker protein essential for activation of t lymphocytes. Its rapid tyrosine-phosphorylation upon t cell receptor (tcr) stimulation recruits downstream signaling molecules for membrane targeting and activation." SIGNOR-149182 MED18 protein Q9BUE0 UNIPROT "Core mediator complex" complex SIGNOR-C405 SIGNOR "form complex" binding 9606 28467824 t miannu "Mediator is a multiprotein co-activator that binds the transcription pre-initiation complex (PIC) and regulates RNA polymerase (Pol) II. The Mediator head and middle modules form the essential core Mediator (cMed), whereas the tail and kinase modules play regulatory roles." SIGNOR-266672 AKT1 protein P31749 UNIPROT PIK3R6 protein Q5UE93 UNIPROT "up-regulates activity" phosphorylation Thr607 SHRPREVtVSLRATG 25753393 t lperfetto "P84 forms a negative regulatory complex with p110gamma to control PI3Kgamma signalling during cell migration|However, phosphorylation at this site was confirmed using an in vitro kinase assay in which Akt kinase was shown to readily phosphorylate Thr607 using a p84 peptide (Figure 1e), where Thr607 in conjunction with surrounding residues forms an Akt kinase consensus sequence|In contrast, although p84-T607A exhibited basal p110γ dimerisation, this interaction could not be further induced with stimulation" SIGNOR-275722 MYOD1 protein P15172 UNIPROT VEGFA protein P15692 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 BTO:0001103 18094043 t lperfetto "We further demonstrate that the myogenic transcription factor, MyoD, and its heterodimeric binding proteins E12 and E47, up-regulate the expression of endogenous VEGF through direct interaction with the VEGF promoter." SIGNOR-257598 JUN protein P05412 UNIPROT miR-155 mirna URS000062749E_9606 RNAcentral "up-regulates quantity by expression" "transcriptional regulation" 9606 24708856 t miannu "We found overexpression of miR-155 led to increase in cJUN, FOS and TRIB2, and decrease in MEIS1, GFI1, cMYC and JARID2." SIGNOR-255767 RARB protein P10826 UNIPROT THR proteinfamily SIGNOR-PF84 SIGNOR up-regulates binding 9606 15650024 t "inferred from family member" gcesareni "We report that the retinoic acid receptors (rars), a distinct class of nuclear receptors, are also efficient heterodimer partners for trs" SIGNOR-270299 CYP11B1 protein P15538 UNIPROT 11-deoxycorticosterone smallmolecule CHEBI:16973 ChEBI "down-regulates quantity" "chemical modification" 9606 BTO:0000048 33117906 t lperfetto "The zona glomerulosa lacks the 17alpha-hydroxylase enzyme, committing pregnenolone to the exclusive production of aldosterone.|In the adrenal steroidogenic pathway, 21-hydroxylase (P450c21) catalyzes the conversion of 17-hydroxyprogesterone (17OHP) to 11-deoxycortisol to form cortisol and the conversion of progesterone to 11-deoxycorticosterone to form aldosterone" SIGNOR-268683 HOXD13 protein P35453 UNIPROT EPHA7 protein Q15375 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 16314414 f miannu "We show that hoxd13 andhoxa13activate transcription from the epha7 promoter and that a mutation of thehoxa13/hoxd13 binding site was sufficient to abolish activation." SIGNOR-142453 WASHC1 protein A8K0Z3 UNIPROT "WASH complex" complex SIGNOR-C258 SIGNOR "form complex" binding 23721880 t lperfetto "The WASH complex is composed of five proteins: KIAA1033 (also known as SWIP), Strumpellin, FAM21, WASH1 and CCDC53." SIGNOR-261020 APC-c complex SIGNOR-C150 SIGNOR DTYMK protein P23919 UNIPROT "down-regulates quantity by destabilization" polyubiquitination 9606 BTO:0000567 16103219 t miannu "We demonstrate that TMPK is recognized and degraded by APC/C-Cdc20/Cdh1-mediated pathways from mitosis to the early G1 phase, whereas TK1 is targeted for degradation by APC/C-Cdh1 after mitotic exit. " SIGNOR-272653 TGFBR1 protein P36897 UNIPROT SMAD3 protein P84022 UNIPROT "up-regulates activity" phosphorylation Ser425 SIRCSSVs 10090 BTO:0005493;BTO:0000165 19458083 t lperfetto "A major event leading to Smad3 activation is the TGF-beta-induced, TbetaRI-mediated phosphorylation at two C-terminal serine residues, Ser-423 and Ser-425, which triggers dissociation of Smad3 from its receptors to form a complex with Smad4 and accumulate in the nucleus" SIGNOR-235380 RASGEF1C protein Q8N431 UNIPROT KRAS protein P01116 UNIPROT up-regulates binding 9606 19201597 t gcesareni "Gefs catalyse the transition from gdp-bound, inactive ras to gtp-bound, active ras." SIGNOR-161508 NECTIN2 protein Q92692 UNIPROT CD226 protein Q15762 UNIPROT "up-regulates activity" binding 9606 BTO:0000914 15039383 t lperfetto "CD226 (DNAM-1) is an adhesion molecule involved in NK and T cell-mediated cytotoxicity against certain tumors. Here, we have identified the human poliovirus receptor-related (PRR) family members CD155 [poliovirus receptor (PVR)] and CD112 (nectin-2/PRR-2) as the ligands for human CD226." SIGNOR-261426 somatostatin smallmolecule CHEBI:64628 ChEBI SSTR1 protein P30872 UNIPROT "up-regulates activity" "chemical activation" 9606 BTO:0002524 31160049 t "Ligand-GPCR dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257581 SMAD6 protein O43541 UNIPROT TAB1 protein Q15750 UNIPROT down-regulates binding 9606 11737269 t lpetrilli "Smad6 interacts with tak1 and tab1, and smad7 with tab1. The interaction of i-smads with tak1 and/or tab1 implies that several mechanisms exist underlying the repression of the tak1-p38 kinase pathway by i-smads." SIGNOR-112642 FUBP1 protein Q96AE4 UNIPROT CDKN1A protein P38936 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 19637194 f irozzo "In our analysis of FBP1 shRNA-transduced Hep3B cells, we found that p21 mRNA levels increase following FBP1 knockdown, suggesting that FBP1 functions as a repressor of p21. Our results identify the tumor suppressor p21 as the second direct FBP1 target gene in addition to the proto-oncogene c-myc." SIGNOR-259125 HNF1B protein P35680 UNIPROT UMOD protein P07911 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 18846391 f miannu "UMOD transcription is activated by the transcription factor HNF1B." SIGNOR-254441 "all-trans-retinoic acid" smallmolecule CHEBI:15367 ChEBI TAL2 protein Q16559 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 24816818 f irozzo "These results demonstrate for the first time that atRA induces Tal2 expression in P19 cells, and suggest that TAL2 commits to the acquisition of neural fate in brain development." SIGNOR-259087 SAMM50 protein Q9Y512 UNIPROT "SAM complex" complex SIGNOR-C422 SIGNOR "form complex" binding 31387448 t lperfetto "The SAM complex of the outer membrane mediates insertion of β-barrel proteins into the outer membrane. hSam50 associates with MTX1 and MTX2." SIGNOR-267683 MMP10 protein P09238 UNIPROT ECM_disassembly phenotype SIGNOR-PH80 SIGNOR up-regulates 17318226 f lperfetto "Historically, MMPs were thought to function mainly as enzymes that degrade structural components of the ECM." SIGNOR-272355 MAPK1 protein P28482 UNIPROT PDE4D protein Q08499-2 UNIPROT down-regulates phosphorylation Ser579 YQSTIPQsPSPAPDD 9606 10828059 t "The effect has been demonstrated using Q08499-5" llicata "The pde4d2 isoform is inhibited by erk2 phosphorylation" SIGNOR-77563 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR NME1 protein P15531 UNIPROT up-regulates phosphorylation Ser120 GRNIIHGsDSVESAE 9606 18234856 t lperfetto "Application of this approach to the discovery of cdk1-cyclin b substrates yielded identification of >70 substrates and phosphorylation sites. Many of these sites are known to be phosphorylated in vivo, but most of the proteins have not been characterized as cdk1-cyclin b substrates." SIGNOR-216825 IRF3 protein Q14653 UNIPROT Immune_response phenotype SIGNOR-PH17 SIGNOR up-regulates 9606 12692549 f lperfetto "The transcription factors interferon regulatory factor 3 (IRF3) and NF-B are required for the expression of many genes involved in the innate immune response." SIGNOR-216316 CyclinE/CDK2 complex SIGNOR-C16 SIGNOR MCM3 protein P25205 UNIPROT up-regulates phosphorylation Thr722 EEMPQVHtPKTADSQ 9606 21965652 t lperfetto "In this study, we demonstrate that mcm3 is a substrate of cyclin e/cdk2 and can be phosphorylated by cyclin e/cdk2 at thr-722." SIGNOR-216694 CTCF protein P49711 UNIPROT MYC protein P01106 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 12032779 f miannu "Several different transcription factors have been implicated in the down-regulation of c-myc expression during differentiation, including C/EBPalpha, CTCF, BLIMP-1, and RFX1." SIGNOR-253827 DNMT1 protein P26358 UNIPROT BAG3 protein O95817 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0001109 18413740 f lperfetto "In contrast, an increase in BAG-1, BAG-3, and BAG-4 gene expression was observed in HCT116 cells overexpressing either DNMT1 (DNMT1+) or DNMT3B (DNMT3B+)" SIGNOR-254110 miR-155 mirna URS000062749E_9606 RNAcentral SPI1 protein P17947 UNIPROT "down-regulates quantity by repression" "post transcriptional regulation" 10090 22195016 t "Our results elucidate a negative feedback circuit in which IGF-1-stimulated miR-133 in turn represses IGF-1R expression to modulate the IGF-1R signaling pathway during skeletal myogenesis." SIGNOR-255915 SHMT1 protein P34896 UNIPROT 4-trimethylammoniobutanal smallmolecule CHEBI:18020 ChEBI "up-regulates quantity" "chemical modification" 9606 11802770 t miannu "HTMLA might be identical to serine hydroxymethyltransferase (SHMT; EC 2.1.2.1), since it has been shown that SHMT purified from rabbit liver acts upon HTML, yielding TMABA and glycine." SIGNOR-269688 MKX protein Q8IYA7 UNIPROT RUNX2 protein Q13950 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0001592 33115953 t miannu "MKX is a meniscus-enriched transcription factor. In human meniscus cells, MKX regulates the expression of meniscus marker genes, OA-related genes, and other transcription factors, including Scleraxis (SCX), SRY Box 5 (SOX5), and Runt domain-related transcription factor 2 (RUNX2)." SIGNOR-267215 "prostaglandin E2" smallmolecule CHEBI:15551 ChEBI GNG12 protein Q9UBI6 UNIPROT up-regulates "chemical activation" 9606 16293724 t gcesareni "Although pge2 promotes nucleotide exchange on gas and subsequent dissociation of gtp-bound gas from gbg subunits." SIGNOR-141820 CSNK1D protein P48730 UNIPROT PER1 protein O15534 UNIPROT "down-regulates quantity by destabilization" phosphorylation 10090 11865049 t miannu "We show here that mPer proteins, negative limbs of the autoregulatory loop, are specific substrates for CKIepsilon and CKIdelta. The CKI phosphorylation of mPer1 and mPer3 proteins results in their rapid degradation, which is dependent on the ubiquitin-proteasome pathway." SIGNOR-267999 RDH5 protein Q92781 UNIPROT retinol smallmolecule CHEBI:50211 ChEBI "down-regulates quantity" "chemical modification" 9606 21621639 t lperfetto "Currently, at least three RDH seem physiologically involved in converting all-trans-retinol into all-trans-retinal: RDH1, RDH10 and DHRS10" SIGNOR-265113 PRKACA protein P17612 UNIPROT IRS1 protein P35568 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser1100 QGCRRRHsSETFSST 9606 17360977 t lperfetto "Tyrosine phosphorylation of IRS-1 initiates insulin signaling, whereas serine/threonine phosphorylation alters the ability of IRS-1 to transduce the insulin signalInsulin increased the phosphorylation of Ser312, Ser616, Ser636, Ser892, Ser1101, and Ser1223" SIGNOR-235675 RPS6K proteinfamily SIGNOR-PF26 SIGNOR RPTOR protein Q8N122 UNIPROT up-regulates phosphorylation Ser719 PCTPRLRsVSSYGNI 9606 SIGNOR-C3 18722121 t llicata "Ser719, ser721, and ser722 are the predominant rsk-dependent phosphorylation sites in raptor raptor phosphorylation regulates mtorc1 activity" SIGNOR-252772 MAP2K4 protein P45985 UNIPROT MAPK8 protein P45983 UNIPROT "up-regulates activity" phosphorylation Tyr185 TSFMMTPyVVTRYYR 9606 BTO:0000007 9724739 t gcesareni "MKK4/7, in turn, phosphorylates JNK on residues 183 and 185 (17ƒ‚€“20). Activated JNK phosphorylates its substrates, c-Jun, ATF2, ELK1, and p53" SIGNOR-249654 PTPN2 protein P17706 UNIPROT STAT5A protein P42229 UNIPROT "down-regulates activity" dephosphorylation 9606 15780598 t lperfetto "Upon ligand binding, IL-2R , IL-6R or LeptinR , IFN-_R , IFN-_R and PRLR or growth hormone (GH) receptor associated JAKs become activated. These JAKs mediate phosphorylation of specific tyrosine residues and recruit STATs. Activated STATs are released from the receptor and translocate to the nucleus. PTP1B dephosphorylates JAK2, TYK2 and STAT5 . The 45-kDa form of TC-PTP was shown to dephosphorylate JAK1 and JAK3 as well as STAT1, STAT3 and STAT5." SIGNOR-133547 AKT1 protein P31749 UNIPROT ZYX protein Q15942 UNIPROT down-regulates phosphorylation Ser142 PQPREKVsSIDLEID 9606 17572661 t llicata "Akt binds and phosphorylates zyxin on serine 142, leading to its association with acinus zyxin is a substrate of caspases, but akt phosphorylation fails to protect its proteolytic degradation" SIGNOR-156122 ING3 protein Q9NXR8 UNIPROT "NuA4 complex" complex SIGNOR-C459 SIGNOR "form complex" binding 9606 14966270 t miannu "NuA4 (for nucleosome acetyltransferase of H4) is a 12-subunit HAT complex responsible for acetylation of histone H4 and H2A N-terminal tails." SIGNOR-269294 AURKB protein Q96GD4 UNIPROT RACGAP1 protein Q9H0H5 UNIPROT "up-regulates activity" phosphorylation Ser387 ETGLYRIsGCDRTVK 9606 BTO:0000567 12689593 t lperfetto "We also report that aurora b phosphorylates mgcracgap on serine residues and that this modification induces latent gap activity toward rhoa in vitro." SIGNOR-100569 CDK1 protein P06493 UNIPROT PBK protein Q96KB5 UNIPROT unknown phosphorylation Thr9 EGISNFKtPSKLSEK 9606 SIGNOR-C17 15541388 t llicata "Topk-thr-9 was phosphorylated by cdk1/cyclin b and topk significantly associates with mitotic spindles." SIGNOR-130439 AMPA proteinfamily SIGNOR-PF58 SIGNOR calcium(2+) smallmolecule CHEBI:29108 ChEBI "up-regulates quantity" relocalization 9606 29953871 t miannu "Ca2+ is arguably the most important second messenger in the brain because of its pivotal roles in presynaptic neurotransmitter release, postsynaptic responses, and plasticity induction. iGluRs and mGluRs can generate intracellular Ca2+ signals, albeit by different mechanisms, whose crosstalk has not been thoroughly explored (Figure 2C). iGluRs allow the influx of extracellular Ca2+ upon pore opening. This is widely acknowledged for NMDARs, which have a high Ca2+ conductance, but Ca2+ flux through AMPARs and KARs can still be substantial." SIGNOR-264941 PTPN1 protein P18031 UNIPROT GHR protein P10912 UNIPROT "down-regulates activity" dephosphorylation Tyr534 NFLMDNAyFCEADAK 10029 12907755 t "PTPH1 only bound Tyr534, whereas PTP1B and TC-PTP bound multiple phosphopeptides. Earlier work suggests that Tyr332, Tyr487, Tyr534, Tyr566, and Tyr627 are all phosphorylated after GH stimulation (21). Apart from Tyr627, all of these also appear good PTP substrates" SIGNOR-248420 RAGAC complex SIGNOR-C113 SIGNOR MTOR protein P42345 UNIPROT "up-regulates activity" relocalization 9606 BTO:0000007 SIGNOR-C3 20381137 t lperfetto "The Rag GTPases interact with mTORC1 and are proposed to activate it in response to amino acids by promoting mTORC1 translocation to a membrane-bound compartment that contains the mTORC1 activator, Rheb" SIGNOR-228657 RET protein P07949 UNIPROT MAPK14 protein Q16539 UNIPROT up-regulates phosphorylation Thr180 RHTDDEMtGYVATRW 9606 17126298 t gcesareni "Dually phosphorylated on thr-180 and tyr-182 by the map2ks map2k3/mkk3, map2k4/mkk4 and map2k6/mkk6 in response to inflammatory citokines, environmental stress or growth factors, which activates the enzyme." SIGNOR-150875 CDK2 protein P24941 UNIPROT CEBPB protein P17676 UNIPROT up-regulates phosphorylation Thr235 SSSSPPGtPSPADAK 9606 SIGNOR-C83 22369944 t fspada "Mass spectrometric analysis revealed that cdk2/cyclina phosphorylates c/ebpbeta on thr(188) and is required for phosphorylation (on ser(184) or thr(179)) of c/ebpbeta by gsk3beta and maintenance of dna binding activity." SIGNOR-196372 MAPK8 protein P45983 UNIPROT MAPK9 protein P45984 UNIPROT up-regulates phosphorylation 9606 17525747 t gcesareni "Our studies revealed a novel mechanism in which phosphorylation of jnk2 is mediated by jnk1 before phosphorylation of p53, and then p53 is directly phosphorylated by jnk2 at ser6." SIGNOR-155205 ROBO proteinfamily SIGNOR-PF14 SIGNOR ATF2 protein P15336 UNIPROT up-regulates phosphorylation Thr71 IVADQTPtPTRFLKN 9606 15916964 t lperfetto "Phosphorylation of atf2 by jnk/p38 on thr69/71 is prerequisite to its transcriptional activities" SIGNOR-137639 CBP/p300 complex SIGNOR-C6 SIGNOR MYOD1 protein P15172 UNIPROT up-regulates acetylation 9606 BTO:0000887 10944526 t lperfetto "Our results provide direct evidence that myod acetylation functionally activates the protein and show that both pcaf and cbp/p300 are candidate enzymes for myod acetylation in vivo." SIGNOR-217220 GATA1 protein P15976 UNIPROT GATA1 protein P15976 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 12432220 f irozzo "Furthermore, GATA-1 has been shown to auto-regulate its own gene expression." SIGNOR-256057 HARS1 protein P12081 UNIPROT AMP smallmolecule CHEBI:456215 ChEBI "up-regulates quantity" "chemical modification" 9606 10430027 t miannu "Histidyl-tRNA synthetase (HisRS) is responsible for the synthesis of histidyl-transfer RNA, which is essential for the incorporation of histidine into proteins. This amino acid has uniquely moderate basic properties and is an important group in many catalytic functions of enzymes." SIGNOR-270489 STAT5A protein P42229 UNIPROT PIM proteinfamily SIGNOR-PF34 SIGNOR "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0004479 29507660 f irozzo "FLT3-ITD is the most frequent tyrosine kinase mutation in acute myeloid leukemia (AML) associated with poor prognosis. We previously reported that activation of STAT5 confers resistance to PI3K/Akt inhibitors on the FLT3-ITD-positive AML cell line MV4-11 and 32D cells driven by FLT3-ITD (32D/ITD) but not by FLT3 mutated in the tyrosine kinase domain (32D/TKD). Here, we report the involvement of Pim kinases expressed through STAT5 activation in acquisition of this resistance." SIGNOR-255733 SKIL protein P12757 UNIPROT SMAD1 protein Q15797 UNIPROT down-regulates binding 9606 SIGNOR-C85 12419246 t gcesareni "Ski also represses bmp signaling through interactions with smad4 and bmp-specific r-smads, smad1 or smad7" SIGNOR-195636 EGFR protein P00533 UNIPROT EGFR protein P00533 UNIPROT "up-regulates activity" phosphorylation Tyr1016 DVVDADEyLIPQQGF 9606 BTO:0000567 10653583 t "Dimerization mediated by a beta hairpin, which protudes from the S1 domains of each ligand bound monomer" lperfetto "After binding of epidermal growth factor (EGF), the EGF receptor (EGFR) becomes autophosphorylated via tyrosine." SIGNOR-236475 PTK2 protein Q05397 UNIPROT PTK2 protein Q05397 UNIPROT up-regulates phosphorylation Tyr861 PIGNQHIyQPVGKPD 9606 BTO:0000671 15694384 t llicata "Once stimulated, fak undergoes autophosphorylation at tyrosine (y) 397, followed by phosphorylation of several sites including y576/y577 which increases fak's kinase activity, as well as at y407, y861, and y925." SIGNOR-133849 CDK1 protein P06493 UNIPROT PAPOLA protein P51003 UNIPROT "up-regulates activity" phosphorylation Ser545 PTSATKTsPLNSSGS 10090 BTO:0000964 34048556 t lperfetto "Once an oocyte resumes meiosis, activated CDK1 and ERK1/2 cooperatively mediate the phosphorylation of three serine residues of PAPalpha, 537, 545 and 558, thereby leading to increased activity." SIGNOR-268339 CDK1 protein P06493 UNIPROT BIRC5 protein O15392 UNIPROT up-regulates phosphorylation Thr34 FLEGCACtPERMAEA 9606 11861764 t gcesareni "Survivin is a member of the inhibitor of apoptosis gene family that has been implicated in both apoptosis inhibition and regulation of mitosisin synchronized cultures, cytosolic survivin abruptly increased at mitosis, physically associated with p34(cdc2), and was phosphorylated by p34(cdc2) on thr(34), in vivo" SIGNOR-115129 AMER1 protein Q5JTC6 UNIPROT GSK3B/Axin/APC complex SIGNOR-C110 SIGNOR "up-regulates activity" relocalization 9606 21304492 t lperfetto "Amer1 binds ck1gamma, recruits axin and gsk3beta to the plasma membrane and promotes complex formation between axin and lrp6." SIGNOR-227991 DCAF1 protein Q9Y4B6 UNIPROT EDVP complex SIGNOR-C530 SIGNOR "form complex" binding 9606 BTO:0000007 19287380 t miannu "We named this E3 ligase complex containing EDD, DDB1 and VPRBP proteins as EDVP complex to distinguish it from the previously identified Cul4-Roc1-DDB1-VPRBP E3 ligase complex. " SIGNOR-271789 CSNK2A1 protein P68400 UNIPROT PTEN protein P60484 UNIPROT "down-regulates activity" phosphorylation Thr366 ASSSTSVtPDVSDNE -1 12297295 t llicata "We used mass spectrometric methods to identify Ser(370) and Ser(385) as in vivo phosphorylation sites of PTEN. These sites also are phosphorylated by CK2 in vitro, and phosphorylation inhibits PTEN activity towards its substrate, PIP3. We also identify a novel in vivo phosphorylation site, Thr(366). " SIGNOR-250940 PRKCD protein Q05655 UNIPROT PLSCR3 protein Q9NRY6 UNIPROT up-regulates phosphorylation Thr21 PPPPYPVtPGYPEPA 9606 16267027 t gcesareni "Ad198-activated pkc-delta induces phosphorylation of mitochondrial pls3 at thr21;pls3 is a critical downstream effector of pkc-delta in ad198-induced apoptosis." SIGNOR-140759 FANCG protein O15287 UNIPROT SPTAN1 protein Q13813 UNIPROT "up-regulates quantity by stabilization" 9606 BTO:0000773 19102630 t lperfetto "In FA cells, deficiencies in FA proteins lead to decreased stability of alphaRIISp |These results demonstrate that one of the FA proteins, FANCG, contains a motif that interacts directly with the SH3 domain of alphaIISp. We propose that this binding of FANCG to alphaIISp may be important for the stability of alphaIISp in cells and the role alphaIISp plays in the DNA repair process.|" SIGNOR-263275 FGF13 protein Q92913 UNIPROT SCN10A protein Q9Y5Y9 UNIPROT "down-regulates activity" binding 9606 BTO:0000938 20679355 t miannu "Sodium channel fast inactivation is modulated by alpha subunit interaction with a family of cytoplasmic proteins termed fibroblast growth factor homologous factors (FHFs). In this paper, we report that all A-type FHFs exert rapid onset long-term inactivation on Nav1.6 and other sodium channels." SIGNOR-253439 "Class II MHC:Antigen" complex SIGNOR-C429 SIGNOR TCR complex SIGNOR-C153 SIGNOR "up-regulates activity" binding 9606 31001252 t scontino "The interaction of T-cell receptors (TCRs) with self- and non-self-peptides in the major histocompatibility complex (MHC) stimulates crucial signaling events, which in turn can activate T lymphocytes." SIGNOR-267992 PRKACA protein P17612 UNIPROT EEF2K protein O00418 UNIPROT "up-regulates activity" phosphorylation Ser500 RLHLPRAsAVALEVQ -1 11171059 t miannu "EEF-2K can be phosphorylated in vitro by cAMP-dependent protein kinase (PKA) and that this induces significant Ca(2+)/calmodulin (CaM)-independent eEF-2K activity. sites of phosphorylation were Ser-365 and Ser-499" SIGNOR-250444 CHRM2 protein P08172 UNIPROT GNAO1 protein P09471 UNIPROT up-regulates 9606 BTO:0000007 12665513 f lperfetto "Here we show that m2 muscarinic receptors and go require taos and mek3/6 as the primary intermediates activating p38 mapk in 293 cells" SIGNOR-235536 MAP3K7 protein O43318 UNIPROT KSR1 protein Q8IVT5 UNIPROT down-regulates phosphorylation Ser406 TRLRRTEsVPSDINN 9606 11741534 t gcesareni "C-tak1 constitutively associates with mammalian ksr1 and phosphorylates serine 392 to confer 14-3-3 binding and cytoplasmic sequestration of ksr1 in unstimulated cells. In response to signal activation, the phosphorylation state of s392 is reduced, allowing the ksr1 complex to colocalize with activated ras and raf-1 at the plasma membrane" SIGNOR-112779 PIAS3 protein Q9Y6X2 UNIPROT SMAD3 protein P84022 UNIPROT "up-regulates activity" binding 9606 14691252 t lperfetto "We have further shown that PIAS3, Smad3, and p300 can form a ternary complex, which is significantly increased by TGF-_ treatment. Taken together, these results suggest that PIAS3 stimulates Smad transcriptional activity through formation of a complex with Smad proteins and p300/CBP." SIGNOR-217725 DPYD protein Q12882 UNIPROT thymine smallmolecule CHEBI:17821 ChEBI "down-regulates quantity" "chemical modification" 10499634 t "Dihydropyrimidine dehydrogenase (DPD) is responsible for degradation of the pyrimidines uracil and thymine and the inactivation of the chemotherapeutic agent 5-fluorouracil. DPD activity is highly variable in cancer populations, and this variation may influence the antitumor efficacy of 5-fluorouracil." SIGNOR-253989 ASPA protein P45381 UNIPROT N-acetyl-L-aspartate(2-) smallmolecule CHEBI:16953 ChEBI "down-regulates quantity" "chemical modification" 9606 17194761 t miannu "N-acetyl-l-aspartate (NAA) is one of the most abundant amino acid derivatives found in the vertebrate brain, second only to glutamate. Aspartoacylase catalyzes hydrolysis of N-acetyl-l-aspartate to aspartate and acetate in the vertebrate brain." SIGNOR-267526 BIRC7 protein Q96CA5 UNIPROT DIABLO protein Q9NR28 UNIPROT down-regulates binding 9606 BTO:0000848 15485396 t gcesareni "These results suggest that ml-iap might regulate apoptosis by sequestering smac and preventing it from antagonizing xiap-mediated caspases, rather than by direct caspases." SIGNOR-129869 PPP3CA protein Q08209 UNIPROT IL6 protein P05231 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 18177723 f lperfetto "Interestingly, since IL-6 production by nerve-mediated skeletal muscle contraction has recently been shown to be partly dependent on the activation of the calcineurin pathway |The fact that IL-6 is produced not only by proliferating satellite cells but also by growing myofibers during hypertrophy" SIGNOR-251733 GRK2 protein P25098 UNIPROT OPRD1 protein P41143 UNIPROT "down-regulates activity" phosphorylation Ser363 RVTACTPsDGPGGGA 9606 BTO:0000007 11040053 t gcesareni "Taken together, we have demonstrated that agonist-induced opioid receptor phosphorylation occurs exclusively at two phosphate acceptor sites (T358 and S363) of GRK2 at the DOR carboxyl terminus." SIGNOR-249660 SP1 protein P08047 UNIPROT SP1/STAT3 complex SIGNOR-C74 SIGNOR "form complex" binding 9606 19723038 t miannu "Sp1 and stat3 seem to synergistically augment renalase transcription." SIGNOR-187790 KAT2B protein Q92831 UNIPROT P300/PCAF complex SIGNOR-C7 SIGNOR "form complex" binding 9606 21131905 t lperfetto "Histone acetyltransferases (hats) gcn5 and pcaf (gcn5/pcaf) and cbp and p300 (cbp/p300) are transcription co-activators." SIGNOR-170276 "phosphatidic acid" smallmolecule CHEBI:16337 ChEBI "long-chain fatty acid anion" smallmolecule CHEBI:57560 ChEBI "up-regulates quantity" "precursor of" 9606 22922100 t miannu "Members of the intracellular phospholipase A1 family of proteins have been implicated in organelle biogenesis and membrane trafficking. The mammalian family comprises three members: phosphatidic acid-preferring phospholipase A1 (PA-PIA1)/DDHD1, p125/Sec23ip and KIAA0725p/DDHD2, all of which have a DDHD domain." SIGNOR-269658 nepicastat chemical CHEBI:139334 ChEBI DBH protein P09172 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-194625 EEF2K protein O00418 UNIPROT EEF2K protein O00418 UNIPROT down-regulates phosphorylation Ser445 SGDSGYPsEKRGELD 9606 22669845 t gcesareni "The combination of eef2k autophosphorylation (targeting ser445) and a yet to be identified kinase (targeting ser441) would be needed to generate the eef2k phosphodegron specifically in response to dna damage." SIGNOR-197725 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR SMAD2 protein Q15796 UNIPROT up-regulates phosphorylation Thr220 QSNYIPEtPPPGYIS 9606 BTO:0000763 12193595 t lperfetto "Phosphorylation of smad2 by erk increases its transcriptional activity /thr220 and ser245, ser250, and ser255 were possible phosphorylation sites. The phosphorylation of peak a peptide by erk1 is consistent with that prediction." SIGNOR-244731 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR SREBF2 protein Q12772 UNIPROT up-regulates phosphorylation 9606 14988395 t "inferred from 70% family members" lperfetto "Insulin-activated erk-mitogen-activated protein kinases phosphorylate sterol regulatory element-binding protein-2 at serine residues 432 and 455 in vivo.Further characterization by electrophoretic mobility shift assay and promoter reporter gene analyses revealed that phosphorylation does not influence protein/dna interaction, but enhances trans-activity." SIGNOR-270141 IL4R protein P24394 UNIPROT STAT5A protein P42229 UNIPROT up-regulates 9606 20824124 t "Several cytokine receptors share subchains and targets. For example, the common gamma chain (CGC) is shared by IL2, IL4, IL7, IL9 and IL15 receptors that lead to the activation of STAT5" SIGNOR-254298 NLGN4X protein Q8N0W4 UNIPROT NRXN3 protein Q9HDB5 UNIPROT "up-regulates activity" binding 9606 BTO:0000938 18923512 t brain lperfetto "Pre- and postsynaptic plasma membranes are always precisely aligned, and are separated by a synaptic cleft of ~20 nm. The cleft contains an undefined proteinaceous material in the middle, and is presumably bridged by synaptic cell-adhesion molecules such as Nrxns and Nlgns that align the pre- and postsynaptic elements and mediate trans-synaptic signaling.|Nlgns bind to both alpha- and beta-Nrxns with nanomolar affinities; binding involves the sixth LNS-domain of alpha-Nrxns which corresponds to the only LNS-domain of beta-Nrxns52. The binding affinities differ characteristically between various pairs of Nlgns and Nrxns, and are controlled by alternative splicing of both Nrxns and Nlgns (Figure 1c)" SIGNOR-264170 MLN protein P12872 UNIPROT MLNR protein O43193 UNIPROT up-regulates binding 9606 BTO:0000938 10381885 t gcesareni "A heterotrimeric guanosine triphosphate-binding protein (g protein)-coupled receptor for motilin was isolated from human stomach" SIGNOR-68721 GUCY1B2 protein O75343 UNIPROT GUCY1A3-B2 complex SIGNOR-C139 SIGNOR "form complex" binding 9606 10977868 t gcesareni "This enzyme is a heterodimeric protein consisting of - and ²-subunits, and expression of both subunits is required for catalytic activity" SIGNOR-244119 PRKACA protein P17612 UNIPROT GMFB protein P60983 UNIPROT "up-regulates activity" phosphorylation Thr27 KFRFRKEtNNAAIIM -1 9030586 t miannu "Protein kinase A (PKA)-phosphorylated GMF is a potent inhibitor of extracellular signal-regulated kinase (ERK) and enhancer of p38; both are subfamilies of mitogen-activated protein (MAP) kinase, suggesting GMF as a bifunctional regulator of the MAP kinase cascades. PKA is capable of phosphorylating threonine 26 and serine 82." SIGNOR-249984 GATA1 protein P15976 UNIPROT Erythrocyte_differentiation phenotype SIGNOR-PH104 SIGNOR "up-regulates activity" 10090 BTO:0004911 12032775 f "The zinc finger transcription factor GATA-1, a central mediator of erythroid gene expression, interacts with multiple proteins including FOG-1, EKLF, SP1, CBP/p300 and PU.1." SIGNOR-259962 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR DHPS protein P49366 UNIPROT "up-regulates activity" phosphorylation Ser233 KNHIPVFsPALTDGS 9606 BTO:0000007 32989218 t miannu "The Ser-233 phosphorylation of DHPS by ERK1/2 is important for its function in cell proliferation." SIGNOR-266376 CDC14B protein O60729 UNIPROT APC protein P25054 UNIPROT up-regulates dephosphorylation 9606 SIGNOR-C110 18662541 t gcesareni "The phosphatase cdc14b translocates from the nucleolus to the nucleoplasm and induces the activation of the ubiquitin ligase apc/ccdh1" SIGNOR-179636 NLGN2 protein Q8NFZ4 UNIPROT NRXN3 protein Q9HDB5 UNIPROT "up-regulates activity" binding 9606 BTO:0000938 18923512 t brain lperfetto "Pre- and postsynaptic plasma membranes are always precisely aligned, and are separated by a synaptic cleft of ~20 nm. The cleft contains an undefined proteinaceous material in the middle, and is presumably bridged by synaptic cell-adhesion molecules such as Nrxns and Nlgns that align the pre- and postsynaptic elements and mediate trans-synaptic signaling.|Nlgns bind to both alpha- and beta-Nrxns with nanomolar affinities; binding involves the sixth LNS-domain of alpha-Nrxns which corresponds to the only LNS-domain of beta-Nrxns52. The binding affinities differ characteristically between various pairs of Nlgns and Nrxns, and are controlled by alternative splicing of both Nrxns and Nlgns (Figure 1c)" SIGNOR-264171 CHIR-124 chemical CID:11502647 PUBCHEM FLT3 protein P36888 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-190976 SRC protein P12931 UNIPROT KCNJ1 protein P48048 UNIPROT down-regulates phosphorylation Tyr337 SKTKEGKyRVDFHNF 9606 12556363 t flangone "Inhibition of c-src with herbimycin a significantly decreased the tyrosine phosphorylation level of romk1... tyrosine dephosphorylation enhances the exocytosis of romk1" SIGNOR-97803 ESCRT-III complex SIGNOR-C379 SIGNOR Viral_budding phenotype SIGNOR-PH125 SIGNOR up-regulates 9606 26775243 f miannu "The ESCRT machinery drives a diverse collection of membrane remodeling events, including multivesicular body biogenesis, release of enveloped retroviruses and both reformation of the nuclear envelope and cytokinetic abscission during mitotic exit." SIGNOR-265534 Gbeta proteinfamily SIGNOR-PF4 SIGNOR CASP9 protein P55211 UNIPROT "down-regulates activity" phosphorylation 9606 12792650 t "inferred from 70% family members" lperfetto "Inhibition of caspase-9 through phosphorylation at thr 125 by erk mapk" SIGNOR-270084 TAL1 protein P17542 UNIPROT ANGPT2 protein O15123 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 22792348 f miannu "Here, we identified angiopoietin-2 (ang-2), which encodes a major regulator of angiogenesis, as a direct transcriptional target of tal1,lyl1and lmo2. Knockdown of any of the three transcription factors in human blood and lymphatic endothelial cells caused ang-2 mrna and protein down-regulation." SIGNOR-198279 BRAF protein P15056 UNIPROT TGFB1 protein P01137 UNIPROT "up-regulates quantity" relocalization 9606 19861538 f miannu "The BRAFV600E oncogene induces transforming growth factor beta secretion leading to sodium iodide symporter repression and increased malignancy in thyroid cancer. BRAF induces TGFβ secretion leading to NIS repression in a MEK-ERK–independent manner but cooperating with the MEK-ERK pathway to induce strong tumor invasion, two major traits acquired during PTC progression." SIGNOR-251987 CAPN2 protein P17655 UNIPROT CDK5/CDK5R1 complex SIGNOR-C144 SIGNOR "up-regulates activity" cleavage 9606 BTO:0000590 25969760 t lperfetto "Calpains also modulate the activity of CDK5. Physiologically, CDK 5 is activated by p35 and its cleaved product p25. The latter has a longer half life than p35 and therefore it is a more potent activator of CDK5. The cleavage of p35 to p25 is mediated by calpain" SIGNOR-251608 "UVB radiation" stimulus SIGNOR-ST17 SIGNOR EDN1 protein P05305 UNIPROT up-regulates 9606 9767234 f miannu "UVB can stimulate the synthesis of IL-1, TNF-a and ET-1, and other cytokines by keratinocytes." SIGNOR-252383 PSMF1 protein Q92530 UNIPROT "26S Proteasome" complex SIGNOR-C307 SIGNOR "down-regulates activity" binding 9606 BTO:0000007 23622245 t lperfetto "We identify the ADP-ribosyltransferase tankyrase (TNKS) and the 19S assembly chaperones dp27 and dS5b as direct binding partners of the proteasome regulator PI31. TNKS-mediated ADP-ribosylation of PI31 drastically reduces its affinity for 20S proteasome alpha subunits to relieve 20S repression by PI31." SIGNOR-263341 EGFR protein P00533 UNIPROT EGFR protein P00533 UNIPROT "up-regulates activity" phosphorylation Tyr1069 EDSFLQRySSDPTGA 9606 10635327 t llicata "Initially, an autophosphorylation reaction creates docking sites for several signaling proteins, including a Cbl binding site at tyrosine 1045 of EGFR." SIGNOR-251093 MYCT1 protein Q8N699 UNIPROT CCNE1 protein P24864 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 30283340 f miannu "MYCT1 overexpression significantly inhibited cell proliferation, arrested cell cycle at G0/G1 phase, and downregulated the expression of cyclins D and E. Moreover, MYCT1 overexpression triggered apoptosis in AML cells, which was accompanied by enhanced cleavage of caspase-3 and -9, upregulated expression of B-cell lymphoma 2 (Bcl-2)-associated X protein (Bax), and downregulated Bcl-2." SIGNOR-261732 CD40 protein P25942 UNIPROT TRAF3 protein Q13114 UNIPROT "up-regulates activity" binding 9606 18635759 t lperfetto "Cd40, a tumor necrosis factor receptor (tnfr) family member, forms a complex containing adaptor molecules traf2 and traf3." SIGNOR-250560 leucine smallmolecule CHEBI:25017 ChEBI Leu-tRNA(Leu) smallmolecule CHEBI:16624 ChEBI "up-regulates quantity" "precursor of" 9606 28271488 t miannu "Aminoacyl-tRNA synthetases (AARSs) are essential enzymes that specifically aminoacylate one tRNA molecule by the cognate amino acid. In mammals, nine synthetases, those specific for amino acids Arg, Asp, Gln, Glu, Ile, Leu, Lys, Met and Pro, associate into a multi-aminoacyl-tRNA synthetase complex, an association which is believed to play a key role in the cellular organization of translation, but also in the regulation of the translational and nontranslational functions of these enzymes." SIGNOR-270418 PPARD protein Q03181 UNIPROT HSD11B2 protein P80365 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0001975 15591138 f miannu "Peroxisome proliferator-activated receptor delta suppresses 11beta-hydroxysteroid dehydrogenase type 2 gene expression in human placental trophoblast cells." SIGNOR-255050 MDC1 protein Q14676 UNIPROT NBN protein O60934 UNIPROT up-regulates binding 9606 19230643 t gcesareni "Mdc1 also undergoes phosphorylation by ck2 after dna damage to generate a phospho-motif on mdc1, which binds directly to nbs1." SIGNOR-184141 FZD1 protein Q9UP38 UNIPROT PPARG protein P37231 UNIPROT down-regulates 9606 BTO:0000222 10937998 f fspada "Wnt signaling maintains preadipocytes in an undifferentiated state through inhibition of the adipogenic transcription factors ccaat/enhancer binding protein alpha (c/ebpalpha) and peroxisome proliferator- activated receptor gamma (ppargamma)" SIGNOR-80598 PHA-665752 chemical CHEBI:90197 ChEBI MET protein P08581 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-206088 pictrelisib chemical CHEBI:65326 ChEBI PIK3CD protein O00329 UNIPROT down-regulates "chemical inhibition" 9606 BTO:0000149 21876152 t gcesareni "Currently, several pi3k inhibitors, including gdc0941 (genentech) and bez235 (novartis pharmaceuticals), have entered phase i clinical trials, and in addition, isoform-specific compounds are being developed" SIGNOR-176298 PRKDC protein P78527 UNIPROT PNKP protein Q96T60 UNIPROT up-regulates phosphorylation Ser126 PPGTPLVsQDEKRDA 9606 21824916 t lperfetto "We demonstrate that pnkp is phosphorylated by the dna-dependent protein kinase (dna-pk) and ataxia-telangiectasia mutated (atm) in vitro. The major phosphorylation site for both kinases was serine 114, with serine 126 being a minor site. Purified pnkp protein with mutation of serines 114 and 126 had decreased dna kinase and dna phosphatase activities and reduced affinity for dna in vitro." SIGNOR-176020 CAMK2B protein Q13554 UNIPROT CYLD protein Q9NQC7 UNIPROT up-regulates phosphorylation Ser772 LFKKIFPsLELNITD 9606 24614225 t lperfetto "Purified camkii phosphorylates cyld on at least three residues (s-362, s-418, and s-772 on the human cyld protein q9nqc7-1) and promotes its deubiquitinase activity." SIGNOR-91403 TIMM23 protein O14925 UNIPROT "TIM23 complex" complex SIGNOR-C423 SIGNOR "form complex" binding 32074073 t lperfetto "The human TIM23 complex is formed by the core components TIM50 (50), TIM23 (23) and TIM17A/B (17A/B). The sorting elements are TIM21 (21) and ROMO1, and the motor elements include TIM44 (44), PAM18 (18; DNAJC15 and DNAJC19), PAM16 (16; MAGMAS), mtHSP70 (Mortalin) and GrpE." SIGNOR-267697 GATA1 protein P15976 UNIPROT Megakaryocyte_differentiation phenotype SIGNOR-PH103 SIGNOR "up-regulates activity" 10090 12032775 f "Studies involving point mutants of GATA-1 have shown that a direct physical interaction between GATA-1 and FOG-1 is essential for normal human erythroid and megakaryocyte maturation in vivo." SIGNOR-259961 IL5 protein P05113 UNIPROT AKT1 protein P31749 UNIPROT up-regulates 9606 21106848 f "It has been reported that IL-5 family members and selected chemotactic factors can activate the PI3K-Akt pathway in human blood eosinophils" SIGNOR-254351 Cullin4-RBX1-DDB1 complex SIGNOR-C119 SIGNOR MAGEA3 protein P43357 UNIPROT "down-regulates quantity by destabilization" polyubiquitination 9606 BTO:0002806 31267705 t miannu " The CRL4‐DCAF12 E3 ubiquitin ligase degrades MAGE‐A3/6" SIGNOR-272265 PTGS2 protein P35354 UNIPROT IL4 protein P05112 UNIPROT up-regulates 9606 22225874 t FFerrentino "Cox2 Is a Direct Srf Target Gene and Controls Il4 Expression" SIGNOR-255967 "L-glutamine zwitterion" smallmolecule CHEBI:58359 ChEBI "guanosine 5'-monophosphate" smallmolecule CHEBI:17345 ChEBI "up-regulates quantity" "precursor of" 9606 6698284 t miannu "The de novo synthesis of guanosine monophosphate (GMP) involves the oxidation of inosine monophosphate (IMP) to xanthosine monophosphate (XMP) followed by amination to GMP. This latter reaction is catalyzed by GMP synthetase. (XMP: I.-glutamine amidoligase (AMP) EC 6.3.5.2)." SIGNOR-268096 CUL5 protein Q93034 UNIPROT DAB1 protein O75553 UNIPROT "down-regulates quantity by destabilization" polyubiquitination 9534 BTO:0000298 24210661 t miannu "SOCS7 promotes Dab1 polyubiquitylation and degradation. SOCS7-CRL5 complexes stimulate the ubiquitylation and turnover of Dab1. SOCS7, a CRL5 substrate adaptor protein, is also required for neocortical layering. SOCS7-CRL5 complexes stimulate the ubiquitylation and turnover of Dab1." SIGNOR-272140 PCSK7 protein Q16549 UNIPROT NFKBIA protein P25963 UNIPROT down-regulates 10090 BTO:0000165;BTO:0000222 BTO:0000887;BTO:0001103 14767066 f lperfetto "The levels of ikb_? Where reduced in cells overexpressing mkk6 [] these results indicated that mkk6 was able to promote the degradation of the NF-kappaB inhibitor, in a p38-dependent manner." SIGNOR-235837 FKBP5 protein Q13451 UNIPROT YY1 protein P25490 UNIPROT "up-regulates activity" 9606 BTO:0000848 34589486 f miannu "FKBP51 Affects the Binding of YY1 Repressor to DR5 Gene. These results suggest that reduced YY1 DNA-binding activity in FKBP51-silenced cells corresponds to reduced YY1 acetylation." SIGNOR-268792 GRM3 protein Q14832 UNIPROT Excitatory_synaptic_transmission phenotype SIGNOR-PH133 SIGNOR up-regulates 9606 BTO:0000938 24564659 f miannu "Excitatory synaptic transmission in the mammalian brain is mediated primarily by the amino acid glutamate, activating two different groups of glutamate receptors: ionotropic and metabotropic." SIGNOR-264353 "perfluorohexanesulfonic acid" chemical CHEBI:132448 ChEBI ESR1 protein P03372 UNIPROT "up-regulates activity" "chemical activation" -1 23764977 t miannu "Seven PFCs [perfluorohexane sulfonate (PFHxS), perfluorooctane sulfonate (PFOS), perfluorooctanoate (PFOA), perfluorononanoate (PFNA), perfluorodecanoate (PFDA), perfluoroundecanoate (PFUnA), and perfluorododecanoate (PFDoA)] were analyzed in vitro for their potential to affect estrogen receptor (ER) and androgen receptor (AR) transactivity as well as aromatase enzyme activity. The PFCs were assessed as single compounds and in an equimolar mixture. PFHxS, PFOS and PFOA significantly induced the ER transactivity, whereas PFHxS, PFOS, PFOA, PFNA and PFDA significantly antagonized the AR activity in a concentration-dependent manner. " SIGNOR-268761 CAMK4 protein Q16566 UNIPROT HNRNPL protein P14866 UNIPROT up-regulates phosphorylation Ser544 GKSERSSsGLLEWES 9606 22570490 t lperfetto "Here we show that the regulation of the stress axis-regulated exon of the slo1 potassium channel transcripts by membrane depolarization requires a highly conserved camkiv target serine (ser-513) of the heterogeneous ribonucleoprotein l. Ser-513 phosphorylation within the rna recognition motif 4 enhanced heterogeneous ribonucleoprotein l interaction with the camkiv-responsive rna element 1 of stress axis-regulated exon and inhibited binding of the large subunit of the u2 auxiliary factor u2af65." SIGNOR-197367 MAPK1 protein P28482 UNIPROT WWC1 protein Q8IX03 UNIPROT unknown phosphorylation Ser548 SSPSPPCsPLMADPL 9606 BTO:0000149 24269383 t llicata "We demonstrated that erk1/2 phosphorylate kibra at ser(548) in cells as well as in vitro." SIGNOR-203286 WEE1 protein P30291 UNIPROT CDK1 protein P06493 UNIPROT down-regulates phosphorylation Tyr15 EKIGEGTyGVVYKGR 9606 16096060 t gcesareni "The wee1 kinase phosphorylates and inhibits cyclin-dependent kinase 1 (cdk1), thereby delaying entry into mitosis until appropriate conditions have been met" SIGNOR-139491 RBX1 protein P62877 UNIPROT NFKB2 protein Q00653 UNIPROT up-regulates ubiquitination 9606 SIGNOR-C5 14676825 t gcesareni "Mechanism of processing of the nf-kappa b2 p100 precursor: identification of the specific polyubiquitin chain-anchoring lysine residue and analysis of the role of nedd8-modification on the scf(beta-trcp) ubiquitin ligase." SIGNOR-120342 SIAH1 protein Q8IUQ4 UNIPROT SNCAIP protein Q9Y6H5 UNIPROT down-regulates ubiquitination 9606 16174773 t lperfetto "Siah proteins ubiquitylate synphilin-1 and promote its degradation through the ubiquitin proteasome system" SIGNOR-140612 CACNA2D3 protein Q8IZS8 UNIPROT p38 proteinfamily SIGNOR-PF16 SIGNOR "up-regulates activity" 9606 31746409 f miannu "The results indicated that the overexpression of CACNA2D3 induced an increase in intracellular Ca2+ and increased the levels of p-p38 MAPK. These data indicated that the p38 MAPK pathway is activated by overexpression of CACNA2D3 and P4 induction." SIGNOR-266857 CDK5RAP2 protein Q96SN8 UNIPROT APP protein P05067 UNIPROT "up-regulates quantity by stabilization" phosphorylation Thr743 VEVDAAVtPEERHLS 9606 15178331 t Manara "The APPcyt is phosphorylated at Thr668 in vivo specifically in the brain. Cyclin‐dependent kinase 5 (Cdk5), a unique member of the Cdk family that is implicated in central nervous system development, participates in this phosphorylation. | In the present study, we demonstrate that APP phosphorylated at Thr668 is less vulnerable to cytoplasmic cleavage by caspase-3 and caspase-8." SIGNOR-260818 histamine smallmolecule CHEBI:18295 ChEBI HRH1 protein P35367 UNIPROT "up-regulates activity" "chemical activation" 10029 7925364 t miannu "The human H1-receptor cDNA was transfected into Chinese hamster ovary cells (CHO) via an eukaryotic expression vector; the receptor protein present on cell membranes specifically bound [3H]mepyramine with a Kd of 3.7 nM. The binding was displaced by H1-histamine-receptor antagonists and histamine. Affinity of histamine and selected histamine antagonists for human H, receptors expressed in CHO cells (CHO H,-30) and a comparison with HI receptors found in guinea pig cerebellum." SIGNOR-258483 CPT1B protein Q92523 UNIPROT (R)-carnitine smallmolecule CHEBI:16347 ChEBI "down-regulates quantity" "chemical modification" 9606 14517221 t miannu "Carnitine palmitoyltransferase 1A (CPT1A) is the key regulatory enzyme of hepatic long-chain fatty acid beta-oxidation. The first component of this system is CPT1, an integral mitochondrial outer membrane protein, which catalyzes the transfer of long-chain acyl group of the acyl-CoA ester to carnitine. CPT1 is tightly regulated by its physiological inhibitor malonyl-CoA, the first intermediate in fatty acid biosynthesis. Three CPT1 isoforms with various tissue distribution and encoded by distinct genes have been identified (1., 2.): a liver (CPT1A or L-CPT1) (8.), a muscle (CPT1B or M-CPT1) (9.), and a brain isoform (CPT1C)." SIGNOR-267121 "1-acyl-sn-glycerol 3-phosphate(2-)" smallmolecule CHEBI:57970 ChEBI "phosphatidic acid" smallmolecule CHEBI:16337 ChEBI "up-regulates quantity" "precursor of" 9606 21173190 t lperfetto "The enzyme 1-acylglycerol-3-phosphate-O-acyltransferase (AGPAT) converts lysophosphatidic acid (LPA) to phosphatidic acid (PA).¬†" SIGNOR-267010 anthra[1,9-cd]pyrazol-6(2H)-one chemical CHEBI:90695 ChEBI MAPK8 protein P45983 UNIPROT down-regulates "chemical inhibition" 9606 11717429 t gcesareni "We report the identification of an anthrapyrazolone series with significant jnk1, -2, and -3 (k(i) = 0.19 microm)." SIGNOR-111983 CSNK1D protein P48730 UNIPROT AXIN1 protein O15169 UNIPROT up-regulates binding 9606 SIGNOR-C110 12000790 t gcesareni "We conclude that a major role of axin in the wnt is to provide the kinase activity that initiates the beta-catenin phosphorylation cascade at s45. This process is mediated by cki, the alfa, delta, or epsilon isoform, all detected in association with axin by lc/ms." SIGNOR-87433 MAPK1 protein P28482 UNIPROT NOXA1 protein Q86UR1 UNIPROT down-regulates phosphorylation Ser282 VGKQAPLsPGLPAMG 9606 BTO:0000007 20110267 t llicata "These results demonstrated a critical role of noxa1 phosphorylation on ser-282 and ser-172 in preventing nox1 hyperactivation through the decrease of noxa1 interaction to nox1 and rac1." SIGNOR-163659 PTPRJ protein Q12913 UNIPROT MAPK1 protein P28482 UNIPROT down-regulates dephosphorylation Tyr205 IMLNSKGyTKSIDIW 9606 19494114 t gcesareni "In this study we show that one of these potential targets, the erk1/2, is indeed a direct dep-1 substrate in vivo." SIGNOR-161536 CTNNB1 protein P35222 UNIPROT AFF3 protein P51826 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 26214578 f irozzo "We demonstrate that AFF3 is a new target of Wnt/β-catenin pathway involved in ACC, acting on transcription and RNA splicing." SIGNOR-259192 MAP3K6 protein O95382 UNIPROT MAPK14 protein Q16539 UNIPROT "up-regulates activity" phosphorylation Thr180 RHTDDEMtGYVATRW 9534 8622669 t Manara "These data indicate that MKK6 phosphorylates p38 MAP kinase on Thr-180 and Tyr-182, the sites of phosphorylation that activate p38 MAP kinase" SIGNOR-260915 AKT proteinfamily SIGNOR-PF24 SIGNOR PDE3B protein Q13370 UNIPROT "up-regulates activity" phosphorylation Ser295 VIRPRRRsSCVSLGE 10090 BTO:0000944 10454575 t "PDE3B is a physiological substrate of Akt and that Akt-mediated phosphorylation of PDE3B on serine-273 is important for insulin-induced activation of PDE3B" SIGNOR-251483 GSK3B protein P49841 UNIPROT Protein_synthesis phenotype SIGNOR-PH29 SIGNOR down-regulates 9606 BTO:0001103 15829723 f apalma "GSK-3beta is a serine/threonine kinase that can block translation that is initiated by eukaryotic initiation factor-2B (24) and may thereby reduce protein synthesis." SIGNOR-255110 FBXW11 protein Q9UKB1 UNIPROT NFKBIA protein P25963 UNIPROT down-regulates ubiquitination Lys22 GPRDGLKkERLLDDR 9606 7479976 t gcesareni "Here we provide evidence that lysine residues 21 and 22 serve as the primary sites for signal-induced ubiquitination of i kappa b alpha." SIGNOR-26577 Gbeta proteinfamily SIGNOR-PF4 SIGNOR CASP8 protein Q14790 UNIPROT down-regulates phosphorylation 9606 BTO:0000149 24342355 t "inferred from 70% family members" lperfetto "We demonstrate that perk 1/2 can phosphorylate pro-caspase-8 at s387 by knocking-down the endogenous pro-caspase-8 using rnai and replacing it with its non-phosphorylatable counterpart (s387a), a significant increase in caspase-8 activity" SIGNOR-270118 SUN3 protein Q8TAQ9 UNIPROT "LINC complex" complex SIGNOR-C303 SIGNOR "form complex" binding 24481844 t lperfetto "LINC complex couples the nuclear lamina to the cytoskeleton. SUN domain proteins, SUN1 and SUN2, located at the inner nuclear membrane (INM) interact with the nuclear lamins, Lamin A/C, B1, and B2, that line the nucleoplasmic face of the INM. SUN domain proteins interact with Nesprins in the perinuclear space (PNS). Nesprins protrude from the outer nuclear membrane (ONM) and interact with the cytoskeleton, often through an intermediate binding partner. Nesprin 1 giant (g) and Nesprin 2g potentially link the NE directly to the Z-disc (Z), whereas Nesprin 1alpha and 2alpha may connect via an unknown intermediate protein. In addition, the shorter isoforms of Nesprin 1 and Nesprin 2 may localize to the INM." SIGNOR-263291 MRPL46 protein Q9H2W6 UNIPROT "39S mitochondrial large ribosomal subunit" complex SIGNOR-C285 SIGNOR "form complex" binding -1 25838379 t lperfetto "We have determined the structure of the intact mitoribosome to 3.5 angstrom resolution by single-particle electron cryo-microscopy. It reveals 80 extensively interconnected proteins, 36 of which are specific to mitochondria, and three rRNA molecules" SIGNOR-262350 MAPK10 protein P53779 UNIPROT CDC25C protein P30307 UNIPROT down-regulates phosphorylation Ser168 SEMKYLGsPITTVPK 9606 20220133 t gcesareni "Here we show that jnk directly phosphorylates cdc25c at serine 168 during g(2) phase of the cell cycle. Cdc25c phosphorylation by jnk negatively regulates its phosphatase activity and thereby cdk1 activation, enabling a timely control of mitosis onset." SIGNOR-164085 CDK5/CDK5R1 complex SIGNOR-C144 SIGNOR MAPT protein P10636 UNIPROT "down-regulates activity" phosphorylation Ser552 VVRTPPKsPSSAKSR 9606 BTO:0000590 12387894 t lperfetto "We found that cdk5 phosphorylated tau(441) at Thr-181, Ser-199, Ser-202, Thr-205, Thr-212, Ser-214, Thr-217, Thr-231, Ser-235, Ser-396, and Ser-404, but not at Ser-262, Ser-400, Thr-403, Ser-409, Ser-413, or Ser-422. GSK-3beta phosphorylated all the cdk5-catalyzed sites above except Ser-235." SIGNOR-251590 CyclinC/CDK3 complex SIGNOR-C545 SIGNOR RB1 protein P06400 UNIPROT "down-regulates activity" phosphorylation Ser811 IYISPLKsPYKISEG 9606 15084261 t gcesareni "The active form of prb is underphosphorylated. Cdk3/cyclin-c-mediated phosphorylation at ser-807 and ser-811 is required for g0-g1 transition." SIGNOR-273181 ATG12 protein O94817 UNIPROT ATG12/5/16L1 complex SIGNOR-C109 SIGNOR "form complex" binding 9606 BTO:0000007 18321988 t lperfetto "Atg12 is conjugated to atg5 and forms an approximately 800-kda protein complex with atg16l (referred to as atg16l complex)." SIGNOR-226689 RARA protein P10276 UNIPROT NR4A1 protein P22736 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 10772826 f lperfetto "Retinoic acid and its receptors repress the expression and transactivation functions of nur77" SIGNOR-76980 XL765 chemical CHEBI:71958 ChEBI PI3K complex SIGNOR-C156 SIGNOR down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-252660 PRKCA protein P17252 UNIPROT GRIA4 protein P48058 UNIPROT up-regulates phosphorylation Ser862 IRNKARLsITGSVGE 9606 12536214 t gcesareni "Receptor internalization, altered;intracellular localization" SIGNOR-97554 AGRP protein O00253 UNIPROT MC3R protein P41968 UNIPROT "down-regulates activity" binding 9606 10318826 t miannu "AGRP is a potent antagonist of the melanocortin-3 receptor and the MC4R and has also been shown to have a lesser degree of inhibitory action at the melanocortin-5 receptor." SIGNOR-252380 USP9X protein Q93008 UNIPROT EPS15 protein P42566 UNIPROT "down-regulates activity" deubiquitination 9606 26748853 t gcesareni "We identify the endocytic protein Eps15 as one of the critical substrates of USP9X" SIGNOR-245052 BCORL1 protein Q5H9F3 UNIPROT HDAC4 protein P56524 UNIPROT "up-regulates activity" binding 9606 BTO:0000567 17379597 t irozzo "BCoR-L1 interacts with Class II HDACs, HDAC4, HDAC5, and HDAC7, suggesting that they are involved in its function as transcriptional corepressor." SIGNOR-259112 ITK protein Q08881 UNIPROT CD28 protein P10747 UNIPROT up-regulates phosphorylation Tyr209 TRKHYQPyAPPRDFA 9606 BTO:0000661 22936936 t lperfetto "We demonstrate that emt can phosphorylate all four tyrosines of the cd28 tailother studies demonstrated that tyr191 within the p190yap motif is one of two major phosphorylation sites in cd28-stimulated jurkat t cells, and the only tyrosine residue within the cd28 cytoplasmic tail that is essential for delivery of costimulatory signals" SIGNOR-198751 TBK1 protein Q9UHD2 UNIPROT IKBKE protein Q14164 UNIPROT "up-regulates activity" binding 9606 18353649 t lperfetto "Whereas nemo assembles some but not all ikk complexes [12,13], recent reports provide strong experimental evidence for a role of tank [also called traf-interacting protein (i-traf)], nak-associated protein (nap1) and similar to nap1 tbk1 adaptor (sintbad) in the assembly of tbk1 and ikk-e kinase complexes that phosphorylate irf3 and irf7 and promote type i ifn gene induction" SIGNOR-178053 PHLPP1 protein O60346 UNIPROT STK4 protein Q13043 UNIPROT up-regulates binding 9606 23431053 t gcesareni "Here, we report that phlpp1 is a binding protein for mst1 and it modulates the hippo pathway by dephosphorylating mst1 at the inhibitory thr(387) of mst1." SIGNOR-201262 HCRT protein O43612 UNIPROT HCRTR1 protein O43613 UNIPROT up-regulates binding 9606 BTO:0000938 BTO:0000142 9491897 t gcesareni "Identification and initial biological characterization of two orexins as well as their two receptors" SIGNOR-53667 AKT proteinfamily SIGNOR-PF24 SIGNOR HNRNPA1 protein P09651 UNIPROT down-regulates phosphorylation Ser199 SQRGRSGsGNFGGGR 9606 18562319 t gcesareni "Our data also suggest that akt negatively regulates hnrnp a1-mediated ires activity via phosphorylation at ser199." SIGNOR-179059 "Class I MHC:Antigen" complex SIGNOR-C426 SIGNOR T_cell_activation phenotype SIGNOR-PH73 SIGNOR up-regulates 9606 31810556 f scontino "High-affinity peptide/MHC class I complexes that successfully pass the aforementioned “quality controls” will be transported through the Golgi apparatus to the cell membrane to elicit antigen-specific CD8+ T cell responses." SIGNOR-267775 BCL2 protein P10415 UNIPROT BAK1 protein Q16611 UNIPROT down-regulates binding 9606 9463381 t amattioni "Bcl-2 bind to bax or five other pro-apoptotic relatives (bak, bad, bik, bid or bim)" SIGNOR-55546 SYVN1 protein Q86TM6 UNIPROT GPR37 protein O15354 UNIPROT "down-regulates quantity by destabilization" polyubiquitination 9606 18241051 t miannu "We demonstrated that endogenous HRD1 interacts with Pael-R, and that HRD1 promotes the degradation of Pael-R and protects cell death caused by the accumulation of Pael-R." SIGNOR-272631 PD318088 chemical CID:10231331 PUBCHEM MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR down-regulates "chemical inhibition" 9606 Other t Selleck lperfetto SIGNOR-244927 KAT2B protein Q92831 UNIPROT H3-5 protein Q6NXT2 UNIPROT "down-regulates activity" acetylation Lys15 ARKSTGGkAPRKQLA 9606 SIGNOR-C465 34811519 t "Acetlyation of H3 causes transcriptional activation, thus has an inhibitory role on H3" lperfetto "The HAT module within the SAGA and ADA complexes acetylates histone H3, mainly on residues K9 and K14." SIGNOR-269625 RELA protein Q04206 UNIPROT TRAF2 protein Q12933 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 9733516 f lperfetto "Thus, our data indicate that nf-kb controls the expression of traf1 and traf2 and c-iap1 and c-iap2" SIGNOR-59960 Temsirolimus chemical CHEBI:79699 ChEBI MTOR protein P42345 UNIPROT down-regulates "chemical inhibition" 9606 21081844 t gcesareni "Temsirolimus, an inhibitor of mammalian target of rapamycin (mtor) complex 1, is approved for the treatment of metastatic renal cell carcinoma (rcc)." SIGNOR-169712 MAP4K4 protein O95819 UNIPROT MAP3K1 protein Q13233 UNIPROT up-regulates phosphorylation 9606 8824585 t gcesareni "Hpk1 binds and phosphorylates mekk1 directly" SIGNOR-44040 ANK3 protein Q12955 UNIPROT DMD protein P11532 UNIPROT "up-regulates quantity" relocalization 10090 BTO:0001103 19109891 t miannu "We present evidence for an ankyrin-based mechanism for sarcolemmal localization of dystrophin and beta-DG. Ankyrin-B thus is an adaptor required for sarcolemmal localization of dystrophin, as well as dynactin-4." SIGNOR-266715 Ub:E2 complex SIGNOR-C497 SIGNOR TRIM35 protein Q9UPQ4 UNIPROT "up-regulates activity" ubiquitination 9606 34199813 t miannu "The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t" SIGNOR-270974 LPAR3 protein Q9UBY5 UNIPROT GNAQ protein P50148 UNIPROT up-regulates binding 9606 12531543 t gcesareni "Lpa3couples to gq" SIGNOR-97400 CDKL5 protein O76039 UNIPROT CDKL5 protein O76039 UNIPROT "up-regulates activity" phosphorylation Tyr171 NNANYTEyVATRWYR -1 16935860 t miannu "Furthermore, we show that CDKL5 can self-associate and mediate the phosphorylation of its own TEY (Thr-Glu-Tyr) motif." SIGNOR-245876 SP1 protein P08047 UNIPROT ASNS protein P08243 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000599 11867623 t Luana "Sp1 and Sp3 Activate Transcription Driven by the AS Promoter" SIGNOR-268019 NUMA1 protein Q14980 UNIPROT TUBB4B protein P68371 UNIPROT up-regulates binding 9606 11956313 t miannu "Direct binding of numa to tubulin is mediated by a novel sequence motif in the tail domain that bundles and stabilizes microtubules." SIGNOR-117078 MAPK1 protein P28482 UNIPROT RPS6KA1 protein Q15418 UNIPROT "up-regulates activity" phosphorylation 9606 12832467 t lperfetto "Efficient rsk activation by erk requires its interaction through a docking site located near the c terminus of rsk" SIGNOR-102645 PTK2 protein Q05397 UNIPROT ATP2B4 protein P23634-6 UNIPROT "up-regulates activity" phosphorylation Tyr1176 LDGEVTPyANTNNNA 9606 12540962 t miannu "Results of co-immunoprecipitation, treatment with tyrosine kinase inhibitors and integrin inhibition experiments suggest that FAK is responsible for PMCA4b tyrosine phosphorylation during platelet activation. equence analysis indicates that Y(1176) is a likely substrate for focal adhesion kinase (FAK), while Y(1122) is not located in a tyrosine phosphorylation motif." SIGNOR-263194 NEUROG3 protein Q9Y4Z2 UNIPROT NEUROD4 protein Q9HD90 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 19028584 f miannu "Ngn3 overexpression altered the expression of a number of regulatory genes, including ash1, ath3, ath5, chx10, neuroD, ngn1, ngn2, and NSCL1. Early gene ngn1 was induced, but ash1, ngn2, ath3, and chx10, whose expressions persist through later phases of neurogenesis, were down-regulated." SIGNOR-254631 58131-57-0 chemical CID:42640 PUBCHEM MDM4 protein O15151 UNIPROT "down-regulates activity" "chemical inhibition" -1 21075910 t miannu "Here we report the identification of a benzofuroxan derivative [7-(4-methylpiperazin-1-yl)-4-nitro-1-oxido-2,1,3-benzoxadiazol-1-ium, NSC207895] that could inhibit MDMX expression in cancer cells through a reporter-based drug screening." SIGNOR-262246 ATR protein Q13535 UNIPROT FANCA protein O15360 UNIPROT up-regulates phosphorylation Ser1449 AAPDADLsQEPHLF 9606 19109555 t lperfetto "The s1449a mutant failed to completely correct a variety of fa-associated phenotypes. The dna damage response is coordinated by phosphorylation events initiated by apical kinases atm (ataxia telangectasia mutated) and atr (atm and rad3-related), and atr is essential for proper fa pathway function. Serine 1449 is in a consensus atm/atr site" SIGNOR-182953 LCK protein P06239 UNIPROT MAPK1 protein P28482 UNIPROT up-regulates 9606 17998336 f gcesareni "The sh3 domain of lck modulates t-cell receptor-dependent activation of extracellular signal-regulated kinase through activation of raf-1." SIGNOR-159164 "3',5'-cyclic AMP" smallmolecule CHEBI:17489 ChEBI PRKAR2B protein P31323 UNIPROT "down-regulates activity" "chemical inhibition" 9606 26687711 t "Inactive PKA exists as a holoenzyme, comprised of two regulatory (R) subunits and two catalytic subunits . In the presence of cAMP, the holoenzyme becomes active by binding two cAMP molecules cooperatively to each R subunit, resulting in a conformational change in the R subunits, thus releasing the two C subunits to phosphorylate downstream targets" SIGNOR-258762 ATR protein Q13535 UNIPROT CHEK1 protein O14757 UNIPROT up-regulates phosphorylation Ser345 LVQGISFsQPTCPDH 9606 15775976 t gcesareni "Atr activation typically leads to chk1 phosphorylation and activation. In response to genotoxic stress, chk1 is phosphorylated on serines 317 (s317) and 345 (s345) by the ataxia-telangiectasia-related (atr) protein kinase." SIGNOR-134716 PIK3R6 protein Q5UE93 UNIPROT PI3K complex SIGNOR-C156 SIGNOR "down-regulates activity" binding 25753393 t lperfetto "P84 forms a negative regulatory complex with p110gamma to control PI3Kgamma signalling during cell migration|Our findings suggest that p84 binding to p110γ may represent a novel negative feedback signal that terminates PI3Kγ activity." SIGNOR-275724 SAFB protein Q15424 UNIPROT FUS protein P35637 UNIPROT "up-regulates activity" relocalization 9606 BTO:0000007 27731383 t "P35637:p.Pro525Leu (mutation disrupting interaction)" "SAFB1 as well as Matrin3 to regulate splicing and ligand-mediated transcription| In addition, depletion of SAFB1 reduced FUS's localization to chromatin-bound fraction and splicing activity, suggesting SAFB1 could tether FUS to chromatin compartment thorough N-terminal DNA-binding motif." SIGNOR-262821 FYN protein P06241 UNIPROT PLCG2 protein P16885 UNIPROT "up-regulates activity" phosphorylation Tyr759 LYDVSRMyVDPSEIN -1 7682059 t lperfetto "The phosphorylation of purified phospholipase C-gamma 1 (PLC-gamma 1) and PLC-gamma 2 by src-family-protein tyrosine kinases (PTKs) P56lck, p53/56lyn, p59hck, p59fyn, and p60src was studied in vitro. All five PTKs phosphorylated PLC-gamma 1 and PLC-gamma 2, suggesting that both PLC-gamma isozymes can be phosphorylated in cells by any of the src-family PTKs in response to the activation of cell surface receptors." SIGNOR-249340 PRKACA protein P17612 UNIPROT GLIS2 protein Q9BZE0 UNIPROT "down-regulates activity" phosphorylation 9606 BTO:0000938 16537363 t lperfetto "Protein kinase a (pka) and glycogen synthase kinase 3beta sequentially phosphorylate gli2 at multiple sites, identified by mutagenesis, thus resulting in a reduction of its transcriptional activity" SIGNOR-145131 AKT1 protein P31749 UNIPROT RAF1 protein P04049 UNIPROT down-regulates phosphorylation 9606 22798428 t gcesareni "Akt negatively regulates the raf and gsk-3 kinases and the cell cycle regulatory transcription factor fkhr." SIGNOR-252531 SP1 protein P08047 UNIPROT CD151 protein P48509 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 20149781 f miannu "SP1 is required for basal activation and chromatin accessibility of CD151 promoter in liver cancer cells." SIGNOR-255195 Interferon-type-I proteinfamily SIGNOR-PF50 SIGNOR RAE1 protein P78406 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 16036565 f miannu "Nup98/Nup96 (41) and Rae1 (17)are up regulated by interferons, which revert the mRNAexport block induced by VSV M protein" SIGNOR-260869 LCK protein P06239 UNIPROT IL2RB protein P14784 UNIPROT unknown phosphorylation Tyr384 ACQVYFTyDPYSEED -1 10214954 t "Recombinant p56(lck) phosphorylates in vitro tyrosine residues within the IL-2Rbeta chain. p56(lck) phosphorylates tyrosine residues 355, 358 and 361 but not 338 of the IL-2Rbeta chain acidic subdomain. p56(lck) also phosphorylates very efficiently the two tyrosines present in the IL-2Rbeta chain C-terminal region, Tyr-392 and Tyr-510." SIGNOR-251376 RUNX1 protein Q01196 UNIPROT "Core Binding Factor complex" complex SIGNOR-C214 SIGNOR "form complex" binding 9606 12495904 t irozzo "The core binding factor (CBF) transcription complex, consisting of the interacting proteins RUNX1 and CBFβ, is essential for normal hematopoiesis" SIGNOR-255710 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR ASB2 protein Q96Q27 UNIPROT "up-regulates activity" phosphorylation Ser371 RIRRSGVsPLHLAAE 24044920 t lperfetto "Indeed, using mass spectrometry, we showed for the first time that ASB2a is phosphorylated and that phosphorylation of serine-323 (Ser-323) of ASB2a is crucial for the targeting of the actin-binding protein filamin A (FLNa) to degradation. |Moreover, inhibition of the extracellular signal-regulated kinases 1 and 2 (Erk1/2) activity reduced ASB2a-mediated FLNa degradation." SIGNOR-272239 ILK protein Q13418 UNIPROT PPP1R12A protein O14974 UNIPROT down-regulates phosphorylation Thr710 DLQEAEKtIGRSRST 9606 12030846 t lperfetto "Mypt1 was phosphorylated by ilk and phosphorylation sites in the n- and c-terminal fragments of mypt1 were detected. From sequence analyses, three sites were identified: a primary site at thr(709), and two other sites at thr(695) and thr(495). phosphorylation of the various sites indicated that thr695 was the major inhibitory site, thr709 had only a slight inhibitory effect" SIGNOR-87928 EIF1 protein P41567 UNIPROT 43S_pre_initiation_complex complex SIGNOR-C453 SIGNOR "form complex" binding 9606 35489072 t lperfetto "In eukaryotes, mRNA is recruited to the 43S pre-initiation complex (43S PIC), which consists of the 40S ribosomal subunit, translation initiation factors eIF1, eIF1A, eIF3, eIF5, and a ternary complex (TC) composed of eIF2, GTP and Met-tRNAiMet. 43S PIC binds to the 5′ end of the mRNA and scans along the 5′ untranslated region (5′UTR) in the 3′ direction to find the start codon (AUG) within the context of an optimal Kozak sequence. Start codon recognition stabilizes the 48S initiation complex (48S IC), initiates dissociation of eIF1, eIF1A, eIF2 and eIF5, and promotes recruitment of the 60S ribosomal subunit to form 80S IC ready to enter the elongation cycle of protein synthesis." SIGNOR-269161 EXTL1 protein Q92935 UNIPROT SHH protein Q15465 UNIPROT down-regulates binding 9606 BTO:0000142 15614771 t gcesareni "A study in mice suggests that ext1 proteins might negatively regulate shh signaling by synthesizing hspgs, which sequester the ligand" SIGNOR-132606 APC protein P25054 UNIPROT ODC1 protein P11926 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 12112318 t "APC-dependent regulation of ornithine decarboxylase in human colon tumor cells|Upon induction of APC expression, ODC promoter activity and RNA levels were suppressed" SIGNOR-253670 F2 protein P00734 UNIPROT "GPIb-IX-V complex" complex SIGNOR-C270 SIGNOR "up-regulates activity" binding 9606 BTO:0000132 25297919 t lperfetto "Besides VWF as a main ligand, GPIbα also binds multiple ligands such as thrombospondin, Factor XII, Factor XI, thrombin, High Molecular Weight kininogen, P-selectin and Mac-1." SIGNOR-261859 SP1 protein P08047 UNIPROT SOD2 protein P04179 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10669635 f lperfetto "These results suggest that PMA stimulates transcription of the Mn-SOD gene through an increase in Sp1 expression and thus implicate Sp1 as an effector mediating the PKC-signaling pathway elicited by extracellular signals." SIGNOR-271693 9-(1-anilinoethyl)-7-methyl-2-(4-morpholinyl)-4-pyrido[1,2-a]pyrimidinone chemical CHEBI:91428 ChEBI PIK3CB protein P42338 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-207278 FASN protein P49327 UNIPROT WNT1 protein P04628 UNIPROT "up-regulates activity" 9606 18838960 f lperfetto "Overexpression of fatty acid synthase is associated with palmitoylation of Wnt1 and cytoplasmic stabilization of beta-catenin in prostate cancer" SIGNOR-242881 N-(cyanomethyl)-4-[2-[4-(4-morpholinyl)anilino]-4-pyrimidinyl]benzamide chemical CHEBI:91407 ChEBI JAK2 protein O60674 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-191247 PTPRF protein P10586 UNIPROT FYN protein P06241 UNIPROT down-regulates dephosphorylation Tyr420 RLIEDNEyTARQGAK 9606 12496362 t lperfetto "Regulation of lck and fyn tyrosine kinase activities by transmembrane protein tyrosine phosphatase leukocyte common antigen-related molecule." SIGNOR-96768 SIRT1 protein Q96EB6 UNIPROT XPA protein P23025 UNIPROT "up-regulates activity" deacetylation Lys67 ANVKAAPkIIDTGGG 9606 BTO:0002806 30327428 t miannu "SIRT1 deacetylates XPA at residues K63, K67, and K215 to promote interactions with ATR" SIGNOR-262294 N-[6,6-dimethyl-5-[(1-methyl-4-piperidinyl)-oxomethyl]-1,4-dihydropyrrolo[3,4-c]pyrazol-3-yl]-3-methylbutanamide chemical CHEBI:91371 ChEBI CDK7 protein P50613 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-206136 oligopeptide smallmolecule CHEBI:25676 ChEBI "peptide antigen" smallmolecule CHEBI:166824 ChEBI "up-regulates quantity" "precursor of" 9606 31810556 t scontino "Within the phagosome, the internalized antigens are partially degraded by Cathepsin S and the GILT complex, a necessary step for further export to cytosol." SIGNOR-267866 EID3 protein Q8N140 UNIPROT Skeletal_muscle_differentiation phenotype SIGNOR-PH1 SIGNOR down-regulates 10090 23720823 f miannu "Here we show that, when over-expressed, FRG1 binds and interferes with the activity of the histone methyltransferase Suv4-20h1 both in mammals and Drosophila. Accordingly, FRG1 over-expression or Suv4-20h1 knockdown inhibits myogenesis. The novel inhibitor of differentiation Eid3 is an FRG1/Suv4-20h1 target involved in the myogenic defects caused by FRG1 over-expression. Eid3 is down-regulated upon muscle differentiation and behaves as a myogenic inhibitor gene." SIGNOR-266641 CHAMP1 protein Q96JM3 UNIPROT Chromosome_segregation phenotype SIGNOR-PH44 SIGNOR up-regulates 9606 BTO:0000567 21063390 f miannu "Proper attachment of microtubules to kinetochores is essential for accurate chromosome segregation. These data suggest that CAMP is required for maintaining kinetochore-microtubule attachment during biorientation." SIGNOR-264901 3-isobutyl-1-methyl-7H-xanthine smallmolecule CHEBI:34795 ChEBI PDE1B protein Q01064 UNIPROT "down-regulates activity" "chemical inhibition" 9606 22014080 t "Until now, very few inhibitors of PDE1 were available for evaluating the contribution of PDE1 in tissue and cell function. Vinpocetine (Ahn et al., 1989) and 8-methoxymethyl-IBMX (Ahn et al., 1997) are common PDE1 inhibitors." SIGNOR-253400 IRF5 protein Q13568 UNIPROT TNF protein P01375 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 21240265 f miannu "Among the genes with differences in expression in the M1 and M2 subsets are those regulated by IRF5, including IL12A, IL12B, IL23A, IL1B, TNF, CCL3(encoding MIP-1Œ±), RANTES, CD1A, CD40, CD86 and CCR7" SIGNOR-254518 PIP3 smallmolecule CHEBI:16618 ChEBI PDPK1 protein O15530 UNIPROT "up-regulates activity" "chemical activation" -1 9094314 t gcesareni "We tested the kinase in the presence of several inositol phospholipids and found that only low micromolar concentrations of the D enantiomers of either phosphatidylinositol 3,4,5-triphosphate (PtdIns(3,4,5)P3) or PtdIns(3,4)P2 were effective in potently activating the kinase, which has been named PtdIns(3,4,5)P3-dependent protein kinase-1 (PDK1)" SIGNOR-243274 Gbeta proteinfamily SIGNOR-PF4 SIGNOR SCNN1B protein P51168 UNIPROT "down-regulates quantity by destabilization" phosphorylation -1 11805112 t "inferred from 70% family members" lperfetto "Using a number of different approaches it was demonstrated that the protein kinase acting on betaThr-613 and gammaThr-623 is the extracellular regulated kinase (ERK). It is suggested that an ERK-mediated phosphorylation of betaThr-613 and gammaThr-623 down-regulates the channel by facilitating its interaction with Nedd4." SIGNOR-270050 5-Fluoro-8-hydroxy-2-(dipropylamino)tetralin chemical CID:122187 PUBCHEM HTR1A protein P08908 UNIPROT "down-regulates activity" "chemical inhibition" 10029 BTO:0000246 9760039 t miannu "Marked differences were observed between the actions of ‘antagonists’ (Table 2; Fig. 2D ). methiothepin and butaclamol, as well asspiperone, exhibited negative efficacy by concentration-dependently inhibiting S GTPgS binding below basal levels, indicating that they act as inverse agonists in this system.WAY 100,135, yUH 301 and the 5-HTreceptor1A and b-adrenergic receptor antagonist ,ytertatolol, acted as ‘neutral’ antagonists, exhibiting antagonist activity without any detectable agonist or inverse agonist effects." SIGNOR-258865 LYN protein P07948 UNIPROT SLAMF1 protein Q13291 UNIPROT unknown phosphorylation Tyr327 ETNSITVyASVTLPE 9606 15315965 t llicata "Cd150-mediated akt phosphorylation required syk and sh2d1a, was negatively regulated by lyn and btk, but was ship independent. Lyn directly phosphorylated y327 in cd150, but the akt pathway did not depend on cd150 tyrosine phosphorylation and cd150-shp-2 association." SIGNOR-127997 UCHL5 protein Q9Y5K5 UNIPROT SMAD3 protein P84022 UNIPROT "up-regulates activity" deubiquitination 9606 16027725 t lperfetto "Here, we report a novel interaction between smads and ubiquitin c-terminal hydrolase uch37, a deubiquitinating enzyme that could potentially reverse smurf-mediated ubiquitination. In gst pull down experiments, uch37 bound weakly to smad2 and smad3, and bound very strongly to smad7 in a region that is distinct from the -py- motif in smad7 that interacts with smurf ubiquitin ligases" SIGNOR-232101 MAPK3 protein P27361 UNIPROT PLA2G4A protein P47712 UNIPROT up-regulates phosphorylation Ser505 LNTSYPLsPLSDFAT 9606 8381049 t gcesareni "Activated map kinase phosphorylates cpla2 at ser-505, causing increased enzymatic activity of cpla2, which is only realized upon translocation of cpla2 to the membrane." SIGNOR-38434 CEP290 protein O15078 UNIPROT Cilium_assembly phenotype SIGNOR-PH64 SIGNOR up-regulates 9606 18694559 f miannu "CEP290 cooperates with Rab8a to promote ciliogenesis and this function is antagonized by CP110" SIGNOR-252147 FBXL18 protein Q96ME1 UNIPROT FBXL7 protein Q9UJT9 UNIPROT "down-regulates quantity by destabilization" binding 10090 BTO:0002268 25654763 t miannu "F-box protein Fbxl18 mediates polyubiquitylation and proteasomal degradation of the pro-apoptotic SCF subunit Fbxl7.. Here, we identified that an orphan F-box protein, Fbxl18, targets Fbxl7 for its polyubiquitylation and proteasomal degradation. Lys 109 within Fbxl7 is an essential acceptor site for ubiquitin conjugation by Fbxl18." SIGNOR-272448 GOT2 protein P00505 UNIPROT "glutamic acid" smallmolecule CHEBI:18237 ChEBI "down-regulates quantity" "chemical modification" 9606 31422819 t "Both isoforms [GOT! AND GOT2] catalyze the reversible interconversion of oxaloacetate and glutamate into aspartate and Œ±-ketoglutarate." SIGNOR-266923 CSNK2A1 protein P68400 UNIPROT CFTR protein P13569 UNIPROT up-regulates phosphorylation Ser422 NNNNRKTsNGDDSLF 9606 21930781 t lperfetto "Cftr possesses two ck2 phosphorylation sites (s422 and t1471)this is consistent with an important role for s422 phosphorylation in increasing cftr activity." SIGNOR-176619 RPS6KA3 protein P51812 UNIPROT NFATC4 protein Q14934 UNIPROT up-regulates phosphorylation Ser285 SSASPALsRRGSLGE 10090 17213202 t lperfetto "Serines 281 and 285 of the nfat3 protein might be target amino acids of rsk2 phosphorylationrsk2 induced nuclear localization of nfat3. Rsk2 phosphorylated nfat3 in vitro (km=3.559 microm), and activation of nfat3 by rsk2 enhanced the promoter activity of nfat3 downstream target genes in vivo." SIGNOR-234469 PBX2 protein P40425 UNIPROT EMX2 protein Q04743 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 15494461 f miannu "EMSA demonstrated HOXA10-Pbx2 binding as a heterodimer to an enhancer of the EMX2 gene, a known target of HOXA10 regulation." SIGNOR-254466 FBXO5 protein Q9UKT4 UNIPROT ANAPC7 protein Q9UJX3 UNIPROT down-regulates binding 9606 11751633 t gcesareni "Emi1 can inhibit apc already activated by cdc20 or cdh1." SIGNOR-113382 PPP2CA protein P67775 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR "down-regulates activity" dephosphorylation Thr308 KDGATMKtFCGTPEY 10090 BTO:0000944 15367694 t "Protein phosphatase 2A negatively regulates insulin's metabolic signaling pathway by inhibiting Akt (protein kinase B) activity in 3T3-L1 adipocytes" SIGNOR-248629 F2 protein P00734 UNIPROT LRP1 protein Q07954 UNIPROT up-regulates binding 9606 8626456 t gcesareni "In vitro binding studies revealed that antithrombin iii (atiii)thrombin, heparin cofactor ii (hcii)thrombin, and ?1-antitrypsin (?1AT)trypsin bound to purified lrp" SIGNOR-41090 PDPK1 protein O15530 UNIPROT SGK1 protein O00141 UNIPROT up-regulates phosphorylation Thr256 EHNSTTStFCGTPEY 9534 12387817 t lperfetto "Thus, it was suggested that NHERF2 mediates the activation and phosphorylation of SGK1 by PDK1 through its first PDZ domain and PIF motif, as a novel SGK1 activation mechanism." SIGNOR-236800 Ub:E2 complex SIGNOR-C497 SIGNOR DCST1 protein Q5T197 UNIPROT "up-regulates activity" ubiquitination 9606 34199813 t miannu "The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t" SIGNOR-271164 CDK13 protein Q14004 UNIPROT POLR2A protein P24928 UNIPROT "up-regulates activity" phosphorylation Ser1623 SPTSPSYsPTSPSYS 9606 BTO:0006413 32917631 t "Ser2 in CTD of PolII" lperfetto "Together, these studies demonstrate the important, yet largely redundant, role for CDK12 and CDK13 for the regulation of POLII CTD phosphorylation at multiple residues, as well as the global role for both of these kinases in regulating POLII occupancy across the genome.|CDK12 and CDK13 are thus evolutionarily related and structurally similar kinases, and biochemical assays have demonstrated that both have POLII C-terminal domain (CTD) kinase activity and the ability to phosphorylate the Ser2 residue of the repetitive CTD heptad sequence" SIGNOR-273047 STAT5A protein P42229 UNIPROT SOCS2 protein O14508 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 12468433 t "We have also found SOCS2 and SOCS3 specifically induced in 32D/Flt3-ITD, both of which are STAT3/5 target genes and known negative regulators of receptor signaling" SIGNOR-261547 FOXO3 protein O43524 UNIPROT Cell_death phenotype SIGNOR-PH109 SIGNOR up-regulates 9606 14976264 f lperfetto "Sirt1 inhibited foxo3's ability to induce cell death." SIGNOR-256645 NOTCH proteinfamily SIGNOR-PF30 SIGNOR RBPJ/NOTCH complex SIGNOR-C97 SIGNOR "form complex" binding BTO:0001103 22045613 t svumbaca "NICD is translocated to the nucleus where it binds recombining binding protein-Jj (RBP-Jj)" SIGNOR-255364 SLC9A4 protein Q6AI14 UNIPROT hydron chemical CHEBI:15378 ChEBI "down-regulates quantity" relocalization 9606 BTO:0000938 31507243 t miannu "Na+/H+ exchangers play pivotal roles in the control of cell and tissue pH by mediating the electroneutral exchange of Na+ and H+ across cellular membranes. " SIGNOR-265594 YAP1 protein P46937 UNIPROT TEAD1 protein P28347 UNIPROT up-regulates binding 9606 23431053 t "Crystallographic data revealed that the N-terminal TEAD-binding domain of YAP wraps around a globular structure formed by the C-terminal domains of TEAD1, 2 and 4" gcesareni "When dephosphorylated, yap/taz enter nuclei and induce gene transcription by interacting with transcription factors tead14." SIGNOR-201465 SLC9A7 protein Q96T83 UNIPROT sodium(1+) chemical CHEBI:29101 ChEBI "up-regulates quantity" relocalization 9606 BTO:0000938 31507243 t miannu "Na+/H+ exchangers play pivotal roles in the control of cell and tissue pH by mediating the electroneutral exchange of Na+ and H+ across cellular membranes. " SIGNOR-265606 DCAF12 protein Q5T6F0 UNIPROT Cullin4-RBX1-DDB1 complex SIGNOR-C119 SIGNOR "up-regulates activity" binding 9606 BTO:0002806 31267705 t miannu " The CRL4‐DCAF12 E3 ubiquitin ligase degrades MAGE‐A3/6" SIGNOR-272264 Ub:E2 complex SIGNOR-C497 SIGNOR LNX2 protein Q8N448 UNIPROT "up-regulates activity" ubiquitination 9606 34199813 t miannu "The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t" SIGNOR-271195 EGFR protein P00533 UNIPROT PIK3R1 protein P27986 UNIPROT up-regulates binding 9606 BTO:0000093 BTO:0000150 26918608 t lperfetto "p85alpha promotes nucleolin transcription and subsequently enhances EGFR mRNA stability and EGF-induced malignant cellular transformation." SIGNOR-33633 RBPJ/NOTCH complex SIGNOR-C97 SIGNOR MYOD1 protein P15172 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0000165 10066785 t lperfetto "Delta-induced Notch signaling mediated by RBP-J inhibits MyoD expression and myogenesis" SIGNOR-219359 RET protein P07949 UNIPROT MAPK14 protein Q16539 UNIPROT up-regulates phosphorylation Tyr182 TDDEMTGyVATRWYR 9606 7535770 t gcesareni "Dually phosphorylated on thr-180 and tyr-182 by the map2ks map2k3/mkk3, map2k4/mkk4 and map2k6/mkk6 in response to inflammatory citokines, environmental stress or growth factors, which activates the enzyme." SIGNOR-28063 NHLRC1 protein Q6VVB1 UNIPROT AGL protein P35573 UNIPROT "down-regulates quantity by destabilization" ubiquitination 9534 BTO:0000298 17908927 t miannu "The E3 ubiquitin ligase Malin interacts with and promotes the ubiquitination of AGL." SIGNOR-271669 BAK1 protein Q16611 UNIPROT BAK1 protein Q16611 UNIPROT up-regulates binding 9606 11175253 t amattioni "Allosteric activation of bak induces its intramembranous oligomerization into a proposed pore for cytochrome c efflux" SIGNOR-105203 "Caspase 8 complex" complex SIGNOR-C231 SIGNOR Cell_death phenotype SIGNOR-PH109 SIGNOR up-regulates 9606 14585074 f amattioni "Downstream of caspase-8 activation, apoptosis induction takes place" SIGNOR-256641 ADAM10 protein O14672 UNIPROT NOTCH1 protein P46531 UNIPROT "up-regulates activity" cleavage 9606 BTO:0000782 28624438 t miannu "ADAM10-mediated Notch1 cleavage is the rate limiting-step for release of the NICD and subsequent activation of Notch1 signaling. In T cells ADAM10-mediated Notch1 shedding controls T cell development" SIGNOR-259838 TWIST2 protein Q8WVJ9 UNIPROT ATM protein Q13315 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0004828 19051271 f miannu "we performed microarray analysis to compare the gene expression profiles in HGC-27 cells, with or without small interfering RNA (siRNA)-mediated depletion of TWIST. Our results showed that NF1, RAP1A, SRPX, RBL2, PFDN4, ILK, F2R, ERBB3, and MYB were up-regulated, whereas AKR1C2, FOS, GDF15, NR2F1, ATM, and CTPS were down-regulated after TWIST depletion" SIGNOR-255499 HUWE1 protein Q7Z6Z7 UNIPROT MCL1 protein Q07820 UNIPROT "down-regulates quantity by destabilization" ubiquitination 9606 BTO:0000093 28939105 t miannu "Mule was identified as Mcl-1 ubiquitin ligase E3 to promote Mcl-1 degradation via the proteasomal pathway [46]. We found that knockdown of Mule (Fig. 4C) but not β-TRCP or FBXW7 (data not shown) prevented Mcl-1 downregulation caused by PKCη depletion." SIGNOR-261909 PDH complex SIGNOR-C402 SIGNOR acetyl-CoA smallmolecule CHEBI:15351 ChEBI "up-regulates quantity" "chemical modification" 9606 29059435 t miannu "The mitochondrial pyruvate dehydrogenase complex (PDC) irreversibly decarboxylates pyruvate to acetyl coenzyme A, thereby linking glycolysis to the tricarboxylic acid cycle and defining a critical step in cellular bioenergetics." SIGNOR-266541 MED14 protein O60244 UNIPROT "Core mediator complex" complex SIGNOR-C405 SIGNOR "form complex" binding 9606 28467824 t miannu "Mediator is a multiprotein co-activator that binds the transcription pre-initiation complex (PIC) and regulates RNA polymerase (Pol) II. The Mediator head and middle modules form the essential core Mediator (cMed), whereas the tail and kinase modules play regulatory roles." SIGNOR-266676 SIRT1 protein Q96EB6 UNIPROT FOXO4 protein P98177 UNIPROT up-regulates deacetylation 9606 15126506 t gcesareni "Deacetylation of foxos involves binding of the nad-dependent deacetylase hsir2(sirt1). Accordingly, hsir2(sirt1)-mediated deacetylation precludes foxo inhibition through acetylation and thereby prolongs foxo-dependent transcription of stress-regulating genes." SIGNOR-124714 CALM3 protein P0DP25 UNIPROT EEF2K protein O00418 UNIPROT up-regulates binding 9606 11015200 t miannu "The calmodulin-binding region is located between amino acids 51 and 96" SIGNOR-266337 MAPK1 protein P28482 UNIPROT RPS6KA2 protein Q15349 UNIPROT up-regulates phosphorylation 9606 19282669 t gcesareni "Erk-activates the rsk family of serine/threonine kinases,rsk1, rsk2, and rsk3." SIGNOR-161515 MET protein P08581 UNIPROT PTK2 protein Q05397 UNIPROT up-regulates phosphorylation Tyr861 PIGNQHIyQPVGKPD 9606 16782899 t llicata "Met-mediated fak phosphorylation could further activate fak. Indeed, we found that met phosphorylates fak at its known phosphorylation sites, including tyr-576 and tyr-577, both of which are located in the activating loop within the catalytic domain" SIGNOR-147199 CCK protein P06307 UNIPROT CCKBR protein P32239 UNIPROT up-regulates binding 9606 10368033 t gcesareni "Cck8 interacts with nanomolar affinities with two different receptors designated cck-a and cck-b" SIGNOR-66339 "8-oxo-7-[(6-sulfo-2-naphthalenyl)hydrazinylidene]-5-quinolinesulfonic acid" chemical CHEBI:95064 ChEBI PTPN6 protein P29350 UNIPROT "down-regulates activity" "chemical inhibition" 9606 20337577 t "NSC-87877 (1, Fig. (7)) was identified as a Shp2 PTP inhibitor with an IC50 of 0.33 μM [83]. NSC-87877 inhibits Shp1 with the same potency." SIGNOR-261913 CAPN2 protein P17655 UNIPROT GSK3A protein P49840 UNIPROT "up-regulates activity" cleavage 9606 25969760 t lperfetto "Thus, it has been shown that calpain cleaves the inhibitory domain of GSK3 generating two fragments of 40 and 30 kDa. This cleavage enhanced activity of the kinase" SIGNOR-251612 CSNK1G1 protein Q9HCP0 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR "down-regulates activity" phosphorylation Ser325 SSNASTIsGRLSPIM -1 11980723 t llicata "Phosphorylation of Ser319 forms a consensus sequence for phosphorylation by CK1, allowing it to phosphorylate Ser322, which in turn primes the CK1-catalysed phosphorylation of Ser325 | Multisite phosphorylation of the region containing Ser319, Ser322, Ser325 and Ser329 provides a signal for the nuclear exclusion of FKHR" SIGNOR-252902 SDCBP protein O00560 UNIPROT p38 proteinfamily SIGNOR-PF16 SIGNOR "up-regulates activity" 9534 BTO:0001444 25122212 f Luana "Overall, these results support the hypothesis that the interaction of E protein PBM with syntenin facilitates the recruitment of syntenin in the cytosol and leads to p38 MAPK activation." SIGNOR-260753 TTL protein Q8NG68 UNIPROT TUBA3E protein Q6PEY2 UNIPROT down-regulates tyrosination 9606 22020298 t miannu "Tubulin tyrosine ligase (ttl) adds a c-terminal tyr to __tubulin as part of a tyrosination/detyrosination cycle present in most eukaryotic cells. / ttl inhibits spontaneous tubulin polymerization" SIGNOR-176924 WNK3 protein Q9BYP7 UNIPROT WNK1 protein Q9H4A3 UNIPROT "up-regulates activity" phosphorylation Ser382 KRASFAKsVIGTPEF 9606 22032326 t Manara "We found that wild-type WNK2 (Figure 8A) or WNK3 (Figure 8B) phosphorylated kinase-inactive WNK1 (1–667, D368A) at Ser382 in vitro." SIGNOR-260789 FLT3 protein P36888 UNIPROT FLT3 protein P36888 UNIPROT "up-regulates activity" phosphorylation Tyr969 VSECPHTyQNRRPFS 9606 31395582 t lperfetto "A mutation at tyrosine 969, which inhibits activation of downstream signaling by FLT3-ITD." SIGNOR-271919 CDKN1A protein P38936 UNIPROT Cell_cycle_block phenotype SIGNOR-PH10 SIGNOR up-regulates 9606 24470334 f "The cell cycle regulator p21 is induced early in myoblast differentiation and functions to block cell cycle progression" SIGNOR-267286 TRIM59 protein Q8IWR1 UNIPROT IRF7 protein Q92985 UNIPROT "down-regulates activity" 9606 "BTO:0000567; BTO:0002181" 22588174 f Giorgia "TRIM59 also inhibited the phosphorylation of IRF3 and IRF7, which induces dimerization, suggesting that TRIM59 negatively regulates kinases for IRF3/7 (IKKe/TBK1) or their upstream signal" SIGNOR-260374 ATP(4-) smallmolecule CHEBI:30616 ChEBI ADP(3-) smallmolecule CHEBI:456216 ChEBI "up-regulates quantity" "precursor of" 9606 10101268 t miannu "The enzymes PtdIns 4-kinase (PI4K, for nomenclature see [3]) and PtdIns(4)P 5-kinase (PI4P5K) catalyse the phosphorylation of PtdIns at the D4 and consecutively at the D5 position." SIGNOR-269098 "AL/b2 integrin" complex SIGNOR-C169 SIGNOR Cell_adhesion phenotype SIGNOR-PH7 SIGNOR up-regulates 9606 25388208 f miannu "Integrin-mediated cell adhesion is important for development, immune responses, hemostasis and wound healing." SIGNOR-269018 MAPK1 protein P28482 UNIPROT MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR "down-regulates activity" phosphorylation 9606 BTO:0000007 10567369 t lperfetto "An ERK2-binding site at the N terminus of MEK1 was reported to mediate their stable association. We examined the importance of this binding site in the feedback phosphorylation of mek1 on thr(292) and thr(386) by erk2" SIGNOR-244912 SP1 protein P08047 UNIPROT RHO protein P08100 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000007 15781457 f miannu "Sp4 and Sp1 are activators of the rod opsin promoter" SIGNOR-225385 FOXO proteinfamily SIGNOR-PF27 SIGNOR Adipogenesis phenotype SIGNOR-PH26 SIGNOR down-regulates 9606 18423396 f fspada "Akt1/pkbalpha was found to be the major regulator of phosphorylation and nuclear export offoxo1, whose presence in the nucleus strongly attenuates adipocyte differentiation." SIGNOR-252911 MAPK9 protein P45984 UNIPROT BCL2L11 protein O43521 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser69 GPLAPPAsPGPFATR 18174237 t gcesareni "Constitutive activation of the c-jun n-terminal kinase (jnk) pathway in sup-t1 cells promoted phosphorylation and degradation of bimel via the proteosome." SIGNOR-250136 PFKM protein P08237 UNIPROT "β-D-fructose 6-phosphate" smallmolecule CHEBI:57634 ChEBI "down-regulates quantity" "chemical modification" 9606 16051738 t miannu "Phosphofructokinase catalyzes the rate-limiting, ATP-mediated phosphorylation of F6P to FBP. PFK is a homo- or heterotetramer with a molecular mass of approximately 380 kDa, and the enzyme is allosterically regulated, among other metabolites, by 2,3-DPG.35." SIGNOR-266467 SUCLG1 protein P53597 UNIPROT "Succinyl-CoA GTP variant" complex SIGNOR-C399 SIGNOR "form complex" binding 9606 32627745 t miannu "Succinyl-CoA synthetase (SCS) catalyzes the only substrate-level phosphorylation in the tricarboxylic acid cycle.  In mammals, SCS is a mitochondrial enzyme and is an α,β-heterodimer with different isoforms: ATP-specific SCS (ATPSCS) and GTP-specific SCS (GTPSCS)." SIGNOR-266263 IKK-complex complex SIGNOR-C14 SIGNOR BAD protein Q92934 UNIPROT down-regulates phosphorylation 9606 23332762 t lperfetto "Ikk phosphorylates bad at serine-26 (ser26) and primes it for inactivation." SIGNOR-216399 PRKACG protein P22612 UNIPROT BAD protein Q92934 UNIPROT "down-regulates activity" phosphorylation Ser99 PFRGRSRsAPPNLWA -1 10949026 t gcesareni "Survival factors, acting through kinases such as Akt and PKA, induce endogenous BAD phosphorylation at two evolutionarily conserved sites, Ser-112 and Ser-136, which leads to the translocation of BAD from the mitochondria to the cytoplasm and the inhibition of BAD-dependent death" SIGNOR-67400 FGFR3 protein P22607 UNIPROT FGFR3 protein P22607 UNIPROT "down-regulates activity" phosphorylation Tyr770 LSAPFEQySPGGQDT 9606 BTO:0000007 11294897 t lperfetto "Ligand stimulation leads to autophosphorylation of fgfr3these results suggest that y770 may negatively regulate the activation of pi 3-kinase by constitutively activated fgfr3" SIGNOR-106746 NTS protein P30990 UNIPROT NTSR2 protein O95665 UNIPROT down-regulates binding 9606 BTO:0000975 9851594 t gcesareni "Neurotensin binding to recombinant neurotensin nt2 receptor expressed in cho cells does not elicit a biological response as determined by second messenger measurements." SIGNOR-62519 RUNX1 protein Q01196 UNIPROT ITGA2B protein P08514 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 17725493 f miannu "We and others have previously shown that RUNX1 and GATA-1 physically interact and cooperate in the activation of megakaryocytic promoters such as alpha IIb integrin and glycoprotein Ibalpha." SIGNOR-254193 SH3GLB1 protein Q9Y371 UNIPROT CBL protein P22681 UNIPROT up-regulates binding 9606 11894095 t gcesareni "Cbl rapidly recruits cin85 (cbl-interacting protein of 85k;ref. 6) and endophilins (regulatory components of clathrin-coated vesicles) to form a complex with activated egf receptors, thus controlling receptor internalization." SIGNOR-115826 CALM1 protein P0DP23 UNIPROT CAMKK1 protein Q8N5S9 UNIPROT up-regulates binding 9606 10770941 t lperfetto "The binding of Ca2+/CaM to CaM-KK is absolutely required for its activation and efficient phosphorylation of target protein kinases" SIGNOR-232178 PPP1R1C protein Q8WVI7 UNIPROT PP1 proteinfamily SIGNOR-PF54 SIGNOR "down-regulates activity" binding 18310074 t lperfetto "IPP5, a novel inhibitor of protein phosphatase 1, suppresses tumor growth and progression of cervical carcinoma cells by inducing G2/M arrest" SIGNOR-275725 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR RPS6KA5 protein O75582 UNIPROT up-regulates phosphorylation Ser360 TEMDPTYsPAALPQS 9606 18267068 t lperfetto "Together, our in vivo and in vitro studies indicate that the pkc/c-raf/mek/erk pathway plays a major role in the s6k1 activation in hypertrophic cardiac growth." SIGNOR-249572 IL10 protein P22301 UNIPROT SCN5A protein Q14524 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 10116 BTO:0000938 BTO:0001264 23357618 f miannu "Interleukin-10 down-regulates voltage gated sodium channels in rat dorsal root ganglion neurons. Consistent with the electrophysiological results, real-time PCR and western blot revealed that IL-10 (200 pg/ml) down-regulated VGSCs in both mRNA and protein levels and reversed the up-regulation of VGSCs by TNF-α." SIGNOR-253496 PIAS1 protein O75925 UNIPROT PRDM1 protein O75626 UNIPROT up-regulates sumoylation Lys816 PLVPVKVkQETVEPM 9606 22555612 t miannu "Blimp_1 is subjected to pias1_mediated sumoylation at lysine 816 / it appears that sumo_modified blimp_1 is a more potent transcriptional repressor." SIGNOR-197265 LYL1 protein P12980 UNIPROT ANGPT2 protein O15123 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 22792348 f miannu "Here, we identified angiopoietin-2 (ang-2), which encodes a major regulator of angiogenesis, as a direct transcriptional target of tal1,lyl1and lmo2. Knockdown of any of the three transcription factors in human blood and lymphatic endothelial cells caused ang-2 mrna and protein down-regulation." SIGNOR-198276 CSNK1D protein P48730 UNIPROT NCOA3 protein Q9Y6Q9 UNIPROT up-regulates phosphorylation Ser601 SDKESKEsSVEGAEN 9606 BTO:0000150 19339517 t lperfetto "In this study, we show that both eralpha and aib1 are substrates for ck1delta in vitro, and identify a novel aib1 phosphorylation site (s601) targeted by ck1delta, significant for the co-activator function of aib1." SIGNOR-184946 SUFU protein Q9UMX1 UNIPROT GLI2 protein P10070 UNIPROT "up-regulates quantity by stabilization" binding 9606 BTO:0000007 20463034 t Gianni "We show that loss of suppressor of fused (Sufu; an inhibitory effector for Gli proteins) results in destabilization of Gli2 and Gli3 full-length activators but not of their C-terminally processed repressors, whereas overexpression of Sufu stabilizes them." SIGNOR-268867 P2RY2 protein P41231 UNIPROT H3-3A protein P84243 UNIPROT "up-regulates activity" demethylation Lys5 kQTARKST 9606 30246379 t miannu "KDM5 subfamily is capable of removing tri‐ and di‐ methyl marks from lysine 4 on histone H3 (H3K4). Depending on the methylation site, its effect on transcription can be either activating or repressing." SIGNOR-264307 ING1 protein Q9UK53 UNIPROT CDKN1A protein P38936 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000599 14522900 f miannu " In this study, we found that a subset of ING family members strongly repressed human alpha-fetoprotein (AFP) promoter activity but stimulated the p21(WAF1) promoter in parallel experiments in the same cell type, similar to the effects of p53. Both ING1 and p53 were able to suppress AFP transcription and cause p21 induction; hSIR2, a negative regulator of the p53 protein, showed the opposite effects on the AFP promoter and, like HDAC1, repressed p21 promoter activity." SIGNOR-254483 CHEK2 protein O96017 UNIPROT TTK protein P33981 UNIPROT up-regulates phosphorylation Thr288 SPDCDVKtDDSVVPC 9606 19151762 t llicata "Phosphorylation at ttk/hmps1 thr288 is enhanced by chk2 in vitro and in vivo after ir" SIGNOR-242665 SMARCA4 protein P51532 UNIPROT SMARCC1 protein Q92922 UNIPROT up-regulates binding 9606 10078207 t miannu "The remodeling activity of brg1 and hbrm is stimulated by baf170/baf155 and is further stimulated when ini1 is added." SIGNOR-65441 DDX20 protein Q9UHI6 UNIPROT FOXL2 protein P58012 UNIPROT up-regulates binding 9606 BTO:0000975 16153597 t miannu "Dp103 further increased the cell killing effect induced by foxl2 probably due to the direct association of dp103 with foxl2 protein." SIGNOR-140388 PRKACA protein P17612 UNIPROT ATF1 protein P18846 UNIPROT "up-regulates activity" phosphorylation Ser63 GILARRPsYRKILKD -1 9016641 t miannu "PKA catalytic subunit phosphorylates ATF-1 at Ser63 and that phosphorylation is essential for efficient DNA binding by ATF-1." SIGNOR-250336 PRKCA protein P17252 UNIPROT MET protein P08581 UNIPROT down-regulates phosphorylation Ser985 PHLDRLVsARSVSPT 9606 8294430 t fstefani "These data show that phosphorylation of ser985 is a key mechanism for the negative regulation of hgf/sf receptor." SIGNOR-37718 PPM1F protein P49593 UNIPROT PAK1 protein Q13153 UNIPROT down-regulates dephosphorylation 9606 20016286 t gcesareni "Pop x2, a pp 2c serine/threonine phosphatase, is known to dephosphorylate pak and downregulate its activity." SIGNOR-162146 PTPN6 protein P29350 UNIPROT JAK3 protein P52333 UNIPROT up-regulates dephosphorylation 9606 11021818 t gcesareni "The expression of shp-1 protein was associated with dephosphorylation of the jak3 kinase." SIGNOR-82764 AKT proteinfamily SIGNOR-PF24 SIGNOR FOXO proteinfamily SIGNOR-PF27 SIGNOR "down-regulates activity" phosphorylation Ser262 TFRPRSSsNASSVST 10090 10217147 t "Here we show that protein kinase B phosphorylates AFX, a human orthologue of daf -16 (refs 5, 6, 9), both in vitro and in vivo." SIGNOR-252839 sunitinib chemical CHEBI:38940 ChEBI FLT1 protein P17948 UNIPROT down-regulates "chemical inhibition" 9606 21423276 t gcesareni "The vegfr/pdgfr inhibitor sunitinib (selleck) was used at 35 mg/kg in citrate-buffered water and administered daily by oral gavage for 7 days." SIGNOR-172908 PAX7 protein P23759 UNIPROT Skeletal_muscle_differentiation phenotype SIGNOR-PH1 SIGNOR down-regulates 9606 BTO:0001103;BTO:0002314 22493066 f lperfetto "Constitutive Notch Activation Upregulates Pax7 and Promotes the Self-Renewal of Skeletal Muscle Satellite Cells" SIGNOR-219371 PHLPP2 protein Q6ZVD8 UNIPROT AKT3 protein Q9Y243 UNIPROT "down-regulates activity" dephosphorylation Ser472 RPHFPQFsYSASGRE 9606 17386267 t gcesareni "Knockdown studies reveal that PHLPP1 specifically modulates the phosphorylation of HDM2 and GSK-3alpha through Akt2, whereas PHLPP2 specifically modulates the phosphorylation of p27 through Akt3" SIGNOR-237439 PRKCA protein P17252 UNIPROT VTN protein P04004 UNIPROT "up-regulates quantity by stabilization" phosphorylation Ser381 RNRKGYRsQRGHSRG -1 9030777 t lperfetto "Phosphorylation of vitronectin on Ser362 by protein kinase C attenuates its cleavage by plasmin." SIGNOR-248962 AKT1 protein P31749 UNIPROT BRAF protein P15056 UNIPROT "down-regulates activity" phosphorylation Ser365 GQRDRSSsAPNVHIN 9606 10869359 t "Akt phosphorylates both S364 and S428. Akt downregulates B-Raf activity in vivo" SIGNOR-251471 EGFR protein P00533 UNIPROT NCK1 protein P16333 UNIPROT "up-regulates activity" binding 10090 BTO:0000944 1333047 t "We show that epidermal growth factor or platelet-derived growth factor stimulation of intact human or murine cells leads to phosphorylation of Nck protein on tyrosine, serine, and threonine residues" SIGNOR-252089 TNFRSF17 protein Q02223 UNIPROT MAPK12 protein P53778 UNIPROT up-regulates 9606 10903733 f miannu "Overexpression of bcma activates the p38 mapk" SIGNOR-79498 IRF3 protein Q14653 UNIPROT ABCC2 protein Q92887 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 15185298 f miannu "Expression of recombinant human IRF3 increased MRP2 promoter activity. " SIGNOR-254533 NCKIPSD protein Q9NZQ3 UNIPROT NCK1 protein P16333 UNIPROT unknown binding 9606 14559906 t gcesareni "Such phosphorylation of spin90 likely promotes the interaction of the spin90.betapix.wasp complex and nck" SIGNOR-118750 afatinib chemical CHEBI:61390 ChEBI ERBB2 protein P04626 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-189359 R547 chemical CID:6918852 PUBCHEM CCNE1 protein P24864 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-206355 PRKACA protein P17612 UNIPROT SOX9 protein P48436 UNIPROT up-regulates phosphorylation Ser181 YQPRRRKsVKNGQAE 9606 15889150 t llicata "We find that activation of camp-dependent protein kinase a (pka) induces phosphorylation of sox9 on its two s64 and s181 pka sites, and its nuclear localization by enhancing sox9 binding to the nucleocytoplasmic transport protein importin beta." SIGNOR-137085 CAMTA1 protein Q9Y6Y1 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR down-regulates 9606 BTO:0005397 21385898 f irozzo "Our findings define properties of CAMTA1 in growth suppression and neuronal differentiation that support its assignment as a 1p36 tumor suppressor gene in neuroblastoma." SIGNOR-259099 WWTR1 protein Q9GZV5 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 23075495 f gcesareni "Yap and taz are two main downstream effectors of the hippo pathway, and they function as transcription co-activators to promote cell proliferation and inhibit apoptosis." SIGNOR-199211 KLHL7 protein Q8IXQ5 UNIPROT TUT1 protein Q9H6E5 UNIPROT "down-regulates quantity by destabilization" binding 9606 BTO:0000675 29032201 t miannu "Kelch-like protein 7 (KLHL7) is a component of Cul3-based Cullin-RING ubiquitin ligase. In this study, we report that KLHL7 increases terminal uridylyl transferase 1 (TUT1) ubiquitination involved in nucleolar integrity." SIGNOR-272318 EP300 protein Q09472 UNIPROT SMAD7 protein O15105 UNIPROT up-regulates acetylation Lys64 RAGCCLGkAVRGAKG 9606 15831498 t gcesareni "Here we present evidence that smad7 interacts with the transcriptional coactivator p300, resulting in acetylation of smad7 on two lysine residues in its n terminus. Acetylation or mutation of these lysine residues stabilizes smad7 and protects it from tgfbeta-induced degradation. we have recently shown that smad7 is acetylated on lysine residues 64 and 70 by p300" SIGNOR-135469 CHUK protein O15111 UNIPROT CREBBP protein Q92793 UNIPROT up-regulates binding 9606 12789342 t gcesareni "Ikk-alpha interacts with creb-binding protein and in conjunction with rel a is recruited to nf-kappab-responsive promoters and mediates the cytokine-induced phosphorylation and subsequent acetylation of specific residues in histone h3." SIGNOR-101539 SP1 protein P08047 UNIPROT NDUFV1 protein P49821 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000931 17786189 f miannu "Sp1 role in the regulation of complex I subunits, was demonstrated by the ability of the Sp1/DNA binding inhibitor, mithramycin, to inhibit the transcription of NDUFV1 and NDUFV2, in neuroblastoma cells. In addition, Sp1 activated NDUFV2 promoter by binding to its three GC-boxes. Both activation and binding were inhibited by mithramycin." SIGNOR-255206 JWOGUUIOCYMBPV-GMFLJSBRSA-N chemical CID:6918328 PUBCHEM HDAC2 protein Q92769 UNIPROT "down-regulates activity" "chemical inhibition" 9606 BTO:0000567 17868033 t "Simone Vumbaca" "Apicidin inhibited rhHDACs 2 and 3 in the nanomolar range." SIGNOR-261127 RPS6K proteinfamily SIGNOR-PF26 SIGNOR MTOR protein P42345 UNIPROT "down-regulates activity" phosphorylation Thr2446 NKRSRTRtDSYSAGQ 9606 15905173 t lperfetto "Importantly, phosphorylation of mTOR by S6K1 occurs at threonine 2446/serine 2448. This region has been shown previously to be part of a regulatory repressor domain. These sites are also constitutively phosphorylated in the breast cancer cell line MCF7 carrying an amplification of the S6K1 geneit has been proposed that other inputs, in addition to phosphorylation of Thr-2446/Ser-2448 by S6K1, are part of the mechanism involved in inhibiting this repressor domain" SIGNOR-137255 Macrophage_activation phenotype SIGNOR-PH126 SIGNOR IL18 protein Q14116 UNIPROT "up-regulates quantity" 9606 BTO:0000801 10653850 f miannu "IL-18, originally described as IFN-γ-inducing factor, is secreted from activated macrophages and Kupffer cells (1–3). The major activity associated with this cytokine is induction of IFN-γ production from CD4+ Th1 cells, T cells, B cells and NK cells, especially in collaboration with IL-12. IL-12 and IL-18 acted in a synergistic manner for the development of T cells into IFN-γ-producing cells without their TCR engagement." SIGNOR-260964 GADD45GIP1 protein Q8TAE8 UNIPROT "39S mitochondrial large ribosomal subunit" complex SIGNOR-C285 SIGNOR "form complex" binding -1 25838379 t lperfetto "We have determined the structure of the intact mitoribosome to 3.5 angstrom resolution by single-particle electron cryo-microscopy. It reveals 80 extensively interconnected proteins, 36 of which are specific to mitochondria, and three rRNA molecules" SIGNOR-262385 CDK1 protein P06493 UNIPROT SP1 protein P08047 UNIPROT up-regulates phosphorylation Thr739 SEGSGTAtPSALITT 9606 BTO:0000887;BTO:0001260 SIGNOR-C17 20150555 t gcesareni "Moreover, we showed that sp1 is a novel mitotic substrate of cdk1/cyclin b1 and is phosphorylated by it at thr 739 before the onset of mitosis." SIGNOR-163738 pyruvate smallmolecule CHEBI:15361 ChEBI acetyl-CoA smallmolecule CHEBI:15351 ChEBI "up-regulates quantity" "precursor of" 9606 29059435 t miannu "The mitochondrial pyruvate dehydrogenase complex (PDC) irreversibly decarboxylates pyruvate to acetyl coenzyme A, thereby linking glycolysis to the tricarboxylic acid cycle and defining a critical step in cellular bioenergetics." SIGNOR-266542 TNF protein P01375 UNIPROT NOTCH4 protein Q99466 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0004914 14586405 f "We found that TNF induced the expression of Notch-1, Notch-4, and Jagged-2 in RSF. The expression of these proteins was detected in the RA synovial tissues." SIGNOR-253607 PPP1CA protein P62136 UNIPROT MAPK1 protein P28482 UNIPROT down-regulates dephosphorylation 9606 12840032 t gcesareni "P-erk1/2 proteins were efficiently dephosphorylated in vitro by protein phosphatases 1 and 2a (pp1/2a) and mapk phosphatase 3 (mkp3)" SIGNOR-103152 haloperidol chemical CHEBI:5613 ChEBI HTR1A protein P08908 UNIPROT "down-regulates activity" "chemical inhibition" 10116 BTO:0000601 8935801 t miannu "Risperidone and its active metabolite 9-OH-risperidone were compared to reference antipsychotic drugs (haloperidol, pipamperone, fluspirilene, clozapine, zotepine) and compounds under development (olanzapine, seroquel, sertindole, ORG-5222, ziprasidone) for in vitro binding to neurotransmitter receptors in brain tissue and on membranes of recombinant cells expressing cloned human receptors and for in vivo occupancy of neurotransmitter receptors in rat and guinea-pig brain following acute treatment (2 h., s.c.). The binding affinities of the compounds for various neurotransmitter receptors were measured using membrane preparations of animal brain regions and of recombinant cells expressing cloned, mostly human receptors. Receptors, tissues and cells are indicated in Table I; results are shown in Table 4A-B." SIGNOR-258521 PRKCA protein P17252 UNIPROT NR1H4 protein Q96RI1 UNIPROT up-regulates phosphorylation Ser164 CKGFFRRsITKNAVY 9606 18755856 t llicata "Phosphorylation of farnesoid x receptor by protein kinase c promotes its transcriptional activity. pkcalpha phosphorylates in vitro fxr in its dna-binding domain on s135 and s154." SIGNOR-180541 TP53 protein P04637 UNIPROT FGF2 protein P09038 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 10029407 f miannu "p53 transcriptionally activates expression of the genes encoding epidermal growth factor receptor, matrix metalloproteinase (MMP)-2, cathepsin D, and thrombospondin-1 but represses expression of the genes encoding basic fibroblast growth factor and multidrug resistance-1." SIGNOR-255431 GGCX protein P38435 UNIPROT F2 protein P00734 UNIPROT "up-regulates activity" carboxylation Glu63 LERECVEeTCSYEEA -1 10556651 t lperfetto "We analyzed the number of glutamic acid (Glu) residues and their positions in the Gla domain (GD) of DCP to investigate the gamma-carboxylation mechanism of VK-dependent carboxylase. Several DCPs were found in each subject studied. The 10 Gla residues of human prothrombin were carboxylated in order from the N-terminal (residues 26, 25, 16, 29, 20, 19, 14, 32, 7 and 6)|In the absence of VK or in the presence of VK antagonists, hepatic VKdependent carboxylase activity is inhibited and des-g-carboxyprothrombin (abnormal prothrombin or PIVKA; protein induced by vitamin K antagonist, prothrombin) is released into the blood." SIGNOR-263680 lysine smallmolecule CHEBI:25094 ChEBI AminoAcids stimulus SIGNOR-ST5 SIGNOR "up-regulates quantity" 29259120 t lperfetto "All extant life employs the same 20 amino acids for protein biosynthesis" SIGNOR-264755 chlorphenamine chemical CHEBI:52010 ChEBI HRH1 protein P35367 UNIPROT "down-regulates activity" "chemical inhibition" -1 12781173 t Luana "Identification of a dual histamine H1/H3 receptor ligand based on the H1 antagonist chlorpheniramine." SIGNOR-257896 PRKCD protein Q05655 UNIPROT PTPN22 protein Q9Y2R2 UNIPROT down-regulates phosphorylation Ser35 FLKLKRQsTKYKADK 9606 BTO:0000782 18056643 t llicata "We show that lyp is phosphorylated exclusively at ser-35 by pkc both in vitro and in vivo. our data establish a mechanism by which pkc could attenuate the cellular function of lyp, thereby augmenting t cell activation." SIGNOR-159591 CAMK2D protein Q13557 UNIPROT CAMK2D protein Q13557 UNIPROT up-regulates phosphorylation 9606 19725819 t areggio "Upon binding of the Ca2+/calmodulin complex to the binding domain of CaMKII, it is activated via autophosphorylation, then remaining active independent of of Ca2+ levels." SIGNOR-255954 EZH2 protein Q15910 UNIPROT HOXA10 protein P31260 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 20565746 t miannu "These data support the proposed regulatory impact of particular PRC2-proteins in expression of HOXA9 and HOXA10 in NK/T-cells. In mammalian cells knockdown of PRC2 components EZH2 or PHF1 led to upregulated HOXA gene expression." SIGNOR-260070 estramustine chemical CHEBI:4868 ChEBI ESR2 protein Q92731 UNIPROT "up-regulates activity" "chemical activation" 9606 14755680 t miannu "A variety of new estrogenic/anti‐estrogenic/selective estrogen receptor modulator (SERM)‐like compounds, including 2‐methoxyestradiol, genistein, resveratrol, licochalcone, Raloxifene, ICI 182,780, and estramustine are being evaluated for their potential in the next generation of PCa therapies." SIGNOR-259299 "Vincristine sulfate" chemical CHEBI:79401 ChEBI TUBB4A protein P04350 UNIPROT "down-regulates activity" "chemical inhibition" 9606 30599272 t miannu "Vincristine is commonly administered as an effective anti-brain tumor drug. Vincristine treatment also impaired the microtubule-associated protein tubulin, and fibronectin, and downregulated MMP10 activity." SIGNOR-259250 RET protein P07949 UNIPROT Gbeta proteinfamily SIGNOR-PF4 SIGNOR up-regulates phosphorylation 9606 16153436 t "inferred from 70% of family members" gcesareni "We hypothesized that ret could directly phosphorylate fak and erk. erk 2 could be phosphorylated at y187 (y204 in erk1)." SIGNOR-269894 TNKS2 protein Q9H2K2 UNIPROT AXIN2 protein Q9Y2T1 UNIPROT "down-regulates quantity by destabilization" ADP-ribosylation 9606 BTO:0000007 19759537 t lperfetto "Together, these findings are consistent with the hypothesis that TNKS promotes the ubiquitination and degradation of axin, which may be mediated, at least in part, through the direct PARsylation of axin." SIGNOR-263380 UQCR11 protein O14957 UNIPROT "Mitochondrial respiratory chain complex III" complex SIGNOR-C279 SIGNOR "form complex" binding 30030361 t lperfetto "Complex III (EC 1.10.2.2) or quinol-cytochrome c reductase performs electron transfer coupled to proton pumping using the ‘Q-cycle’ mechanism [79,80]. Structurally, it is a tightly bound symmetrical dimer (cIII2), being each ‘monomer’ composed of three catalytic core (MT-CYB, CYC1 and UQCRFS1) and seven supernumerary subunits" SIGNOR-262196 MT-CYB protein P00156 UNIPROT "Mitochondrial respiratory chain complex III" complex SIGNOR-C279 SIGNOR "form complex" binding 30030361 t lperfetto "Complex III (EC 1.10.2.2) or quinol-cytochrome c reductase performs electron transfer coupled to proton pumping using the ‘Q-cycle’ mechanism [79,80]. Structurally, it is a tightly bound symmetrical dimer (cIII2), being each ‘monomer’ composed of three catalytic core (MT-CYB, CYC1 and UQCRFS1) and seven supernumerary subunits" SIGNOR-262193 SMAD3 protein P84022 UNIPROT BCL2 protein P10415 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 16766264 f irozzo "This protection is conferred by Smad3’s ability to promote apoptosis by repressing Bcl-2 transcription in vivo through a GC-rich element in the Bcl-2 promoter." SIGNOR-256294 UNC5D protein Q6UXZ4 UNIPROT DCC protein P43146 UNIPROT "down-regulates activity" binding 9606 BTO:0001484 25881791 t miannu "In the presence of netrin-1, UNC5 co-immuno-precipitates with DCC, suggesting the formation of a ternary complex of netrin-1 with ecto-domains of DCC and UNC5. DCC binding to netrin-1 alone leads to axon attraction. Importantly, DCC has the ability to switch the netrin-1-mediated responses from attraction to repulsion when another receptor UNC5 co-exists. DCC binding to netrin-1 alone leads to axon attraction. Importantly, DCC has the ability to switch the netrin-1-mediated responses from attraction to repulsion when another receptor UNC5 co-exists." SIGNOR-268167 TNF protein P01375 UNIPROT DIO proteinfamily SIGNOR-PF83 SIGNOR "down-regulates quantity by repression" "transcriptional regulation" 10116 9397972 f "inferred from family member" scontino "From the results in Figs. 1-3, it is clear that several cytokines reduce the expression of 5‚Äô-DI mRNA and enzymatic activity in FRTL-5 cells. These include TNF-a, IL-lb and INF-y." SIGNOR-270239 ACD protein Q96AP0 UNIPROT RPA3 protein P35244 UNIPROT "down-regulates activity" binding SIGNOR-C306 18680434 t lperfetto "The current model for how telomeres repress ATR signaling proposes that POT1/TPP1 prevents the binding of RPA to the single-stranded telomeric DNA" SIGNOR-263329 MMP2 protein P08253 UNIPROT ECM stimulus SIGNOR-ST20 SIGNOR down-regulates 17318226 f lperfetto "Historically, MMPs were thought to function mainly as enzymes that degrade structural components of the ECM." SIGNOR-272387 "Raf265 derivative" chemical CID:23654923 PUBCHEM RAF1 protein P04049 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-206394 PKC proteinfamily SIGNOR-PF53 SIGNOR PPP1R14B protein Q96C90 UNIPROT "up-regulates activity" phosphorylation Thr57 VRRQGKVtVKYDRKE 10606530 t lperfetto "Recombinant tagged PHI-1 was phosphorylated by protein kinase C at two sites, one a Ser and one a Thr; phosphorylation enhanced inhibitory potency 50-fold." SIGNOR-265740 PRKCD protein Q05655 UNIPROT ADRB2 protein P07550 UNIPROT "down-regulates activity" phosphorylation Ser345 ELLCLRRsSLKAYGN -1 1848190 t lperfetto "We investigate the role of the beta 2-adrenergic receptor phosphorylation by protein kinase C in this regulatory process. Mutation of the serine-261, -262, -344 and -345 of the beta 2-adrenergic receptor prevented the phorbol-ester-induced phosphorylation of the receptor. This mutation also abolished the phorbol-ester-induced decrease in high-affinity agonist binding and potency of the beta 2-adrenergic receptor. We suggest that protein kinase C mediated phosphorylation of the receptor promotes its functional uncoupling." SIGNOR-248857 WNK3 protein Q9BYP7 UNIPROT SLC12A6 protein Q9UHW9 UNIPROT "down-regulates activity" phosphorylation Thr1048 YQEKVHMtWTKDKYM 9606 24043619 t Manara "WNK3, which inhibits the activity of KCC3, promoted phosphorylation of Ser-96 as well as Thr-991 and Thr-1048. " SIGNOR-260910 SLC9A6 protein Q92581 UNIPROT sodium(1+) chemical CHEBI:29101 ChEBI "up-regulates quantity" relocalization 9606 BTO:0000938 31507243 t miannu "Na+/H+ exchangers play pivotal roles in the control of cell and tissue pH by mediating the electroneutral exchange of Na+ and H+ across cellular membranes. " SIGNOR-265605 AKT1 protein P31749 UNIPROT FSTL1 protein Q12841 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 18718903 f miannu "Akt1 Overexpression in Skeletal Muscle Increases Capillary Vessel Formation and Up-regulates Fstl1 Expression" SIGNOR-266605 MMP20 protein O60882 UNIPROT ECM stimulus SIGNOR-ST20 SIGNOR down-regulates 17318226 f lperfetto "Historically, MMPs were thought to function mainly as enzymes that degrade structural components of the ECM." SIGNOR-272388 PRKCD protein Q05655 UNIPROT PA2G4 protein Q9UQ80 UNIPROT up-regulates phosphorylation Ser360 ELKALLQsSASRKTQ 9606 BTO:0000938 21145366 t gcesareni "Trk receptor activation by both ngf and bdnf induced phosphorylation of ebp1 at the s360 upon the activation of protein kinase c (pkc ) and triggered dissociation of p48 from retinoblastoma (rb" SIGNOR-170348 IYD protein Q6PHW0 UNIPROT 3,5-diiodo-L-tyrosine smallmolecule CHEBI:15768 ChEBI "down-regulates quantity" "chemical modification" 9606 28153798 t scontino "MIT and DIT, which are deiodinated by iodotyrosine dehalogenase (DEHAL1) that seems to be present in the apical plasma membrane. MIT and DIT are liberated, and the deiodination of these molecules by DEHAL1 is important for providing a sustained source of intrathyroidal iodide." SIGNOR-267036 CENPE protein Q02224 UNIPROT Spindle_assembly phenotype SIGNOR-PH60 SIGNOR up-regulates 20383333 f lperfetto "Additionally, cdr2 knockdown lead to a decrease (Table 3) in four other transcripts (AURKA, CENPE, SPC25 and TTK), which are involved in kinetochore and spindle biology" SIGNOR-252013 LIPH protein Q8WWY8 UNIPROT LPAR2 protein Q9HBW0 UNIPROT up-regulates binding 9606 BTO:0000661 9525886 t gcesareni "When overexpressed in jurkat t cells, the edg4 protein mediated lpa-induced activation of a serum response element reporter gene with lpa concentration dependence (ec50 of 10 nm) and specificity." SIGNOR-56093 FOXE1 protein O00358 UNIPROT TPO protein P07202 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0001073 27347897 t scontino "TSH regulates TPO expression through the cAMP pathway and acts with thyroid-specific transcription factors such as TTF-1, TTF-2 and Pax-8" SIGNOR-267279 MAPK6 protein Q16659 UNIPROT MAPK6 protein Q16659 UNIPROT up-regulates phosphorylation Ser189 YSHKGHLsEGLVTKW 9606 8621539 t lperfetto "Ser189 of erk3, which corresponds to thr183, one of the activating phosphorylation sites of erk2, is autophosphorylated in vitro and phosphorylated in vivo." SIGNOR-40097 XIAP protein P98170 UNIPROT CASP9 protein P55211 UNIPROT "down-regulates quantity by destabilization" binding 9606 11242052 t lperfetto "A conserved XIAP-interaction motif in caspase-9 and Smac/DIABLO regulates caspase activity and apoptosis" SIGNOR-105702 SIRT1 protein Q96EB6 UNIPROT EP300 protein Q09472 UNIPROT down-regulates deacetylation Lys1024 TELKTEIkEEEDQPS 9606 BTO:0000150 19047049 t gcesareni "Sirt1 induces deacetylation and repression of p300 itself (81). Mutational analysis demonstrated that sirt1 repression of p300 involves both lysine 1020 and lysine 1024" SIGNOR-182511 POLD1 protein P28340 UNIPROT "DNA polymerase delta" complex SIGNOR-C376 SIGNOR "form complex" binding -1 12403614 t lperfetto "Reconstitution and characterization of the human DNA polymerase delta four-subunit holoenzyme." SIGNOR-265518 NfKb-p65/p50 complex SIGNOR-C13 SIGNOR Survival phenotype SIGNOR-PH13 SIGNOR up-regulates 9606 14585074 f amattioni "Activation of the nf-kb pathway regulates a variety of ant-apoptotic factors" SIGNOR-96834 PRKAA1 protein Q13131 UNIPROT CRTC1 protein Q6UUV9 UNIPROT down-regulates phosphorylation 9606 SIGNOR-C15 21331044 t gcesareni "Here we show that both ampk and calcineurin modulate longevity exclusively through post-translational modification of crtc-1, the sole c. elegans crtc. We demonstrate that crtc-1 is a direct ampk target." SIGNOR-172136 UBE2O protein Q9C0C9 UNIPROT SMAD6 protein O43541 UNIPROT down-regulates ubiquitination Lys173 LLLEQELkTVTYSLL 9606 23455153 t gcesareni "We showed that ube2o functions as an e2-e3 hybrid to monoubiquitinate smad6 at lysine 174" SIGNOR-192255 "hydrogen peroxide" smallmolecule CHEBI:16240 ChEBI ROS stimulus SIGNOR-ST2 SIGNOR up-regulates 9606 35681445 f lperfetto "The ROS, including superoxide anion, hydrogen peroxide, and nitric oxide, play both beneficial and detrimental roles depending upon their levels and cellular microenvironment." SIGNOR-272278 BMP2 protein P12643 UNIPROT SMAD1 protein Q15797 UNIPROT up-regulates 9606 22298955 f lperfetto "Neogenin, a transmembranous protein, was reported to regulate bmp receptor association with lipid raft, where bmp induces canonical smad1/5/8 phosphorylation." SIGNOR-195561 ABL1 protein P00519 UNIPROT EGFR protein P00533 UNIPROT up-regulates phosphorylation Tyr1172 ISLDNPDyQQDFFPK 9606 16943190 t gcesareni "We show that activated abl phosphorylates the egfr primarily on tyrosine 1173." SIGNOR-149273 4-(2,6-dichlorobenzamido)-N-(piperidin-4-yl)-pyrazole-3-carboxamide chemical CHEBI:91326 ChEBI CCNB1 protein P14635 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-189969 ATP5F1D protein P30049 UNIPROT "ATP synthase" complex SIGNOR-C264 SIGNOR "form complex" binding 9606 21874297 t miannu "Human mitochondrial ATP synthase, or complex V, consists of two functional domains, F1 and Fo. F1 comprises 5 different subunits (three α, three β, and one γ, δ and ε) and is situated in the mitochondrial matrix. Fo contains subunits c, a, b, d, F6, OSCP and the accessory subunits e, f, g and A6L." SIGNOR-261402 USP36 protein Q9P275 UNIPROT FBL protein P22087 UNIPROT "up-regulates quantity by stabilization" deubiquitination 9606 BTO:0000567 19208757 t lperfetto "USP36 deubiquitylated the nucleolar proteins nucleophosmin/B23 and fibrillarin, and stabilized them by counteracting ubiquitylation-mediated proteasomal degradation. " SIGNOR-272291 ATM protein Q13315 UNIPROT FANCD2 protein Q9BXW9 UNIPROT up-regulates phosphorylation Ser1401 LQGEEIKsQNSQEST 9606 12086603 t lperfetto "These results suggest that s222 and either s1401, s1404, or s1408 are sites of atm-dependent phosphorylation in vitro.Phosphorylation Of fancd2 is required for activation of an s phase checkpoint" SIGNOR-90109 SKA1 protein Q96BD8 UNIPROT "SKA complex" complex SIGNOR-C364 SIGNOR "form complex" binding -1 22483620 t lperfetto "We show that the structure of the Ska core complex is a W-shaped dimer of coiled coils, formed by intertwined interactions between Ska1, Ska2, and Ska3." SIGNOR-265197 KLHL25 protein Q9H0H3 UNIPROT ACLY protein P53396 UNIPROT "down-regulates quantity by destabilization" binding 9606 BTO:0002552 27664236 t miannu "Here, we found that CUL3 interacts with ACLY through its adaptor protein, KLHL25 (Kelch-like family member 25), to ubiquitinate and degrade ACLY in cells. " SIGNOR-272333 SHMT1 protein P34896 UNIPROT "glycine zwitterion" smallmolecule CHEBI:57305 ChEBI "up-regulates quantity" "chemical modification" 9606 11802770 t miannu "HTMLA might be identical to serine hydroxymethyltransferase (SHMT; EC 2.1.2.1), since it has been shown that SHMT purified from rabbit liver acts upon HTML, yielding TMABA and glycine." SIGNOR-269689 WT1 protein P19544 UNIPROT AREG protein P15514 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 10490105 t lperfetto "The Wilms Tumor Suppressor WT1 Encodes a Transcriptional Activator of amphiregulin" SIGNOR-251745 EFNA1 protein P20827 UNIPROT EPHA8 protein P29322 UNIPROT up-regulates binding 9606 9576626 t gcesareni "Ephrins are cell-surface tethered guidance cues that bind to eph receptor tyrosine kinases in trans on opposing cells." SIGNOR-56968 RLIM protein Q9NVW2 UNIPROT ZFP42 protein Q96MM3 UNIPROT "down-regulates quantity by destabilization" ubiquitination 22596162 t lperfetto "RNF12 causes ubiquitination and proteasomal degradation of REX1, and Rnf12 knockout embryonic stem cells show an increased level of REX1." SIGNOR-269002 SMURF1 protein Q9HCE7 UNIPROT RABEP2 protein Q9H5N1 UNIPROT unknown ubiquitination -1 20804422 t miannu "Recombinant proteins were used to profile substrate ubiquitination by the Smurf1 ubiquitin ligase on a global scale using protein microarrays. T Proteins ubiquitinated on the protein microarray were confirmed as potential substrates of the Smurf1 activity using an off chip in vitro ubiquitination assay." SIGNOR-272690 ESR1 protein P03372 UNIPROT CYP19A1 protein P11511 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 11973645 t lperfetto "By binding to S1, ERalpha down-regulates the aromatase promoter activity." SIGNOR-271683 DUSP1 protein P28562 UNIPROT MAPK14 protein Q16539 UNIPROT "down-regulates activity" dephosphorylation 10090 17158101 t gcesareni "Our results show that Notch specifically induces expression of MKP-1, a member of the dual-specificity MAPK phosphatase, which directly inactivates p38 to negatively regulate C2C12 myogenesis." SIGNOR-236867 KDM5C protein P41229 UNIPROT SYN1 protein P17600 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 10090 31691806 f miannu "The KDM5C decrease was associated with a lack of repression of downstream target genes Scn2a, Syn1 and Bdnf in the embryonic brain of Arx-null mice." SIGNOR-264314 FYN protein P06241 UNIPROT ITPR1 protein Q14643 UNIPROT up-regulates phosphorylation Tyr353 NAQEKMVySLVSVPE 9606 14761954 t lperfetto "We have identified tyrosine 353 (tyr353) in the ip3-binding domain of type 1 ip3r (ip3r1) as a phosphorylation site for fyntyrosine phosphorylation of ip3r1 increased ip3 binding at low ip3 concentrations (<10 nm)." SIGNOR-121795 PRKACA protein P17612 UNIPROT BAD protein Q92934 UNIPROT down-regulates phosphorylation Ser118 GRELRRMsDEFVDSF 9606 10949026 t gcesareni "Ser-155 is the major phosphoacceptor site for pka on bad, but that pka also phosphorylates ser-112 and ser-136. Phosphorylated bad appears to be the inactive moiety. These results implicate pkac as the candidate kinase for s112 phosphorylation in vivo." SIGNOR-81129 ULK1 protein O75385 UNIPROT PRKAA1 protein Q13131 UNIPROT "down-regulates activity" phosphorylation 9606 SIGNOR-C15 21460634 t lperfetto "Ulk1/2 in turn phosphorylates all three subunits of ampk and thereby negatively regulates its activity." SIGNOR-173047 PPARGC1A protein Q9UBK2 UNIPROT PPARGC1A protein Q9UBK2 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000887;BTO:0001103 17609368 f lperfetto "Furthermore, ampk directly phosphorylates pgc-1?, And this phosphorylation mediates an increase in pgc-1? Protein action on the pgc-1? Promoter." SIGNOR-156783 CSNK1E protein P49674 UNIPROT ROR2 protein Q01974 UNIPROT up-regulates phosphorylation 9606 15375164 t gcesareni "We also show that ror2 is phosphorylated by ckiepsilon on serine/threonine residues." SIGNOR-129117 NSFL1C protein Q9UNZ2 UNIPROT CTSL protein P07711 UNIPROT "down-regulates activity" binding -1 15498563 t lperfetto "The SEP domain of p47 acts as a reversible competitive inhibitor of cathepsin L." SIGNOR-265043 U0126.EtOH chemical CHEBI:90692 ChEBI MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR down-regulates "chemical inhibition" 9606 Other t Selleck lperfetto SIGNOR-244961 SMURF2 protein Q9HAU4 UNIPROT TGFBR1 protein P36897 UNIPROT "down-regulates activity" ubiquitination 9606 17317136 t lperfetto "Recruitment of ww and hect domain e3-ubiquitin ligases smurf1 and 2 to induce type i receptor ubiquitination and subsequent receptor degradation;" SIGNOR-153423 valine smallmolecule CHEBI:27266 ChEBI AminoAcids stimulus SIGNOR-ST5 SIGNOR "up-regulates quantity" 29259120 t lperfetto "All extant life employs the same 20 amino acids for protein biosynthesis" SIGNOR-264747 CCND1 protein P24385 UNIPROT HDAC2 protein Q92769 UNIPROT up-regulates binding 9606 15713663 t gcesareni "Cyclin d1 bound hdac in vivo and preferentially physically associated with hdac1, hdac2, hdac3, and hdac5." SIGNOR-134053 "GABA-A (a1-b1-g2) receptor" complex SIGNOR-C330 SIGNOR Excitatory_synaptic_transmission phenotype SIGNOR-PH133 SIGNOR down-regulates 9606 BTO:0000227 18790874 f brain lperfetto "GABAA receptors (GABAA-Rs) are the major inhibitory receptors in the central nervous system (CNS). |Mammalian GABAA-Rs are all anion-selective channels. Increased chloride permeability generally reduces neuronal excitability (inhibition)" SIGNOR-263776 HECTD3 protein Q5T447 UNIPROT CASP8 protein Q14790 UNIPROT "down-regulates activity" polyubiquitination Lys231 KVYQMKSkPRGYCLI 9606 BTO:0000007 24287696 t miannu "HECTD3, a new E3 ubiquitin ligase, interacts with caspase-8 death effector domains and ubiquitinates caspase-8 with K63-linked polyubiquitin chains that do not target caspase-8 for degradation but decrease the caspase-8 activation. HECTD3 ubiquitinates caspase-8 with K63-linked polyubiquitin chains at K215." SIGNOR-272077 Aldolase proteinfamily SIGNOR-PF75 SIGNOR "glycerone phosphate(2-)" smallmolecule CHEBI:57642 ChEBI "up-regulates quantity" "chemical modification" 9606 16051738 t miannu "Aldolase catalyzes the reversible conversion of FBP to glyceraldehyde-3-phosphate and dihydroxyacetone phosphate (DHAP; Figure 1). Aldolase is a tetramer of identical subunits of 40 kDa each, and 3 distinct isoenzymes have been identified: aldolase A, B, and C." SIGNOR-266486 PMP22 protein Q01453 UNIPROT MPZ protein P25189 UNIPROT "up-regulates activity" binding 9606 10212299 t miannu "Our data provide the first direct evidence for the formation of P0–PMP22 complexes at the plasma membrane. These protein interactions probably participate in holding adjacent Schwann cell membranes together and in stabilizing myelin compaction." SIGNOR-251898 sunitinib chemical CHEBI:38940 ChEBI FLT3 protein P36888 UNIPROT "down-regulates activity" "chemical inhibition" -1 22037378 t Luana "Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here." SIGNOR-258290 14-3-3 proteinfamily SIGNOR-PF7 SIGNOR FOXO proteinfamily SIGNOR-PF27 SIGNOR down-regulates binding 9606 BTO:0001130 1010227 t gcesareni "Progressive increase in akt activation during prostate cancer progression led to increase phosphorylation of foxo3a and binding with 14-3-3, which potentially affected its transcriptional activity in age-specific manner." SIGNOR-252819 STAT3 protein P40763 UNIPROT IL10 protein P22301 UNIPROT up-regulates "transcriptional regulation" 9606 28713870 f svumbaca "These data argue that, in TH2 cells, STAT3 is required for T cell IL-10 production, which in turn reinforces its own expression" SIGNOR-256234 (~{s})-(4-Fluoranyl-2-Propyl-Phenyl)-(1~{h}-Imidazol-2-Yl)methanol chemical CID:126961334 PUBCHEM F2RL1 protein P55085 UNIPROT "down-regulates activity" "chemical inhibition" -1 28445455 t "Simone Vumbaca" "The antagonist AZ8838 binds in a fully occluded pocket near the extracellular surface. | Antagonist AZ3451 binds to a remote allosteric site outside the helical bundle. We propose that antagonist binding prevents structural rearrangements required for receptor activation and signalling." SIGNOR-261118 miR-155 mirna URS000062749E_9606 RNAcentral INPP5D protein Q92835 UNIPROT "down-regulates quantity by repression" "post transcriptional regulation" 9606 24708856 t miannu "We found overexpression of miR-155 led to increase in cJUN, FOS and TRIB2, and decrease in MEIS1, GFI1, cMYC and JARID2." SIGNOR-255764 RNF8 protein O76064 UNIPROT ACD protein Q96AP0 UNIPROT "up-regulates quantity by stabilization" polyubiquitination Lys147 QDLDVQKkLYDCLEE 9606 22101936 t miannu "The Rnf8 RING-finger domain is essential for Tpp1 stability and retention at telomeres. Rnf8 physically interacts with Tpp1 to generate Ubc13-dependent Lys63 polyubiquitin chains that stabilize Tpp1 at telomeres. The conserved Tpp1 residue Lys233 is important for Rnf8-mediated Tpp1 ubiquitylation and localization to telomeres." SIGNOR-272722 RIMS1 protein Q86UR5 UNIPROT UNC13B protein O14795 UNIPROT "up-regulates activity" relocalization 9606 31679900 t miannu "N-terminal interactions of RIMs with RAB3 and MUNC13 regulate DCV fusion. Through N-terminal interactions, RIMs position MUNC13 and recruit DCVs via RAB3, which is located on the vesicle" SIGNOR-264385 EEF1A2 protein Q05639 UNIPROT Leu-tRNA(Leu) smallmolecule CHEBI:16624 ChEBI up-regulates relocalization 9606 23699257 t lperfetto "During protein synthesis, eEF1A binds to and delivers aminoacylated tRNAs (aa-tRNAs) to the elongating ribosome (Fig. 1). GTP bound to eEF1A is hydrolyzed upon codon-anticodon match between an aa-tRNA in the A site of the ribosome and mRNA bound to the ribosome." SIGNOR-269533 "Elongator complex" complex SIGNOR-C466 SIGNOR TUBA3E protein Q6PEY2 UNIPROT "up-regulates activity" acetylation 9606 BTO:0000007 19185337 t miannu "Elongator Subunits Interact with the Microtubules and Are Required for Proper Acetylation of α-Tubulin." SIGNOR-269718 ILK protein Q13418 UNIPROT CFL1 protein P23528 UNIPROT down-regulates phosphorylation Ser3 sGVAVSDG 9606 18252715 t gcesareni "Actin (de)polymerization is regulated by cofilin, the ser(3) phosphorylation (ps(3)cofilin) of which inhibits its actin-severing activity. To determine how ilk regulates ps(3)cofilin, we examined the effects of ilk on ps(3)cofilin using normal rie1 cells." SIGNOR-160756 MMP23B protein O75900 UNIPROT ECM stimulus SIGNOR-ST20 SIGNOR down-regulates 17318226 f lperfetto "Historically, MMPs were thought to function mainly as enzymes that degrade structural components of the ECM." SIGNOR-272390 8-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-8-azaspiro[4.5]decane-7,9-dione chemical CHEBI:92539 ChEBI ADRA1D protein P25100 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-190642 MMP11 protein P24347 UNIPROT ECM stimulus SIGNOR-ST20 SIGNOR down-regulates 17318226 f lperfetto "Historically, MMPs were thought to function mainly as enzymes that degrade structural components of the ECM." SIGNOR-272379 DCAF1 protein Q9Y4B6 UNIPROT LATS1 protein O95835 UNIPROT "down-regulates quantity by destabilization" binding 9606 BTO:0005907 25026211 t miannu "CRL4 DCAF1 ubiquitylates and inhibits Lats." SIGNOR-272226 MECP2 protein P51608 UNIPROT Neuron_maturation phenotype SIGNOR-PH169 SIGNOR up-regulates 10090 BTO:0000601 17532643 f Luana "Our studies suggest that MeCP2 plays a central role in neuronal maturation, which might be mediated through epigenetic control of expression pathways that are instrumental in both dendritic development and synaptogenesis." SIGNOR-264968 GSK3B protein P49841 UNIPROT CTNND1 protein O60716 UNIPROT unknown phosphorylation Ser252 MEGYRAPsRQDVYGP -1 12885254 t "GSK3beta selectively phosphorylates p120 on S252 and T310 in Vitro" SIGNOR-251234 CDK2 protein P24941 UNIPROT ZC3HC1 protein Q86WB0 UNIPROT down-regulates phosphorylation Ser395 PGLEVPSsPLRKAKR 9606 17389604 t gcesareni "Moreover, we found cyclin b1/cdk1 to phosphorylate nipa at ser-395 in mitosis. Mutation of both ser-359 and ser-395 impaired effective inactivation of the scfnipa complex, resulting in reduced levels of mitotic cyclin b1" SIGNOR-154051 IFNL2 protein Q8IZJ0 UNIPROT IFNLR1 protein Q8IU57 UNIPROT up-regulates binding 9606 12469119 t gcesareni "Il-28 and il-29 interacted with a heterodimeric class ii cytokine receptor that consisted of il-10 receptor beta (il-10rbeta) and an orphan class ii receptor chain, designated il-28ralpha." SIGNOR-96206 ERN1 protein O75460 UNIPROT OS9 protein Q13438 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 18417469 f miannu "Here we characterize the function in ER quality control of two proteins derived from alternative splicing of the OS-9 gene. OS-9.1 and OS-9.2 are ubiquitously expressed in human tissues and are amplified in tumors. They are transcriptionally induced upon activation of the Ire1/Xbp1 ER-stress pathway." SIGNOR-261063 CUL3 protein Q13618 UNIPROT KCTD10 protein Q9H3F6 UNIPROT "up-regulates activity" binding 9606 19782033 t miannu "BACURDs form ubiquitin ligase complexes, which selectively ubiquitinate RhoA, with Cul3. Our studies reveal a previously unknown mechanism for controlling RhoA degradation and regulating RhoA function in various biological contexts, which involves a Cul3/BACURD ubiquitin ligase complex." SIGNOR-264234 SMAD3 protein P84022 UNIPROT NOTCH proteinfamily SIGNOR-PF30 SIGNOR up-regulates binding 9606 14638857 t gcesareni "Nicd and smad3 were shown to interact directly, both in vitro and in cells, in a ligand-dependent manner, and smad3 could be recruited to csl-binding sites on dna in the presence of csl and nicd" SIGNOR-254325 MMP26 protein Q9NRE1 UNIPROT ECM stimulus SIGNOR-ST20 SIGNOR down-regulates 17318226 f lperfetto "Historically, MMPs were thought to function mainly as enzymes that degrade structural components of the ECM." SIGNOR-272393 MMP27 protein Q9H306 UNIPROT ECM stimulus SIGNOR-ST20 SIGNOR down-regulates 17318226 f lperfetto "Historically, MMPs were thought to function mainly as enzymes that degrade structural components of the ECM." SIGNOR-272394 "3-[({4-[4-({[1-(2-chlorophenyl)ethoxy]carbonyl}amino)-3-methyl-1,2-oxazol-5-yl]phenyl}methyl)sulfanyl]propanoic acid" chemical CHEBI:91194 ChEBI LPAR3 protein Q9UBY5 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-193564 3-(1-methyl-3-indolyl)-4-[1-[1-(2-pyridinylmethyl)-4-piperidinyl]-3-indolyl]pyrrole-2,5-dione chemical CHEBI:91368 ChEBI PRKCB protein P05771 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-191493 HMGCS2 protein P54868 UNIPROT acetyl-CoA smallmolecule CHEBI:15351 ChEBI "down-regulates quantity" "chemical modification" 29597274 t lperfetto "Mitochondrial 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) synthase (mHS, EC 2.3.3.10) catalyzes the condensation reaction between acetyl-CoA and acetoacetyl-CoA in ketone body synthesis" SIGNOR-267658 TNFRSF17 protein Q02223 UNIPROT MAPK14 protein Q16539 UNIPROT up-regulates 9606 10903733 f miannu "Overexpression of bcma activates the p38 mapk" SIGNOR-79504 PDGFRB protein P09619 UNIPROT PTK2 protein Q05397 UNIPROT up-regulates phosphorylation Tyr194 ALEKKSNyEVLEKDV 9606 20802513 t llicata "In this study, we demonstrate that growth factor receptors including hepatocyte growth factor receptor met, epidermal growth factor receptor, and platelet-derived growth factor receptor directly phosphorylate fak on tyr194 in the ferm domain collectively, this study provides the first example to explain how fak is activated by receptor tyrosine kinases." SIGNOR-167658 MMP3 protein P08254 UNIPROT ECM stimulus SIGNOR-ST20 SIGNOR down-regulates 17318226 f lperfetto "Historically, MMPs were thought to function mainly as enzymes that degrade structural components of the ECM." SIGNOR-272396 SMC3 protein Q9UQE7 UNIPROT MXD4 protein Q14582 UNIPROT "down-regulates activity" binding 9534 BTO:0000318 9528857 t 2 miannu "We identified a novel ZIP-containing protein, Mmip1 (Mad member interacting protein 1) that strongly dimerizes with all four Mad members, but not with c-myc. Mmip1 can inhibit DNA binding by Max-Mad heterodimers and, in vivo, can reverse the suppressive e€ects of Mad proteins on c-myc functions." SIGNOR-241284 TAOK2 protein Q9UL54 UNIPROT MAP2K6 protein P52564 UNIPROT "up-regulates activity" phosphorylation Ser207 ISGYLVDsVAKTIDA 9606 BTO:0000007 11279118 t lperfetto "Suggesting that tao2 selectively activates mek3 and mek6 of the p38 pathway in intact cells" SIGNOR-106465 SETBP1 protein Q9Y6X0 UNIPROT SET protein Q01105 UNIPROT up-regulates binding 9606 22566606 t miannu "Setbp1 was shown to form a complex with set and pp2a, enhancing the stability of set and its inhibition of pp2a." SIGNOR-197324 "Caspase 3 complex" complex SIGNOR-C221 SIGNOR IKBKB protein O14920 UNIPROT down-regulates cleavage Asp242 VRQKSEVdIVVSEDL 9606 11741536 t gcesareni "Ikappab kinase (ikk) beta was specifically proteolyzed by caspase-3-related caspases at aspartic acid residues 78, 242, 373, and 546 during tumor necrosis factor (tnf)-alpha-induced apoptosis." SIGNOR-256441 SSU72 protein Q9NP77 UNIPROT POLR2A protein P24928 UNIPROT "up-regulates activity" dephosphorylation Ser1616 TPQSPSYsPTSPSYS -1 15125841 t "Phosphorylation of serine-2 (S2) and serine-5 (S5) of the C-terminal domain (CTD) of RNA polymerase II (RNAP II) is a dynamic process that regulates the transcription cycle and coordinates recruitment of RNA processing factors. The Fcp1 CTD phosphatase catalyzes dephosphorylation of S2-P.| Depletion of Ssu72 impairs transcription in vitro" SIGNOR-248803 ITGB1BP1 protein O14713 UNIPROT ITGB7 protein P26010 UNIPROT "down-regulates activity" binding 9606 19118207 t miannu "Integrins also bind to many PTBdomain-containing proteins (Calderwood et al., 2003) – including Dok1 and integrincytoplasmic-domain-associated protein 1 (ICAP1) – and these can compete with talin for binding to integrin and so can impair activation" SIGNOR-257664 TET2 protein Q6N021 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR down-regulates 9606 BTO:0000738 25601757 f irozzo "Cell proliferation was stimulated by the knockdown of either TET2 or WT1 gene in KG-1 cells, but not additively by the co-depletion of both genes. Collectively, these results suggest that TET2 and WT1 function in the same pathway to inhibit leukemia cell proliferation and colony formation." SIGNOR-255704 SMAD1/4 complex SIGNOR-C85 SIGNOR DLX5 protein P56178 UNIPROT up-regulates "transcriptional regulation" 10090 BTO:0000165 12815054 f ggiuliani "Over-expression of Smad1 or Smad5, mediators of BMP-signaling, also induced Dlx5 expression even in the absence of BMP-2 treatment concomitant with positive ALP staining" SIGNOR-255789 JAK1 protein P23458 UNIPROT JAK1/STAT1/STAT3 complex SIGNOR-C120 SIGNOR "form complex" binding 10090 15284024 t lperfetto "Stimulation of EGFR induces Tyr701 phosphorylation of STAT1 and initiates complex formation of STAT1 and STAT3 with JAK1 and JAK2. Thereafter, the STATs translocate to the nucleus within 15 min." SIGNOR-235608 MMP7 protein P09237 UNIPROT ECM stimulus SIGNOR-ST20 SIGNOR down-regulates 17318226 f lperfetto "Historically, MMPs were thought to function mainly as enzymes that degrade structural components of the ECM." SIGNOR-272397 MMP8 protein P22894 UNIPROT ECM stimulus SIGNOR-ST20 SIGNOR down-regulates 17318226 f lperfetto "Historically, MMPs were thought to function mainly as enzymes that degrade structural components of the ECM." SIGNOR-272398 MMP9 protein P14780 UNIPROT ECM stimulus SIGNOR-ST20 SIGNOR down-regulates 17318226 f lperfetto "Historically, MMPs were thought to function mainly as enzymes that degrade structural components of the ECM." SIGNOR-272399 DDR1 protein Q08345 UNIPROT TM4SF1 protein P30408 UNIPROT "up-regulates activity" binding 30187813 t lperfetto "Gao et al have demonstrated that in metastatic breast cancer cell, DDR1 interacts with cell surface Transmembrane 4 L Six Family Member 1 (TM4SF1) and regulates tumor dormancy and reactivation [3]. The interaction between DDR1 and TM4SF1 is collagen dependent and control Protein Kinase C Alpha (PKCa) mediated downstream JAK-STAT signaling pathway [3] (Figure 3). Interestingly the data also showed that TM4SF1 failed to interact with DDR2. " SIGNOR-272400 TM4SF1 protein P30408 UNIPROT DVL2 protein O14641 UNIPROT "up-regulates activity" binding 33015133 t lperfetto "TM4SF1 is a partner of DVL2 and positively modulates Wnt/beta-catenin signaling by enhancing DVL2-Axin interaction." SIGNOR-272402 DDR1 protein Q08345 UNIPROT PTPN11 protein Q06124 UNIPROT "up-regulates activity" relocalization 9615 BTO:0000837 16611743 t lperfetto "Overexpression of DDR1a/b increased the interaction of DDR1 with SHP-2 and up-regulated the tyrosine phosphatase activity of SHP-2." SIGNOR-272403 PTPN11 protein Q06124 UNIPROT STAT3 protein P40763 UNIPROT "down-regulates activity" dephosphorylation Tyr705 DPGSAAPyLKTKFIC 9615 BTO:0000837 16611743 t lperfetto "In addition, SHP-2 dephosphorylates tyrosine-phosphorylated Stat1/3/5A (Ohtani et al., 2000; Wu et al., 2002; Chen et al., 2003), and downregulates Stat3-mediated biological actions (Ohtani et al., 2000).|Inhibition of collagen-induced Stat3 tyrosine-705 (Stat3-p-Tyr)" SIGNOR-272404 PDZD8 protein Q8NEN9 UNIPROT MSN/PDZD8 complex SIGNOR-C61 SIGNOR "form complex" binding 9606 21549406 t miannu "These results demonstrated that both human moesin and its newly identified binding partner, pdzd8 had similar effects on host mt networks, suggesting that they are likely to function as part of a stable mt regulatory complex." SIGNOR-173650 PRKCA protein P17252 UNIPROT GRIA2 protein P42262 UNIPROT unknown phosphorylation Ser683 TKEFFRRsKIAVFDK -1 8848293 t lperfetto "Only two peptides containing Ser-662 and Ser-696 were found to be efficiently phosphorylated by protein kinase C (PKC). The peptide including Ser-696 was also phosphorylated by protein kinase G (PKG)." SIGNOR-248954 TARDBP protein Q13148 UNIPROT Protein_aggregates phenotype SIGNOR-PH142 SIGNOR "up-regulates quantity" 9606 BTO:0000312 22051914 f lperfetto "Pathological protein aggregates, identified as compact or skein-like ubiquitinated inclusions, are a cardinal feature of ALS.4–6 The identification of TDP-43 as the major protein constituent of these inclusions initi- ated a major shift in our understanding of the patho- biology of ALS" SIGNOR-262278 USP20 protein Q9Y2K6 UNIPROT CLSPN protein Q9HAW4 UNIPROT "up-regulates quantity by stabilization" deubiquitination 9606 BTO:0000007 25355518 t miannu "USP20 deubiquitinates and stabilizes Claspin." SIGNOR-272821 UBE2V1 protein Q13404 UNIPROT TRAF6 protein Q9Y4K3 UNIPROT "up-regulates activity" binding 9606 BTO:0000007 11057907 t lperfetto "We find that traf6, a ring domain protein, functions together with ubc13/uev1a to catalyze the synthesis of unique polyubiquitin chains linked through lysine-63 (k63) of ubiquitin" SIGNOR-83603 AKT2 protein P31751 UNIPROT FOXO3 protein O43524 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser253 APRRRAVsMDNSNKY 19951971 t lperfetto "AKT phosphorylates FOXO3a at three conserved sites (Thr32, Ser253 and Ser315), therefore creating binding sites for the 14-3-3 chaperone proteins and leading to the active export of FOXO3a to the cytoplasm where it is targeted for proteasomal degradation." SIGNOR-249640 KLF4 protein O43474 UNIPROT TP53 protein P04637 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 17308127 t lperfetto "Previous work has shown that the Kruppel-like factor 4 (KLF4) transcription factor represses p53 transcription by binding to the PE21 element." SIGNOR-270544 PRKACA protein P17612 UNIPROT ALOX5 protein P09917 UNIPROT "down-regulates activity" phosphorylation Ser524 GMRGRKSsGFPKSVK -1 15280375 t lperfetto "These results indicate that PKA phosphorylates 5-LO on Ser-523, which inhibits the catalytic activity of 5-LO and reduces cellular LT generation." SIGNOR-264410 PYY protein P10082 UNIPROT NPY4R protein P50391 UNIPROT up-regulates binding 9606 7592911 t gcesareni "Human y4 bound human pp family members in i-pyy membrane binding assays with a distinctive rank order (table 1): pp > pyy > npy > npy free acid." SIGNOR-29767 paroxetine chemical CHEBI:7936 ChEBI SLC6A4 protein P31645 UNIPROT "down-regulates activity" "chemical inhibition" 9606 BTO:0000007 18487050 t Luana "For [3H]paroxetine, [3H]citalopram, [3H]nisoxetine, and [3H]WIN35,428 the following KD values were obtained on the human monoamine transporters hSERT, hNET, and hDAT by homologous competition experiments: 0.69 nM [3H]paroxetine, 4.46 nM [3H]citalopram, 6.77 nM [3H]nisoxetine, and 24.1 [3H]WIN35,428. " SIGNOR-257795 RET protein P07949 UNIPROT RET protein P07949 UNIPROT up-regulates phosphorylation Tyr1096 RYPNDSVyANWMLSP 9606 14711813 t llicata "Mass spectrometric analysis revealed that ret tyr(806), tyr(809), tyr(900), tyr(905), tyr(981), tyr(1062), tyr(1090), and tyr(1096) were autophosphorylation sites." SIGNOR-121149 PEX6 protein Q13608 UNIPROT Protein_localization_to_peroxisome phenotype SIGNOR-PH86 SIGNOR up-regulates 9606 26476099 f "The Pex1 and Pex6 proteins are members of the AAA family of ATPases and are involved in peroxisome biogenesis." SIGNOR-253617 NfKb-p65/p50 complex SIGNOR-C13 SIGNOR M1_polarization phenotype SIGNOR-PH54 SIGNOR up-regulates 9606 30060484 f miannu "The bacterial endotoxin LPS is a known agonist of TLR2 that activates the expression of proinflammatory cytokines and the phosphorylation of MAPKs and NFκB [49]. In addition, the activation of the MAPK and NFκB signaling cascades drive inflammation and macrophage polarization. " SIGNOR-249519 TRAF6 protein Q9Y4K3 UNIPROT RUSC1 protein Q9BVN2 UNIPROT "down-regulates quantity by destabilization" polyubiquitination 9606 BTO:0000007 19365808 t miannu " We demonstrated that NESCA and NEMO interact by their N-terminal region. Beside to NEMO, we revealed that NESCA directly associates to the E3 ubiquitin ligase TRAF6, which in turn catalyzes NESCA polyubiquitination. Finally, we demonstrated that NESCA overexpression strongly inhibits TRAF6-mediated polyubiquitination of NEMO. " SIGNOR-272774 Ub:E2 complex SIGNOR-C497 SIGNOR TRIM50 protein Q86XT4 UNIPROT "up-regulates activity" ubiquitination 9606 34199813 t miannu "The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t" SIGNOR-271190 SKP2 protein Q13309 UNIPROT CCND1 protein P24385 UNIPROT "down-regulates quantity by destabilization" binding 9606 BTO:0003725 11439327 t miannu "We show that SK-UT-1B cells express a novel splice variant of Skp2 that localizes to the cytoplasm and that cyclin D1 ubiquitination takes place in the nucleus. We propose that the translocation of Skp2 into the nucleus is required for the ubiquitination of cyclin D1 and that the absence of the SCF(Skp2) complex in the nucleus of SK-UT-1B cells is the mechanism underlying the ubiquitination defect observed in this cell line." SIGNOR-272575 SP3 protein Q02447 UNIPROT MAOB protein P27338 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 11259630 f miannu "Cotransfection experiments show that Sp1 and its closely related family member Sp4 can trans-activate MAO B promoter activity through the proximal cluster of Sp1 sites and its activation can be repressed by the over-expression of Sp3 and a related family member BTEB2." SIGNOR-253870 MAPK8 protein P45983 UNIPROT BCL2L11 protein O43521 UNIPROT up-regulates phosphorylation 9606 12591950 t gcesareni "Jnk phosphorylates two members of the bh3-only sub of bcl2-related proteins (bim and bmf)." SIGNOR-98399 "Caspase 3 complex" complex SIGNOR-C221 SIGNOR RAD51 protein Q06609 UNIPROT "down-regulates quantity by destabilization" cleavage 9606 BTO:0002882 11684015 t lperfetto "The RAD51 protein has been shown to be a substrate for caspase-3|he activated caspase-3 fragments (19 kDa and 17 kDa) and caspase-3 cleaved RAD51 fragment (∼23 kDa) was detected by Western analysis (Figure 3E). Activation of caspase-3 and the signature proteolytic degradation product of RAD51 only occurred in parental 32Dcl3 cells after treatment with cisplatin" SIGNOR-271708 ITSN1 protein Q15811 UNIPROT CDC42 protein P60953 UNIPROT "up-regulates activity" "guanine nucleotide exchange factor" 9606 BTO:0000567 30540523 t lperfetto "Significantly, here we identify the long isoform of ITSN-1, which has Cdc42 GEF activity| We propose that GCC88 recruits ITSN-1-L to the TGN, which in turn activates Cdc42 at the trans-face of the Golgi (Figure 9A)." SIGNOR-260612 RUVBL2 protein Q9Y230 UNIPROT "NuA4 complex" complex SIGNOR-C459 SIGNOR "form complex" binding 9606 14966270 t miannu "NuA4 (for nucleosome acetyltransferase of H4) is a 12-subunit HAT complex responsible for acetylation of histone H4 and H2A N-terminal tails." SIGNOR-269291 LRFN4 protein Q6PJG9 UNIPROT Synaptic_plasticity phenotype SIGNOR-PH158 SIGNOR up-regulates 9606 BTO:0000938 21736948 f miannu "The SALM (synaptic adhesion-like molecule) family of adhesion molecules, also known as Lrfn, belongs to the superfamily of leucine-rich repeat (LRR)-containing adhesion molecules. Proteins of the SALM family, which includes five known members (SALMs 1-5), have been implicated in the regulation of neurite outgrowth and branching, and synapse formation and maturation.SALM3 and SALM5, but not other SALMs, possess synaptogenic activity, inducing presynaptic differentiation in contacting axons." SIGNOR-264092 CLASP1 protein Q7Z460 UNIPROT MAPRE1 protein Q15691 UNIPROT "up-regulates activity" binding 9606 BTO:0000567 15631994 t lperfetto "CLIP-associating protein (CLASP) 1 and CLASP2 are mammalian microtubule (MT) plus-end binding proteins, which associate with CLIP-170 and CLIP-115.|We demonstrate that the middle part of CLASPs binds directly to EB1 and to MTs. | Both EB1- and cortex-binding domains of CLASP are required to promote MT stability." SIGNOR-265094 blinatumomab antibody DB09052 DRUGBANK CD19 protein P15391 UNIPROT "down-regulates activity" binding 9606 BTO:0000731 25883042 t miannu "Blinatumomab, a bispecific antibody construct targeting CD19, is the most advanced member of bispecific T-cell engager (BiTE®) molecules.Blinatumomab recently gained approval in the United States by the U.S. Food and Drug Administration for treatment of Philadelphia chromosome-negative B-precursor relapsed/refractory acute lymphoblastic leukemia." SIGNOR-259888 Ub:E2 complex SIGNOR-C497 SIGNOR RAG1 protein P15918 UNIPROT "up-regulates activity" ubiquitination 9606 34199813 t miannu "The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t" SIGNOR-271067 FGFR4 protein P22455 UNIPROT FGFR4 protein P22455 UNIPROT up-regulates phosphorylation Tyr643 GVHHIDYyKKTSNGR 9606 BTO:0001130 18670643 t lperfetto "Binding of fgf to fgf receptors leads to receptor dimerization and subsequent tyrosine autophosphorylation and phosphorylation of target substrates. Autophosphorylation on tyrosine is considered to have at least two functions. One such function is the stimulation of the intrinsic protein tyrosine kinase activity by an allosteric mechanismthis antibody specifically recognizes tyr642/643 in fgfr-4." SIGNOR-179780 DTL protein Q9NZJ0 UNIPROT TDG protein Q13569 UNIPROT "down-regulates quantity by destabilization" binding 9606 BTO:0000007 24962565 t miannu "TDG Is Polyubiquitinated by CRL4Cdt2 E3 Ubiquitin Ligase in a PIP Degron-dependent Manner" SIGNOR-272847 GSK2126458 chemical CID:25167777 PUBCHEM PIK3CD protein O00329 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-192901 IRAK1 protein P51617 UNIPROT IRAK1 protein P51617 UNIPROT "up-regulates activity" phosphorylation Thr387 RTQTVRGtLAYLPEE -1 11960013 t "In vitro the IRAK-1 activation loop is a good substrate for IRAK-4, and that T387 and S376 are the main sites of phosphorylation by both IRAK-1 and IRAK-4." SIGNOR-251330 ACLY protein P53396 UNIPROT "coenzyme A(4-)" smallmolecule CHEBI:57287 ChEBI "down-regulates quantity by destabilization" "chemical modification" 9606 19286649 t miannu "ATP citrate lyase (ACL) is a cytosolic enzyme that catalyzes the synthesis of acetyl-CoA and oxaloacetate using citrate, CoA, and ATP as substrates and Mg(2+) as a necessary cofactor." SIGNOR-268081 WNT7B protein P56706 UNIPROT MYOD1 protein P15172 UNIPROT up-regulates 9606 BTO:0000887;BTO:0001103 22944199 f gcesareni "In explant cultures of mouse paraxial mesoderm, wnt1 induced expression of the mrf myf5, whereas wnt7a or wnt6 preferentially activated the mrf myod." SIGNOR-198925 SRC protein P12931 UNIPROT DDR2 protein Q16832 UNIPROT up-regulates phosphorylation Tyr736 FGMSRNLySGDYYRI 9606 16186108 t gcesareni "Here, using baculoviral co-expression of the ddr2 cytosolic domain and src, we show that src targets three tyrosine residues (tyr-736, tyr-740, and tyr-741) in the activation loop of ddr2 for phosphorylation. This phosphorylation by src stimulates ddr2 cis-autophosphorylation of additional tyrosine residues." SIGNOR-140728 RORA protein P35398 UNIPROT ITPR1 protein Q14643 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 BTO:0001011 19381306 t miannu "RORα regulates the expression of several genes in Purkinje cells. RORα becomes highly expressed in postmitotic Purkinje cells. It regulates their maturation, particularly dendritic differentiation. Dendritogenesis and the expression of several genes, including Shh, Itpr1, Pcp4, Calb1, Pcp2, and Slc1a6, normally expressed in mature Purkinje cells, are inhibited in RORα-deficient mice." SIGNOR-266847 SMO protein Q99835 UNIPROT GNB1 protein P62873 UNIPROT up-regulates binding 9606 23074268 t gcesareni "Consistent with its predicted topology, smo couples to a specific family of inhibitory g protein (gis) to regulate hh signaling." SIGNOR-199174 MDM2 protein Q00987 UNIPROT PBXIP1 protein Q96AQ6 UNIPROT "down-regulates quantity by destabilization" polyubiquitination 9606 BTO:0000093 24488098 t miannu ". Accordingly, we identified the microtubule-associated HPIP, a positive regulator of oncogenic AKT signaling, as a novel MDM2 substrate. MDM2-dependent HPIP degradation occurs in breast cancer cells on its phosphorylation by the estrogen-activated kinase TBK1. " SIGNOR-272850 NUP54 protein Q7Z3B4 UNIPROT NPC complex SIGNOR-C263 SIGNOR "form complex" binding 27016207 t lperfetto "The protein inventory of the NPC has been studied for a very diverse set of eukaryotes, including trypanosomes, fungi, plants, animals, and humans [4], [5], [6], [7], [8], [9]. In all cases, about 30 different Nups were found (Fig. 2)." SIGNOR-262078 "alpha-D-glucose 1-phosphate(2-)" smallmolecule CHEBI:58601 ChEBI UDP-alpha-D-glucose(2-) chemical CHEBI:58885 ChEBI "up-regulates quantity" "precursor of" 9606 8631325 t miannu "UDP-Glc pyrophosphorylase (EC 2.7.7.9) catalyses the interconversion of MgUTP plus Glc1P and UDP-Glc plus MgPPi." SIGNOR-267924 "Caspase 6 complex" complex SIGNOR-C228 SIGNOR LMNA protein P02545 UNIPROT down-regulates cleavage 9606 11058599 t amattioni "Lamin a breakdown is largely mediated by caspase-6 during the execution phase of apoptosis." SIGNOR-256457 NF1 protein P21359 UNIPROT Adenylate_cyclase proteinfamily SIGNOR-PF92 SIGNOR up-regulates 9606 BTO:0000938 24431436 f miannu "Nf1encodes neurofibromin, a protein with multiple functions including ras inactivation (ras gtpase-activating protein or rasgap) and adenylyl cyclase (ac) activation" SIGNOR-267846 MRPL42 protein Q9Y6G3 UNIPROT "39S mitochondrial large ribosomal subunit" complex SIGNOR-C285 SIGNOR "form complex" binding -1 25838379 t lperfetto "We have determined the structure of the intact mitoribosome to 3.5 angstrom resolution by single-particle electron cryo-microscopy. It reveals 80 extensively interconnected proteins, 36 of which are specific to mitochondria, and three rRNA molecules" SIGNOR-262354 "GABA-A (a4-b3-d) receptor" complex SIGNOR-C327 SIGNOR Excitatory_synaptic_transmission phenotype SIGNOR-PH133 SIGNOR down-regulates 9606 BTO:0000227 18790874 f brain lperfetto "GABAA receptors (GABAA-Rs) are the major inhibitory receptors in the central nervous system (CNS). |Mammalian GABAA-Rs are all anion-selective channels. Increased chloride permeability generally reduces neuronal excitability (inhibition)" SIGNOR-263775 PCDHAC2 protein Q9Y5I4 UNIPROT ITGB1 protein P05556 UNIPROT "up-regulates activity" binding 9606 BTO:0000227 16697637 t miannu "The clustered protocadherins comprise the largest subfamily of the cadherin superfamily and are predominantly expressed in the nervous system. Pcdh-alpha proteins interact with beta1-integrin to promote cell adhesion." SIGNOR-269038 UVRAG protein Q9P2Y5 UNIPROT BECN1 protein Q14457 UNIPROT "up-regulates activity" binding 9606 BTO:0000567 17106237 t lperfetto "UVRAG interacts with Beclin 1, leading to activation of autophagy and thereof inhibition of tumorigenesis." SIGNOR-150825 CASP6 protein P55212 UNIPROT N protein P59595 UNIPROT "up-regulates activity" cleavage Asp400 VTLLPAAdMDDFSRQ 9534 BTO:0001444 18155731 t Luana "Caspase-6 is activated through the intrinsic pathway and mediates C-terminal cleavage of SARS-CoV N at residues 400 and 403" SIGNOR-260211 BBS2 protein Q9BXC9 UNIPROT "BBsome complex" complex SIGNOR-C288 SIGNOR "form complex" binding 9606 BTO:0004910 19081074 t lperfetto "We recently showed that seven highly conserved BBS proteins form a stable complex, the BBSome, that functions in membrane trafficking to and inside the primary cilium.|As a first step in characterizing this protein, we investigated the biochemical properties of its binding to the core BBSome (previously defined as the BBS1, -2, -4, -5, -7, -8, and -9 complex). We subjected the native LAP-BBS4 eluate to velocity sedimentation analysis (Figure 1C). BBIP10 clearly cosedimented with BBS4 at 14S, suggesting that BBIP10 strongly associates with the core BBSome" SIGNOR-262557 MIS12 protein Q9H081 UNIPROT "MIS12 complex" complex SIGNOR-C362 SIGNOR "form complex" binding -1 27881301 t lperfetto "Human MIS12C (also known as MIND complex or Mtw1 complex in Saccharomyces cerevisiae) contains the MIS12, PMF1, NSL1, and DSN1 subunits" SIGNOR-265190 HOXA10 protein P31260 UNIPROT EMX2 protein Q04743 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 15494461 f miannu "EMSA demonstrated HOXA10-Pbx2 binding as a heterodimer to an enhancer of the EMX2 gene, a known target of HOXA10 regulation." SIGNOR-254465 LCK protein P06239 UNIPROT ZAP70 protein P43403 UNIPROT "up-regulates activity" binding 9606 phosphorylation:Tyr319 TSVYESPySDPEELK 8798643 t lperfetto "Phosphopeptide encompassing the motif harboring tyr319, ysdp, interacted with lcksh2;tyr319-mediated binding of the sh2 domain of lck is crucial for zap-70 activation and consequently for the propagation of the signaling cascade leading to t-cell activation" SIGNOR-43659 Ub:E2 complex SIGNOR-C497 SIGNOR RNF217 protein Q8TC41 UNIPROT "up-regulates activity" ubiquitination 9606 34199813 t miannu "The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t" SIGNOR-270951 1124329-14-1 chemical CID:56973724 PUBCHEM TTK protein P33981 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-190137 Guanabenz chemical CHEBI:5553 ChEBI ADRA2A protein P08913 UNIPROT "up-regulates activity" "chemical activation" 9606 BTO:0000007 9605427 t miannu "AR agonists stimulated binding of [35S]GTPgS to HEK 293 cell membranes containing the human a2a, a2b, or a2c ARs (Fig. 6). EPI and NE were full agonists; clonidine and oxymetazoline were partial agonists, while antagonists (e.g. rauwolscine, 5 mM) did not stimulate [35S]GTPgS incorporation (Table 3). Although a few agonists showed a great deal of selectivity for a single receptor subtype, the rank order of agonist potency for selected compounds at the human receptors (Table 3) was: a2a: Dexmedetomidine . guanabenz . UK-14304 .clonidine . ST-91 . NE a2b: Dexmedetomidine . clonidine . guanabenz . NE .ST-91 . UK-14304 a2c: Dexmedetomidine . NE . UK-14304 . ST-91 $ clonidine .. guanabenz" SIGNOR-258909 CREB1 protein P16220 UNIPROT SNAI2 protein O43623 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 15955695 f miannu "In cancer tissue, the expression levels of EAR-2, COUP-TF1, EARgamma, Snail, and Slug decrease, and aromatase expression is then up-regulated through the binding of ERRalpha to S1 and the binding of CREB1 or related factors to CREaro." SIGNOR-253791 FSTL1 protein Q12841 UNIPROT DIP2A protein Q14689 UNIPROT "up-regulates activity" binding 9606 BTO:0005562 20054002 t miannu "We identified DIP2A as a novel FSTL1-binding partner from the membrane fraction of endothelial cells. Co-immunoprecipitation assays revealed a direct physical interaction between FSTL1 and DIP2A. The work in the current study identifies DIP2A as a novel receptor for FSTL1 that mediates Akt activation and cell survival and function in cardiovascular cells in vitro." SIGNOR-266603 ENO1 protein P06733 UNIPROT 2-phosphonato-D-glycerate(3-) smallmolecule CHEBI:58289 ChEBI "down-regulates quantity" "chemical modification" 9606 29767008 t miannu "Alpha-enolase (ENO1), also known as 2-phospho-D-glycerate hydrolase, is a metalloenzyme that catalyzes the conversion of 2-phosphoglyceric acid to phosphoenolpyruvic acid in the glycolytic pathway. Subsequent studies have shown that three types of enolase isoenzymes exist in mammals: Œ±-enolase (ENO1) is present in almost all mature tissues; Œ≤-enolase (ENO3) exists primarily in muscle tissues; and Œ≥-enolase (ENO2) occurs mainly in nervous and neuroendocrine tissues. All enolases are composed of two identical subunits." SIGNOR-266528 KREMEN2 protein Q8NCW0 UNIPROT LRP6 protein O75581 UNIPROT down-regulates binding 9606 12050670 t gcesareni "Here we show that the transmembrane proteins kremen1 and kremen2 are high-affinity dkk1 receptors that functionally cooperate with dkk1 to block wnt/beta-catenin signalling. Kremen2 forms a ternary complex with dkk1 and lrp6, and induces rapid endocytosis and removal of the wnt receptor lrp6 from the plasma membrane." SIGNOR-88894 PSMC6 protein P62333 UNIPROT "26S Proteasome" complex SIGNOR-C307 SIGNOR "form complex" binding 9606 BTO:0000007 29636472 t lperfetto "Here, we report near-atomic resolution cryo-EM structures of the activated human proteasome|The proteasome is composed of a 28-subunit barrel-shaped core particle (CP) and two 19- subunit regulatory particles (RP)5–8 capped at both sides of the CP|Human proteasomes were purified through affinity chromatography on a large scale from a stable HEK293 cell line" SIGNOR-263370 SPP1 protein P10451 UNIPROT "A9/b1 integrin" complex SIGNOR-C166 SIGNOR "up-regulates activity" binding 9606 24241034 t lperfetto "Synovial fibroblasts and macrophages derived from arthritic joints spontaneously secreted tenascin-C and osteopontin. Synovial fibroblasts and macrophages obtained from patients with RA expressed α9β1 integrins, a common receptor for osteopontin and tenascin-C." SIGNOR-253311 CDKN1A protein P38936 UNIPROT CCNB1 protein P14635 UNIPROT down-regulates binding 9606 19158493 t gcesareni "P21-mediated degradation of cyclin b1 in response to dna damage is necessary for the maintenance of g2 cell cycle arrest." SIGNOR-183498 SIRT5 protein Q9NXA8 UNIPROT GLS protein O94925 UNIPROT "up-regulates activity" binding 9606 BTO:0006301 30910998 t Monia "Immunoprecipitation assays of interaction between GLS and SIRT5 in HepG2 cells infected with lentivirus containing empty or BAG3 construct. Ectopic BAG3 expression decreases the interaction between GLS and SIRT5. It has been reported that SIRT5 is responsible for desuccinylation of GLS35, immunoprecipitation (IP) was then performed." SIGNOR-261207 IFNW1 protein P05000 UNIPROT IFNAR1 protein P17181 UNIPROT up-regulates binding 9606 11278538 t gcesareni "Ifn-alpha, ifn-beta, and ifn-omega, induce somewhat different cellular effects but act through a common receptor complex, ifnar, composed of subunits ifnar-1 and ifnar-2." SIGNOR-105979 MAPK3 protein P27361 UNIPROT METTL3 protein Q86U44 UNIPROT "up-regulates quantity by stabilization" phosphorylation Ser525 YGMIERLsPGTRKIE 9606 BTO:0000007 33217317 t miannu "Mass spectrometry analysis showed that ERK phosphorylates METTL3 at three highly conserved residues: S43, S50, and S525 (Figures 2D and 2E). Mutational analysis further confirmed these three sites as main ERK phosphorylation sites (Figure 2F). Phosphorylation of METTL3 increases interaction with USP5, decreasing ubiquitination to stabilize the m6 A methyltransferase complex." SIGNOR-265947 EIF4B protein P23588 UNIPROT EIF4A1 protein P60842 UNIPROT "up-regulates activity" binding -1 11418588 t "Either eIF4B or eIF4H stimulated the initial rate and amplitude of eIF4A-dependent duplex unwinding, and the magnitude of stimulation is dependent on duplex stability" SIGNOR-261293 ROCK1 protein Q13464 UNIPROT PTEN protein P60484 UNIPROT up-regulates phosphorylation Ser229 VKIYSSNsGPTRRED 9606 BTO:0000672 15793569 t llicata "In addition, active rhoa is able to stimulate the phospholipid phosphatase activity of pten in human embryonic kidney cells and leukocytes, and this regulation seems to require rhoa's downstream effector, rhoa-associated kinase (rock). together with the observation that individual substitution of ser 229 and thr 223 restored some of the rescuing ability (fig. 4b), we conclude that effective regulation of pten by sdf-1 may require more than one of these residues." SIGNOR-134851 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR PPARG protein P37231 UNIPROT "up-regulates quantity by expression" phosphorylation 10090 BTO:0000011 12270934 t lperfetto "Our results suggest that activation of the MEK/ERK signaling pathway during the initial 12 h of adipogenesis enhances the activity of factors that regulate both C/EBPalpha and PPARgamma expression." SIGNOR-235334 ATM protein Q13315 UNIPROT TP53BP1 protein Q12888 UNIPROT up-regulates phosphorylation Ser1219 DDTESLHsQGEEEFD 9606 22621922 t gcesareni "Here we report phosphorylation of 53bp1 at several novel residues, using mass spectrometry and phospho-specific antibodies, and show that ionising radiation-stimulated phosphorylation of these residues requires atm." SIGNOR-197611 EP400 protein Q96L91 UNIPROT "NuA4 complex" complex SIGNOR-C459 SIGNOR "form complex" binding 9606 14966270 t miannu "NuA4 (for nucleosome acetyltransferase of H4) is a 12-subunit HAT complex responsible for acetylation of histone H4 and H2A N-terminal tails." SIGNOR-269289 CREBBP protein Q92793 UNIPROT MEF2C protein Q06413 UNIPROT up-regulates binding 9606 SIGNOR-C6 11062529 t gcesareni "The cofactors grip-1, cbp/p300 and pcaf have hat activity and function as co-activators for mef-2c during myogenesis." SIGNOR-83843 JAK2 protein O60674 UNIPROT STAT1 protein P42224 UNIPROT up-regulates phosphorylation Tyr701 DGPKGTGyIKTELIS 9606 BTO:0000567 15322115 t lperfetto "Phosphorylation at tyr701 by the janus family of tyrosine kinases (jak) leads to stat1 dimerization via its src homology 2 domains, exposure of a dimer-specific nuclear localization signal, and subsequent nuclear translocation." SIGNOR-235709 CAD protein P27708 UNIPROT CAD protein P27708 UNIPROT "up-regulates activity" phosphorylation Thr1037 QQCRVLGtSPEAIDS -1 11986331 t llicata "Autophosphorylation resulted in a 2-fold increase in CPSase activity, an increased sensitivity to the feedback inhibitor UTP, and decreased allosteric activation by 5-phosphoribosyl-1-pyrophosphate" SIGNOR-250610 JNK proteinfamily SIGNOR-PF15 SIGNOR BCL2L1 protein Q07817 UNIPROT down-regulates phosphorylation Thr47 GTESEMEtPSAINGN 9606 10617621 t lperfetto "Sapk phosphorylates bcl-x(l) on threonine 47 (thr-47) and threonine 115 (thr-115) in vitro and in vivo. In contrast to wild-type bcl-x(l), a mutant bcl-x(l) with the two threonines substituted by alanines (ala-47, ala-115) is a more potent inhibitor of ionizing radiation-induced apoptosis" SIGNOR-73642 Ub:E2 complex SIGNOR-C497 SIGNOR ARIH1 protein Q9Y4X5 UNIPROT "up-regulates activity" ubiquitination 9606 34199813 t miannu "The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t" SIGNOR-271012 PRKCB protein P05771 UNIPROT CHAT protein P28329 UNIPROT up-regulates phosphorylation Thr373 TVLVKDStNRDSLDM 9606 BTO:0000938 BTO:0000142 12486117 t "The effect has been demonstrated using P28329-3" gcesareni "We show that chat is differentially phosphorylated by protein kinase c (pkc) isoforms on four serines (ser-440, ser-346, ser-347, and ser-476) and one threonine (thr-255). This phosphorylation is hierarchical, with phosphorylation at ser-476 required for phosphorylation at other serines. Phosphorylation at some, but not all, sites regulates basal catalysis and activation." SIGNOR-96632 LRRK2 protein Q5S007 UNIPROT CADPS2 protein Q86UW7 UNIPROT "up-regulates quantity" "transcriptional regulation" 9606 28647363 f gianni "This approach enabled us to disclose a differential effect of high levels of LRRK2 and aSyn on CADPS2 promoter activity. Specifically, CADPS2 transcriptional activity was enhanced by high cellular levels of LRRK2 and reduced by overexpression of aSyn. Consistently, CADPS2 mRNA levels were diminished in aSyn overexpressing cells." SIGNOR-268928 PLK3 protein Q9H4B4 UNIPROT ATF2 protein P15336 UNIPROT up-regulates phosphorylation Thr69 SVIVADQtPTPTRFL 9606 21098032 t gcesareni "Kinase activity of plk3 was significantly activated by hyperosmotic stimulation. Further downstream, active plk3 phosphorylated atf-2 at the thr-71 site in vivo and in vitro." SIGNOR-170004 ADRB2 protein P07550 UNIPROT GNAS protein Q5JWF2 UNIPROT "up-regulates activity" binding 9606 14500986 t "We have found that signaling via the erythrocyte beta2-adrenergic receptor and heterotrimeric guanine nucleotide-binding protein (Galphas) regulated the entry of the human malaria parasite Plasmodium falciparum." SIGNOR-256149 CyclinE/CDK2 complex SIGNOR-C16 SIGNOR SF3B1 protein O75533 UNIPROT up-regulates phosphorylation Thr244 GRAKGSEtPGATPGS 9606 12105215 t lperfetto "To map the set of phosphorylation sites in sap155-(223-322) that determine its interaction with nipp1, we have identified phosphorylation sites of cyclin e-cdk2 by the sequencing of proteolytically derived phosphopeptide). Three phosphorylation sites were identified as thr244, thr248, and thr313" SIGNOR-216686 NPM1 protein P06748 UNIPROT FBP1 protein P09467 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0003081;BTO:0000849 30616754 t lperfetto "For instance, nucleophosmin (NPM1) and zinc-finger protein X-linked (ZFX) bind to the E-box and ZFX binding site on the FBP1 promoter, respectively, and restrain FBP1 expression to facilitate aerobic glycolysis in PDAC and melanoma" SIGNOR-267594 MMP2 protein P08253 UNIPROT TGFB1 protein P01137 UNIPROT up-regulates cleavage 9606 10652271 t gcesareni "We also demonstrate that mmp-9, as well as its relative, mmp-2, cleave latent transforming growth factor-beta (tgf-beta), which constitutes a novel mechanism of tgf-beta activation" SIGNOR-74384 COL6A2 protein P12110 UNIPROT ECM_synthesis phenotype SIGNOR-PH8 SIGNOR up-regulates 9606 21949456 t "Muscle basement membrane consists primarily of a type IV collagen network, however types VI, XV, and XVIII are also present." SIGNOR-254674 NfKb-p65/p50 complex SIGNOR-C13 SIGNOR HSD11B2 protein P80365 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 15659537 f miannu "Overexpression of p50 inhibited HSD11B2 promoter activity and overexpression of Egr-1 inhibited transactivation of the HSD11B2 promoter by p65/p50." SIGNOR-253877 SPAG9 protein O60271 UNIPROT MAP3K5 protein Q99683 UNIPROT unknown binding 10090 BTO:0000165;BTO:0000222;BTO:0002181 SIGNOR-C21 22337877 t lperfetto "Cdo and jlp interacted with ask1 or tak1 in 293t cells and c2c12 myoblasts" SIGNOR-235545 S1PR3 protein Q99500 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates binding 9606 10488065 t gcesareni "Edg-3 and edg-5 couple not only to gibut also to gqand g13" SIGNOR-70713 GLI1 protein P08151 UNIPROT CCND1 protein P24385 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 23074268 f gcesareni "Canonical hh signaling plays an essential role in cell proliferation throught introduction of the genes encoding cyclin d1 and n-myc" SIGNOR-199126 RPS6K proteinfamily SIGNOR-PF26 SIGNOR RANBP3 protein Q9H6Z4 UNIPROT unknown phosphorylation Ser126 VKRERTSsLTQFPPS 9606 18280241 t llicata "Rsk phosphorylates serine 58 of ranbp3 in vitro and in vivo" SIGNOR-252770 MYOF protein Q9NZM1 UNIPROT Myoblast_fusion phenotype SIGNOR-PH98 SIGNOR up-regulates 10090 16280346 f "These data support a role for myoferlin in the maturation of myotubes and the formation of large myotubes that arise from the fusion of myoblasts to multinucleate myotubes" SIGNOR-255973 NF1 protein P21359 UNIPROT ADCY2 protein Q08462 UNIPROT up-regulates 9606 24431436 f miannu "Nf1encodes neurofibromin, a protein with multiple functions including ras inactivation (ras gtpase-activating protein or rasgap) and adenylyl cyclase (ac) activation" SIGNOR-203983 RBBP5 protein Q15291 UNIPROT "MLL/SET subcomplex" complex SIGNOR-C87 SIGNOR "form complex" binding 9606 24680668 t miannu "Dimethylation of h3k4 requires a sub-complexincluding wrad (wdr5, rbbp5, ash2l, and dpy-30), which binds to each set1 family member forming a minimal corecomplexthat is required for multiple lysine methylation." SIGNOR-204825 CDK2 protein P24941 UNIPROT PPP1CA protein P62136 UNIPROT "down-regulates activity" phosphorylation Thr320 NPGGRPItPPRNSAK 9606 12202491 t gcesareni "Both of these pp1 isoforms contain an arg-pro-ile/val-thr-pro-pro-arg sequence near the c terminus, a known site of phosphorylation by cdc/cdk kinases, and phosphorylation attenuates phosphatase activity" SIGNOR-92265 NRG3 protein P56975 UNIPROT ERBB4 protein Q15303 UNIPROT up-regulates binding 9606 BTO:0000887 9275162 t gcesareni "The neuregulins (also called heregulins and neu differentiation factors) nrg-1 and nrg-2 bind erbb-3 and erbb-4;and nrg-3 and nrg-4 bind erbb-4." SIGNOR-50614 HES1 protein Q14469 UNIPROT DTX1 protein Q86Y01 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0000970 20208568 f gcesareni "The notch target gene hes1 causes transcriptional inhibition of deltex1 by directly binding to the promoter of deltex1." SIGNOR-164071 HCK protein P08631 UNIPROT BCR-ABL "fusion protein" SIGNOR-FP6 SIGNOR up-regulates phosphorylation Tyr177 ADAEKPFyVNVEFHH 9606 9407116 t lperfetto "The src family kinase hck interacts with bcr-abl by a kinase-independent mechanism and phosphorylates the grb2-binding site of bcr" SIGNOR-53964 "bisphenol A" chemical CHEBI:33216 ChEBI AR protein P10275 UNIPROT "down-regulates activity" "chemical inhibition" -1 31995776 t miannu "This study investigated the endocrine-disrupting activity of BPA, BPF, and BPS alone or as a mixture and the agonistic and antagonistic activity of the BPs using an in vitro bioassay to detect ER-, AR-, and AhR-mediated activity. Here, we evaluated the endocrine-disrupting risks of the bisphenols by investigating their agonist and antagonist activities with the estrogen (ER), androgen (AR), and aryl hydrocarbon (AhR) receptors. Our results showed that BPA, BPS, and BPF (BPs) have estrogen agonist and androgen antagonist activities and decrease the ERα protein level. ." SIGNOR-268732 PRKDC protein P78527 UNIPROT IRF3 protein Q14653 UNIPROT up-regulates phosphorylation Thr135 GGGSTSDtQEDILDE 9606 11867762 t lperfetto "Phosphorylation of irf-3 by dna-pk after virus infection results in its nuclear retention and delayed proteolysis" SIGNOR-115331 cholesta-5,7-dien-3beta-ol smallmolecule CHEBI:17759 ChEBI calciol smallmolecule CHEBI:28940 ChEBI "up-regulates quantity" "precursor of" 9606 BTO:0001253 30080183 t lperfetto "Ultraviolet radiation results in the conversion of 7-dehydrocholesterol to pre-vitamin D, which isomerizes to vitamin D in the skin" SIGNOR-270561 PRKACA protein P17612 UNIPROT VIM protein P08670 UNIPROT "down-regulates activity" phosphorylation Ser51 LRPSTSRsLYASSPG -1 2500966 t miannu "Ser-46 was phosphorylated preferentially by cAMP-dependent protein kinase. Both kinases reacted with Ser-6, Ser-24, Ser-38, Ser-50, and Ser-65. Domain- and sequence-specific phosphorylation of vimentin induces disassembly of the filament structure." SIGNOR-250069 INTS9 protein Q9NV88 UNIPROT "Integrator complex" complex SIGNOR-C265 SIGNOR "form complex" binding 7227 26220997 t lperfetto "Integrator is a metazoan-specific multisubunit, multifunctional protein complex composed of 14 subunits named Int1–Int14 (Integrator subunits) " SIGNOR-261471 RXRB protein P28702 UNIPROT NR2F1 protein P10589 UNIPROT up-regulates binding 9606 10900149 t gcesareni "Arp-1/rxr, coup-tfi/rxr, and arp-1/coup-tfi heterodimers bound the fp330-3' site" SIGNOR-79449 NBR1 protein Q14596 UNIPROT SQSTM1 protein Q13501 UNIPROT up-regulates binding 9606 19250911 t gcesareni "Nbr1 and p62 interact and form oligomers." SIGNOR-184273 SMURF1 protein Q9HCE7 UNIPROT SMAD6 protein O43541 UNIPROT "down-regulates activity" relocalization 9606 22298955 t lperfetto "Smurf1, with its WW domain, specifically binds to the PY motif of Smad6 and transports Smad6 into the cytoplasm." SIGNOR-105931 Wnt proteinfamily SIGNOR-PF40 SIGNOR LPR5/6 complex SIGNOR-C219 SIGNOR "up-regulates activity" binding 9606 23209147 t miannu "FZD and LRP5/6 transduce Wnt signal via engaging downstream cytoplasmic components, among which two scaffolding proteins, Dishevelled and Axin, have prominent roles." SIGNOR-256174 EXOC8 protein Q8IYI6 UNIPROT "Exocyst_EXOC6B variant" complex SIGNOR-C491 SIGNOR "form complex" binding 9606 26240175 t miannu "The exocyst is an octameric protein complex that is implicated in the tethering of secretory vesicles to the plasma membrane prior to SNARE-mediated fusion." SIGNOR-270783 NDN protein Q99608 UNIPROT CDKN2A protein P42771 UNIPROT up-regulates 9606 24392140 f lperfetto "In HEK293A cells transfected with luciferase reporter constructs, necdin relieves Bmi1-dependent repression of p16 promoter activity," SIGNOR-253383 "Av/b5 integrin" complex SIGNOR-C178 SIGNOR Cell_adhesion phenotype SIGNOR-PH7 SIGNOR up-regulates 9606 25388208 f miannu "Integrin-mediated cell adhesion is important for development, immune responses, hemostasis and wound healing." SIGNOR-269027 ITGB1BP1 protein O14713 UNIPROT ITGB4 protein P16144 UNIPROT "down-regulates activity" binding 9606 19118207 t miannu "Integrins also bind to many PTBdomain-containing proteins (Calderwood et al., 2003) – including Dok1 and integrincytoplasmic-domain-associated protein 1 (ICAP1) – and these can compete with talin for binding to integrin and so can impair activation" SIGNOR-257658 ID3 protein Q02535 UNIPROT MYOD/E2-2 complex SIGNOR-C129 SIGNOR "down-regulates activity" binding 10090 9242638 t 2 miannu "All three Ids bound with high affinity to E proteins .Each Id was able to disrupt the ability of E protein-MyoD complexes to transactivate from a muscle creatine kinase reporter construct in vivo." SIGNOR-241155 ABL1 protein P00519 UNIPROT AHSA1 protein O95433 UNIPROT "up-regulates activity" phosphorylation Tyr223 LTSPEELyRVFTTQE 9606 26235616 t Manara "Here, we show that c-Abl kinase phosphorylates Y223 in human Aha1 (hAha1), promoting its interaction with Hsp90. This, consequently, results in an increased Hsp90 ATPase activity" SIGNOR-260938 MAPK1 protein P28482 UNIPROT NCOA6 protein Q14686 UNIPROT "up-regulates activity" phosphorylation Ser884 NKDVTLTsPLLVNLL -1 11773444 t miannu "In vitro phosphorylation studies with His-tagged TRBP (795–931) suggested that S884 can be phosphorylated by MAPK (ERK2) in vitro (Fig. 10A).Analysis of in vitro and in vivo receptor interactions with TRBP suggested that S884 allowed selective interactions for ERβ, TR, and RXR vs. ERα." SIGNOR-265882 ERBB4 protein Q15303 UNIPROT PI3K complex SIGNOR-C156 SIGNOR up-regulates binding 9606 16729043 t gcesareni "Pi3k is the sole binding partner to six tyrosines of erbb3 and one in erbb4." SIGNOR-252674 CBX4 protein O00257 UNIPROT ZEB2 protein O60315 UNIPROT "down-regulates quantity by destabilization" sumoylation Lys391 QTGLLKIkTEPLDFN 9534 16061479 t Luisa "Pc2 can act directly as an E3 ligase for SIP1 sumoylation.SIP1 sumoylation having a negative effect on its repression of E-cadherin transcription." SIGNOR-268955 DRD2 protein P14416 UNIPROT GNB5 protein O14775 UNIPROT "up-regulates activity" binding 9606 21303898 t miannu "The D2-class dopamine receptors (D2, D3, and D4) couple to the Gi/o family of G proteins and thus induce inhibition of AC" SIGNOR-264993 PTK2B protein Q14289 UNIPROT PTK2 protein Q05397 UNIPROT up-regulates phosphorylation Tyr407 IIDEEDTyTMPSTRD 9606 16760434 t gcesareni "Activated rock phosphorylates fak on ser732, which is essential for phosphorylation of tyr407 and for cell migration. We further show that pyk2 is activated by vegf-induced clustering of integrin v 3 and is responsible for the phosphorylation of tyr407." SIGNOR-147070 HES5 protein Q5TA89 UNIPROT NEUROG2 protein Q9H2A3 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 10090 BTO:0000938 30030829 f lperfetto "The basic-helixloop-helix factors HES1 and HES5 repress the expression of the proneural genes (Ascl1, Atoh1, Neurog1 and Neurog2) and thereby inhibit NSCs differentiation and neuron production" SIGNOR-265143 POT1 protein Q9NUX5 UNIPROT RPA1 protein P27694 UNIPROT "down-regulates activity" binding SIGNOR-C306 18680434 t lperfetto "The current model for how telomeres repress ATR signaling proposes that POT1/TPP1 prevents the binding of RPA to the single-stranded telomeric DNA" SIGNOR-263325 CSNK2A2 protein P19784 UNIPROT PPP1R8 protein Q12972 UNIPROT "up-regulates activity" phosphorylation Ser204 KNSRVTFsEDDEIIN -1 9407077 t llicata "Phosphorylation of NIPP-1 in a heterodimeric complex with the catalytic subunit of protein phosphatase-1 resulted in an activation of the holoenzyme without a release of NIPP-1. Sequencing and phosphoamino acid analysis of tryptic phosphopeptides enabled us to identify Ser178 and Ser199 as the phosphorylation sites of protein kinase A, whereas Thr161 and Ser204 were phosphorylated by protein kinase CK2." SIGNOR-251023 PHLPP1 protein O60346 UNIPROT STK4 protein Q13043 UNIPROT "up-regulates activity" dephosphorylation Thr387 TMKRRDEtMQPAKPS 9606 20513427 t "PHLPPs dephosphorylate Mst1 on the T387 inhibitory site, which activate Mst1 and its downstream effectors p38 and JNK to induce apoptosis." SIGNOR-248329 CD28 protein P10747 UNIPROT GRB2 protein P62993 UNIPROT up-regulates binding 9606 7737275 t fspada "In this study, we demonstrate that the co-stimulatory antigen cd28 binds to grb-2 by means of a cytoplasmic pymnm motif, which is the same motif bound by pi 3-kinase." SIGNOR-32509 CEBPA protein P49715 UNIPROT SOX4 protein Q06945 UNIPROT down-regulates "transcriptional regulation" 9606 24183681 t apalma "In summary, our data demonstrate that C/EBPα negatively regulates Sox4 transcription via direct DNA-binding." SIGNOR-255675 CYCS protein P99999 UNIPROT APAF1 protein O14727 UNIPROT "up-regulates activity" binding 9606 16977332 t lperfetto "Apaf-1 exists in an inactive conformation in cells and is activated through binding to cytochrome c and dATP." SIGNOR-149574 MAPK1 protein P28482 UNIPROT SMAD3 protein P84022 UNIPROT "down-regulates activity" phosphorylation Ser208 DAGSPNLsPNPMSPA 9606 19914161 t lpetrilli "Phosphorylation of the linker region of smads mediated by erk2, gsk3?, And cdk2/4 negatively regulates smad activity by preventing their relocation to the nucleus, by inhibiting their interactions with coactivators, or by accelerating their degradation;in contrast, erk2 phosphorylated all four smad1 residues almost evenly, while showing a preference for s204 over s208 and s213 in smad3" SIGNOR-161613 TGFB2 protein P61812 UNIPROT TGFB2 protein P61812 UNIPROT up-regulates binding 9606 16885528 t gcesareni "The active form of tgf-b is a dimer stabilized by hydrophobic interactions and usually further strengthened by an intersubunit disulfide bridge" SIGNOR-148608 ATR protein Q13535 UNIPROT ATM protein Q13315 UNIPROT "up-regulates activity" phosphorylation Ser1981 SLAFEEGsQSTTISS 9606 17124492 t lperfetto "Atr-dependent phosphorylation and activation of atm in response to uv treatment or replication fork stalling. Here, we show that atm phosphorylation at ser1981, a characterised autophosphorylation site, is atr-dependent and atm-independent following replication fork stalling or uv treatment" SIGNOR-150870 Laminin-10 complex SIGNOR-C182 SIGNOR Laminin-10 complex SIGNOR-C182 SIGNOR "up-regulates activity" binding 10090 BTO:0001086 18757303 t lperfetto "Recombinant human LN-511 alone was suffi- cient to enable self-renewal of mouse ES cells for up to 169 days (31 passages). Cells cultured on LN-511 maintained expression of pluripotency markers, such as Oct4, Sox2, Tert, UTF1, and Nanog|ES cells interacted with LN-511 via 􏰇1-integrins, mostly a6b1 and aVb1." SIGNOR-253277 SBDS protein Q9Y3A5 UNIPROT EIF6 protein P56537 UNIPROT up-regulates 9606 BTO:0001271 21536732 f miannu "Human sbds is an essential cofactor for the efl1 gtpase, and together they cooperate to directly catalyze the release of eif6 from mammalian pre-60s ribosomal subunits" SIGNOR-173536 SIRT1 protein Q96EB6 UNIPROT FOXL2 protein P58012 UNIPROT down-regulates deacetylation 9606 19010791 t miannu "We find that foxl2 activity is repressed by the sirt1 deacetylase." SIGNOR-182306 torkinib chemical CHEBI:90679 ChEBI MTOR protein P42345 UNIPROT "down-regulates activity" "chemical inhibition" -1 22037378 t Luana "Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here." SIGNOR-258268 PTPN11 protein Q06124 UNIPROT GAB1 protein Q13480 UNIPROT down-regulates dephosphorylation Tyr627 KGDKQVEyLDLDLDS 9606 10068651 t lperfetto "Tyrosine phosphorylation of gab2 was induced by stimulation through gp130, il-2r, il-3r, tpor, scfr, and tcr. Gab1 and gab2 were shown to be substrates for shp-2 in vitro." SIGNOR-236262 SMAD7 protein O15105 UNIPROT TGFBR1 protein P36897 UNIPROT "down-regulates activity" binding 9606 9892110 t lperfetto "SMAD7 functions as an antagonist to TGFB by binding to the TBRI and thus inhibiting activation of SMAD2 and SMAD3." SIGNOR-64088 CLK1 protein P49759 UNIPROT RBM17 protein Q96I25 UNIPROT "up-regulates activity" phosphorylation Ser204 DSRPRSQsSKAAIPP 9534 BTO:0001538 23519612 t miannu "In this work, we show that Cdc2-like kinase 1 (Clk1) phosphorylates SPF45 on eight serine residues." SIGNOR-262706 CMC1 protein Q7Z7K0 UNIPROT "MITRAC complex" complex SIGNOR-C538 SIGNOR "form complex" binding 9606 BTO:0000007 23260140 t "By analyzing MITRAC12 interaction partners, we show that recently identified assembly factors, such as c12orf62, CMC1, and the novel assembly factor MITRAC15, are constituents of MITRAC complexes" SIGNOR-272481 CSNK2A1 protein P68400 UNIPROT NFKBIA protein P25963 UNIPROT down-regulates phosphorylation Ser283 NLQMLPEsEDEESYD 9606 BTO:0000782 8622692 t llicata "Casein kinase ii phosphorylates i kappa b alpha at s-283, s-289, s-293, and t-291 and is required for its degradation." SIGNOR-40502 YAP1 protein P46937 UNIPROT FBXO32 protein Q969P5 UNIPROT down-regulates 9606 BTO:0000222;BTO:0002314 BTO:0000887;BTO:0001103 23038772 f gcesareni "The downregulation of fbox32 expression by high yap activity in activated satellite cells may contribute to sustaining high levels of myod in activated satellite cells." SIGNOR-199069 CDK1 protein P06493 UNIPROT CDKN1B protein P46527 UNIPROT down-regulates phosphorylation Thr187 NAGSVEQtPKKPGLR 9606 10931950 t gcesareni "Phosphorylation of kip1 on thr-187, by cdk1 and cdk2 leads to protein ubiquitination and proteasomal degradation." SIGNOR-80230 RARB protein P10826 UNIPROT THR proteinfamily SIGNOR-PF84 SIGNOR "up-regulates activity" binding 9606 15650024 t "inferred from family member" gcesareni "We report that the retinoic acid receptors (rars), a distinct class of nuclear receptors, are also efficient heterodimer partners for trs" SIGNOR-267807 TRAF6 protein Q9Y4K3 UNIPROT IRAK1 protein P51617 UNIPROT "up-regulates activity" ubiquitination Lys180 SPAPSSTkPGPESSV 9606 18347055 t "K63-linked polyubiquitination of proximal signaling proteins is a common mechanism used by diverse innate immune receptors for recruiting IKK and activating NF-_B" SIGNOR-252252 GNA12 protein Q03113 UNIPROT ARHGEF12 protein Q9NZN5 UNIPROT "up-regulates activity" binding 10090 12024019 t "P115 RhoGEF stimulates the intrinsic GTP hydrolysis activity of G alpha 12/13 subunits and acts as an effector for G13-coupled receptors by linking receptor activation to RhoA activation." SIGNOR-256522 PHF3 protein Q92576 UNIPROT "RNA Polymerase II" complex SIGNOR-C391 SIGNOR "down-regulates activity" binding 9606 BTO:0000007 34667177 t miannu "PHF3 interacts with RNA polymerase II through the SPOC domain. PHF3 negatively regulates mRNA levels. Here, we identify PHD-finger protein 3 (PHF3) as a regulator of transcription and mRNA stability that docks onto Pol II CTD through its SPOC domain. Our data suggest that PHF3 acts as a prominent effector of neuronal gene regulation by bridging transcription with mRNA decay. PHF3 SPOC preferentially binds RNA Pol II CTD phosphorylated on Serine-2" SIGNOR-266964 GSK3A protein P49840 UNIPROT MAPT protein P10636 UNIPROT down-regulates phosphorylation Ser579 NVKSKIGsTENLKHQ 9606 BTO:0000938 9771888 t "The effect has been demonstrated using P10636-8" gcesareni "Tau is phosphorylated by gsk-3 at several sites found in alzheimer disease and its biological activity markedly inhibited only after it is prephosphorylated by a-kinase." SIGNOR-60651 (2R,3S,4S,5R)-2-(6-amino-2-fluoro-9-purinyl)-5-(hydroxymethyl)oxolane-3,4-diol chemical CHEBI:94701 ChEBI RRM1 protein P23921 UNIPROT "down-regulates activity" "chemical inhibition" -1 7048062 t miannu "In vitro biological activity of 9-beta-D-arabinofuranosyl-2-fluoroadenine and the biochemical actions of its triphosphate on DNA polymerases and ribonucleotide reductase from HeLa cells. 2-F-araATP was a potent inhibitor of ribonucleotide reductase" SIGNOR-258404 MYOG protein P15173 UNIPROT "SWI/SNF complex" complex SIGNOR-C92 SIGNOR up-regulates binding 9606 BTO:0001103 17194702 t lperfetto "Upon the expression of myogenin, myogenin, mef2d, and brg1 localize to the myogenin promoter to maintain myogenin expression./ Swi/snf chromatin-remodeling activity is required for myogenin expression in differentiated skeletal muscle" SIGNOR-217740 GSK1059615 chemical CHEBI:71955 ChEBI PIK3CB protein P42338 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-192774 Ub:E2 complex SIGNOR-C497 SIGNOR TRAF5 protein O00463 UNIPROT "up-regulates activity" ubiquitination 9606 34199813 t miannu "The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t" SIGNOR-271084 TFAP2B protein Q92481 UNIPROT TP53 protein P04637 UNIPROT "up-regulates quantity by stabilization" binding 9606 21556774 t miannu "These data suggest that AP-2Œ≤ enhances transactivation of p53 and regulates CRYAB transcription via p53. Further study demonstrated that AP-2Œ≤ interacts with p53 and augments its protein stability. Taken together, our results indicate that AP-2Œ≤ up-regulates the transcription of the CRYAB gene through stabilizing p53." SIGNOR-255422 IPA-3 chemical CHEBI:101355 ChEBI PKN1 protein Q16512 UNIPROT "down-regulates activity" "chemical inhibition" 9606 BTO:0003897 23894351 t lperfetto "In the current study, an allosteric small molecule PAK1 inhibitor, IPA-3, was evaluated for the potential in suppressing hepatocarcinogenesis. Consistent with other reports, inhibition of PAK1 activity was observed in several human HCC cell lines treated with various dosages of IPA-3." SIGNOR-262017 AKT1 protein P31749 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 24743741 f "Activation of PDGFRα stimulates proliferation of PDGFRα(+) cells through PI3K-Akt and MEK2-MAPK signaling pathways, and aberrant accumulation of PDGFRα(+) cells was conspicuous in muscles of patients with both genetic and non-genetic muscle diseases." SIGNOR-254372 CDK8 protein P49336 UNIPROT NOTCH proteinfamily SIGNOR-PF30 SIGNOR down-regulates phosphorylation 9606 15546612 t gcesareni "Purified recombinant cycc:cdk8 phosphorylates the notch icd within the tad and pest domains, and expression of cycc:cdk8 strongly enhances notch icd hyperphosphorylation and pest-dependent degradation by the fbw7/sel10 ubiquitin ligase in vivo." SIGNOR-254312 YARS1 protein P54577 UNIPROT ATP(4-) smallmolecule CHEBI:30616 ChEBI "down-regulates quantity" "chemical modification" 9606 16429158 t miannu "YARS (also known as TyrRS) catalyzes the aminoacylation of tRNATyr with tyrosine by a two-step mechanism. Tyrosine is first activated by ATP to form tyrosyl-adenylate and is then transferred to tRNATyr" SIGNOR-270519 ATM protein Q13315 UNIPROT MDM2 protein Q00987 UNIPROT "down-regulates activity" phosphorylation Ser395 SQESEDYsQPSTSSS 9606 BTO:0002552 11331603 t lperfetto "Atm phosphorylates mdm2 on s395 in vitro. Moreover, s395 appears to be phosphorylated in an atm-dependent manner in vivo the precise mechanism through which s395 phosphorylation attenuates mdm2 function is unclear." SIGNOR-107256 adrenaline smallmolecule CHEBI:33568 ChEBI ADRB1 protein P08588 UNIPROT "up-regulates activity" "chemical activation" 10030 BTO:0000457 20590599 t Luana "Of the agonists studied here, there was a general trend that those with highest intrinsic efficacy were so across all three receptor subtypes (i.e. at the top of Tables 3–5, e.g. fenoterol, terbutaline, metaproterenol and adrenaline)" SIGNOR-257876 PRTN3 protein P24158 UNIPROT F2R protein P25116 UNIPROT "down-regulates activity" cleavage Val72 GLTEYRLvSINKSSP -1 10978167 t lperfetto "PAR1E and PAR2E (10 microM) were incubated in the presence of the different proteases | The enzymes were used at the following concentrations: 0.5 unit/mL thrombin, 2.5 nM trypsin, 20 nM plasmin, 20 nM cathepsin G, 20 nM elastase, 20 nM proteinase 3, and 2 units/mL calpain I and II|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus.|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus.|Plasmin, calpain and leukocyte elastase, cathepsin G, and proteinase 3 cleaved at multiple sites and would be expected to disable PAR1 by cleaving COOH-terminal to the activation site." SIGNOR-263579 ASH1L protein Q9NR48 UNIPROT NRXN1 protein Q9ULB1 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0000942 27229316 t Gianni "Our results reveal that a novel process of activity-dependent transcriptional repression exists in neurons and that Ash1L mediates the long-term repression of nrxn1α, thus implicating an important role for epigenetic modification in brain functioning." SIGNOR-269056 REST protein Q13127 UNIPROT PENK protein P01210 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 21832040 f miannu "HIPPI could bind to the promoter of REST and increased its expression in neuronal as well as non-neuronal cells. Such activation of REST down-regulated expression of REST target genes, such as brain-derived neurotrophic factor (BDNF) or proenkephalin (PENK)." SIGNOR-255074 PGD protein P52209 UNIPROT 6-phospho-D-gluconate smallmolecule CHEBI:16863 ChEBI "down-regulates quantity" "chemical modification" 9606 34775382 t miannu "6 PG undergoes oxidative decarboxylation by 6-phosphogluconate dehydrogenase (6PGD) producing Ru5P and the second NADPH molecule." SIGNOR-267060 TRIM27 protein P14373 UNIPROT MAPK12 protein P53778 UNIPROT up-regulates 9606 BTO:0000671 12807881 f miannu "We found rfp-mediated activation of both exogenous and endogenous forms of the other stress-activated mapk, p38." SIGNOR-102025 metformin chemical CHEBI:6801 ChEBI NR0B2 protein Q15466 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 17909097 f gcesareni "In this study, we found that metformin increased shp gene expression via ampk activation and inhibited the expression of the hepatic gluconeogenic genes pepck and g6pase via upregulation of shp." SIGNOR-158059 SLBP protein Q14493 UNIPROT H3-3A protein P84243 UNIPROT "up-regulates quantity by expression" "translation regulation" 9606 BTO:0001938 19155325 t lperfetto "Synthesis of mature histone mRNA requires only a single processing reaction: an endonucleolytic cleavage between a conserved stem-loop and a purine-rich downstream element to form the 3' end. The stem-loop binding protein (SLBP) is required for processing, and following processing, histone mRNA is transported to the cytoplasm, where SLBP participates in translation of the histone mRNA|We used radiolabeled probes generated by PCR targeting the open reading frame (ORF) to detect histones H2A, H2B, H3, H4, and H1 and used 7SK snRNA as a loading control (Fig. 2A). The abundance of histone H2A, H2B, H3, and H4 mRNAs is reduced to 37% to 70% of control levels in the SLBP knockdown cells when compared to the C2 control." SIGNOR-265418 CSNK2A1 protein P68400 UNIPROT MS4A1 protein P11836 UNIPROT unknown phosphorylation Ser231 KSNIVLLsAEEKKEQ 9606 7678037 t llicata "These data suggest taht CKII can phosphorylate more than one site on CD20 molecule. | Taken together, this data shown that insulin can increase serine/ threonine phosphorylation and may stimulate CKII activity in B cells." SIGNOR-250915 FOXN3 protein O00409 UNIPROT PIM2 protein Q9P1W9 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0002552 24403608 t Luana "CHES1/FOXN3 regulates cell proliferation by repressing PIM2 and protein biosynthesis." SIGNOR-261607 RAG1 protein P15918 UNIPROT MTOR protein P42345 UNIPROT up-regulates relocalization 9606 22790199 t gcesareni "Rag gtpases, together with a multi-protein complex called ragulator, mediate amino acid-mediated mtor recruitment to the lysosome surface where mtor becomes activated." SIGNOR-198242 PTK2 protein Q05397 UNIPROT TLN1 protein Q9Y490 UNIPROT "up-regulates activity" binding 9606 15688067 t miannu "Focal adhesion kinase (FAK) is activated by growth factors and integrins during migration, and functions as a receptor-proximal regulator of cell motility. At contacts between cells and the extracellular matrix, FAK functions as an adaptor protein to recruit other focal contact proteins or their regulators, which affects the assembly or disassembly of focal contacts. Whereas it was first hypothesized that FAK might bind directly to the cytoplasmic tails of integrins, accumulated evidence supports an indirect association of FAK with integrins through binding to integrin-associated proteins such as paxillin and talin." SIGNOR-257731 EFNA1 protein P20827 UNIPROT EPHA2 protein P29317 UNIPROT up-regulates binding 9606 9576626 t tpavlidou "Ephrin-a1 binds and activates the tyrosine kinase activity of eph-a2, and has a dissociation constant of 20_30 nm" SIGNOR-56901 CDK1 protein P06493 UNIPROT DDX3X protein O00571 UNIPROT down-regulates phosphorylation Thr204 LTRYTRPtPVQKHAI 9606 SIGNOR-C17 16280325 t lperfetto "Thr204 to glu204 ddx3 mutant protein lost its function, suggesting that phosphorylation at thr204 affects ddx3 function. Thr204 was phosphorylated by cyclin b/cdc2. Thr323 in motif ib was also phosphorylated by cyclin b/cdc2 kinase. We propose a novel function of cyclin b/cdc2 kinase in mitosis, which is to cause a loss of ddx3 function to repress cyclin a expression and to decrease ribosome biogenesis and translation during mitosis." SIGNOR-141565 IRS2 protein Q9Y4H2 UNIPROT PI3K complex SIGNOR-C156 SIGNOR "up-regulates activity" binding 10090 BTO:0004087 24811175 t lperfetto "Insulin receptor substrate 1 (IRS-1) and IRS-2 are cytoplasmic adaptor proteins that mediate the activation of signaling pathways in response to ligand stimulation of upstream cell surface receptors. Despite sharing a high level of homology and the ability to activate PI3K, only Irs-2 positively regulates aerobic glycolysis in mammary tumor cells." SIGNOR-252696 HNF1B protein P35680 UNIPROT ALB protein P02768 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 1673926 f Regulation miannu "VHNF1 transactivated the albumin promoter in transfection experiments" SIGNOR-251930 ABL1 protein P00519 UNIPROT PLSCR1 protein O15162 UNIPROT unknown phosphorylation Tyr74 PVYNQPVyNQPVGAA 9606 11390389 t Manara "Our data establish that the Abl SH3 domain binds to the N-terminal proline-rich segment of PLSCR1 and that ABL1 phosphorylates Tyr residues of the PLSCR1 polypeptide, most likely Tyr69 and Tyr74 within the tandem repeat sequence" SIGNOR-260808 GNB5 protein O14775 UNIPROT ADCY1 protein Q08828 UNIPROT "down-regulates activity" binding 9606 BTO:0004032 21303898 t miannu "The D2-class dopamine receptors (D2, D3, and D4) couple to the Gi/o family of G proteins and thus induce inhibition of AC" SIGNOR-264996 MAPK8 protein P45983 UNIPROT BCL2 protein P10415 UNIPROT down-regulates phosphorylation Thr69 SRDPVARtSPLQTPA 9606 10567572 t gcesareni "G(2)/m-phase cells proved more susceptible to death signals, and phosphorylation of bcl-2 appeared to be responsible, as a ser70ala substitution restored resistance to apoptosis. We noted that ask1 and jnk1 were normally activated at g(2)/m phase, and jnk was capable of phosphorylating bcl-2.." SIGNOR-72361 GTP smallmolecule CHEBI:15996 ChEBI GNAS protein P63092 UNIPROT up-regulates "chemical activation" 9606 17095603 t gcesareni "Galfa subunits cycle between inactive (gdp-bound) and active (gtp-bound) states, and the lifetime of the active state is limited by gtp hydrolysis." SIGNOR-150552 DDB2 protein Q92466 UNIPROT DDB2/DDB1 complex SIGNOR-C39 SIGNOR "form complex" binding 9606 9418871 t miannu "Ddb was identified as a heterodimeric protein (48 and 127 kda) that binds to uv-damaged dna" SIGNOR-54099 ENAH protein Q8N8S7 UNIPROT Neurite_outgrowth phenotype SIGNOR-PH134 SIGNOR up-regulates 9606 18508258 f miannu "Here we review recent findings into Ena/VASP function in neurite initiation, axon outgrowth and guidance." SIGNOR-268392 IL27 protein Q8NEV9 UNIPROT IL27RA protein Q6UWB1 UNIPROT up-regulates binding 9606 BTO:0000782;BTO:0000876 14764690 t gcesareni "Wsx-1 and glycoprotein 130 constitute a signal-transducing receptor for il-27." SIGNOR-121799 MAPK3 protein P27361 UNIPROT MKNK2 protein Q9HBH9 UNIPROT up-regulates phosphorylation 9606 9155017 t gcesareni "Erk and p38 phosphorylate mnk1 and mnk2, which stimulates their in vitro kinase activity." SIGNOR-48355 KIT protein P10721 UNIPROT SLA protein Q13239 UNIPROT "down-regulates activity" phosphorylation Tyr120 SETKKGFySLSVRHR 9534 24284075 t miannu "Oncogenic c-Kit-D816V phosphorylates SLAP on residues Y120, Y258 and Y273. Mutation of the SLAP tyrosine phosphorylation sites rescues its activity" SIGNOR-263140 TLR4 protein O00206 UNIPROT TLR4 protein O00206 UNIPROT up-regulates binding 9606 24352680 t fstefani "Upon activation, tlrs hetero- or homodimerize inducing the recruitment of adaptor proteins via the cytoplasmic tir domain" SIGNOR-203484 MGLL protein Q99685 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR down-regulates 9606 26997225 f irozzo "Overexpression of MGLL inhibits proliferation and delays cell cycle progression in QGY-7703 cells. Forced overexpression of MGLL in human HCC cells resulted in marked inhibition in cell proliferation with a significant delay in cell cycle progression [.]" SIGNOR-259139 CD40 protein P25942 UNIPROT Inflammation phenotype SIGNOR-PH12 SIGNOR up-regulates 9606 BTO:0000782;BTO:0000776 19904719 f fstefani "Cd40 has been found to be essential in mediating a broad variety of immune and inflammatory responses including t cell-dependent immunoglobulin class switching, memory b cell development" SIGNOR-189109 MAP2K6 protein P52564 UNIPROT MAP2K6 protein P52564 UNIPROT "up-regulates activity" phosphorylation 9606 BTO:0000007 10347227 t lperfetto "However, the autocatalytic activities of both mkk6 and mkk7 were enhanced by their coexpression with either mekk3 or mekk2." SIGNOR-236122 CHEK1 protein O14757 UNIPROT CLSPN protein Q9HAW4 UNIPROT up-regulates phosphorylation Thr916 DELLDLCtGKFTSQA 9606 16963448 t gcesareni "We found that thr-916 on claspin is phosphorylated by chk1, suggesting that chk1 regulates claspin during checkpoint response." SIGNOR-149411 AKT proteinfamily SIGNOR-PF24 SIGNOR CARHSP1 protein Q9Y2V2 UNIPROT unknown phosphorylation Ser52 TRRTRTFsATVRASQ 9606 BTO:0000671 15910284 t lperfetto "These and other results demonstrate that crhsp24 is phosphorylated at ser52 by pkbalpha in response to igf-1, at ser52 by pkbalpha and rsk in response to egf" SIGNOR-137430 PRKACA protein P17612 UNIPROT CACNA1C protein Q13936 UNIPROT "up-regulates activity" phosphorylation Ser1897 LLRKANPsRCHSRES 10090 28119464 t "These findings reveal an essential role for _1C phosphorylation at Ser1928 in stimulating CaV1.2 channel activity and vasoconstriction by AKAP-targeted PKA upon exposure to increased glucose and in diabetes" SIGNOR-251709 CTDSPL protein O15194 UNIPROT RB1 protein P06400 UNIPROT "up-regulates activity" dephosphorylation Ser807 PGGNIYIsPLKSPYK 9606 15051889 t "ppRB (RB phosphorylated at Ser-807/811|Possible Mechanisms of HYA22 Action in Tumorigenesis: Dephosphorylation of RB by Transient Expression of HYA22 Isoforms." SIGNOR-248304 glucose chemical CHEBI:17234 ChEBI Hexokinase proteinfamily SIGNOR-PF76 SIGNOR "up-regulates quantity by stabilization" 9606 BTO:0004424 26323688 t "inferred from family member" "Consistently, treatment of cells with 2-deoxy-d-glucose (2DG), which completely inhibits glucose metabolism, leads to HK2 degradation and cell death in combination with C43" SIGNOR-270265 CEBPB protein P17676 UNIPROT GOT1 protein P17174 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 8454627 t "In cotransfection experiments, the C/EBP beta protein trans-activated 10-15-fold the cAspAT gene promoter in HepG2 cells. Deletion studies revealed that regions P2 and P4 are critical for promoter activity. In gel retardation experiments, the P4 region bound different C/EBP-related proteins in different tissues" SIGNOR-254051 CAMK2A protein Q9UQM7 UNIPROT PDC protein P20941 UNIPROT unknown phosphorylation Ser54 KEILRQMsSPQSRNG 11331285 t llicata "In this study, we report that Pd was rapidly phosphorylated by Ca(2+)/calmodulin-dependent kinase II, resulting in 100-fold greater inhibition of Gbetagamma binding than cAMP-dependent protein kinase phosphorylation. Furthermore, Pd phosphorylation by Ca(2+)/calmodulin-dependent kinase II at Ser-54 and Ser-73 led to binding of the phosphoserine-binding protein 14-3-3." SIGNOR-250636 MAT2B protein Q9NZL9 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR down-regulates 9606 BTO:0001938 30942439 f miannu "MAT2B Promotes Proliferation and Inhibits Apoptosis in Osteosarcoma by Targeting Epidermal Growth Factor Receptor and Proliferating Cell Nuclear Antigen" SIGNOR-261243 PRTN3 protein P24158 UNIPROT F2RL1 protein P55085 UNIPROT "down-regulates activity" cleavage Val55 VTGKGVTvETVFSVD -1 10978167 t lperfetto "PAR1E and PAR2E (10 microM) were incubated in the presence of the different proteases | The enzymes were used at the following concentrations: 0.5 unit/mL thrombin, 2.5 nM trypsin, 20 nM plasmin, 20 nM cathepsin G, 20 nM elastase, 20 nM proteinase 3, and 2 units/mL calpain I and II|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus.|Mass spectrometry studies of PAR2E predicted activation of PAR2 by trypsin through cleavage at the Arg36-Ser37 site, no effect of thrombin, and inactivation of the receptor by plasmin, calpain and leukocyte elastase, cathepsin G, and proteinase 3" SIGNOR-263599 linagliptin chemical CHEBI:68610 ChEBI DPP4 protein P27487 UNIPROT "down-regulates activity" "chemical inhibition" 9606 18052023 t Luana "Herein, we report the discovery of the novel, potent, and selective DPP-4 inhibitor 1 (BI 1356)9 originating from the class of xanthines (Chart 1)" SIGNOR-257764 BPTF protein Q12830 UNIPROT HNuRF complex SIGNOR-C448 SIGNOR "form complex" binding 9606 BTO:0000007 14609955 t miannu "hNURF is a chromatin remodeler. Here, we describe the purification of the first human SNF2L complex. The subunit composition suggests that it represents the human ortholog of the dNURF complex. In this regard, the hNURF complex also contains BPTF and RbAP46/48. Surprisingly, hNURF does not contain the inorganic pyrophosphatase protein NURF38. Nonetheless, the biochemical activity of hNURF is similar as it displayed predominantly nucleosome-stimulated ATPase activity, as well as potent chromatin-remodeling activity on oligonucleosomal arrays." SIGNOR-268817 F2RL1 protein P55085 UNIPROT RARG protein P13631 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0000007 21072196 f miannu "PAR-2 activation up-regulated four genes more than 5 fold (DUSP6, WWOX, AREG, SERPINB2) and down-regulated another six genes more than 3 fold (TXNIP, RARG, ITGB4, CTSD, MSC and TM4SF15)." SIGNOR-254858 GLUL protein P15104 UNIPROT ammonium smallmolecule CHEBI:28938 ChEBI "down-regulates quantity" "chemical modification" 9606 30158707 t miannu "Glutamine synthetase, encoded by the gene GLUL, is an enzyme that converts glutamate and ammonia to glutamine. certain cell types express glutamine synthetase (GS; also called glutamate-ammonia ligase; GLUL), the enzyme capable of de novo glutamine production from glutamate and ammonia in an ATP and Mg2+/Mn2+ requiring reaction." SIGNOR-267825 RPS29 protein P62273 UNIPROT "40S cytosolic small ribosomal subunit" complex SIGNOR-C286 SIGNOR "form complex" binding -1 25901680 t lperfetto "Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins." SIGNOR-262422 GSK3B protein P49841 UNIPROT GYS1 protein P13807 UNIPROT "down-regulates activity" phosphorylation Ser645 RPASVPPsPSLSRHS -1 6772446 t "Glycogen synthase kinase-3 phosphorylates three serine residues on glycogen synthase (sites 3a, 3b and 3c) which are all located in the same nine-amino-acid segment of the polypeptide chain. The sequence in this region is: Arg-Tyr-Pro-Arg-Pro-Ala-Ser(P)-Val-Pro-Pro-Ser(P)-Pro-Ser-Leu-Ser(P)-Arg-." SIGNOR-253006 ANK2 protein Q01484 UNIPROT DCTN4 protein Q9UJW0 UNIPROT "up-regulates quantity" relocalization 10090 BTO:0001103 19109891 t miannu "We present evidence for an ankyrin-based mechanism for sarcolemmal localization of dystrophin and beta-DG. Ankyrin-B thus is an adaptor required for sarcolemmal localization of dystrophin, as well as dynactin-4." SIGNOR-266713 AKT1 protein P31749 UNIPROT BRCA1 protein P38398 UNIPROT up-regulates phosphorylation Ser694 QTSKRHDsDTFPELK 9606 20085797 t lperfetto "We identify a novel akt phosphorylation site in brca1 at s694 which is responsive to activation of these signaling pathways. These data suggest akt phosphorylation of brca1 increases total protein expression by preventing proteasomal degradation" SIGNOR-163472 PCSK7 protein Q16549 UNIPROT KHSRP protein Q92945 UNIPROT down-regulates phosphorylation 9606 BTO:0000222 BTO:0000887 16364914 t gcesareni "Ksrp phosphorylated by p38 displays compromised binding to are-containing transcripts and fails to promote their rapid decay,although it retains the ability to interact with the mrna degradation machinery." SIGNOR-143167 INHBA protein P08476 UNIPROT ACVR2B protein Q13705 UNIPROT "up-regulates activity" binding 9606 8622651 t gcesareni "Activin binds directly to ActR-IIB, and this complex associates with ActR-IB, which does not bind ligand on its own. In the resulting complex, ActR-IB becomes hyperphosphorylated, and this requires the kinase activity of ActR-IIB." SIGNOR-235142 CHEK2 protein O96017 UNIPROT PML protein P29590 UNIPROT unknown phosphorylation Ser117 ESLQRRLsVYRQIVD 9606 12402044 t llicata "Hcds1/chk2 phosphorylates pml at ser 117 in vitro. hcds1/chk2 phosphorylates pml in vivo." SIGNOR-94872 BMPR1B protein O00238 UNIPROT SMAD5 protein Q99717 UNIPROT up-regulates phosphorylation 9606 19620713 t gcesareni "Two types of bmp-induced signaling pathways are known, the smad and p38 mapk pathways. In the former case, bmpr1 phosphorylates smad-1,-5,-8, which forms a complex with smad4 that translocates into the nucleus and regulates gene expression." SIGNOR-187193 MAS1 protein P04201 UNIPROT FLNA protein P21333 UNIPROT "up-regulates activity" binding 9606 26460884 t miannu "We further determined that GPCRs, AT1R, and MAS directly recruited FLNa and promoted its phosphorylation by cellular S/T kinases in an agonist-dependent manner. Our studies thus provide a structural framework for filamin in GPCR signaling, potentially regulating a variety of cellular responses. MAS likely binds filamin constitutively and hence leads to constitutive filamin phosphorylation. These results emphasize that it is the active receptor that mediates filamin phosphorylation by PKA or other cellular S/T kinases" SIGNOR-260627 PTN protein P21246 UNIPROT ALK protein Q9UM73 UNIPROT up-regulates binding 9606 11278720 t gcesareni "We conclude from this series of experiments that ptn specifically binds to the alk orphan receptor as a high affinity ligand at least in part via the putative ligand binding domain described above." SIGNOR-106411 CDK3 protein Q00526 UNIPROT RB1 protein P06400 UNIPROT down-regulates phosphorylation Ser811 IYISPLKsPYKISEG 9606 15084261 t gcesareni "The active form of prb is underphosphorylated. Cdk3/cyclin-c-mediated phosphorylation at ser-807 and ser-811 is required for g0-g1 transition." SIGNOR-124212 AMPK complex SIGNOR-C15 SIGNOR FOXO3 protein O43524 UNIPROT "up-regulates activity" phosphorylation Ser626 SLECDMEsIIRSELM 9606 17711846 t gcesareni "Phosphorylation by AMPK leads to the activtion of FOXO3 transcriptional activity without affecting FOXO3 subcellular localization." SIGNOR-249688 PHLPP1 protein O60346 UNIPROT AKT1 protein P31749 UNIPROT "down-regulates activity" dephosphorylation Ser473 RPHFPQFsYSASGTA 9606 BTO:0001544 19261608 t "The Abl kinase inhibitors and depletion of Bcr-Abl induced the expression of PHLPP1 and PHLPP2, which dephosphorylated Ser-473 on Akt1, -2, and -3, resulting in inhibited proliferation of CML cells.|Thus, Bcr-Abl represses the expression of PHLPP1 and PHLPP2 and continuously activates Akt1, -2, and -3 via phosphorylation on Ser-473, resulting in the proliferation of CML cells." SIGNOR-248327 5-phospho-beta-D-ribosylaminium(1-) smallmolecule CHEBI:58681 ChEBI N(1)-(5-phospho-beta-D-ribosyl)glycinamide(1-) smallmolecule CHEBI:143788 ChEBI "up-regulates quantity" "precursor of" 9606 34283828 t miannu "In humans, GART [phosphoribosylglycinamide formyltransferase (EC 2.1.2.2) / phosphoribosylglycinamide synthetase (EC 6.3.4.13) / phosphoribosylaminoimidazole synthetase (EC 6.3.3.1)] is a trifunctional protein which catalyzes the second, third, and fifth reactions of the ten step de novo purine synthesis (DNPS) pathway. The second step of DNPS is conversion of phosphoribosylamine (5-PRA) to glycineamide ribonucleotide (GAR)." SIGNOR-267296 DET1 protein Q7L5Y6 UNIPROT "DCX DET1-COP1" complex SIGNOR-C24 SIGNOR "form complex" binding 9606 17452440 t lperfetto "Mammalian det1 regulates cul4a activity and forms stable complexes with e2 ubiquitin-conjugating enzymes" SIGNOR-154508 SNAI2 protein O43623 UNIPROT JAG1 protein P78504 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000150 20509143 f miannu "SLUG up-regulation engenders breast cancer cells with stem cell-like properties including enhanced expression of CD44 and Jagged-1 in conjunction with estrogen receptor alpha down-regulation, growth as mammospheres, and extracellular matrix invasiveness." SIGNOR-255151 PRKACA protein P17612 UNIPROT RAP1A protein P62834 UNIPROT "down-regulates activity" phosphorylation Ser180 KKKPKKKsCLLL 9534 9867809 t miannu "Phosphorylation of Rap1A by PKA abolished its binding activity to CRR. a mutant Rap1A(S180E), whose sole PKA phosphorylation residue, Ser-180, was substituted by an acidic residue, Glu, to mimic its phosphorylated form, failed to suppress Ras-dependent Raf-1 activation in COS-7 cells." SIGNOR-250042 YY1 protein P25490 UNIPROT ACTC1 protein P68032 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 10090 9171244 f miannu "Expression of YY1 inhibited cardiac alpha-actin promoter activity, whereas coexpression of Nkx-2.5 and SRF was able to partially reverse YY1 repression." SIGNOR-255616 SLC9A2 protein Q9UBY0 UNIPROT hydron chemical CHEBI:15378 ChEBI "down-regulates quantity" relocalization 9606 BTO:0000938 31507243 t miannu "Na+/H+ exchangers play pivotal roles in the control of cell and tissue pH by mediating the electroneutral exchange of Na+ and H+ across cellular membranes. " SIGNOR-265592 PPP3CA protein Q08209 UNIPROT Calcineurin complex SIGNOR-C155 SIGNOR "form complex" binding 9606 14623295 t miannu "Calcineurin is a heterodimer consisting of a catalytic subunit with a molecular mass of about 59 kDa (calcienurin A or CNA) and a regulatory subunit with a molecular mass of 19 kDa (calcineurin B or CNB)." SIGNOR-255291 RPS6KA1 protein Q15418 UNIPROT EEF2K protein O00418 UNIPROT "down-regulates activity" phosphorylation Ser366 SPQVRTLsGSRPPLL 9606 BTO:0000669 11500364 t lperfetto "We show that two such kinases, p70 s6 kinase (regulated via mtor) and p90(rsk1) (activated by erk), phosphorylate eef2k at a conserved serine and inhibit its activity" SIGNOR-109708 PPP1CB protein P62140 UNIPROT TP53 protein P04637 UNIPROT "down-regulates activity" dephosphorylation Ser15 PSVEPPLsQETFSDL 9606 16501611 t "Protein serine/threonine phosphatase-1 dephosphorylates p53 at Ser-15 and Ser-37 to modulate its transcriptional and apoptotic activities|In addition, our results reveal that one of the molecular mechanisms by which PP-1 promotes cell survival is to dephosphorylate p53, and thus negatively regulate p53-dependent death pathway." SIGNOR-248572 MAPK14 protein Q16539 UNIPROT MAPKAPK2 protein P49137 UNIPROT "up-regulates activity" phosphorylation Ser272 SNHGLAIsPGMKTRI 9606 BTO:0000130 14499342 t lperfetto "Mapk-activated protein kinase-2 (mk2) is activated by p38 mapk in human neutrophils." SIGNOR-118036 ANKRD11 protein Q6UB99 UNIPROT Dendritic_spine_morphogenesis phenotype SIGNOR-PH183 SIGNOR up-regulates 10090 BTO:0000142 29274743 f miannu "We found that Ankrd11 knockdown disrupted dendrite and spine formation in developing pyramidal neurons." SIGNOR-266730 MAPK8IP1 protein Q9UQF2 UNIPROT MAP2K7 protein O14733 UNIPROT up-regulates binding 9606 10490659 t gcesareni "Both jip1 and jip2 selectively bind the mapkk isoform mkk7." SIGNOR-70848 LAMA4 protein Q16363 UNIPROT Laminin-8 complex SIGNOR-C181 SIGNOR "form complex" binding 10809728 t lperfetto "Laminins are a large family of heterotrimeric extracellular matrix glycoproteins that, in addition to having structural roles, take part in the regulation of processes such as cell migration, differentiation, and proliferation. The laminin alpha(4) chain is widely distributed both in adults and during development in tissues such as cardiac, skeletal and smooth muscle fibers, vascular endothelia, lungs, and in peripheral nerves. It can associate with laminin beta(1)/gamma(1) chains to form laminin-8 and with the beta(2)/gamma(1) chains to form laminin-9." SIGNOR-253226 Ub:E2 complex SIGNOR-C497 SIGNOR RNF40 protein O75150 UNIPROT "up-regulates activity" ubiquitination 9606 34199813 t miannu "The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t" SIGNOR-271109 YARS1 protein P54577 UNIPROT tyrosine smallmolecule CHEBI:18186 ChEBI "down-regulates quantity" "chemical modification" 9606 16429158 t miannu "YARS (also known as TyrRS) catalyzes the aminoacylation of tRNATyr with tyrosine by a two-step mechanism. Tyrosine is first activated by ATP to form tyrosyl-adenylate and is then transferred to tRNATyr" SIGNOR-270518 AKT1 protein P31749 UNIPROT CDKN1B protein P46527 UNIPROT down-regulates binding 9606 23400686 t gcesareni "Furthermore, akt promotes cell cycle progression through downregulation of the cyclin dependent kinase inhibitor p27kip1." SIGNOR-252534 MRPL9 protein Q9BYD2 UNIPROT "39S mitochondrial large ribosomal subunit" complex SIGNOR-C285 SIGNOR "form complex" binding -1 25838379 t lperfetto "We have determined the structure of the intact mitoribosome to 3.5 angstrom resolution by single-particle electron cryo-microscopy. It reveals 80 extensively interconnected proteins, 36 of which are specific to mitochondria, and three rRNA molecules" SIGNOR-262343 MYC protein P01106 UNIPROT CCND1 protein P24385 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 12835716 t gcesareni "C-myc directly activates transcription of cyclin d1, cyclin d2 and cdk4, and leads to cdk 4/6 activation" SIGNOR-102731 EDA protein Q92838 UNIPROT EDAR protein Q9UNE0 UNIPROT up-regulates binding 9606 18304980 t gcesareni "Ultimately, in mammals, eda-a1 and eda-a2 trimers each bind a different receptor, edar and xedar, respectively, through their trimerized tnf domain." SIGNOR-161109 PIPP smallmolecule CID:24755493 PUBCHEM LRP6 protein O75581 UNIPROT up-regulates 9606 18772438 f gcesareni "Wnt3a stimulates the formation of phosphatidylinositol 4,5-bisphosphates [ptdins (4,5)p2] through frizzled and dishevelled, the latter of which directly interacted with and activated pip5ki. In turn, ptdins (4,5)p2 regulated phosphorylation of lrp6 at thr1479 and ser1490" SIGNOR-180797 SMAD7 protein O15105 UNIPROT MAP3K1 protein Q13233 UNIPROT down-regulates 9606 10085121 f lperfetto "Overexpression of smad7 can inhibit the mekk-1-mediated stimulation of smad2 transcriptional activity" SIGNOR-65572 CyclinE/CDK2 complex SIGNOR-C16 SIGNOR COIL protein P38432 UNIPROT up-regulates phosphorylation Ser184 NEEAKRKsPKKKEKC 9606 BTO:0000567;BTO:0000938 11102515 t lperfetto "In particular, we have recently found that the cdk2/cyclin e complex can phosphorylate coilin in vitro . there is but a single consensus cdk2/cyclin e phosphorylation site in coilin, located at serine 184. when serine 184 was mutated to an alanine (s184a), mimicking a dephosphorylated state, a nucleolar mislocalization similar to that of gfp-coilin(1__†€ †_248) was observed" SIGNOR-216733 TGFBR1 protein P36897 UNIPROT TP63 protein Q9H3D4 UNIPROT unknown phosphorylation Ser68 FLEQPICsVQPIDLN 9606 23166821 t llicata "We show that phosphorylation of _np63_ at s66/68 in response to ultraviolet (uv) irradiation is mediated by alk5" SIGNOR-199785 PXDN protein Q92626 UNIPROT Epithelial-mesenchymal_transition phenotype SIGNOR-PH45 SIGNOR up-regulates 9606 BTO:0000567 29305973 f miannu "Our findings show that Snai1 mediates repression of PXDN and consolidate a role for this ECM-modifier during EMT." SIGNOR-265253 CASP6 protein P55212 UNIPROT CASP8 protein Q14790 UNIPROT up-regulates cleavage 9606 11455969 t gcesareni "This pathway can either be ampli?ed By caspase- 8-mediated cleavage of bid and by the downstream, caspase-6- mediated cleavage of caspase-8." SIGNOR-109411 ANKRD11 protein Q6UB99 UNIPROT BDNF protein P23560 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 BTO:0000142 29274743 t miannu "Neurite growth-related genes such as Trkb, Bdnf, Gap43, Coronin 1B, and Rab13 are downregulated in ANKRD11-deficient neurons. " SIGNOR-266732 MCM6 protein Q14566 UNIPROT MCM complex SIGNOR-C268 SIGNOR "form complex" binding 9606 19946136 t "The Mcm2-7 complex serves as the eukaryotic replicative helicase, the molecular motor that both unwinds duplex DNA and powers fork progression during DNA replication." SIGNOR-261676 EVX1 protein P49640 UNIPROT GSC protein P56915 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0001086 22178155 f miannu "We found that EVX1 repressed GSC expression and promoted formation of posterior streak-like progeny in response to BMP4, and conversely that GSC repressed EVX1 expression and was required for development of anterior streak-like progeny in response to activin." SIGNOR-254139 GSK3B protein P49841 UNIPROT APC protein P25054 UNIPROT up-regulates phosphorylation 9606 SIGNOR-C110 SIGNOR-C110 10698523 t lperfetto "Gsk-3beta-dependent phosphorylation of apc." SIGNOR-75366 CSNK2A1 protein P68400 UNIPROT SNAI1 protein O95863 UNIPROT "up-regulates quantity by stabilization" phosphorylation Ser11 SFLVRKPsDPNRKPN 9606 19923321 t lperfetto "Serines 11 and 92 participate in the control of snail1 stability and positively regulate snail1 repressive function and its interaction with msin3a corepressor. Furthermore, serines 11 and 92 are required for snail1-mediated emt and cell viability, respectively. Pka and ck2 have been characterized as the main kinases responsible for in vitro snail1 phosphorylation at serine 11 and 92, respectively." SIGNOR-161771 PRKDC protein P78527 UNIPROT USF1 protein P22415 UNIPROT up-regulates phosphorylation 9606 19303849 t miannu "Feeding induces the recruitment of dna-pk to usf-1 and its phosphorylation, which then allows recruitment of p/caf, resulting in usf-1 acetylation and fas promoter activation." SIGNOR-184849 PRKCA protein P17252 UNIPROT F3 protein P13726 UNIPROT up-regulates phosphorylation Ser285 RKAGVGQsWKENSPL 9606 23195225 t lperfetto "We previously showed that the phosphorylation of ser253 within the cytoplasmic domain of human tissue factor (tf) initiates the incorporation and release of this protein into cell-derived microparticles. Furthermore, subsequent phosphorylation of ser258 terminates this process. The phosphorylation of ser253 is known to be mediated by protein kinase c_" SIGNOR-199872 RPS6K proteinfamily SIGNOR-PF26 SIGNOR CIC protein Q96RK0 UNIPROT down-regulates phosphorylation Ser173 PGKRRTQsLSALPKE 9606 BTO:0000848 21087211 t gcesareni "Specifically, 14-3-3 binds to p90(rsk)-phosphorylated ser?_??_ Of capic?_A thereby modulating dna binding to its hmg (high-mobility group) box, whereas erk phosphorylations prevent binding of a c-terminal nls (nuclear localization sequence) to importin ?4 (kpna3)" SIGNOR-252778 CTNNA3 protein Q9UI47 UNIPROT CTNNB1 protein P35222 UNIPROT "up-regulates quantity" relocalization 9606 BTO:0000586 21598020 t miannu "Overexpression of CTNNA3 in a CTNNA1 negative colon carcinoma cell line resulted in the reassembly of the adherens and tight junctions through the recruitment of CTNNA3 interacting partners such as E-cadherin, β-catenin, plakoglobin, and ZO-14" SIGNOR-265493 DAGLA protein Q9Y4D2 UNIPROT 2-arachidonoylglycerol smallmolecule CHEBI:52392 ChEBI "up-regulates quantity" "chemical modification" 9606 26787883 t miannu "Diacylglycerol lipases (DAGLŒ± and DAGLŒ≤) convert diacylglycerol to the endocannabinoid 2-arachidonoylglycerol." SIGNOR-264264 "RFX complex" complex SIGNOR-C104 SIGNOR HLA-DOB protein P13765 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" -1 11258423 f "The RFX complex is comprised of three proteins – RFX5, RFXB, and RFXAP – all of which are required for expression of MHCII genes|In our current studies, we have utilized electrophoretic mobility shift assays to characterize the DNA binding of the RFX5(1–330)2•RFXAP•RFXB complex to the proximal regulatory region from the HLA-DRα gene to gain insight into the DNA binding properties of the RFX complex" SIGNOR-254000 ERBB4 protein Q15303 UNIPROT CBL protein P22681 UNIPROT up-regulates binding 9606 18793634 t gcesareni "Erbb4 might not be able to directly recruit cbl, and therefore downregulation of this receptor is slow." SIGNOR-180895 ponatinib chemical CHEBI:78543 ChEBI FGFR2 protein P21802 UNIPROT "down-regulates activity" "chemical inhibition" 9606 23468082 t miannu "Ponatinib is an oral multitargeted kinase inhibitor that potently inhibits all 4 members of the FGFR family." SIGNOR-259278 progesterone smallmolecule CHEBI:17026 ChEBI 11-deoxycorticosterone smallmolecule CHEBI:16973 ChEBI "up-regulates quantity" "precursor of" 9606 BTO:0000048 25855791 t lperfetto "Cytochrome P450 (P450)4 21A2 is the major steroid 21-hydroxylase, which catalyzes the 21-hydroxylation of progesterone and 17alpha-hydroxyprogesterone (17alpha-OH-progesterone) to form 11-deoxycorticosterone and 11-deoxycortisol, respectively" SIGNOR-268631 GTF2I protein P78347 UNIPROT HSPA5 protein P11021 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 19097122 f miannu "Transcription factor TFII-I causes transcriptional upregulation of GRP78 synthesis in prostate cancer cells." SIGNOR-254221 F2 protein P00734 UNIPROT F5 protein P12259 UNIPROT "up-regulates activity" 9606 BTO:0000131 29880919 t lperfetto "Thrombin also activates the cofactors FVIII (to FVIIIa) and FV (to FVa) and activates platelets such that they provide a procoagulant membrane surface to which these proteins then bind" SIGNOR-263530 NKX2-2 protein O95096 UNIPROT ERMN protein Q8TAM6 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 21221725 t lperfetto "Further study revealed that Nkx2.2 could bind JN promoter and its overexpression increase the promoter activity of JN." SIGNOR-268965 USF1 protein P22415 UNIPROT CBS protein P35520 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 12427542 f miannu "We previously described essential transactivating roles for specificity protein 1 (Sp1), Sp3, nuclear factor Y (NF-Y), and USF-1 in the regulation of the CBS-1b promoter." SIGNOR-254814 PTPN1 protein P18031 UNIPROT STAT5B protein P51692 UNIPROT down-regulates dephosphorylation Tyr699 TAKAVDGyVKPQIKQ 9606 BTO:0000149 10993888 t gcesareni "A cytosolic protein-tyrosine phosphatase ptp1b specifically dephosphorylates and deactivates prolactin-activated stat5a and stat5b." SIGNOR-82042 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR PAPOLA protein P51003 UNIPROT "up-regulates activity" phosphorylation Ser545 PTSATKTsPLNSSGS 10090 BTO:0000964 34048556 t lperfetto "Once an oocyte resumes meiosis, activated CDK1 and ERK1/2 cooperatively mediate the phosphorylation of three serine residues of PAPalpha, 537, 545 and 558, thereby leading to increased activity." SIGNOR-268342 mTORC1 complex SIGNOR-C3 SIGNOR EIF4EBP1 protein Q13541 UNIPROT "down-regulates activity" phosphorylation 10090 BTO:0002572 20670887 t lperfetto "Specifically as part of mTORC1, mTOR directly phosphorylates the ribosomal protein S6 kinases (S6K1 and S6K2) and the eukaryotic initiation factor 4E (eIF4E)-binding proteins (4E-BP1 and 4E-BP2)phosphorylation of the 4E-BPs leads to their inhibition and release from eIF4E at the 5_ cap of mRNAs" SIGNOR-235745 MAPK14 protein Q16539 UNIPROT STAT3 protein P40763 UNIPROT up-regulates phosphorylation Ser727 NTIDLPMsPRTLDSL 9606 18691976 t gcesareni "Kinase-selective enrichment enables quantitative phosphoproteomics of the kinome across the cell cycle." SIGNOR-179912 MRPS5 protein P82675 UNIPROT "28S mitochondrial small ribosomal subunit" complex SIGNOR-C266 SIGNOR "form complex" binding 9606 25838379 t miannu "The mammalian mitochondrial ribosome (mitoribosome) has a highly protein-rich composition with a small sedimentation coefficient of 55 S, consisting of 39 S large and 28 S small subunits. . We report here the identification of 28 S small subunit proteins." SIGNOR-261441 PPP1CA protein P62136 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR down-regulates dephosphorylation 9606 20186153 t lperfetto "Several stps have been reported to negatively regulate akt pathway. It has been shown that pp1 dephosphorylates akt and regulates cell survival." SIGNOR-244436 RCAN1 protein P53805 UNIPROT Calcineurin complex SIGNOR-C155 SIGNOR "down-regulates activity" binding 9606 12554096 t "MCIP proteins can bind to and inhibit calcineurin, a calcium/calmodulin-regulated serine/threonine protein phosphatase that is activated during cardiac hypertrophy and failure" SIGNOR-252341 PIM1 protein P11309 UNIPROT RPS19 protein P39019 UNIPROT up-regulates phosphorylation 9606 BTO:0000007 16266891 t gcesareni "The pim-1/rps19 interaction was demonstrated both in vitro and in living cells and led to phosphorylation of rps19 in an in vitro kinase assay." SIGNOR-141411 miR-155 mirna URS000062749E_9606 RNAcentral CEBPB protein P17676 UNIPROT "down-regulates quantity" "post transcriptional regulation" 9606 25477897 t miannu "MiR-155 directly inhibits src homology 2 domaincontaining inositol-5-phosphatase (SHIP1) as well as CCAATenhancer-binding protein-beta (CEBP-β) to mediate leukemogenesis" SIGNOR-255770 ADCY10 protein Q96PN6 UNIPROT "3',5'-cyclic AMP" smallmolecule CHEBI:17489 ChEBI "up-regulates quantity" "chemical modification" 9606 15385642 t miannu "Adenylyl cyclases (AC), a family of enzymes that catalyze the synthesis of cyclic AMP, are critical regulators of cellular functions." SIGNOR-265008 CBL protein P22681 UNIPROT PDGFRB protein P09619 UNIPROT "down-regulates quantity by destabilization" polyubiquitination 9606 10514377 t miannu "Ubiquitination of the PDGF β-receptor (Rβ) by the c-Cbl RING in an SH2-dependent manner." SIGNOR-272553 EXOC2 protein Q96KP1 UNIPROT "Exocyst_EXOC6 variant" complex SIGNOR-C492 SIGNOR "form complex" binding 9606 26240175 t miannu "The exocyst is an octameric protein complex that is implicated in the tethering of secretory vesicles to the plasma membrane prior to SNARE-mediated fusion." SIGNOR-270785 PHF3 protein Q92576 UNIPROT POLR2A protein P24928 UNIPROT "down-regulates activity" binding 9606 BTO:0000007 phosphorylation:Ser1594 GAMSPSYsPTSPAYE 34667177 t miannu "PHF3 interacts with RNA polymerase II through the SPOC domain. PHF3 negatively regulates mRNA levels. Here, we identify PHD-finger protein 3 (PHF3) as a regulator of transcription and mRNA stability that docks onto Pol II CTD through its SPOC domain. Our data suggest that PHF3 acts as a prominent effector of neuronal gene regulation by bridging transcription with mRNA decay. PHF3 SPOC preferentially binds RNA Pol II CTD phosphorylated on Serine-2" SIGNOR-266965 TP53 protein P04637 UNIPROT AIFM2 protein Q9BRQ8 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 12135761 t miannu "The p53 tumor suppressor protein induces cell cycle arrest or apoptosis in response to cellular stresses. We have identified PRG3 (p53-responsive gene 3), which is induced specifically under p53-dependent apoptotic conditions in human colon cancer cells, and encodes a novel polypeptide of 373 amino acids with a predicted molecular mass of 40.5 kDa. these results support the hypothesis that the expression of the PRG3 gene in cells undergoing p53‐dependent apoptosis involves direct activation of its promoter by p53." SIGNOR-261808 ARRB2 protein P32121 UNIPROT KIF3A protein Q9Y496 UNIPROT up-regulates binding 9606 23074268 t gcesareni "Betaarrestin 2 was subsequentialy shown to bridge smo to the kinestesin motor kif3 to promote ciliary accumulation of smo in mammalian cells" SIGNOR-199107 IL7 protein P13232 UNIPROT IL7R protein P16871 UNIPROT up-regulates binding 9606 BTO:0000782 8204885 t fspada "Antibody r34.34 was further found to be directed against an epitope interfering with binding of interleukin-7 (il-7) to pre-alp cells. Expression cloning from a pre-alp cdna library showed that r34.34 antigen is cdw127, the 75- to 80-kd il-7 receptor. Proliferation of the b-lineage all cell lines reh and mieliki was inhibited by il-7, and this effect was specifically reverted by moab r34.34. In addition, antibody r34.34 specifically inhibited il-7-dependent proliferation of normal bcp, pre-alp cells, and peripheral t cells. These results imply that both inhibitory and proliferative effects of il-7 can be mediated through the same receptor on various lineages." SIGNOR-37012 CAD protein P27708 UNIPROT "Pyrimidine biosynthesis" phenotype SIGNOR-PH187 SIGNOR "up-regulates activity" 9606 15096496 f "The CPSase activity of CAD is the major locus of control of de novo pyrimidine biosynthesis" SIGNOR-267196 DPF2 protein Q92785 UNIPROT Differentiation phenotype SIGNOR-PH37 SIGNOR down-regulates 9606 BTO:0000725 24332853 f miannu "Here, DPF2 appears to be another important regulator of myeloid differentiation that can cooperate with PRMT4 to maintain the “stemness” of HSPCs." SIGNOR-261969 RHOXF1 protein Q8NHV9 UNIPROT BCL2 protein P10415 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 23317270 f lperfetto "ShRNA knock down of RHOXF1 resulted in significantly decreased BCL2 expression in both cell lines but no change in CASP8 expression." SIGNOR-268957 TAOK2 protein Q9UL54 UNIPROT STK3/4 proteinfamily SIGNOR-PF41 SIGNOR up-regulates phosphorylation 9606 23431053 t "inferred from 70% of family members" gcesareni "In addition, the thousand-and-one (tao) amino acids kinase or taok13 has been shown to directly phosphorylate and activate hpo or mst1/2." SIGNOR-269939 INPPL1 protein O15357 UNIPROT MAPK8IP1 protein Q9UQF2 UNIPROT up-regulates 9606 18486448 f gcesareni "Ship2 positively modulated the mlk3/jip1-mediated jnk1 activation" SIGNOR-178652 USP7 protein Q93009 UNIPROT TP53 protein P04637 UNIPROT up-regulates deubiquitination 9606 16082221 t gcesareni "Hausp counteracts the destabilizing effect of mdm2 by direct deubiquitination of p53." SIGNOR-139456 FLT3 protein P36888 UNIPROT STAT5A protein P42229 UNIPROT "up-regulates activity" phosphorylation 10090 BTO:0001516 12796379 t "FLT3-ITDs induced a strong activation of STAT5. FLT3-ITD mutants induce an autophosphorylation of the receptor, interleukin 3-independent growth in Ba/F3 cells, and a strong STAT5 and mitogen-activated protein kinase (MAPK) activation." SIGNOR-261516 SOX2 protein P48431 UNIPROT ABCC6 protein O95255 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 21531766 f miannu "ID4-mediated SOX2 induction enhanced ABCC3 and ABCC6 expression through direct transcriptional regulation, indicating that ID4 regulates the chemoresistance of iGSCs by promoting SOX2-mediated induction of ABC transporters." SIGNOR-255182 SMAD4 protein Q13485 UNIPROT SMAD1/4 complex SIGNOR-C85 SIGNOR "form complex" binding 9606 9436979 t lperfetto "Bone morphogenetic protein (BMP) receptors signal by phosphorylating Smad1, which then associates with Smad4; this complex moves into the nucleus and activates transcription." SIGNOR-103618 CSNK1D protein P48730 UNIPROT MDM2 protein Q00987 UNIPROT down-regulates phosphorylation Ser262 DSEDYSLsEEGQELS 9606 20708156 t gcesareni "Cki phosphorylates mdm2 at multiple sites to trigger mdm2/beta-trcp1 interactionbeta-trcp promotes mdm2 turnover and ubiquitination" SIGNOR-167517 2-(2-chloro-4-iodoanilino)-N-(cyclopropylmethoxy)-3,4-difluorobenzamide chemical CHEBI:91353 ChEBI MAP2K2 protein P36507 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-191024 ETFB protein P38117 UNIPROT ETF complex SIGNOR-C463 SIGNOR "form complex" binding 9606 33450351 t miannu "Human ETF is nuclear encoded by two separate genes, ETFA and ETFB, respectively. After translation, the two subunits are imported to the mitochondrial matrix space and assemble into a heterodimer containing one FAD and one AMP as cofactors." SIGNOR-269452 celecoxib chemical CHEBI:41423 ChEBI PTGS2 protein P35354 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-190928 NFE2L2 protein Q16236 UNIPROT SOD2 protein P04179 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 22493435 t miannu "BTG2 was found to up-regulate expression of antioxidant enzymes known to be regulated by NFE2L2, including catalase, SOD1, and SOD2" SIGNOR-254652 GSK3B protein P49841 UNIPROT DPYSL2 protein Q16555 UNIPROT "down-regulates activity" phosphorylation Thr514 SVTPKTVtPASSAKT 10116 BTO:0000938 15652488 t lperfetto "Here, we showed that glycogen synthase kinase-3beta (gsk-3beta) phosphorylated crmp-2 at thr-514 and inactivated it" SIGNOR-133255 SNAP23 protein O00161 UNIPROT "STX11-SNAP23 SNARE complex" complex SIGNOR-C272 SIGNOR "form complex" binding 9606 BTO:0000132 22767500 t lperfetto "Coimmunoprecipitation experiments showed that syntaxin-11 can form SNARE complexes with both VAMP-8 and SNAP-23. " SIGNOR-261895 PDPK1 protein O15530 UNIPROT RPS6KB1 protein P23443 UNIPROT "up-regulates activity" phosphorylation Thr252 HDGTVTHtFCGTIEY -1 9445476 t gcesareni "The results presented here are consistent with PDK1 as the in vivo kinase responsible for mediating Thr252 phosphorylation in the catalytic domain of p70s6k." SIGNOR-243338 4-amino-5-fluoro-3-[5-(4-methyl-1-piperazinyl)-1,3-dihydrobenzimidazol-2-ylidene]-2-quinolinone chemical CHEBI:91395 ChEBI FLT3 protein P36888 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-191406 MAP3K5 protein Q99683 UNIPROT MAP2K3 protein P46734 UNIPROT "up-regulates activity" phosphorylation 9534 BTO:0004055 8974401 t lperfetto "ASK1 activated SEK1 and MKK3 up to 7.0- and 11.8-fold, respectively" SIGNOR-226672 CADM2 protein Q8N3J6 UNIPROT PTK2 protein Q05397 UNIPROT "up-regulates activity" 9606 BTO:0000007 29506532 f Gianni "The results indicated that CADM2 […} modulates EMT process and migration ability via focal adhesion kinase (FAK) /AKT signaling pathway in HCC." SIGNOR-268855 S100A8 protein P05109 UNIPROT "Calprotectin complex" complex SIGNOR-C293 SIGNOR "form complex" binding 9867828 t lperfetto "Using the two-hybrid system we analyzed the dimerization of MRP8 (S100A8) and MRP14 (S100A9), two S100 proteins expressed in myeloid cells. It is reported that the MRP8-MRP14 heteromer is the clearly preferred complex in both man and mouse." SIGNOR-262832 IGF1 protein P05019 UNIPROT PPP3CB protein P16298 UNIPROT up-regulates 10090 10448861 f lperfetto "Treatment with igf-1 or insulin and dexamethasone mobilizes intracellular calcium, activates the ca2+/calmodulin-dependent phosphatase calcineurin, and induces the nuclear translocation of the transcription factor nf-atc1." SIGNOR-235825 MAPK8 protein P45983 UNIPROT MAPK8IP3 protein Q9UPT6 UNIPROT up-regulates phosphorylation Thr275 TTGTKSNtPTSSVPS 9606 15767678 t gcesareni "Phosphoamino acid analysis confirmed that jnk caused thr phosphorylation of jip3 (fig. _(fig.3c).3c). This phosphorylation on thr was markedly decreased when thr266, thr276, and thr287 were replaced with ala. These data indicate that jnk phosphorylated jip3 on thr266, thr276, and thr287 in vitro." SIGNOR-134545 UBE2D2 protein P62837 UNIPROT VPS18 protein Q9P253 UNIPROT "up-regulates activity" binding 9606 BTO:0000007 16203730 t miannu "VPS18 Ubiquitylates SNK in Vitro and in Vivo. The ubiquitylation of proteins by hVPS18 was selectively mediated by UbcH4. " SIGNOR-271549 PCM1 protein Q15154 UNIPROT CETN3 protein O15182 UNIPROT up-regulates relocalization 9606 12403812 t miannu "Rna silencing of pcm-1 leads to reduced assembly of centrin, pericentrin, and ninein at the centrosome" SIGNOR-95016 CEBPA protein P49715 UNIPROT Basophil_diff phenotype SIGNOR-PH116 SIGNOR "up-regulates activity" 10090 BTO:0000725 23990620 f "Notably, enforced overexpression of C/EBP-α in BMCPs results in exclusive differentiation into basophils, whereas conditional deletion of C/EBP-α in these same cells promotes mast cell differentiation,1 suggesting that C/EBP-α is an essential “switch factor” for basophil lineage choice" SIGNOR-259968 FGFR2 protein P21802 UNIPROT PTEN protein P60484 UNIPROT unknown phosphorylation Tyr240 RREDKFMyFEFPQPL 9606 22891331 t llicata "Fgfrs phosphorylate pten at tyrosine 240" SIGNOR-191793 PLP1 protein P60201 UNIPROT Myelination phenotype SIGNOR-PH206 SIGNOR up-regulates 26519753 f SimoneGraziosi "Proteolipid protein (PLP) is a major component only in the CNS myelin of terrestrial species and is involved in compaction of the extracellular apposition." SIGNOR-269265 TWIST1 protein Q15672 UNIPROT MMP2 protein P08253 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0003879 20646316 f miannu "Individual genes upregulated by TWIST1 known to promote EMT and/or GBM invasion included SNAI2, MMP2, HGF, FAP and FN1." SIGNOR-255525 6-(7-hydroxy-5,6-dihydropyrrolo[1,2-c]imidazol-7-yl)-N-methyl-2-naphthalenecarboxamide chemical CHEBI:94965 ChEBI CYP17A1 protein P05093 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-207141 "Cullin 1-RBX1-Skp1" complex SIGNOR-C529 SIGNOR FBXL7 protein Q9UJT9 UNIPROT "down-regulates quantity by destabilization" polyubiquitination Lys109 RLASRPQkEQASIDR 10090 BTO:0002268 25654763 t miannu "F-box protein Fbxl18 mediates polyubiquitylation and proteasomal degradation of the pro-apoptotic SCF subunit Fbxl7.. Here, we identified that an orphan F-box protein, Fbxl18, targets Fbxl7 for its polyubiquitylation and proteasomal degradation. Lys 109 within Fbxl7 is an essential acceptor site for ubiquitin conjugation by Fbxl18." SIGNOR-272450 AKT proteinfamily SIGNOR-PF24 SIGNOR PHF20 protein Q9BVI0 UNIPROT down-regulates phosphorylation Ser291 ELRRRKIsKGCEVPL 9606 22334668 t llicata "Akt phosphorylates phf20 at ser(291) in vitro and in vivo, which results in its translocation from the nucleus to the cytoplasm and attenuation of phf20 function." SIGNOR-196112 ABL1 protein P00519 UNIPROT ABL1 protein P00519 UNIPROT "up-regulates activity" phosphorylation Tyr393 RLMTGDTyTAHAGAK 9606 11781820 t lperfetto "Phosphorylation of tyr412 can occur autocatalytically by a trans-mechanism and cause activation of otherwise inactive c-abl, suggesting a positive feedback loop on c-abl activity." SIGNOR-113659 GPR119 protein Q8TDV5 UNIPROT GNAQ protein P50148 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257366 PRKCH protein P24723 UNIPROT GSK3A protein P49840 UNIPROT down-regulates phosphorylation Ser21 SGRARTSsFAEPGGG 9606 11884598 t gcesareni "Furthermore, several pkc isotypes phosphorylate gsk-3 in vitro and in vivo. in the presence of atp, several isoforms (?, ___, _, ?, And of pkc phosphorylated both gsk-3? At ser 21 and gsk-3_ at ser 9" SIGNOR-115730 R547 chemical CID:6918852 PUBCHEM CDK2 protein P24941 UNIPROT "down-regulates activity" "chemical inhibition" -1 22037378 t miannu "Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here." SIGNOR-259793 BLOC1S4 protein Q9NUP1 UNIPROT BLOC-1 complex SIGNOR-C381 SIGNOR "form complex" binding 9606 BTO:0002946 22203680 t lperfetto "We show that BLOC-1 is an elongated complex that contains one copy each of the eight subunits pallidin, Cappuccino, dysbindin, Snapin, Muted, BLOS1, BLOS2, and BLOS3. The complex appears as a linear chain of eight globular domains, ∼300 A long and ∼30 A in diameter." SIGNOR-265932 KLHL12 protein Q53G59 UNIPROT LNPK protein Q9C0E8 UNIPROT "up-regulates activity" binding 9606 BTO:0000007 32433973 t miannu "  Lunapark Is Ubiquitylated by the CRL3KLHL12 Ubiquitin Ligase Complex. Taken together, these results demonstrate that Lunapark is ubiquitylated by the CRL3KLHL12 ubiquitin ligase, and the CRL3KLHL12-dependent ubiquitylation of Lunapark does not lead to its proteasomal degradation. Inhibition of Lunapark Ubiquitylation Affects Lysosomal Recruitment of mTORC1" SIGNOR-272197 PAX6 protein P26367 UNIPROT PCSK1 protein P29120 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 19034419 f miannu "PAX6 can bind to the promoter and directly upregulate production of prohormone convertase (PC)1/3, an enzyme essential for conversion of proinsulin to insulin." SIGNOR-254900 nimodipine chemical CHEBI:7575 ChEBI NR3C2 protein P08235 UNIPROT "down-regulates activity" "chemical inhibition" -1 18250364 t Luana "Here we report a surprising finding, that the dihydropyridine CCBs have MR antagonist activity. A number of dihydropyridine CCBs compete for aldosterone binding to the MR ligand binding domain (LBD), block aldosterone-induced recruitment of coactivators, and inhibit aldosterone-induced gene expression. " SIGNOR-257765 CSNK2A3 protein Q8NEV1 UNIPROT SCN2A protein Q99250 UNIPROT "up-regulates activity" phosphorylation Ser1112 VPIAVGEsDFENLNT 9606 BTO:0000938 19064667 t lperfetto "We found that the ankyrin-binding motif of Na(v)1.2 that determines channel concentration at the AIS depends on a glutamate residue (E1111), but also on several serine residues (S1112, S1124, and S1126). We showed that phosphorylation of these residues by protein kinase CK2 (CK2) regulates Na(v) channel interaction with ankyrins. | inhibition of CK2 activity reduced sodium channel accumulation at the AIS of neurons. In conclusion, CK2 contributes to sodium channel organization by regulating their interaction with ankyrin G." SIGNOR-275751 MTHFR protein P42898 UNIPROT Chromatine_condensation phenotype SIGNOR-PH21 SIGNOR up-regulates 9606 BTO:0000567 24769206 f miannu "MTHFR promotes heterochromatin maintenance at the centromeric region." SIGNOR-263889 [4-[2-(1H-indazol-3-yl)ethenyl]phenyl]-(1-piperazinyl)methanone chemical CHEBI:91441 ChEBI ABL1 protein P00519 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-193612 CLK1 protein P49759 UNIPROT PTPN1 protein P18031 UNIPROT "up-regulates activity" phosphorylation Ser50 RNRYRDVsPFDHSRI 9606 10480872 t gcesareni "The clk family kinases, clk1 and clk2, phosphorylate and activate the tyrosine phosphatase, ptp-1b.|Phosphorylation of PTP-1B at Ser(50) by CLK1 or CLK2 is responsible for its enzymatic activation." SIGNOR-70563 SRC protein P12931 UNIPROT EMD protein P50402 UNIPROT down-regulates phosphorylation Tyr59 SSSAASSySFSDLNS 9606 BTO:0000567 BTO:0000887 19789182 t llicata "Src phosphorylated emerin specifically at y59, y74 and y95; interestingly y-to-f substitutions at identified src sites reduced recombinant emerin binding to endogenous baf" SIGNOR-188308 KAT6A protein Q92794 UNIPROT RUNX1 protein Q01196 UNIPROT up-regulates binding 9606 SIGNOR-C54 11742995 t miannu "The activation domain of aml1 is required for its interaction with moz / moz activates aml1_mediated transcription" SIGNOR-113056 "Av/b1 integrin" complex SIGNOR-C175 SIGNOR POU5F1 protein Q01860 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 BTO:0001086 18757303 f lperfetto "Recombinant human LN-511 alone was suffi- cient to enable self-renewal of mouse ES cells for up to 169 days (31 passages). Cells cultured on LN-511 maintained expression of pluripotency markers, such as Oct4, Sox2, Tert, UTF1, and Nanog|ES cells interacted with LN-511 via 􏰇1-integrins, mostly a6b1 and aVb1." SIGNOR-253272 IKBKB protein O14920 UNIPROT IKBKB protein O14920 UNIPROT "down-regulates activity" phosphorylation Ser705 LPEPAKKsEELVAEA 9606 10195894 t "Once activated, IKKbeta autophosphorylated at a carboxyl-terminal serine cluster. Such phosphorylation decreased IKK activity and may prevent prolonged activation of the inflammatory response." SIGNOR-251283 KPNA6 protein O60684 UNIPROT NOTCH proteinfamily SIGNOR-PF30 SIGNOR up-regulates relocalization 9606 20454918 t gcesareni "Nicd binds via one of its four potential nuclear localization signals to importins alfa3, alfa4, and alfa7. importins alpha3, alpha4 (and to a lesser extent, alpha7) mediate nuclear import of nicd and thus are directly involved in notch signaling." SIGNOR-254332 STK4 protein Q13043 UNIPROT LATS1 protein O95835 UNIPROT up-regulates phosphorylation Thr1079 EHAFYEFtFRRFFDD 9606 15688006 t milica "We show that Mst2 and hWW45 interact with each other in human cells and that both Mst2 and Mst1 are able to phosphorylate Lats1 and Lats2, thereby stimulating Lats kinase activity." SIGNOR-133555 THAP12 protein O43422 UNIPROT EIF2S1 protein P05198 UNIPROT unknown phosphorylation Ser52 MILLSELsRRRIRSI -1 10542257 t lperfetto "The mammalian kinases PKR and HRI and the yeast kinase GCN2 specifically phosphorylate Ser-51 on the alpha subunit of the translation initiation factor eIF2. " SIGNOR-249029 TRADD protein Q15628 UNIPROT FADD protein Q13158 UNIPROT "up-regulates activity" binding 9606 18545270 t lperfetto "Tradd recruits fadd" SIGNOR-177958 G3BP2 protein Q9UN86 UNIPROT NFKBIA protein P25963 UNIPROT "down-regulates activity" relocalization 9606 BTO:0000567 10969074 t SARA "IkappaBalpha interacts with G3BP2 both in vivo and in vitrothrough the IkappaBalpha CRS. Overexpression of G3BP2 directly promotes retention of IkappaBalpha in the cytoplasm." SIGNOR-260985 SLC46A1 protein Q96NT5 UNIPROT dihydrofolate(2-) smallmolecule CHEBI:57451 ChEBI "up-regulates quantity" relocalization 9606 BTO:0000575 17129779 t lperfetto "However, the current study establishes that a major function of this gene product is proton-coupled folate transport required for folate homeostasis in man, and we have thus amended the name to PCFT/HCP1." SIGNOR-268264 LYN protein P07948 UNIPROT PLCG1 protein P19174 UNIPROT "up-regulates activity" phosphorylation Tyr783 EGRNPGFyVEANPMP -1 7682059 t lperfetto "The phosphorylation of purified phospholipase C-gamma 1 (PLC-gamma 1) and PLC-gamma 2 by src-family-protein tyrosine kinases (PTKs) P56lck, p53/56lyn, p59hck, p59fyn, and p60src was studied in vitro. All five PTKs phosphorylated PLC-gamma 1 and PLC-gamma 2, suggesting that both PLC-gamma isozymes can be phosphorylated in cells by any of the src-family PTKs in response to the activation of cell surface receptors." SIGNOR-249382 ROCK1 protein Q13464 UNIPROT MAPK8 protein P45983 UNIPROT "up-regulates activity" phosphorylation 9606 15068801 t gcesareni "Instead, we found that rock activates jnk, which then phosphorylates c-jun and atf2 when bound to the c-jun promoter." SIGNOR-123717 ABL1 protein P00519 UNIPROT WASL protein O00401 UNIPROT "up-regulates activity" phosphorylation Tyr175 EITTNRFyGPQVNNI -1 16199863 t "Abl phosphorylates N-WASP on tyrosines 175 and 256. Phosphorylation at this site stabilizes the active conformation of N-WASP, resulting in comet tail elongation." SIGNOR-251436 SYK protein P43405 UNIPROT SYK protein P43405 UNIPROT "up-regulates activity" phosphorylation Tyr323 STVSFNPyEPELAPW 9606 BTO:0000776 9820500 t lperfetto "These represented sites of tyrosine phosphorylation previously identified from the study of in vitro autophosphorylated Syk. Phosphorylation was observed on peptides corresponding to Tyr130, Tyr317, Tyr342, Tyr346, Tyr519, and Tyr520" SIGNOR-246605 SEMA4D protein Q92854 UNIPROT PLXNB1 protein O43157 UNIPROT up-regulates binding 9606 12198496 t gcesareni "Binding of sema 4d to plexin b1 stimulates the tyrosine kinase activity of met, resulting in tyrosine phosphorylation of both receptors." SIGNOR-92201 "MLL1 complex" complex SIGNOR-C89 SIGNOR H3-3A protein P84243 UNIPROT "down-regulates activity" methylation Lys5 kQTARKST 9606 24680668 t miannu "Dimethylation of h3k4 requires a sub-complex including wrad (wdr5, rbbp5, ash2l, and dpy-30), which binds to each set1 family member forming a minimal corecomplexthat is required for multiple lysine methylation." SIGNOR-268802 GGCX protein P38435 UNIPROT F2 protein P00734 UNIPROT "up-regulates activity" carboxylation Glu69 EETCSYEeAFEALES -1 10556651 t lperfetto "We analyzed the number of glutamic acid (Glu) residues and their positions in the Gla domain (GD) of DCP to investigate the gamma-carboxylation mechanism of VK-dependent carboxylase. Several DCPs were found in each subject studied. The 10 Gla residues of human prothrombin were carboxylated in order from the N-terminal (residues 26, 25, 16, 29, 20, 19, 14, 32, 7 and 6)|In the absence of VK or in the presence of VK antagonists, hepatic VKdependent carboxylase activity is inhibited and des-g-carboxyprothrombin (abnormal prothrombin or PIVKA; protein induced by vitamin K antagonist, prothrombin) is released into the blood." SIGNOR-263682 PRKACA protein P17612 UNIPROT AKAP12 protein Q02952 UNIPROT "up-regulates activity" phosphorylation Ser627 KKRVRRPsESDKEDE -1 14657015 t lperfetto "Following receptor activation, gravin binding to the receptor increases, a process dependent upon PKA-catalyzed phosphorylation of two canonical PKA sites (Ser696–698 and Ser772) located within the AKAP domain of gravin." SIGNOR-271841 TUBG1 protein P23258 UNIPROT Microtubule_polimerization phenotype SIGNOR-PH106 SIGNOR up-regulates 9606 BTO:0000567 19029337 f miannu "It has been reported that NEDD1 directly interacts with and recruits the γ-tubulin ring complex to centrosomes and to spindle MTs to promote MT nucleation and spindle assembly" SIGNOR-261423 LRIG3 protein Q6UXM1 UNIPROT ERBB4 protein Q15303 UNIPROT up-regulates 9606 23723069 f miannu "Lrig3 opposes lrig1 negative regulatory activity and stabilizes erbb receptors." SIGNOR-202183 PPP1CC protein P36873 UNIPROT TGFBR1 protein P36897 UNIPROT down-regulates dephosphorylation 9606 14718519 t lpetrilli "We found smad7 interacts with growth arrest and dna damage protein, gadd34, a regulatory subunit of the protein phosphatase 1 (pp1) holoenzyme, which subsequently recruits catalytic subunit of pp1 (pp1c) to dephosphorylate t?RI." SIGNOR-121277 serotonin smallmolecule CHEBI:28790 ChEBI HTR2B protein P41595 UNIPROT "up-regulates activity" "chemical activation" 9606 BTO:0000938 25601315 t miannu "Serotonin or 5-hydroxytryptamine (5-HT) remains one of the most widely studied chemical messengers. Serotonin produces a myriad of physiological effects in humans, mediated through 14 distinct receptor subtypes, of which 13 are G protein coupled receptors (GPCRs), and one ligand-gated cation channel" SIGNOR-264286 PTPN1 protein P18031 UNIPROT ABL1 protein P00519 UNIPROT down-regulates dephosphorylation 9606 9566916 t gcesareni "These results illustrate selectivity in the effects of ptps in a cellular context and suggest that ptp1b may function as a specific, negative regulator of p210 bcr-abl signalling in vivo." SIGNOR-56815 AKT2 protein P31751 UNIPROT GLI1 protein P08151 UNIPROT up-regulates 9606 17845852 f gcesareni "Ras and akt signaling enhances the nuclear localization of gli1, counteracting its suppression by other modifiers that retain it in the cytoplasm, such as suppressor of fused (sufu)." SIGNOR-157770 acetate smallmolecule CHEBI:30089 ChEBI acetyl-CoA(4-) smallmolecule CHEBI:57288 ChEBI "up-regulates quantity" "precursor of" 10843999 t lperfetto "The gene encodes acetyl-CoA synthetase (ACS), the cytosolic enzyme that activates acetate so that it can be used for lipid synthesis or for energy generation. |The recombinant enzyme produced acetyl-CoA from acetate in a reaction that required ATP." SIGNOR-271824 PRKACA protein P17612 UNIPROT PTPN7 protein P35236 UNIPROT down-regulates phosphorylation 9606 19047375 t gcesareni "B2 adrenergic receptor stimulation induces the pka dependent phosphorylation of heptp and releases bound p38 mapk" SIGNOR-182522 belinostat chemical CHEBI:61076 ChEBI HDAC6 protein Q9UBN7 UNIPROT "down-regulates activity" "chemical inhibition" -1 17868033 t Luana "Our findings suggest that hydroxamic acid-derived compounds such as TSA, NVP-LAQ824, panobinostat, ITF2357, vorinostat and belinostat act as potent pan-HDAC isoform inhibitors. A notable observation was the similarity between belinostat and vorinostat in the biochemical isoform assays; both compounds exhibit similar EC50 values in all but the HDAC8 assay." SIGNOR-257745 ERRFI1 protein Q9UJM3 UNIPROT EGFR protein P00533 UNIPROT "down-regulates activity" binding -1 18046415 t "The cytoplasmic protein MIG6 (mitogen-induced gene 6; also known as ERRFI1) interacts with and inhibits the kinase domains of EGFR and ERBB2" SIGNOR-252076 MAP3K1 protein Q13233 UNIPROT MAP2K4 protein P45985 UNIPROT "up-regulates activity" phosphorylation Thr261 LVDSIAKtRDAGCRP 9606 9712898 t lperfetto "The gck-ctd-mekk1 interaction is sufficiently stable to support mekk1 s phosphorylation of its substrate, sek1" SIGNOR-236380 RARA protein P10276 UNIPROT CTNNB1 protein P35222 UNIPROT down-regulates 9606 10607566 f gcesareni "We shown that retinoic acid (ra) decreases the activity of the beta-catenin-lef/tcf signaling pathway" SIGNOR-73274 H2AX protein P16104 UNIPROT MDC1 protein Q14676 UNIPROT up-regulates binding 9606 16377563 t fstefani "Here, we demonstrate that mammalian mdc1/nfbd1 directly binds to phospho-h2ax (gammah2ax) by specifically interacting with the phosphoepitope at the gammah2ax carboxyl terminus." SIGNOR-143377 MAPK14 protein Q16539 UNIPROT ELK1 protein P19419 UNIPROT up-regulates phosphorylation Ser389 LSPIAPRsPAKLSFQ 9606 9130707 t gcesareni "We demonstrate here that elk-1 is barely activated by a third subclass of map kinases (p38), most likely because the critical residues ser383 and ser389 are poorly phosphorylated by p38 map kinase." SIGNOR-47634 MAP3K8 protein P41279 UNIPROT MAP3K14 protein Q99558 UNIPROT "up-regulates activity" phosphorylation Thr559 TGDYIPGtETHMAPE 9606 9742107 t lperfetto "In studies of NIK, we found that Thr-559 located within the activation loop of its kinase domain regulates NIK action. Alanine substitution of Thr-559 but not other serine or threonine residues within the activation loop abolishes its activity and its ability to phosphorylate and activate IKKalpha" SIGNOR-249387 CDK5RAP2 protein Q96SN8 UNIPROT BUB1B protein O60566 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 19282672 t Giulio "These data indicate that CDK5RAP2 is a positive regulator of both the BUBR1 promoter and the MAD2 promoter" SIGNOR-260312 MMP9 protein P14780 UNIPROT ECM_disassembly phenotype SIGNOR-PH80 SIGNOR up-regulates 17318226 f lperfetto "Historically, MMPs were thought to function mainly as enzymes that degrade structural components of the ECM." SIGNOR-272376 PAK1 protein Q13153 UNIPROT "Histone H3" proteinfamily SIGNOR-PF69 SIGNOR unknown phosphorylation 9606 12151336 t gcesareni "Histone h3 is a substrate of pak1 both in vitro and in vivo, and it specifically interacted with pak1 but not pak2 or pak3. Site-directed mutagenesis indicated that pak1 phosphorylates histone h3 on ser10." SIGNOR-265363 CBP/p300 complex SIGNOR-C6 SIGNOR RELA protein Q04206 UNIPROT up-regulates acetylation 9606 16382138 t lperfetto "Rela is also acetylated at several sites by p300 and cbp" SIGNOR-217210 BCL2 protein P10415 UNIPROT Cell_death phenotype SIGNOR-PH109 SIGNOR down-regulates 9606 1286168 f lperfetto "Bcl-2 functions to inhibit apoptosis in a variety of in vitro and in vivo experiments, suggesting interference with a central mechanism of apoptosis" SIGNOR-256637 practolol chemical CHEBI:258351 ChEBI ADRB1 protein P08588 UNIPROT "down-regulates activity" "chemical inhibition" 10030 BTO:0000246 10079020 t Luana "In our CHO cells transfected with the human β1- and β2-adrenoceptors, the binding affinities of atenolol, metoprolol, betaxolol and practolol correlate with previously published β1- (P=0.03) and β2-adrenoceptor (P=0.03) binding affinities in human lung tissue" SIGNOR-258336 CSNK2A1 protein P68400 UNIPROT NFKBIA protein P25963 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser32 LLDDRHDsGLDSMKD 10398585 t lperfetto "Serine 32 and serine 36 of IkappaBalpha are directly phosphorylated by protein kinase CKII in vitro|Phosphorylation of IkappaBalpha at serine 32 (S32) and serine 36 (S36) is necessary for this stimuli-induced degradation" SIGNOR-249332 halothane chemical CHEBI:5615 ChEBI KCNK3 protein O14649 UNIPROT "up-regulates activity" "chemical activation" 10090 20519544 t Luana "We further demonstrate that TASK channels are required for normal sensitivity to immobilizing effects of halothane and isoflurane and to sedative/hypnotic effects of halothane." SIGNOR-257846 AKT proteinfamily SIGNOR-PF24 SIGNOR STK4 protein Q13043 UNIPROT down-regulates phosphorylation Thr120 IIRLRNKtLTEDEIA 9606 19940129 t llicata "Akt interacts with mst1 and phosphorylates a highly conserved residue threonine 120 of mst1, which leads to inhibition of its kinase activity and nuclear translocation as well as the autophosphorylation of thr(183)." SIGNOR-161829 IRS2 protein Q9Y4H2 UNIPROT PIK3CG protein P48736 UNIPROT up-regulates binding 9606 12850284 t gcesareni "There was a high level of irs-2 expression and insulin-stimulated tyrosyl phosphorylation as early as embryonic day 15 with robust pi3k binding and activation" SIGNOR-103174 serotonin(1+) smallmolecule CHEBI:350546 ChEBI HTR1B protein P28222 UNIPROT "up-regulates activity" "chemical activation" 9606 BTO:0002524 31160049 t "Ligand-GPCR dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257517 "STX11-VAMP8 SNARE complex" complex SIGNOR-C273 SIGNOR Membrane_fusion phenotype SIGNOR-PH122 SIGNOR up-regulates 9606 BTO:0000782 22767500 f lperfetto "Coimmunoprecipitation experiments showed that syntaxin-11 can form SNARE complexes with both VAMP-8 and SNAP-23. |The SNAREs form transmembrane complexes that mediate membrane fusion and granule cargo release." SIGNOR-261900 SIRT5 protein Q9NXA8 UNIPROT CPS1 protein P31327 UNIPROT "up-regulates activity" "post translational modification" 9606 BTO:0000567 24703693 t deglutarylation lperfetto "Glutarylation suppresses CPS1 activity, which is targeted by SIRT5 for removal|SIRT5 can catalyze the enzymatic removal of lysine glutarylation" SIGNOR-267643 MAPK3 protein P27361 UNIPROT WWC1 protein Q8IX03 UNIPROT unknown phosphorylation Ser548 SSPSPPCsPLMADPL 9606 BTO:0000149 24269383 t llicata "We demonstrated that erk1/2 phosphorylate kibra at ser(548) in cells as well as in vitro." SIGNOR-203290 FZD5 protein Q13467 UNIPROT DVL1 protein O14640 UNIPROT "up-regulates activity" binding 9606 23151663 t areggio "Upon ligand binding, DVL proteins are recruited to Frizzled receptors at the plasma membrane and co-recruit cytoplasmic transducers, such as Axin, CK1 and GSK3 binding protein (GBP), presumably along with their partners, to promote ?-catenin-dependent signalling. " SIGNOR-258957 PORCN protein Q9H237 UNIPROT WNT3A protein P56704 UNIPROT "up-regulates activity" palmitoylation Ser209 KCKCHGLsGSCEVKTC 9606 BTO:0000007 20826466 t "And WNT3A binding to WLS requires PORCN-dependent lipid modification of WNT3A at serine 209. Inhibition of vacuolar acidification results in accumulation of the WNT3A-WLS complex both in cells and at the plasma membrane." SIGNOR-256598 MLF1 protein P58340 UNIPROT COPS3 protein Q9UNS2 UNIPROT up-regulates binding 9606 15861129 t miannu "As downstream elements of mlf1 leading to cell growth arrest due to p53 accumulation, we identified two factors, csn3, the third component of the cop9 signalosome (csn), and cop1, a recently characterized e3 ubiquitin ligase for p53" SIGNOR-135937 LDHB protein P07195 UNIPROT pyruvate smallmolecule CHEBI:15361 ChEBI "down-regulates quantity" "chemical modification" 9606 24929216 t lperfetto "Glucose and alanine produce pyruvate which is reduced to lactate by lactate dehydrogenase in the cytoplasm without oxygen consumption. Lactate removal takes place via its oxidation to pyruvate by lactate dehydrogenase." SIGNOR-267656 PTEN protein P60484 UNIPROT PIP3 smallmolecule CHEBI:16618 ChEBI "down-regulates quantity" "chemical modification" 9606 11875759 t lperfetto "PTEN dephosphorylates PI3P, lowering its cellular levels and resulting in the down-regulation of AKT." SIGNOR-228145 EFR3B protein Q9Y2G0 UNIPROT PI4KA protein P42356 UNIPROT "up-regulates quantity" binding 9606 BTO:0000007 34504076 t miannu "PI4KA is recruited to plasma membrane by the adapter protein EFR3, which has two isoforms, EFR3A and EFR3B" SIGNOR-269093 serine smallmolecule CHEBI:17822 ChEBI AminoAcids stimulus SIGNOR-ST5 SIGNOR "up-regulates quantity" 29259120 t lperfetto "All extant life employs the same 20 amino acids for protein biosynthesis" SIGNOR-264760 PRKACA protein P17612 UNIPROT GLI2 protein P10070 UNIPROT down-regulates phosphorylation 9606 16885213 t gcesareni "In the absence of hh ligands, cubitus interruptus (in drosophila) and gli2 and gli3 (in vertebrates) are phosphorylated by protein kinase a and glycogen synthase kinase-3beta and are proteolytically processed in vertebrates, pka-mediated phosphorylation of gli2 and gli3 initiates a phosphorylation cascade that leads to processing into repressors of transcription or frank degradation" SIGNOR-148478 "Caspase 3 complex" complex SIGNOR-C221 SIGNOR SPTAN1 protein Q13813 UNIPROT down-regulates cleavage 9606 BTO:0000150;BTO:0000567 9624143 t amattioni "Caspase-3 is required for alpha-fodrin cleavage but dispensable for cleavage of other death substrates in apoptosis." SIGNOR-256450 DUSP1 protein P28562 UNIPROT ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR down-regulates dephosphorylation 9606 10617468 t "inferred from 70% of family members" gcesareni "The mitogen-activated protein (map) kinase cascade is inactivated at the level of map kinase by members of the map kinase phosphatase (mkp) family, including mkp-1." SIGNOR-269930 pazopanib chemical CHEBI:71219 ChEBI CSF1R protein P07333 UNIPROT "down-regulates activity" "chemical inhibition" 9606 BTO:0001949 18620382 t Luana "Pyrimidine 13 showed good potency against all the human VEGFR receptors with an IC50 of 10, 30, and 47 nM for VEGFR-1, -2, and -3, respectively. Significant activity was also seen against the closely related tyrosine receptor kinases PDGFRβ, c-Kit, FGF-R1, and c-fms with IC50’s of 84, 74, 140, and 146 nM, respectively." SIGNOR-257740 PRKACA protein P17612 UNIPROT GLI2 protein P10070 UNIPROT down-regulates phosphorylation 9606 17419683 t gcesareni "In the absence of hh ligands, cubitus interruptus (in drosophila) and gli2 and gli3 (in vertebrates) are phosphorylated by protein kinase a and glycogen synthase kinase-3beta and are proteolytically processed in vertebrates, pka-mediated phosphorylation of gli2 and gli3 initiates a phosphorylation cascade that leads to processing into repressors of transcription or frank degradation" SIGNOR-154273 HOXD3 protein P31249 UNIPROT ITGA5 protein P08648 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 14610084 t Luana "The homeobox transcription factor Hox D3 promotes integrin alpha5beta1 expression and function during angiogenesis." SIGNOR-261649 SRC protein P12931 UNIPROT GSN protein P06396 UNIPROT up-regulates phosphorylation Tyr465 VPVDPATyGQFYGGD 9606 10210201 t lperfetto "Identification of tyr438 as the major in vitro c-src phosphorylation site in human gelsolin recently" SIGNOR-67014 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR CDC25C protein P30307 UNIPROT up-regulates phosphorylation Ser214 SRSGLYRsPSMPENL 9606 10864927 t lperfetto "Activation of human cdc25c at the g2/m transition occurs concomitantly with phosphorylation of five serine/threonine-proline sites: thr48, thr67, ser122, thr130, and ser214, presumably by cdc2-cyclin b." SIGNOR-216765 TXK protein P42681 UNIPROT LCP2 protein Q13094 UNIPROT up-regulates phosphorylation Tyr113 SSFEEDDyESPNDDQ 9606 10660534 t lperfetto "Resting lymphocyte kinase (rlk/txk) targets lymphoid adaptor slp-76 in the cooperative activation of interleukin-2 transcription in t-cells. In this study, we report that rlk phosphorylates slp-76 at its n-terminal yesp/yepp sites. A third tyrosine within the amino-terminal region (y145) appears to be the most important for optimal slp-76 function" SIGNOR-74844 PRKAA1 protein Q13131 UNIPROT HDAC5 protein Q9UQL6 UNIPROT down-regulates phosphorylation Ser498 RPLSRTQsSPLPQSP 9606 SIGNOR-C15 21892142 t gcesareni "Another recently described set of transcriptional regulators targeted by ampk and its related family members across a range of eukaryotes are the class iia family of histone deacetylases (hdacs)" SIGNOR-176483 GNAI3 protein P08754 UNIPROT Adenylate_cyclase proteinfamily SIGNOR-PF92 SIGNOR "down-regulates activity" binding 9606 19703466 t miannu "Adenylate cyclase is regulated by stimulatory hormones through Gs(alpha s beta gamma) and inhibitory hormones through Gi(alpha i beta gamma)" SIGNOR-267851 "TREX complex" complex SIGNOR-C444 SIGNOR mRNA-nucleus_export phenotype SIGNOR-PH127 SIGNOR up-regulates 9606 22928037 f miannu "The conserved TREX complex, which contains UAP56, Aly, CIP29, and the multi-subunit THO complex, functions in mRNA export." SIGNOR-268514 MAPK14 protein Q16539 UNIPROT SMARCD3 protein Q6STE5 UNIPROT "up-regulates activity" phosphorylation 9606 21902831 t lperfetto "P38 phosphorylates the baf60 subunit of the swi-snf chromatin remodelling complex, and p38 recruits this complex to differentiation-specific loci." SIGNOR-176557 DDX21 protein Q9NR30 UNIPROT JUN protein P05412 UNIPROT "up-regulates activity" binding 9606 "BTO:0000007 ; BTO:0001282" 11823437 t SARA "C-Jun and RHII/Gu proteins interact in human cells at their endogenous level of expression. The helicase activity of RHII/Gu specifically facilitates c-Jun-mediated transcription." SIGNOR-260977 RALA protein P11233 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR "up-regulates activity" phosphorylation Thr455 ALGTPVLtPPTEAAS 10090 BTO:0000944 11689711 t gcesareni "We conclude that Ral-mediated phosphorylation of threonines 447 and 451 is required for proper activity of AFX-WT." SIGNOR-252985 EEF1B2 protein P24534 UNIPROT "EEF1B complex" complex SIGNOR-C460 SIGNOR "form complex" binding 9606 23699257 t lperfetto "An inactive eEF1A-GDP moiety leaves the ribosome and must be recycled to eEF1A-GTP before binding another aa-tRNA. This GTP exchange process is the function of the nucleotide exchange factor eEF1B complex, which exchanges GDP for GTP to regenerate active eEF1A. The requirement for a guanine nucleotide exchange factor, the eEF1B complex, which in metazoans is composed of the subunits α, δ, and γ (also called eEF1B, eEF1D, and eEF1G, respectively)" SIGNOR-269390 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR BCL2 protein P10415 UNIPROT "up-regulates quantity by stabilization" phosphorylation Ser70 RDPVARTsPLQTPAA 9534 BTO:0004055 10677502 t lperfetto "Erk1 and erk2 directly phosphorylate bcl2 exclusively at ser-70." SIGNOR-244501 CCL25 protein O15444 UNIPROT ACKR4 protein Q9NPB9 UNIPROT "up-regulates activity" binding 9606 BTO:0001938 23341447 t Luana " In the present study, however, we demonstrate for the first time the concentration-dependent recruitment of β-arrestins to the atypical chemokine receptor CCX-CKR upon stimulation with CCL19, CCL21, or CCL25 using three different methodologies in various transfected cell lines." SIGNOR-268418 PYGM protein P11217 UNIPROT glycogen smallmolecule CHEBI:28087 ChEBI "down-regulates quantity" "chemical modification" 9606 3346228 t "Mammalian glycogen phosphorylases are found in at least three isozymic forms that can be distinguished by functional and structural properties as well as by the tissues in which they are preferentially expressed [‚Ķ] Each phosphorylase isozyme fulfills different physiological requirements even though all forms of the enzyme catalyze the same reaction, the phosphorolysis of glycogen to yield glucose 1-phosphate." SIGNOR-267389 PPP2CB protein P62714 UNIPROT AKT3 protein Q9Y243 UNIPROT "down-regulates activity" dephosphorylation Ser472 RPHFPQFsYSASGRE 9606 18160256 t "Overexpression of BTBD10 increased phosphorylation levels of Akts at both Thr(308) and Ser(473) while the reduction of the endogenous BTBD10 level resulted in a decrease in the phosphorylation levels of Akts. In vitro analysis indicated that BTBD10 bound to protein phosphatase 2A (PP2A) and inhibited dephosphorylation of Akts by PP2A." SIGNOR-248610 SMURF proteinfamily SIGNOR-PF29 SIGNOR BMPR1A protein P36894 UNIPROT down-regulates ubiquitination 9606 22298955 t "inferred from 70% family members" gcesareni "Smurf1 and smurf2 are e3 ubiquitin ligases known to suppress tgf-beta signaling through degra-dation of smads and receptors for tgf-beta and bmps" SIGNOR-270212 NfKb-p65/p50 complex SIGNOR-C13 SIGNOR Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 11359934 f gcesareni "The nuclear factor-kappaB (NF-kappaB) family of transcription factors has been shown to regulate proliferation in several cell types." SIGNOR-245043 ETS1 protein P14921 UNIPROT ATP2A3 protein Q93084 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 BTO:0000255 12119294 t Luana "Ets-1 was able to transactivate the SERCA3 promoter in MoBr 204 as cotransfection of an Ets-1 expression vector increased the activity of the −97/+301-Luc construct by 6-fold." SIGNOR-261601 XAV939 chemical CHEBI:62878 ChEBI TNKS protein O95271 UNIPROT "down-regulates activity" "chemical inhibition" -1 19759537 t "In biochemical activity assays, XAV939 strongly inhibited TNKS1 and TNKS2, with half-maximal inhibitory concentration values of 0.011 and 0.004 μM, respectively, but displayed much weaker effects on PARP1 and PARP2" SIGNOR-259994 NfKb-p65/p50 complex SIGNOR-C13 SIGNOR CD80 protein P33681 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 12860928 f miannu "Upon CD40 signaling, transcription of the CD80 gene is induced by the nuclear factor (NF)-kappaB transcription factor." SIGNOR-254783 SHH protein Q15465 UNIPROT AKT1 protein P31749 UNIPROT up-regulates 9606 BTO:0000222;BTO:0002314 BTO:0000887 17688959 f gcesareni "Most importantly, we report that shh induces mapk/erk and phosphoinositide 3-kinase (pi3k)-dependent akt phosphorylation and that activation of both signaling pathways is essential for shh's signaling in muscle cells. However, the effect of shh on akt phosphorylation is more robust than that on mapk/erk, and data suggest that shh influences these pathways in a manner similar to igf-i." SIGNOR-157291 HMOX1 protein P09601 UNIPROT heme smallmolecule CHEBI:30413 ChEBI "down-regulates quantity" "chemical modification" 9606 10490932 t Regulation miannu "Heme oxygenase (HO), by catabolizing heme to bile pigments, down-regulates cellular hemoprotein, hemoglobin, and heme" SIGNOR-251911 RBPJ protein Q06330 UNIPROT NFKB2 protein Q00653 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 9528780 f gcesareni "Rbp-jkappa is a strong transcriptional repressor of nf-kappab2. Moreover, this repression can be overcome by activated notch-1." SIGNOR-56100 MAPK8 protein P45983 UNIPROT IRF3 protein Q14653 UNIPROT up-regulates phosphorylation Ser173 PCPQPLRsPSLDNPT 9606 19153595 t lperfetto "In this study, we show that another kinase, c-jun-nh(2)-terminal kinase (jnk), phosphorylates irf3 on its n-terminal serine 173 residuejnk1 can synergize the action of irf3(5d), but not the s173a-irf3(5d) mutant" SIGNOR-183489 AKT1 protein P31749 UNIPROT CFLAR protein O15519 UNIPROT "down-regulates quantity" phosphorylation Ser273 LLRDTFTsLGYEVQK 9606 19339247 t gcesareni "TNFalpha enhanced FLIP(L) serine phosphorylation, which was increased by activated Akt-1. Serine 273, a putative Akt-1 phosphorylation site in FLIP(L), was critical for the activation-induced reduction of FLIP(L). Thus, these observations document a novel mechanism where by TNFalpha facilitates the reduction of FLIP(L) protein, which is dependent on the phosphatidylinositol 3-kinase/Akt signaling." SIGNOR-252548 MAPK3 protein P27361 UNIPROT RPS6KB1 protein P23443 UNIPROT "up-regulates activity" phosphorylation Thr444 RFIGSPRtPVSPVKF 10116 15774499 t lperfetto "Thr 421/Ser 424 have been reported to be targeted by ERK1, 2 (39), JNK or p38 MAPKs (36). Interestingly, with a comparable kinetics, FSH represses ERK1, 2 constitutive phosphorylation in Sertoli cells isolated from 19-d-old rats" SIGNOR-134662 SRC protein P12931 UNIPROT RPS6KB2 protein Q9UBS0 UNIPROT unknown phosphorylation Tyr45 GLEPVGHyEEVELTE 9606 16640565 t llicata "Src kinase phosphorylates s6k in the n-terminus. tyrosine y39/45 in s6k1/2 is a substrate for src kinase in vitro. tyrosine y39/45 in s6k1/2 is a substrate for src kinase in vivo." SIGNOR-146292 JAK1 protein P23458 UNIPROT JAK3 protein P52333 UNIPROT up-regulates 9606 10825200 f gcesareni "Syk activation required jak3, probably indirectly via activation of jak1." SIGNOR-77551 CRTC2 protein Q53ET0 UNIPROT TSC22D3 protein Q99576 UNIPROT "up-regulates quantity" "transcriptional regulation" 9606 26652733 t "CRTC2 knockdown attenuates glucocorticoid-responsive GILZ mRNA expression in HeLa cells" SIGNOR-256109 Synaptonemal_complex complex SIGNOR-C351 SIGNOR Meiotic_recombination phenotype SIGNOR-PH162 SIGNOR up-regulates 9606 33262143 f miannu "The synaptonemal complex (SC) is a meiosis-specific structure formed between homologous chromosomes during prophase that promotes DSB formation and biases repair of DSBs to homologs over sister chromatids." SIGNOR-264204 ADA protein P00813 UNIPROT inosine smallmolecule CHEBI:17596 ChEBI "up-regulates quantity" "chemical modification" -1 15926889 t Luana "Adenosine deaminase (ADA; EC 3.5.4.4) catalyses the deamination of adenosine and 2′-deoxyadenosine to inosine and deoxyinosine. Two different isoenzymes of ADA designated as ADA1 and ADA2 were found in mammals and lower vertebrates" SIGNOR-269737 FLT4 protein P35916 UNIPROT SHC1 protein P29353 UNIPROT unknown phosphorylation Tyr350 EPPDHQYyNDFPGKE 9606 9927207 t llicata "We have investigated which of the shc tyrosine residues are targeted by the vegfr3/ flt4 kinase and the role of the shc ptb and sh2 domains in this process. Our results show that y239/ y240 and y313 are simultaneously phosphorylated by the kinase, creating grb2 binding sites." SIGNOR-64076 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR SREBF1 protein P36956 UNIPROT up-regulates phosphorylation Ser117 YPSMPAFsPGPGIKE 9606 10915800 t lperfetto "Map kinases erk1/2 phosphorylate sterol regulatory element-binding protein (srebp)-1a at serine 117 in vitro. mutation of serine 117 to alanine abolished erk2-mediated phosphorylation in vitro and the map kinase-related transcriptional activation of srebp-1a by insulin and platelet-derived growth factor in vivo." SIGNOR-244754 EFR3A protein Q14156 UNIPROT PI4KA protein P42356 UNIPROT "up-regulates quantity" binding 9606 BTO:0000007 34504076 t miannu "PI4KA is recruited to plasma membrane by the adapter protein EFR3, which has two isoforms, EFR3A and EFR3B" SIGNOR-269092 PPP5C protein P53041 UNIPROT MAP3K5 protein Q99683 UNIPROT "down-regulates activity" dephosphorylation Thr842 CTETFTGtLQYMAPE 10090 11689443 t llicata "After exposure of cells to H2O2, ASK1 is transiently activated by autophosphorylation at Thr845. The protein then associates with PP5 (protein serine/threonine phosphatase 5), which inactivates ASK1 by dephosphorylation of Thr845." SIGNOR-248540 HOXB8 protein P17481 UNIPROT TAGLN protein Q01995 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 10116 BTO:0002196 15886193 t Luana "Results from these experiments demonstrated that in 10T1/2 cells Hoxa10-1 increased the activity of the telokin promoter 3-fold without affecting the activity of the other promoters analyzed (Fig. 2A). Similar results were also observed in A10 SMC (data not shown). In contrast, Hoxb8 significantly repressed the activity of the telokin, smooth muscle α-actin, and SM22α promoters by 70, 50, and 70%, respectively" SIGNOR-261642 MMP27 protein Q9H306 UNIPROT ECM_disassembly phenotype SIGNOR-PH80 SIGNOR up-regulates 17318226 f lperfetto "Historically, MMPs were thought to function mainly as enzymes that degrade structural components of the ECM." SIGNOR-272371 Kindlin proteinfamily SIGNOR-PF48 SIGNOR ITGB1 protein P05556 UNIPROT "up-regulates activity" binding 9606 29544897 t miannu "Kindlins bind with β-integrin cytoplasmic tails and execute broad biological functions including directed cell migration, proliferation, differentiation and survival." SIGNOR-258999 LEF1 protein Q9UJU2 UNIPROT CEBPA protein P49715 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 19620402 f miannu "We have identified LEF-1 as a decisive transcription factor in granulopoiesis controlling proliferation and granulocytic differentiation by direct activation of its target gene, C/EBPalpha." SIGNOR-254551 NR5A1 protein Q13285 UNIPROT HSD3B2 protein P26439 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0001555 19022561 f miannu "We found that both SF1 and LRH1 can transcriptionally cooperate with the AP-1 family members c-JUN and c-FOS, known to be associated with enhanced proliferation of endometrial carcinoma cells, to further enhance activation of the STAR, HSD3B2, and CYP19A1 PII promoters." SIGNOR-254868 Ub:E2 complex SIGNOR-C497 SIGNOR TRAF6 protein Q9Y4K3 UNIPROT "up-regulates activity" ubiquitination 9606 34199813 t miannu "The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t" SIGNOR-270981 Linsitinib chemical CID:11640390 PUBCHEM INSR protein P06213 UNIPROT "down-regulates activity" "chemical inhibition" 10090 24712877 t lperfetto "Effects of the antitumor drug OSI-906, a dual inhibitor of IGF-1 receptor and insulin receptor, on the glycemic control, β-cell functions, and β-cell proliferation in male mice" SIGNOR-262029 Gbeta proteinfamily SIGNOR-PF4 SIGNOR MCL1 protein Q07820 UNIPROT up-regulates phosphorylation 9606 BTO:0000150 18676833 t "inferred from 70% family members" fstefani "We then showed that erk could phosphorylate mcl-1 at two consensus residues, thr 92 and 163, which is required for the association of mcl-1 and pin1, resulting in stabilization of mcl-1." SIGNOR-270042 GLUL protein P15104 UNIPROT "L-glutamine zwitterion" smallmolecule CHEBI:58359 ChEBI "up-regulates quantity" "chemical modification" 9606 30158707 t miannu "Glutamine synthetase, encoded by the gene GLUL, is an enzyme that converts glutamate and ammonia to glutamine. certain cell types express glutamine synthetase (GS; also called glutamate-ammonia ligase; GLUL), the enzyme capable of de novo glutamine production from glutamate and ammonia in an ATP and Mg2+/Mn2+ requiring reaction." SIGNOR-267826 BTC protein P35070 UNIPROT EGFR protein P00533 UNIPROT up-regulates binding 9606 23382875 t gcesareni "Betacellulin is synthesized primarily as a transmembrane precursor, which is then processed to mature molecule by proteolytic events;ten growth factors and their erbb specificities are depicted: egf, amphiregulin((ar), and tgfalfa bind erbb-1, betacellulin, heparin binding egf-like growth factor, and epiregulin bing both erbb-1 and erbb-4." SIGNOR-200813 prednisolone chemical CHEBI:8378 ChEBI NR3C1 protein P04150 UNIPROT up-regulates "chemical activation" 9606 8342904 t ashma gcesareni SIGNOR-251698 RASGEF1C protein Q8N431 UNIPROT NRAS protein P01111 UNIPROT up-regulates binding 9606 19201597 t gcesareni "Gefs catalyse the transition from gdp-bound, inactive ras to gtp-bound, active ras." SIGNOR-161511 NOTCH1 protein P46531 UNIPROT HIF1A protein Q16665 UNIPROT "up-regulates activity" relocalization 9606 BTO:0000938 16256737 t lperfetto "The notch intracellular domain interacts with hif-1alpha and hif-1alpha is recruited to notch-responsive promoters upon notch activation under hypoxic conditions." SIGNOR-141315 RNF216 protein Q9NWF9 UNIPROT TICAM1 protein Q8IUC6 UNIPROT "down-regulates quantity by destabilization" ubiquitination 9606 BTO:0000007 16968706 t miannu "Triad3A promotes proteolytic degradation of adapter proteins. A, Triad3A promotes down-regulation of TIRAP, TRIF, and RIP1 proteins." SIGNOR-271609 RUNX3 protein Q13761 UNIPROT ELANE protein P08246 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0004850 14594802 f miannu "We find that LEF-1 and CBFalpha co-activate ELA2 expression." SIGNOR-254554 RAPGEF6 protein Q8TEU7 UNIPROT NRAS protein P01111 UNIPROT up-regulates "guanine nucleotide exchange factor" 9606 19201597 t gcesareni "Gefs catalyse the transition from gdp-bound, inactive ras to gtp-bound, active ras." SIGNOR-183799 GSK3B protein P49841 UNIPROT AXIN1 protein O15169 UNIPROT up-regulates phosphorylation 9606 SIGNOR-C110 SIGNOR-C110 23579495 t lperfetto "Phosphorylation by GSK3 kept Axin activated (open) for _-catenin interaction and poised for engagement of LRP6." SIGNOR-201683 AKT3 protein Q9Y243 UNIPROT BAD protein Q92934 UNIPROT down-regulates phosphorylation Ser99 PFRGRSRsAPPNLWA 9606 10949026 t gcesareni "Ser-136 is the major phosphoacceptor site for akt;akt can weakly phosphorilate ser-155." SIGNOR-81122 NUMB protein P49757 UNIPROT NOTCH proteinfamily SIGNOR-PF30 SIGNOR down-regulates BTO:0001103 12361602 t apalma "Numb is an inhibitor of Notch signaling that interacts with the intracellular portion of Notch and antagonizes its activity by preventing nuclear translocation" SIGNOR-255374 ABCA1 protein O95477 UNIPROT MEGF10 protein Q96KG7 UNIPROT "up-regulates activity" binding 9606 BTO:0000567 17205124 t miannu "ABCA1 and MEGF10 interact during engulfment. MEGF10 function can be modulated by the ATP binding cassette transporter ABCA1, ortholog to CED-7. by the combined use of cellular and biochemical approaches we provide evidence that ABCA1 and MEGF10 interact at the molecular level." SIGNOR-265164 AKT1 protein P31749 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR "down-regulates activity" phosphorylation Ser197 APRRRAAsMDSSSKL 10090 BTO:0004245 10217147 t "Here we show that protein kinase B phosphorylates AFX, a human orthologue of daf -16 (refs 5, 6, 9), both in vitro and in vivo." SIGNOR-252861 XAV939 chemical CHEBI:62878 ChEBI TNKS protein O95271 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-207830 SMAD1/4 complex SIGNOR-C85 SIGNOR PPARG protein P37231 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 18854943 f fferrentino "This Smad1/4 complex can directly interact with Shn-2 and C/EBP a on the PPAR g promoter thus, resulting in the transcriptional activation of PPAR g" SIGNOR-253551 ROR2 protein Q01974 UNIPROT ROR2 protein Q01974 UNIPROT up-regulates binding 9606 23151663 t gcesareni "Wnt5a induces homodimerization and activation of ror2 receptor tyrosine kinase" SIGNOR-199588 PCSK7 protein Q16549 UNIPROT PPP2CA protein P67775 UNIPROT up-regulates phosphorylation 9606 11259586 t gcesareni "This together with the rapid kinetics of pp1-pp2a activation following p38 activation suggests that pp1 and/or pp2a complexes are direct targets for p38-mediated phosphorylation" SIGNOR-105783 PRKD1 protein Q15139 UNIPROT CTNNB1 protein P35222 UNIPROT up-regulates phosphorylation Thr112 EGMQIPStQFDAAHP 9606 BTO:0001130 19141652 t lperfetto "This study provides evidence that pkd1 interacts with and phosphorylates beta-catenin at thr(112) and thr(120) we postulate that pkd1 phosphorylation is required to maintain _-catenin transcription activity." SIGNOR-183384 CNOT4 protein O95628 UNIPROT KDM5C protein P41229 UNIPROT "down-regulates quantity by destabilization" ubiquitination 9606 19346402 t miannu " In our study, we show that the protein level of the yeast histone H3 Lys 4 (H3 K4) demethylase Jhd2/Kdm5 is modulated through polyubiquitination by the E3 ubiquitin ligase Not4 and turnover by the proteasome.  Finally, we show that human NOT4 can polyubiquitinate human JARID1C/SMCX, a homolog of Jhd2, suggesting that this is likely a conserved mechanism. We propose that Not4 is an E3 ubiquitin ligase that monitors and controls a precise amount of Jhd2 protein so that the proper balance between histone demethylase and histone methyltransferase activities occur in the cell, ensuring appropriate levels of H3 K4 trimethylation and gene expression." SIGNOR-271468 CALM3 protein P0DP25 UNIPROT Calcineurin complex SIGNOR-C155 SIGNOR up-regulates binding 9606 11796223 t miannu "Calcium-bound calmodulin associates with calcineurin (cn), releasing the phosphatase from the repressive effects on an autoinhibitory domain." SIGNOR-266347 PTPN6 protein P29350 UNIPROT KCNH2 protein Q12809 UNIPROT down-regulates dephosphorylation 9606 12361947 t gcesareni "Our results show that erg-1 is a shp-1 substrate constituting the first report that an ion current is regulated by shp-1." SIGNOR-94007 SLBP protein Q14493 UNIPROT H3-2 protein Q5TEC6 UNIPROT "up-regulates quantity by expression" "translation regulation" 9606 BTO:0001938 19155325 t lperfetto "Synthesis of mature histone mRNA requires only a single processing reaction: an endonucleolytic cleavage between a conserved stem-loop and a purine-rich downstream element to form the 3' end. The stem-loop binding protein (SLBP) is required for processing, and following processing, histone mRNA is transported to the cytoplasm, where SLBP participates in translation of the histone mRNA|We used radiolabeled probes generated by PCR targeting the open reading frame (ORF) to detect histones H2A, H2B, H3, H4, and H1 and used 7SK snRNA as a loading control (Fig. 2A). The abundance of histone H2A, H2B, H3, and H4 mRNAs is reduced to 37% to 70% of control levels in the SLBP knockdown cells when compared to the C2 control." SIGNOR-265415 EGLN3 protein Q9H6Z9 UNIPROT IKBKG protein Q9Y6K9 UNIPROT "down-regulates activity" binding 9606 BTO:0000007 23732909 t lperfetto "Here we report that EGLN3, but not EGLN1 or -2, interacts with and inhibits K63-linked ubiquitination of IKKγ. The effect appears to be related to inhibition of IKKγ ubiquitination mediated by cIAP1 rather than to stimulation of IKKγ deubiquitination by the deubiquitinases A20 and CYLD (cylindromatosis). EGLN3 does not affect the protein levels of cIAP1 or its E2 ubiquitin-conjugating enzymes UbcH5 and Ubc13. EGLN3 hydroxylase activity is not responsible for its effect on IKKγ ubiquitination and NF-κB signaling. Instead, interaction with IKKγ is required for the ability of EGLN3 to inhibit IKKγ ubiquitination and IKK-NF-κB signaling." SIGNOR-262005 MARCHF8 protein Q5T0T0 UNIPROT HLA-DRB4 protein P13762 UNIPROT "down-regulates quantity by destabilization" polyubiquitination Lys254 FIYFRNQkGHSGLQP 9606 19117940 t miannu "Two E3 ligases, MARCH I and MARCH VIII, have been shown to polyubiquitinate lysine residue 225 in the cytoplasmic tail of I-Abeta and HLA-DRbeta. We show that lysine residue 219 in the cytoplasmic tail of DRalpha is also subject to polyubiquitination." SIGNOR-271407 SRC protein P12931 UNIPROT SPTAN1 protein Q13813 UNIPROT up-regulates phosphorylation Tyr1176 AVQQQEVyGMMPRDE 9606 11971983 t llicata "Using mutagenesis on recombinant peptides, we identified the residue y1176 located in the calpain cleavage site of alpha ii-spectrin, near the sh3 domain, as an in vitro substrate for src kinase and lmw-ptp a. phosphorylation of this residue decreases spectrin sensitivity to calpain in vitro." SIGNOR-86718 CBY1 protein Q9Y3M2 UNIPROT CTNNB1 protein P35222 UNIPROT down-regulates binding 9606 12712206 t gcesareni "Here we report a conserved nuclear protein, named chibby, which was identified in a screen for proteins that directly interact with the c-terminal region of beta-catenin. In mammalian cultured cells we demonstrate that chibby inhibits beta-catenin-mediated transcriptional activation by competing with lef-1 to bind to beta-catenin." SIGNOR-100835 PRKACA protein P17612 UNIPROT SLC8B1 protein Q6J4K2 UNIPROT "up-regulates activity" phosphorylation Ser258 YQRQRRGsLFCPMPV 36476859 t "Phosphosite is derived from the graphical abstract" lperfetto "However, the PDE2-inhibitory effect is eliminated when the mitochondrial S258A NCLX mutant that mimics a non-PKA phosphorylated state of NCLX is expressed. Altogether, our findings indicate that NCLX is regulated by the mitochondrial PDE2A2 form.|We show that caffeine, by inhibiting PDE2, enhances PKA phosphorylation leading to mitochondrial NCLX activation, thereby reducing neuronal excitotoxicity and enhancing learning in mice. |Moreover, PDE2 acts by diminishing mitochondrial cAMP, thus promoting NCLX phosphorylation at its PKA site." SIGNOR-275727 MAPK3 protein P27361 UNIPROT mTORC1 complex SIGNOR-C3 SIGNOR up-regulates phosphorylation 9606 21757713 t lperfetto "The phosphorylation of Raptor on these sites enhances mTORC1 activity, and contributes largely to arsenite-induced mTORC1 activation." SIGNOR-217544 CAMKK1 protein Q8N5S9 UNIPROT CAMK4 protein Q16566 UNIPROT up-regulates phosphorylation 9606 10770941 t lperfetto "Ca(2+)/calmodulin-dependent protein kinase kinase (CaM-KK) is a novel member of the CaM kinase family, which specifically phosphorylates and activates CaM kinase I and IV" SIGNOR-232181 LCK protein P06239 UNIPROT LCK protein P06239 UNIPROT "up-regulates activity" phosphorylation Tyr394 RLIEDNEyTAREGAK 9606 2250907 t lperfetto "They also demonstrate that replacement of the major site of autophosphorylation of p56lck (tyrosine 394) by a phenylalanine residue abolishes the ability to activate p56lck by CD4 cross-linking, implying that this residue is critical for the positive regulation of the Lck tyrosine kinase activity by CD4." SIGNOR-81372 IL15RA protein Q13261 UNIPROT IL2RB protein P14784 UNIPROT up-regulates binding 9606 BTO:0000887;BTO:0001103 17709786 t milica "The il-15 receptor comprises a heterotrimeric complex consisting of the common ?cytokine Receptor (?c), the il-2 ? Receptor subunit (il-2r?), And an il-15-specific ? Receptor (il-15r?)" SIGNOR-157418 PCDHAC1 protein Q9H158 UNIPROT ITGB1 protein P05556 UNIPROT "up-regulates activity" binding 9606 BTO:0000227 16697637 t miannu "The clustered protocadherins comprise the largest subfamily of the cadherin superfamily and are predominantly expressed in the nervous system. Pcdh-alpha proteins interact with beta1-integrin to promote cell adhesion." SIGNOR-269037 RIMBP3 protein Q9UFD9 UNIPROT RIMS3 protein Q9UJD0 UNIPROT "down-regulates activity" binding 10116 BTO:0001009 11988172 t miannu "SH3 domains of RBPs interact with RIMs. The enhancement of depolarization-induced secretion in PC12 cells by fusion proteins that suppress the associations of RBPs with RIMs and α1 suggests that RBPs may repress RIMs, either directly or through associated proteins." SIGNOR-264370 α-Catenin proteinfamily SIGNOR-PF72 SIGNOR JUP protein P14923 UNIPROT "up-regulates quantity" relocalization 9606 BTO:0000586 21598020 t miannu "Overexpression of CTNNA3 in a CTNNA1 negative colon carcinoma cell line resulted in the reassembly of the adherens and tight junctions through the recruitment of CTNNA3 interacting partners such as E-cadherin, β-catenin, plakoglobin, and ZO-14" SIGNOR-265819 3,3',5'-triiodothyronine smallmolecule CHEBI:28774 ChEBI Skeletal_muscle_differentiation phenotype SIGNOR-PH1 SIGNOR up-regulates 9606 24692351 f scontino "Skeletal muscle has been recognized as a key TH target for contractile function, regeneration, and transport as well as for metabolism and glucose disposal (237, 238). TH stimulation favors transition to fast-twitch fibers and transition to a faster myosin heavy chain (MHC) form." SIGNOR-267619 5,15-Diphenyl-21H,23H-porphine chemical CID:10895852 PUBCHEM STAT3 protein P40763 UNIPROT "down-regulates activity" "chemical inhibition" 9606 26260587 t gcesareni "15-DPP is an effective STAT3 inhibitor and blocks IL10-mediated signalling in macrophages leading to altered regulation of CNV" SIGNOR-238549 betamethasone chemical CHEBI:3077 ChEBI NR3C1 protein P04150 UNIPROT up-regulates "chemical activation" 9606 17561562 t dermatitis gcesareni SIGNOR-251686 noradrenaline smallmolecule CHEBI:33569 ChEBI adrenaline smallmolecule CHEBI:33568 ChEBI "up-regulates quantity" "precursor of" 9606 7961964 t brain lperfetto "In the adrenal medulla NA (noradrenaline) is N-methylated by the enzyme phenylethanolamine N-methyl transferase (PNMT, EC 2.1.1.28) to form A (adrenaline)." SIGNOR-264183 CDK1 protein P06493 UNIPROT FANCG protein O15287 UNIPROT up-regulates phosphorylation Ser387 PRFSPPPsPPGPCMP 9606 15367677 t gcesareni "S387a mutant abolished fancg fusion protein phosphorylation by cdc2." SIGNOR-129061 CSNK2A1 protein P68400 UNIPROT GAP43 protein P17677 UNIPROT unknown phosphorylation Ser203 PTETGESsQAEENIE -1 1828073 t llicata "Phosphorylation of neuromodulin (GAP-43) by casein kinase II. Identification of phosphorylation sites and regulation by calmodulin.|" SIGNOR-250867 RNF216 protein Q9NWF9 UNIPROT TLR8 protein Q9NR97 UNIPROT "down-regulates quantity by destabilization" polyubiquitination 9606 BTO:0000007 31385713 t miannu "E3 ligase RNF216 (ring finger protein 216) targets TLR8 for ubiquitination and degradation. " SIGNOR-272257 MAPK1 protein P28482 UNIPROT POLR2A protein P24928 UNIPROT down-regulates phosphorylation Ser1951 SPGYSPTsPTYSLTS 9606 14662762 t lperfetto "Erk1/2 are major ser-5 kinases after h2o2 treatment. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination." SIGNOR-120168 CD40LG protein P29965 UNIPROT CD40 protein P25942 UNIPROT "up-regulates activity" binding 9606 BTO:0000776 12324477 t lperfetto "Ramos cells were mixed with increasing numbers of transfected cells that expressed cd70 (cd27l) or cd154 (cd40l), both of which are expressed by activated T cells, in the presence of anti-igm ab. Cd27 ligation as well as cd40 ligation inhibited bcr-mediated apoptosis in a dose-dependent manner. cd40 binds its ligand cd40l." SIGNOR-93432 CCT128930 chemical CID:17751819 PUBCHEM AKT2 protein P31751 UNIPROT down-regulates "chemical inhibition" 9606 Other t "Selleck;ATP-competitive inhibitor of Akt2" gcesareni SIGNOR-190868 PRKD1 protein Q15139 UNIPROT SNAI1 protein O95863 UNIPROT "down-regulates activity" phosphorylation Ser11 SFLVRKPsDPNRKPN 9606 20940406 t lperfetto "Pkd1 phosphorylates ser(11) (s11) on transcription factor snail, a master emt regulator and repressor of e-cadherin expression, triggering nuclear export of snail via 14-3-3_ binding. Pkd1 regulates the expression of e-cadherin at the promoter level through direct phosphorylation of the transcriptional repressor snai1. Pkd1-mediated phosphorylation of snai1 occurs in the nucleus and generates a nuclear, inactive dna/snai1 complex that shows decreased interaction with its co-repressor ajuba." SIGNOR-168537 HLA1 proteinfamily SIGNOR-PF87 SIGNOR "Class I MHC" complex SIGNOR-C425 SIGNOR "form complex" binding -1 28367149 t scontino "One Ig domain is present in each chain of MHC class II, while the second Ig-type domain of MHC class I is provided by non-covalent association of the invariant light chain beta-2 microglobulin (beta2m) with the HC.|The MHC class I HC folds and assembles with beta2m in the lumen of the endoplasmic reticulum (ER)" SIGNOR-267776 BNIP2 protein Q12982 UNIPROT CDC42 protein P60953 UNIPROT "up-regulates activity" binding 9606 BTO:0000222 18678706 t lperfetto "Cdo-bnip-2-cdc42 complex stimulates cdc42 activation which in turn promotes p38 alpha/beta activity and cell differentiation." SIGNOR-179861 bufexamac chemical CHEBI:31317 ChEBI HDAC6 protein Q9UBN7 UNIPROT "down-regulates activity" "chemical inhibition" 9606 BTO:0000664 21258344 t Luana " We also identified the anti-inflammatory drug bufexamac as a class IIb (HDAC6, HDAC10) HDAC inhibitor." SIGNOR-257892 "Caspase 1 complex" complex SIGNOR-C220 SIGNOR GSDMD protein P57764 UNIPROT "up-regulates activity" cleavage Asp275 CLHNFLTdGVPAEGA 9606 BTO:0000007 26375003 t lperfetto "Co-expression of GSDMD with caspase-1, 4, 5 or 11 but not apoptotic caspases (caspase-2, 8 and 9) in 293T cells induced the same cleavage of GSDMD|inflammatory caspases specifically cleave GSDMD after the 272FLTD275 (or 273LLSD276) sequence |" SIGNOR-256415 SOHLH2 protein Q9NX45 UNIPROT KIT protein P10721 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0002181 22328502 t Luana "Our results suggest that SOHLH1 and SOHLH2 directly stimulate Kit transcription in postnatal spermatogonia, thus activating the signaling involved in spermatogonia differentiation and spermatogenetic progression." SIGNOR-266206 naloxone chemical CHEBI:7459 ChEBI OPRM1 protein P35372 UNIPROT "down-regulates activity" "chemical inhibition" 10029 BTO:0000246 9686407 t miannu "Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors." SIGNOR-258941 CYC-116 chemical CID:6420138 PUBCHEM AURKB protein Q96GD4 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-191224 SMAD2/STAT3/EP300 complex SIGNOR-C203 SIGNOR RORC protein P51449 UNIPROT up-regulates 9606 26194464 t "MARCO ROSINA" "Thus, pSmad2L (Ser255) forms complex with p300 and STAT3 to bind to the proximal promoter of the Rorc and Il17a genes." SIGNOR-255026 PIAS1 protein O75925 UNIPROT RPA2 protein P15927 UNIPROT up-regulates sumoylation 9606 20016603 t gcesareni "Pias1 and pias4 promote brca1 accumulation and sumoylation, rpa phosphorylation, and dsb repair" SIGNOR-162153 DTX1 protein Q86Y01 UNIPROT NOTCH1 protein P46531 UNIPROT "up-regulates activity" ubiquitination 10090 BTO:0000165 11226752 t gcesareni "Murine homologs of deltex define a novel gene family involved in vertebrate Notch signaling and neurogenesis" SIGNOR-236870 CXCL8 protein P10145 UNIPROT CXCR1 protein P25024 UNIPROT up-regulates binding 9606 11350788 t gcesareni "Il-8 activates both the cxcr1 and the cxcr2 on microvascular endothelial cells, using different signal transduction cascades." SIGNOR-107920 IRF8 protein Q02556 UNIPROT CYBB protein P04839 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0001412 11483597 f miannu "we found that tyrosine phosphorylated ICSBP activates CYBB and NCF2 transcription, during late myeloid differentiation, by interacting with PU.1, IRF1 and CBP." SIGNOR-222710 MAPK13 protein O15264 UNIPROT STMN1 protein P16949 UNIPROT down-regulates phosphorylation Ser25 QAFELILsPRSKESV 9606 BTO:0000782 8325880 t gcesareni "Serine 25 of oncoprotein 18 is a major cytosolic target for the mitogen-activated protein kinase|The present study shows that the MAP kinase has a 20-fold preference for Ser25 as opposed to Ser38 of Op18, while cdc2 kinases have a 5-fold preference for the Ser38 residue." SIGNOR-37848 PIK3R4 protein Q99570 UNIPROT PIK3C3 protein Q8NEB9 UNIPROT up-regulates binding 9606 8999962 t gcesareni "Recombinant p150 associated with ptdins 3-kinase in vitro in a stable manner, resulting in a 2-fold increase in lipid kinase activity." SIGNOR-45664 ACVR1 protein Q04771 UNIPROT SMAD1 protein Q15797 UNIPROT "up-regulates activity" phosphorylation Ser463 SPHNPISsVS 10090 9748228 t gcesareni "Biochemical analysis revealed that constitutively active ALK2 associated with and phosphorylated Smad1 on the COOH-terminal SSXS motif, and also regulated Smad5 and Smad8 phosphorylation." SIGNOR-247674 TEAD1 protein P28347 UNIPROT CCND1 protein P24385 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 22286761 f gcesareni "Yap directly induced the transcription of ccnd1 and foxm1, in cooperation with tead transcription factor." SIGNOR-195534 SRC protein P12931 UNIPROT CTNND1 protein O60716 UNIPROT "up-regulates activity" phosphorylation Tyr280 HRFHPEPyGLEDDQR -1 11382764 t lperfetto "Identification of Src phosphorylation sites in the catenin p120ctn.Using selected tyrosine to phenylalanine p120 mutants as dominant negative reagents, it may now be possible to selectively block events postulated to be dependent on p120 tyrosine phosphorylation.combinations of Tyr _ Phe mutations at residues 96, 112, 228, 257, 280, 291, 296, and 302" SIGNOR-246492 regorafenib chemical CHEBI:68647 ChEBI PDGFRB protein P09619 UNIPROT "down-regulates activity" "chemical inhibition" 9606 26254357 t miannu "A novel multi-kinase inhibitor, regorafenib (Figure 1), inhibits vascular endothelial growth factor receptor (VEGFR) 1, VEGFR2, and VEGFR3, that play key roles in angiogenesis, and fibroblast growth factor receptor (FGFR) 1, platelet-derived growth factor receptor-β (PDGFR-β), tyrosine kinase with immunoglobulin and epidermal growth factor homology domain 2 (TIE2) and the mutant oncogenic kinase KIT, RET, B-RAF" SIGNOR-259180 DLG4 protein P78352 UNIPROT Synaptic_plasticity phenotype SIGNOR-PH158 SIGNOR up-regulates 9606 BTO:0000938 19075115 f miannu "Postsynaptic density 95 (PSD-95) is an important regulator of synaptic structure and plasticity." SIGNOR-264053 SRC protein P12931 UNIPROT CASP9 protein P55211 UNIPROT "up-regulates activity" phosphorylation Tyr251 LQFPGAVyGTDGCPV 29844931 t lperfetto "As a result, we established that Src was able to directly phosphorylate caspase-9 at tyrosine 251, leading to elevated caspase-9 activity." SIGNOR-272998 "Immunoglobulin kappa light chain" protein P0DOX7 UNIPROT BCR-Mk complex SIGNOR-C433 SIGNOR "form complex" binding 9606 BTO:0000776 32323265 t scontino "An antibody is composed of two identical HCs and two identical LCs (either kappa or lambda ), consisting of variable (V) and constant (C) regions linked by disulfide bonds. Pro- genitor B cells rearrange their Ig heavy chain (HC) genes to differentiate into precursor B (pre- B) cells that express μ HCs." SIGNOR-268186 Telatinib chemical CID:9808844 PUBCHEM PDGFRB protein P09619 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-207230 "bisindolylmaleimide i" chemical CID:2396 PUBCHEM PRKCA protein P17252 UNIPROT down-regulates "chemical inhibition" 9606 Other t CellSignaling gcesareni SIGNOR-190344 SOSTDC1 protein Q6X4U4 UNIPROT WNT9B protein O14905 UNIPROT "down-regulates activity" 10090 22829579 f lperfetto "Our laboratory identified an almost twofold upregulation of sclerostin domain-containing 1 (Sostdc1; also referred to as WISE, USAG-1, ectodin), a dual Bmp/Wnt inhibitor, in postnatal day (P)1 pancreata from transgenic mice misexpressing hepatocyte nuclear factor (Hnf)6 in islet endocrine cells." SIGNOR-242739 CHUK protein O15111 UNIPROT NCOA3 protein Q9Y6Q9 UNIPROT up-regulates phosphorylation 9606 BTO:0000150 15808510 t gcesareni "Ikkalpha phosphorylates eralpha, aib1/src-3, and histone h3." SIGNOR-135050 2-(2-chloro-4-iodoanilino)-N-(cyclopropylmethoxy)-3,4-difluorobenzamide chemical CHEBI:91353 ChEBI MAP2K1 protein Q02750 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-191021 DPF2 protein Q92785 UNIPROT "Embryonic stem cell-specific SWI/SNF" complex SIGNOR-C484 SIGNOR "form complex" binding 10090 BTO:0001086 19279220 t miannu "An embryonic stem cell chromatin remodeling complex, esBAF, is essential for embryonic stem cell self-renewal and pluripotency" SIGNOR-270719 MKNK1 protein Q9BUB5 UNIPROT EIF4E protein P06730 UNIPROT up-regulates phosphorylation 9606 9878069 t gcesareni "Mnk1 and mnk2 regulate protein synthesis by phosphorylating the initiation factor eif4e." SIGNOR-62936 Gbeta proteinfamily SIGNOR-PF4 SIGNOR PCBP2 protein Q15366 UNIPROT "up-regulates quantity by stabilization" phosphorylation Thr213 SASFPHTtPSMCLNP 10090 BTO:0000667 17475908 t miannu "All together, these data indicate that ERK-dependent phosphorylation of hnRNP-E2 at serines 173, 189, and 272, and threonine 213 is responsible for increased hnRNP-E2 protein stability in BCR/ABL-transformed cells." SIGNOR-262671 EGFR protein P00533 UNIPROT MUC1 protein P15941 UNIPROT "up-regulates activity" phosphorylation Tyr1229 SSTDRSPyEKVSAGN 9606 BTO:0000150 11483589 t lperfetto "We also show that the activated egf-r phosphorylates the muc1 cytoplasmic tail on tyrosine at a yekv motif that functions as a binding site for the c-src sh2 domain. The results demonstrate that egf-r-mediated phosphorylation of muc1 induces binding of muc1 to c-src in cells" SIGNOR-109538 LATS1 protein O95835 UNIPROT YAP1 protein P46937 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser397 TYHSRDEsTDSGLSM 9606 BTO:0000007 20048001 t lperfetto "We show that YAP is phosphorylated by Lats on Ser 381 in one of the HXRXXS motifs, and this phosphorylation provides the priming signal for CK1delta/epsilon to phosphorylate a phosphodegron in YAP. The phosphorylated phosphodegron recruits beta-TRCP, leading to YAP ubiquitination and degradation under conditions of elevated Hippo pathway activity, such as cell contact inhibition" SIGNOR-218034 ALDH2 protein P05091 UNIPROT HDAC3 protein O15379 UNIPROT "up-regulates activity" binding -1 phosphorylation:Thr429 MQILKFKtIEEVVGR 28056995 t lperfetto "Consistent with previous data, HDAC3 only bound to the ATP6V0E2 promoter in the presence of ALDH2.|Taken together, our data demonstrate that in the macrophages of LDLR-KO or ALDH2 rs671 mutant, AMPK phosphorylates ALDH2 at T356, which enables its nuclear translocation. Once in the nucleus, ALDH2 binds to HDAC3 and suppresses the transcription and protein expression of ATP6V0E2." SIGNOR-271867 EEF1G protein P26641 UNIPROT "EEF1B complex" complex SIGNOR-C460 SIGNOR "form complex" binding 9606 23699257 t lperfetto "An inactive eEF1A-GDP moiety leaves the ribosome and must be recycled to eEF1A-GTP before binding another aa-tRNA. This GTP exchange process is the function of the nucleotide exchange factor eEF1B complex, which exchanges GDP for GTP to regenerate active eEF1A. The requirement for a guanine nucleotide exchange factor, the eEF1B complex, which in metazoans is composed of the subunits α, δ, and γ (also called eEF1B, eEF1D, and eEF1G, respectively)" SIGNOR-269391 WWP1 protein Q9H0M0 UNIPROT AMOTL2 protein Q9Y2J4 UNIPROT "up-regulates activity" ubiquitination Lys347 EKAGRIEkLESEIQR 9606 BTO:0000007 34404733 t lperfetto "AMOTL2 mono-ubiquitination by WWP1 promotes contact inhibition by facilitating LATS activation|Here, we provide evidence that the E3 ligase WWP1 (WW-domain containing protein 1) mono-ubiquitinates AMOTL2 (angiomotin-like 2) at K347 and K408." SIGNOR-271873 PRL protein P01236 UNIPROT KRT15 protein P19012 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000667 20103718 f Regulation miannu "PRL up-regulated expression of keratins K5 and K14 and the epithelial stem cell-associated keratins K15 and K19 in organ-cultured HFs and/or isolated HF keratinocytes." SIGNOR-251904 "Lig4-Xrcc4 complex" complex SIGNOR-C354 SIGNOR DNA_repair phenotype SIGNOR-PH57 SIGNOR up-regulates -1 19837014 t miannu "The DNA ligase IV-Xrcc4 complex is responsible for the ligation of broken DNA ends in the non-homologous end-joining (NHEJ) pathway of DNA double strand break repair in mammals." SIGNOR-264534 CSNK2A2 protein P19784 UNIPROT XRCC1 protein P18887 UNIPROT "up-regulates activity" phosphorylation Thr523 AGSTDENtDSEEHQE 9606 BTO:0000567 15367657 t llicata "XRCC1 is phosphorylated in vivo and in vitro by CK2, and CK2 phosphorylation of XRCC1 on S518, T519, and T523 largely determines aprataxin binding to XRCC1 though its FHA domain | In addition, we present data to show that the acute loss of aprataxin by small interfering RNA (siRNA) renders HeLa cells sensitive to MMS through a mechanism that destabilizes XRCC1." SIGNOR-251052 PTPN1 protein P18031 UNIPROT ACTN1 protein P12814 UNIPROT "down-regulates activity" dephosphorylation Tyr12 DSQQTNDyMQPEEDW 9534 BTO:0000298 16291744 t "down-regulates binding to src" lperfetto "Here we report that protein-tyrosine phosphatase 1B (PTP 1B) is an alpha-actinin phosphatase. PTP 1B-dependent dephosphorylation of alpha-actinin was seen in COS-7 cells|No dephosphorylation was observed in cells coexpressing the alpha-actinin phosphorylation mutant Y12F and PTP 1B. |A reversible interaction between alpha-actinin and Src enables the dephosphorylation of alpha-actinin by PTP 1B, releasing Src" SIGNOR-270539 (S)-malate(2-) smallmolecule CHEBI:15589 ChEBI pyruvate smallmolecule CHEBI:15361 ChEBI "up-regulates quantity" "precursor of" 9606 33064660 t miannu "Malic enzyme 1 (ME1) is a cytosolic protein that catalyzes the conversion of malate to pyruvate while concomitantly generating NADPH from NADP." SIGNOR-267721 FYN protein P06241 UNIPROT BCR-Ml complex SIGNOR-C434 SIGNOR "up-regulates activity" phosphorylation 9606 BTO:0000776 32323266 t scontino "The CD79 molecules contain signaling molecules called immunoreceptor tyrosine-based activation motifs (ITAMs) in their intracellular portion. ITAMs are bound by the SRC kinases such as LYN, FYN and B-lymphoid tyrosine kinase (BLK). The crosslinking of BCR by specific antigens induces phosphorylation of ITAM tyrosines by these SRC kinases." SIGNOR-268210 NRAS protein P01111 UNIPROT BRAF protein P15056 UNIPROT "up-regulates activity" binding 9606 21779497 t lperfetto "The raf family of proteins (raf-1, a-raf, and b-raf) is serine/threonine kinases that bind to the effector region of ras-gtp, thus inducing translocation of the protein to the plasma membrane. Once there, raf proteins are activated and phosphorylated by different protein kinases." SIGNOR-175219 KRAS protein P01116 UNIPROT PIK3CD protein O00329 UNIPROT up-regulates binding 9606 21779497 t gcesareni "Grb2 binds and activates sos, which then activates ras, and this activates p110 independently of p85./it was also described that ras interacts with pi3k in a direct manner./lysine residue 227 is essential for the interaction of ras with pi3k" SIGNOR-175210 CyclinA2/CDK2 complex SIGNOR-C83 SIGNOR SP1 protein P08047 UNIPROT "up-regulates activity" phosphorylation Ser59 GGQESQPsPLALLAA 10090 BTO:0000944 11598016 t gcesareni "Mutation of Sp1 Ser59 abrogates the cyclin A€“CDK augmentation of Sp1-dependent transcriptional transactivation" SIGNOR-248240 "Ub:E1 (UBA1 substrate)" complex SIGNOR-C495 SIGNOR UBE2D1 protein P51668 UNIPROT "up-regulates activity" ubiquitination 9606 34199813 t miannu "The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t" SIGNOR-271311 ITGA7 protein Q13683 UNIPROT "a7/b1 integrin" complex SIGNOR-C126 SIGNOR "form complex" binding 9606 BTO:0000222;BTO:0002319 10199978 t lperfetto "The alpha7beta1 integrin is a laminin receptor on the surface of skeletal myoblasts and myofibers. Alternative forms of both the alpha7 and beta1 chains are expressed in a developmentally regulated fashion during myogenesis. These different alpha7beta1 isoforms localize at specific sites on myofibers and appear to have distinct functions in skeletal muscle." SIGNOR-241508 GNG2 protein P59768 UNIPROT GNB1 protein P62873 UNIPROT "up-regulates activity" binding 10696571 t "GNG2 dissociates from the activated receptor, bound with GNB1 as stable dimer." SIGNOR-251106 192927-92-7 chemical CID:11957576 PUBCHEM HTR1D protein P28221 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-193814 EIF2S1 protein P05198 UNIPROT HBG1 protein P69891 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 24714526 f miannu "Reduction of globin inclusions and induction of ATF4 and HbF by the HRI-eIF2αP signaling provide strong bases for targeting this pathway for novel pharmaceutical therapy of hemoglobinopathy." SIGNOR-251819 AMPK complex SIGNOR-C15 SIGNOR TSC1 protein Q92574 UNIPROT up-regulates phosphorylation 9606 19584320 t lperfetto "Under energy starvation conditions, the amp-activated protein kinase (ampk) phosphorylates tsc2 and enhances its activity." SIGNOR-216487 MAPK8IP1 protein Q9UQF2 UNIPROT MAP3K12 protein Q12852 UNIPROT down-regulates binding 9606 11432832 t gcesareni "Jip inhibits dlk dimerization." SIGNOR-109046 NfKb-p65/p50 complex SIGNOR-C13 SIGNOR MMP9 protein P14780 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 15536164 f miannu "Biglycan, NGAL, and MMP-9 are transcriptionally up-regulated by NF-kappaB, a transcription factor that is activated in FAP nerves and SG." SIGNOR-254798 FIG4 protein Q92562 UNIPROT MCOLN1 protein Q9GZU1 UNIPROT "up-regulates activity" 9606 23165282 f miannu "PI(3,5)P2 begins to be synthesized on endosomal membranes and is additionally required for the activation of lysosomal TRPML1/MCOLN1 channels. Thus, a deficiency of FIG4/PI(3,5)P2 would impair TRPML1/MCOLN1 channel function, leading to the accumulation of calcium in the lysosomes." SIGNOR-253536 UNC80 protein Q8N2C7 UNIPROT NALCN protein Q8IZF0 UNIPROT "up-regulates activity" binding 9606 BTO:0000142 22196327 t miannu "The NALCN complex in the brain consists of NALCN, UNC80 and UNC79. UNC80 directly associates with NALCN and UNC79 forms part of the complex by its interaction with UNC80." SIGNOR-265184 "DNA polymerase delta" complex SIGNOR-C376 SIGNOR DNA_replication phenotype SIGNOR-PH53 SIGNOR up-regulates 9534 BTO:0004055 12930972 f lperfetto "Processive DNA synthesis by DNA polymerases delta and epsilon requires the cellular replication factor C (RF‐C) and proliferating cell nuclear antigen (PCNA)." SIGNOR-265513 TLE4 protein Q04727 UNIPROT PAX2 protein Q02962 UNIPROT "down-regulates activity" binding 9606 BTO:0000007 25631048 t "In cell culture, Grg4 suppresses Pax2-mediated transcriptional activation and inhibits phosphorylation of the Pax2 activation domain by WNT signaling and JNK" SIGNOR-251710 "D-ribofuranose 5-phosphate(2-)" smallmolecule CHEBI:78346 ChEBI "5-phospho-α-D-ribose 1-diphosphate" smallmolecule CHEBI:58017 ChEBI "up-regulates quantity" "precursor of" 9606 16939420 t miannu "PRPP (phosphoribosylpyrophosphate) is an important metabolite essential for nucleotide synthesis and PRS (PRPP synthetase) catalyses synthesis of PRPP from R5P (ribose 5-phosphate) and ATP." SIGNOR-267077 PTPA protein Q15257 UNIPROT AKT1 protein P31749 UNIPROT down-regulates dephosphorylation Ser473 RPHFPQFsYSASGTA 9606 21159657 t gcesareni "Consistent with previous reports (2830), we found that expression of sv40st, suppression of either pp2a c or b resulted in elevated levels of akt phosphorylation (ser473)" SIGNOR-252607 PPP1R15A protein O75807 UNIPROT PPP1CC protein P36873 UNIPROT up-regulates binding 9606 14718519 t gcesareni "We found smad7 interacts with growth arrest and dna damage protein, gadd34, a regulatory subunit of the protein phosphatase 1 (pp1) holoenzyme, which subsequently recruits catalytic subunit of pp1 (pp1c) to dephosphorylate tbetari." SIGNOR-120471 GSK3B protein P49841 UNIPROT CDX2 protein Q99626 UNIPROT unknown phosphorylation Ser287 EPLSPVSsLQASVPG -1 16027724 t "GSK-3, p38 and CDK2 can phosphorylate Cdx2 through the 4S motif in vitro, but only CDK2 was shown to be active in vivo. the compound mutant 4S>A (serines 281, 285, 289 and 293 replaced by alanines)" SIGNOR-251228 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR TSC2 protein P49815 UNIPROT "down-regulates activity" phosphorylation 9606 BTO:0000150;BTO:0001130;BTO:0001271;BTO:0000527 19188143 t lperfetto "Phosphorylation of tsc2 (by akt and erk;refs. 28, 29) and tsc1(by ikkbeta;ref. 30) results in the disruption of the tsc1/2 complex, and thereby activates the oncogenic mtor signaling contributing to tumor progression" SIGNOR-244602 N(2)-formyl-N(1)-(5-phospho-beta-D-ribosyl)glycinamide(2-) smallmolecule CHEBI:147286 ChEBI 2-formamido-N(1)-(5-O-phosphonato-beta-D-ribosyl)acetamidine smallmolecule CHEBI:147287 ChEBI "up-regulates quantity" "precursor of" 9606 33179964 t miannu "The first two reactions catalyzed by TGART are sequential and produce FGAR, which is then acted upon by the third enzyme in the pathway, formylglycinamidine synthase (PFAS/FGAMS).The transferred ammonia is then used to convert FGAR to FGAM. The FGAMS protein exhibits interesting biophys ical properties and will be covered later in this review. The FGAM produced by FGAMS is then converted into AIR by the AIRS domain of TGART, resulting in a five membered ring closure." SIGNOR-267307 MAPK1 protein P28482 UNIPROT NUP50 protein Q9UKX7 UNIPROT "down-regulates activity" phosphorylation Ser315 TQSKPVSsPFPTKPL 9606 19767751 t llicata "Erk phosphorylates nup50 at ser221 and ser315 erk phosphorylation of the fg repeat region of nup50 reduced its affinity for importin-beta family proteins, importin-beta and transportin." SIGNOR-188135 PHF10 protein Q8WUB8 UNIPROT "Embryonic stem cell-specific SWI/SNF" complex SIGNOR-C484 SIGNOR "form complex" binding 10090 BTO:0001086 19279220 t miannu "An embryonic stem cell chromatin remodeling complex, esBAF, is essential for embryonic stem cell self-renewal and pluripotency" SIGNOR-270716 AKT proteinfamily SIGNOR-PF24 SIGNOR BRCA1 protein P38398 UNIPROT up-regulates phosphorylation Thr509 LKRKRRPtSGLHPED 9606 BTO:0000150 17428466 t lperfetto "Phosphatidylinositol 3-kinase/akt signaling enhances nuclear localization and transcriptional activity of brca1. mutation of threonine 509 in brca1, the site of akt phosphorylation, to an alanine, attenuates the ability of heregulin to induce brca1 nuclear accumulation" SIGNOR-244168 TERF2IP protein Q9NYB0 UNIPROT "Shelterin complex" complex SIGNOR-C306 SIGNOR "form complex" binding 9606 BTO:0000567 15383534 t lperfetto "Telosome, a mammalian telomere-associated complex formed by multiple telomeric proteins|Gel filtration reveals a complex consisting of POT1 , RAP1, TRF1, ACD, TERF2 and TINF2 proteins." SIGNOR-263319 PI4KB protein Q9UBF8 UNIPROT "Receptor_mediated_ endocytosis" phenotype SIGNOR-PH121 SIGNOR up-regulates 9534 BTO:0001444 22253445 f lperfetto "PI4KB knockdown inhibits SARS-CoV S-mediated entry, whereas PI3KR1 knockdown increases SARS-CoV S-mediated entry" SIGNOR-260734 WNT10A protein Q9GZT5 UNIPROT FZD3 protein Q9NPG1 UNIPROT up-regulates binding 9606 15578921 t gcesareni "Wnt proteins bind to the frizzled receptors and lrp5/6 co-receptors, and through stabilizing the critical mediator betBeta-catenin, initiate a complex signaling cascade that plays an important role in regulating cell proliferation and differentiation." SIGNOR-131616 ZMIZ1 protein Q9ULJ6 UNIPROT MYC protein P01106 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 26522984 t miannu "The N-terminal domain (NTD) of Zmiz1 is important for driving Myc transcription and proliferation […] Zmiz1 directly interacted with Notch1 via a tetratricopeptide repeat domain at a special class of Notch-regulatory sites." SIGNOR-263939 IL17A protein Q16552 UNIPROT KLF3 protein P57682 UNIPROT up-regulates "transcriptional regulation" 9606 23332504 f fspada "Specifically, il-17 suppresses klf15, a pro-adipogenic tf, and enhances expression of klf2 and klf3, which are anti-adipogenic. " SIGNOR-210114 NFIL3 protein Q16649 UNIPROT IL3 protein P08700 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9580 7565758 t Luana "NF-IL3A transactivates the IL-3 promoter through the A region sequences." SIGNOR-266222 ABI1 protein Q8IZP0 UNIPROT CBL protein P22681 UNIPROT up-regulates binding 9606 17395426 t gcesareni "Here we uncover a novel interaction between abi-1 and the cbl ubiquitin ligase and show that abi-1 mediates cbl accumulation to the plasma membrane upon stimulation by egf." SIGNOR-154162 RPS6K proteinfamily SIGNOR-PF26 SIGNOR RPS6 protein P62753 UNIPROT up-regulates phosphorylation Ser240 RLSSLRAsTSKSESS 9606 21233202 t lperfetto "In response to mitogenic stimuli, rps6 undergoes ordered c-terminal phosphorylation by p70 s6 kinases and p90 ribosomal s6 kinases on four conserved ser residues (ser-235, ser-236, ser-240, and ser-244) whose modification potentiates rps6 cap binding activity" SIGNOR-252765 HGF protein P14210 UNIPROT MET protein P08581 UNIPROT up-regulates binding 9606 8380735 t gcesareni "Hgf is the ligand for p190met, the receptor tyrosine kinase encoded by the met proto-oncogene." SIGNOR-38429 EGFR protein P00533 UNIPROT ERRFI1 protein Q9UJM3 UNIPROT "up-regulates activity" phosphorylation Tyr394 KKVSSTHyYLLPERP 10090 BTO:0000944 phosphorylation:Tyr395 KVSSTHYyLLPERPP 26280531 t """here we found that the epidermal growth factor receptor (EGFR) phosphorylates Mig6 on Y394 and that this phosphorylation is primed by prior phosphorylation of an adjacent residue, Y395, by Src.""" SIGNOR-252091 4-(4-chloro-2-methylphenoxy)-N-hydroxybutanamide chemical CHEBI:94504 ChEBI HDAC6 protein Q9UBN7 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-191433 TNFSF13B protein Q9Y275 UNIPROT TNFRSF13B protein O14836 UNIPROT up-regulates binding 9606 10956646 t gcesareni "Tumor necrosis factor (tnf) receptor superfamily member taci is a high affinity receptor for tnf family members april and blys." SIGNOR-81360 14-3-3 proteinfamily SIGNOR-PF7 SIGNOR KHSRP protein Q92945 UNIPROT down-regulates binding 9606 17177604 t gcesareni "Akt phosphorylates ksrp at a unique serine residue, creating a functional binding site for the molecular chaperone 14-3-3. As a consequence, akt activation impairs ksrp ability to interact with the exoribonucleolytic complex exosome and, in turn, to promote rapid mrna decay." SIGNOR-151212 CDH1 protein P12830 UNIPROT α-Catenin proteinfamily SIGNOR-PF72 SIGNOR "up-regulates activity" binding 9606 24336504 t miannu "Additionally, the E-cadherin associated protein _-catenin regulates YAP directly by sequestering YAP/14-3-3 complexes in the cytoplasm." SIGNOR-265821 MDM4 protein O15151 UNIPROT MDM2 protein Q00987 UNIPROT "up-regulates quantity by stabilization" binding 9606 10218570 t miannu "MDM2 has been shown to be degraded by the ubiquitin-proteasome pathway, while MDMX was a stable protein. Interaction of MDMX with MDM2 through the C-terminal RING finger domains resulted in inhibiting degradation of MDM2. These data indicate that MDMX functions as a regulator of MDM2." SIGNOR-272932 CASP3 protein P42574 UNIPROT ROCK1 protein Q13464 UNIPROT up-regulates cleavage 9606 11283607 t gcesareni "Rock i is cleaved by casp3 at a conserved detd1113/g sequence and its carboxy-terminal inhibitory domain is removed, resulting in deregulated and constitutive kinase activity." SIGNOR-106546 GSK3A protein P49840 UNIPROT UNG protein P13051 UNIPROT "down-regulates quantity by destabilization" phosphorylation Thr60 AGQEEPGtPPSSPLS 9606 BTO:0000812 phosphorylation:Ser64 EPGTPPSsPLSAEQL 27875297 t lperfetto "Here we show that glycogen synthase kinase 3 (GSK-3) interacts with and phosphorylates UNG2 at Thr60 and that Thr60 phosphorylation requires a Ser64 priming phosphorylation event.|phosphorylation of Thr60 and Ser64 creates a cyclin E/c-Myc-like phosphodegron that promotes polyubiquitylation and proteasome-mediated degradation" SIGNOR-264887 HOOK2 protein Q96ED9 UNIPROT CNTRL protein Q7Z7A1 UNIPROT up-regulates binding 9606 17140400 t miannu "Hook2 localizes to the centrosome, binds directly to centriolin/cep110 and contributes to centrosomal function" SIGNOR-150956 PROC protein P04070 UNIPROT F7 protein P08709 UNIPROT "down-regulates activity" cleavage 9606 BTO:0000131 29880919 t lperfetto "Activated protein C (APC), which cleaves and inactivates both FVIIIa and FVa, thereby shutting down both the tenase and prothrombinase complexes" SIGNOR-263527 PDPK1 protein O15530 UNIPROT ITGB3 protein P05106 UNIPROT "down-regulates activity" phosphorylation Thr779 LYKEATStFTNITYR -1 10896934 t miannu "PDK1 specifically phosphorylates Thr-753 in 3. Our data argue that phosphorylation of Thr-753, which is conserved in many subunits, reduces the ability of PTB-containing proteins to bind the NXX(pY) motif in 3." SIGNOR-250266 CAMK2A protein Q9UQM7 UNIPROT NCOR2 protein Q9Y618 UNIPROT down-regulates phosphorylation Ser2426 ASGDRPPsVSSVHSE 9606 22888005 t lperfetto "We demonstrated that camkii directly bound and phosphorylated smrt at ser-1407, thereby facilitating smrt translocation from the nucleus to the cytoplasm and proteasome-dependent degradation." SIGNOR-191773 PALB2 protein Q86YC2 UNIPROT RAD51 protein Q06609 UNIPROT up-regulates binding 9606 19423707 t miannu "We propose that both palb2 chromatin association and its oligomerization serve to secure the brca2 x rad51 repair machinery at the sites of dna damage." SIGNOR-185656 ENAH protein Q8N8S7 UNIPROT Axonal_growth_cone_formation phenotype SIGNOR-PH199 SIGNOR up-regulates 9606 18508258 f miannu "Here we review recent findings into Ena/VASP function in neurite initiation, axon outgrowth and guidance." SIGNOR-268389 AQP5 protein P55064 UNIPROT CyclinD/CDK4 complex SIGNOR-C18 SIGNOR "up-regulates activity" binding phosphorylation:Ser156 STDSRRTsPVGSPAL 18583321 t lperfetto "We performed immunoprecipitation and western blotting analysis in transfected cell lines using CDK4 and cyclin D1 antibodies. As expected, cells transfected with AQP5 WT showed an increase of the CDK4/cyclin D1 complex, whereas cells transfected with vector did not|hAQP5 Increases Phosphorylation of Retinoblastoma Protein through Cyclin D1/CDK4 Complex" SIGNOR-272089 CDKN1A protein P38936 UNIPROT CDK6 protein Q00534 UNIPROT down-regulates binding 9606 7626805 t gcesareni "P21cip1 is a cyclin-dependent kinase (cdk) inhibitor that is transcriptionally activated by p53 in response to dna damage.We Have explored the interaction of p21 with the currently known cdks. p21 effectively inhibits cdk2, cdk3, cdk4, and cdk6 kinases" SIGNOR-30030 PK proteinfamily SIGNOR-PF80 SIGNOR STAT3 protein P40763 UNIPROT up-regulates phosphorylation Tyr705 DPGSAAPyLKTKFIC 9606 22306293 t llicata "Pkm2 activates transcription of mek5 by phosphorylating stat3 at y705. pkm2 regulates mek5 transcription via activation of stat3" SIGNOR-268152 Ub:E2 complex SIGNOR-C497 SIGNOR TRIM54 protein Q9BYV2 UNIPROT "up-regulates activity" ubiquitination 9606 34199813 t miannu "The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t" SIGNOR-270967 ARP2/3 complex SIGNOR-C146 SIGNOR F-actin_assembly phenotype SIGNOR-PH18 SIGNOR up-regulates 9606 12479800 f lperfetto "The Arp2/3 complex concentrates at leading edges, where it catalyzes the growth of branched actin networks that are believed to provide the protrusive force for leading edge extension." SIGNOR-251511 MTMR3 protein Q13615 UNIPROT MTOR protein P42345 UNIPROT "down-regulates activity" 9606 BTO:0000007 SIGNOR-C3 26787466 t lperfetto "The PtdIns3-phosphatase MTMR3 interacts with mTORC1 and suppresses its activity." SIGNOR-245105 WDR45 protein Q9Y484 UNIPROT ATG2B protein Q96BY7 UNIPROT "up-regulates activity" binding 9606 BTO:0001938 28561066 t miannu "WIPI4 interacts with ATG2, AMPK and ULK1. Upon starvation and AMPK activation, WIPI4-ATG2 dissociates from AMPK and ULK1 and localizes at nascent autophagosomes, potentially supporting further autophagosome maturation." SIGNOR-268484 PTK6 protein Q13882 UNIPROT AKT1 protein P31749 UNIPROT up-regulates phosphorylation Tyr315 TFCGTPEyLAPEVLE 9606 BTO:0000150 BTO:0001129 20606012 t gcesareni "Here we demonstrate that AKT is a direct substrate of PTK6 and that AKT tyrosine residues 315 and 326 are phosphorylated by PTK6." SIGNOR-252618 AKT proteinfamily SIGNOR-PF24 SIGNOR FOXO1 protein Q12778 UNIPROT down-regulates relocalization 10090 BTO:0002572 18423396 t lperfetto "Akt1/PKBalpha was found to be the major regulator of phosphorylation and nuclear export of FoxO1, whose presence in the nucleus strongly attenuates adipocyte differentiation" SIGNOR-252351 PRKD1 protein Q15139 UNIPROT PIP4K2A protein P48426 UNIPROT down-regulates phosphorylation Thr376 KAAHAAKtVKHGAGA 9606 16563698 t lperfetto "We conclude that the type ii pip kinases are physiological targets for pkd phosphorylation, and that this modification is likely to regulate inositol lipid turnover by inhibition of these lipid kinases." SIGNOR-145370 CSNK2A1 protein P68400 UNIPROT CLTB protein P09497 UNIPROT unknown phosphorylation Ser13 GFFSSSEsGAPEAAE -1 3128543 t llicata "To date, the only evidence for a functional distinction of LCa and LCb is the preferential phosphorylation of LCb, which takes place at serine residues and is mediated by coated vesicle-associated casein kinase II. As a first step toward determining the function of light chain diversity, we have mapped the in vitro phosphorylation sites on LCb. We use [32P]ATP to phosphorylate LCb within coated vesicles, followed by sequencing of 32P-labeled chymotryptic peptides thereof, to identify serine residues at positions 11 and 13 as the phosphorylation sites." SIGNOR-250843 FOXO4 protein P98177 UNIPROT IDH1 protein O75874 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 25648147 t miannu "We identify FOXOs as transcriptional activators of IDH1. FOXOs promote IDH1 expression and thereby maintain the cytosolic levels of α-ketoglutarate and NADPH." SIGNOR-260091 FLT1 protein P17948 UNIPROT FLT1 protein P17948 UNIPROT up-regulates phosphorylation Tyr1213 GSSDDVRyVNAFKFM 9606 11583921 t tpavlidou "Vegfr-1 mutated at y1213, y1242, and y1333 were constructed and expressed in pae cells, to the same level as that of pae/vegfr-1 cells. The mutated vegfr-1 y1213f expressed in pae cells was kinase inactive." SIGNOR-110850 BCR-ABL "fusion protein" SIGNOR-FP6 SIGNOR JAK2 protein O60674 UNIPROT "up-regulates activity" phosphorylation Tyr1007 VLPQDKEyYKVKEPG 10090 11593427 t irozzo "In this report, we show that Bcr–Abl forms a complex with Jak2, and induces tyrosine phosphorylation of Jak2; full phosphorylation requires the SH2 domain of Bcr–Abl. We found that Y1007 of Jak2 was phosphorylated in Bcr–Abl positive cells; phosphorylation of Jak2 Y1007 is known to be required for Jak2 kinase activation." SIGNOR-255812 MELK protein Q14680 UNIPROT MELK protein Q14680 UNIPROT up-regulates phosphorylation Ser171 HLQTCCGsLAYAAPE 9606 16216881 t gcesareni "We have mapped no less than 16 autophosphorylation sites including serines, threonines, and a tyrosine residue and show that the phosphorylation of thr167 and ser171 is required for the activation of melk." SIGNOR-140958 PPP2CA protein P67775 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR up-regulates dephosphorylation Ser253 APRRRAVsMDNSNKY 9606 20110348 t gcesareni "Protein phosphatase 2a reactivates foxo3a through a dynamic interplay with 14-3-3 and aktpp2a-mediated dephosphorylation of t32/s253 is required for dissociation of 14-3-3, nuclear translocation, and transcriptional activation of foxo3a." SIGNOR-252973 ITGB1BP1 protein O14713 UNIPROT "A6/b1 integrin" complex SIGNOR-C164 SIGNOR "down-regulates activity" binding 9606 19118207 t miannu "Integrins also bind to many PTBdomain-containing proteins (Calderwood et al., 2003) – including Dok1 and integrincytoplasmic-domain-associated protein 1 (ICAP1) – and these can compete with talin for binding to integrin and so can impair activation" SIGNOR-257644 ketoprofen chemical CHEBI:6128 ChEBI PTGS2 protein P35354 UNIPROT "down-regulates activity" "chemical inhibition" 9606 BTO:0001061 18667313 t Luana "Profens, that is, Ketoprofen 1, Suprofen 2 (Fig. 1), were chosen because of their interesting inhibitory activity against cyclooxygenase and of their different selectivity versus the two isoforms COX-1/COX-2. " SIGNOR-257811 GNAO1 protein P09471 UNIPROT TAOK2 protein Q9UL54 UNIPROT up-regulates 9606 BTO:0000007 12665513 f lperfetto "These results suggest that go alpha q205l activates p38 through taos and mek3/6." SIGNOR-235542 HDAC1 protein Q13547 UNIPROT FSHR protein P23945 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 23086931 f miannu "Chromatin modifier MTA2 participates in the down-regulation of FSHR transcription. MTA2 is a potent corepressor of FSHR transcription, because it can recruit histone deacetylase-1 onto the FSHR promoter and participates in the down-regulation of FSHR expression upon FSH treatment." SIGNOR-254225 1-[4-[[2-(2-amino-5-pyrimidinyl)-7-methyl-4-(4-morpholinyl)-6-thieno[3,2-d]pyrimidinyl]methyl]-1-piperazinyl]-2-hydroxy-1-propanone chemical CHEBI:93753 ChEBI PIK3CG protein P48736 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-192620 "all-trans-retinoic acid" smallmolecule CHEBI:15367 ChEBI RAR proteinfamily SIGNOR-PF45 SIGNOR "up-regulates activity" "chemical activation" 9606 17132853 t miannu "The physiological effects of retinoic acids (RAs) are mediated by members of two families of nuclear receptors, the retinoic acid receptors (RARs) and the retinoid X receptors (RXRs), which are encoded by three distinct human genes, RXRalpha, RXRbeta, and RXRgamma." SIGNOR-256197 NRL protein P54845 UNIPROT RHO protein P08100 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0000007 15277472 f miannu "KLF15 repressed transactivation of rhodopsin and IRBP promoters alone and in combination with the transcriptional activators Crx and/or Nrl." SIGNOR-253819 BMPR2 protein Q13873 UNIPROT BMPR1A protein P36894 UNIPROT up-regulates phosphorylation 9606 SIGNOR-C29 SIGNOR-C29 18756288 t gcesareni "Bmp ligands bind to the bmp receptors bmpr1 and bmpr2, and bmpr2 then phosphorylates and activates bmpr1." SIGNOR-180545 PIK-90 chemical CID:6857685 PUBCHEM PIK3CG protein P48736 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-206232 NGF protein P01138 UNIPROT SCN9A protein Q15858 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10116 BTO:0003306 24493753 f miannu "Long-term (more than 24 h) treatment with nerve growth factor (NGF) upregulated Nav1.7 functional expression in the strongly metastatic MAT-LyLu rat PCa cell line; acute application had no effect" SIGNOR-253495 SHANK3 protein Q9BYB0 UNIPROT NMDA proteinfamily SIGNOR-PF56 SIGNOR "up-regulates quantity" relocalization 9606 BTO:0000938 28179641 t miannu "SHANK proteins are ‘master’ scaffolding proteins that tether and organize intermediate scaffolding proteins. They are located at excitatory synapses, where they are crucial for proper synaptic development and function. SAPAP proteins subsequently bind to the PDZ domain of members of the SHANK protein family. SHANK proteins then bind to the actin cytoskeleton and to Homer protein, which in turn interacts with mGluRs. Through these extended links, PSD95, SAPAP, SHANK and Homer proteins form a quaternary complex that brings together mGluR and NMDAR complexes in the PSD (FIG. 3)." SIGNOR-264701 SMAD6 protein O43541 UNIPROT SMAD3 protein P84022 UNIPROT "down-regulates activity" binding 9606 9892110 t lperfetto "Smad6 and smad7, can prevent tgfb signaling by interacting either with the receptor or with smad2 and smad3" SIGNOR-64071 AT-406 chemical CID:25022340 PUBCHEM BIRC2 protein Q13490 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-189954 SMAD3/SMAD4 complex SIGNOR-C9 SIGNOR JUN protein P05412 UNIPROT "up-regulates activity" binding 9606 9732876 t lperfetto "Smad3 and smad4 also act together with c-jun and c-fos to activate transcription in response to tgf-beta, through a tgf-beta-inducible association of c-jun with smad3 and an interaction of smad3 and c-fos" SIGNOR-229545 CASP3 protein P42574 UNIPROT GAS2 protein O43903 UNIPROT up-regulates cleavage Asp278 MLQISRVdGKTSPIQ 9606 10564664 t gcesareni "We now demonstrate that gas2 is a substrate of caspase-3 but not of caspase-6. Proteolytic processing both in vitro and in vivo is dependent on aspartic residue 279." SIGNOR-72347 TESK2 protein Q96S53 UNIPROT CFL1 protein P23528 UNIPROT "down-regulates activity" phosphorylation Ser3 sGVAVSDG 9606 BTO:0000567 11418599 t lperfetto "Like tesk1, tesk2 phosphorylated cofilin specifically at ser-3 and induced formation of actin stress fibers and focal adhesions." SIGNOR-108753 BMPR1A protein P36894 UNIPROT SMAD5 protein Q99717 UNIPROT up-regulates 10090 BTO:0000165 10564272 f lperfetto "We found that both smad6 and smad7 inhibit the activation of smad1 and smad5 by bmpr-ia/alk-3 and bmpr-ib/alk-6, as well as that by alk-2" SIGNOR-235361 MAPK3 protein P27361 UNIPROT PML protein P29590 UNIPROT up-regulates phosphorylation Ser530 DGPPSPRsPVIGSEV 9606 BTO:0001271 15093545 t "The effect has been demonstrated using P29590-4" gcesareni "Phosphorylation of pml by mitogen-activated protein kinases plays a key role in arsenic trioxide-mediated apoptosis." SIGNOR-124317 EIF2AK2 protein P19525 UNIPROT Immune_response phenotype SIGNOR-PH17 SIGNOR up-regulates 9606 27712625 f miannu "The activated kinases then phosphorylate the signal transducers and transcription factors STAT1 and STAT2, which form a complex with IRF9 (ISGF3) that enters the nucleus to transactivate promoters of an antiviral gene expression program. Genes that are specifically upregulated by IFNs are collectively called ISGs (IFN-stimulated genes). The kinase PKR is an ISG product acting as a signaling PRR on one hand (see earlier), but its main function in antiviral defense is the inhibition of protein synthesis.PKR has a broad antiviral spectrum." SIGNOR-260159 "BRCC ubiquitin ligase complex" complex SIGNOR-C295 SIGNOR TP53 protein P04637 UNIPROT unknown ubiquitination 9606 BTO:0000007 14636569 t lperfetto "However, since the same domain of p53 is also the target of ubiquitination by MDM2 protein, further in vivo experiments are required to demonstrate the biological relevance of p53 ubiquitination by BRCC.|The Extreme C Terminus of p53 Is Ubiquitinated by BRCC" SIGNOR-263210 PAH protein P00439 UNIPROT tyrosine smallmolecule CHEBI:18186 ChEBI "up-regulates quantity" "chemical modification" 9606 NBK536726 t brain lperfetto "L-phenylalanine is converted into L-tyrosine in the liver, by the enzyme phenylalanine hydroxylase (PH) in the presence of oxygen, iron, and tetrahydrobiopterin as cofactors" SIGNOR-263989 serotonin smallmolecule CHEBI:28790 ChEBI HTR7 protein P34969 UNIPROT "up-regulates activity" "chemical activation" 9606 BTO:0000938 25601315 t miannu "Serotonin or 5-hydroxytryptamine (5-HT) remains one of the most widely studied chemical messengers. Serotonin produces a myriad of physiological effects in humans, mediated through 14 distinct receptor subtypes, of which 13 are G protein coupled receptors (GPCRs), and one ligand-gated cation channel" SIGNOR-264289 GSTA1 protein P08263 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR down-regulates 9606 BTO:0000018 29928434 f irozzo "In addition, the downregulation of GSTA1 in A549 cells significantly induced cell apoptosis in vitro. In conclusion, GSTA1 plays an important role in regulation of cell proliferation and cell apoptosis in A549 cell line." SIGNOR-256297 PRKAA1 protein Q13131 UNIPROT MFF protein Q9GZY8 UNIPROT "up-regulates activity" phosphorylation Ser155 GRLKRERsMSENAVR 9606 26816379 t gcesareni "A screen for substrates of AMPK identified mitochondrial fission factor (MFF), a mitochondrial outer-membrane receptor for DRP1, the cytoplasmic guanosine triphosphatase that catalyzes mitochondrial fission." SIGNOR-245953 "5-phospho-α-D-ribose 1-diphosphate" smallmolecule CHEBI:58017 ChEBI "orotidine 5'-phosphate(3-)" smallmolecule CHEBI:57538 ChEBI "up-regulates quantity" "precursor of" 9606 2912371 t miannu "Uridine 5'-phosphate (UMP) synthase contains two sequential catalytic activities for the synthesis of orotidine 5'-phosphate (OMP) from orotate (EC 2.4.2.10, orotate phosphoribosyltransferase) and the decarboxylation of OMP to form UMP (EC 4.1.1.23, OMP decarboxylase)." SIGNOR-267435 CAMK2G protein Q13555 UNIPROT GRIA4 protein P48058 UNIPROT unknown phosphorylation Ser862 IRNKARLsITGSVGE 10366608 t llicata "We found that GluR4 is phosphorylated on serine 842 within the C-terminal domain in vitro and in vivo. Serine 842 is phosphorylated by PKA, PKC, and CaMKII in vitro and is phosphorylated in transfected cells by PKA." SIGNOR-250699 "Caspase 3 complex" complex SIGNOR-C221 SIGNOR Cell_death phenotype SIGNOR-PH109 SIGNOR up-regulates 9606 14585074 f amattioni "Caspase-3 is responsible for apoptosis execution" SIGNOR-256548 ID3 protein Q02535 UNIPROT MYOD/HEB complex SIGNOR-C128 SIGNOR "down-regulates activity" binding 10090 9242638 t 2 miannu "All three Ids bound with high affinity to E proteins .Each Id was able to disrupt the ability of E protein-MyoD complexes to transactivate from a muscle creatine kinase reporter construct in vivo." SIGNOR-241137 leucine smallmolecule CHEBI:25017 ChEBI SESN2 protein P58004 UNIPROT "down-regulates activity" "chemical inhibition" 9606 26449471 t "We find that leucine, but not arginine, disrupts the Sestrin2- GATOR2 interaction by binding to Sestrin2 with a dissociation constant of 20micromolar, which is the leucine concentration that half-maximally activates mTORC1" SIGNOR-254897 APAF1 protein O14727 UNIPROT CASP9 protein P55211 UNIPROT "up-regulates activity" binding 9606 15829969 t lperfetto "During apoptosis, Apaf-1 binds to cytochrome c and in the presence of ATP/dATP forms an apoptosome, leading to the recruitment and activation of the initiator caspase, caspase-9 ." SIGNOR-135381 budesonide chemical CHEBI:3207 ChEBI NR3C1 protein P04150 UNIPROT up-regulates "chemical activation" 9606 9657565 t "allergic rhinitis" gcesareni SIGNOR-251689 NEDD4L protein Q96PU5 UNIPROT SMAD3 protein P84022 UNIPROT down-regulates ubiquitination 9606 19917253 t gcesareni "Through its ww domain, nedd4l specifically recognizes a tgf-beta-induced phosphothr-protyr motif in the linker region, resulting in smad2/3 polyubiquitination and degradation" SIGNOR-161713 SUFU protein Q9UMX1 UNIPROT GLIS2 protein Q9BZE0 UNIPROT down-regulates relocalization 9606 BTO:0001130 16316410 t gcesareni "Negative regulation of gli1 and gli2 activator function by suppressor of fused through multiple mechanisms.Together, these observations reveal that su(fu) regulates the activity of gli1 and gli2 through distinct cytoplasmic and nuclear mechanisms." SIGNOR-142608 pemetrexed chemical CHEBI:63616 ChEBI DHFR protein P00374 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-205819 Sin3B_complex complex SIGNOR-C409 SIGNOR H3Y1 protein P0DPK2 UNIPROT "down-regulates activity" binding 9606 21041487 t miannu "We report here the identification of a mammalian complex containing the corepressor Sin3B, the histone deacetylase HDAC1, Mrg15, and the PHD finger-containing Pf1 and show that this complex plays important roles in regulation of transcription. Sin3B, Pf1, Mrg15, and HDAC1 associate within a stable complex that binds H3K4me3/H3K36me3-enriched nucleosomes. We identify mammalian Pf1, a PHD finger protein, as a homologue of Rco1, and show that all four components, Sin3B, HDAC1, Mrg15, and Pf1, can form a stable complex, which is recruited downstream of the transcriptional start site through complex interactions with histones. these results indicate that the Pf1/Sin3B-containing complex is recruited at discrete sites within actively transcribed loci, likely through its interaction with H3K4me3/H3K36me3-enriched chromatin." SIGNOR-266975 MAPK1 protein P28482 UNIPROT SORBS3 protein O60504 UNIPROT unknown phosphorylation Ser530 DGPQLPTsPRLTAAA 9606 15184391 t "The effect has been demonstrated using O60504-2" llicata "Vinexin was directly phosphorylated by erk2 upon stimulation with egf at the serine 189 of vinexin _." SIGNOR-125221 WNT3A protein P56704 UNIPROT LRP5 protein O75197 UNIPROT "up-regulates activity" binding 9606 15578921 t gcesareni "Wnt proteins bind to the frizzled receptors and lrp5/6 co-receptors, and through stabilizing the critical mediator betBeta-catenin, initiate a complex signaling cascade that plays an important role in regulating cell proliferation and differentiation." SIGNOR-131826 AKT1 protein P31749 UNIPROT GATA1 protein P15976 UNIPROT up-regulates phosphorylation Ser310 QTRNRKAsGKGKKKR 9606 16107690 t llicata "We found that akt directly phosphorylates the transcription factor gata-1 at serine 310 and that this site-specific phosphorylation is required for the transcriptional activation of the timp-1 promoter." SIGNOR-139782 MAPK1 protein P28482 UNIPROT XPO5 protein Q9HAV4 UNIPROT "down-regulates activity" phosphorylation Ser497 GSLCSVFsPSFVQWE 9606 BTO:0000007 27846390 t lperfetto "Here we show that ERK suppresses pre-miRNA export from the nucleus through phosphorylation of exportin-5 (XPO5) at T345/S416/S497. After phosphorylation by ERK, conformation of XPO5 is altered by prolyl isomerase Pin1, resulting in reduction of pre-miRNA loading. " SIGNOR-262981 JAG2 protein Q9Y219 UNIPROT NOTCH proteinfamily SIGNOR-PF30 SIGNOR up-regulates binding 9606 10958687 t "inferred from 70% of family members" gcesareni "Binding of delta1, jagged1, and jagged2 to notch2 rapidly induces cleavage, nuclear translocation, and hyperphosphorylation of notch2" SIGNOR-269935 STAT6 protein P42226 UNIPROT HSD3B2 protein P26439 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 15632317 f miannu "IL-4 induces HSD3B1 gene expression, along with IL-13, through STAT 6 activation." SIGNOR-255249 CyclinE/CDK2 complex SIGNOR-C16 SIGNOR SIRT2 protein Q8IXJ6 UNIPROT down-regulates phosphorylation Ser368 PNPSTSAsPKKSPPP 9606 BTO:0000938 18332217 t lperfetto "We define ser-331 as the site phosphorylated by cyclin e-cdk2, cyclin a-cdk2, and p35-cdk5 both in vitro and in cells. Importantly, phosphorylation at ser-331 inhibits the catalytic activity of sirt2." SIGNOR-216725 STAT1 protein P42224 UNIPROT IRF2 protein P14316 UNIPROT "up-regulates activity" binding 9606 15778351 t miannu "We show that IRF-2 forms a complex with STAT1 and the cytokine-responsive region of the TAP1 promoter in any TPO or IFN-gamma target cells tested. Interaction of IRF-2 and STAT1 on the promoter depends on the DNA-binding domain of IRF-2." SIGNOR-254532 TRIM27 protein P14373 UNIPROT MAPK13 protein O15264 UNIPROT up-regulates 9606 12807881 f miannu "We found rfp-mediated activation of both exogenous and endogenous forms of the other stress-activated mapk, p38." SIGNOR-102028 ATR protein Q13535 UNIPROT BRCA1 protein P38398 UNIPROT up-regulates phosphorylation 9606 23422745 t gcesareni "The phosphorylation of atr and atm substrates, chk1, chk2, h2ax, and brca1 was significantly reduced or abrogated in mutant cells." SIGNOR-201050 MTSS1 protein O43312 UNIPROT GLI1 protein P08151 UNIPROT up-regulates binding 9606 BTO:0001253 15545630 t gcesareni "Mim is a shh-responsive gene that can potentiate gli transcriptional activity.MIM Appears to regulate target gene expression through its association with the gli complex" SIGNOR-130542 NFATC2 protein Q13469 UNIPROT MYOF protein Q9NZM1 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0001103 23612709 f miannu "Activated NFATc2 stimulates myoblast fusion through the increased production of IL-4 and myoferlin" SIGNOR-255465 DUSP1 protein P28562 UNIPROT MAPK9 protein P45984 UNIPROT down-regulates dephosphorylation 9606 BTO:0000782 8626452 t fstefani "We assayed the relative ability of mkp-2, pac1, and mkp-1 to dephosphorylate erk2 and the other related map kinases, jnk2 and p38. the dual specific phosphatases pac1 and mkp-1 previously have been implicated in the in vivo inactivation of erk or of erk and jnk, respectively." SIGNOR-40879 PRKCE protein Q02156 UNIPROT ATF2 protein P15336 UNIPROT up-regulates phosphorylation Thr52 HKHKHEMtLKFGPAR 9606 BTO:0000848;BTO:0001286 22304920 t lperfetto "Pkc_ phosphorylation of atf2 on thr52. Pkc_ promotes oncogenic functions of atf2 in the nucleus while blocking its apoptotic function at mitochondria" SIGNOR-195761 CCND1 protein P24385 UNIPROT CDK4 protein P11802 UNIPROT up-regulates binding 9606 BTO:0000150 23562856 t gcesareni "D-type cyclins (cyclin d1, d2, or d3) and their associated cyclin-dependent kinases (cdk4, cdk6) connect signals from cytokines to the cell cycle machinery, and they propel cells through the g1 restriction point and into the s phase when activated by cyclin d1, cdk4 is able to phosphorylate prb," SIGNOR-201666 NR3C1 protein P04150 UNIPROT KLF15 protein Q9UIH9 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 BTO:0002572 20956975 f lperfetto "We identified glucocorticoid response element sites in the first intron of KLF15 by bioinformatical promoter analysis and confirmed their functional relevance by demonstrating GR interaction by chromatin immunoprecipitation" SIGNOR-236212 ATM protein Q13315 UNIPROT EIF4EBP1 protein Q13541 UNIPROT down-regulates phosphorylation Ser112 KRAGGEEsQFEMDI 9606 11146653 t lperfetto "Here we report that atm... phosphorylates 4e-bp1 at ser 111cells lacking atm kinase activity exhibit a significant decrease in the insulin-induced dissociation of 4e-bp1 from eif-4e." SIGNOR-85619 GSK3B protein P49841 UNIPROT BICD1 protein Q96G01 UNIPROT "up-regulates activity" phosphorylation Thr597 KEPSPTKtPTISPVI 9606 BTO:0000567 17139249 t miannu "Therefore, at least Ser585 and Thr597 in BICD1 are important phosphorylation sites for BICD1 to exert its functions, and GSK-3β-dependent phosphorylation is required for the interaction of BICD1 with dynein." SIGNOR-262744 ALK protein Q9UM73 UNIPROT SFPQ protein P23246 UNIPROT down-regulates phosphorylation Tyr293 RRPGEKTyTQRCRLF 9606 BTO:0000785 17537995 t lperfetto "Furthermore, psf was shown to be a direct substrate of purified alk kinase domain in vitro, and psf tyr293 was identified as the site of phosphorylation. Psf phosphorylation also increased its binding to rna and decreased the psf-mediated suppression of gage6 expression." SIGNOR-155298 TP53 protein P04637 UNIPROT LRBA protein P50851 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 15064745 f miannu "We also show that LRBA promoter activity and endogenous LRBA mRNA levels are reduced by p53 and increased by E2F1, indicating that mutations in the tumor suppressors p53 and Rb could contribute to the deregulation of LRBA." SIGNOR-253847 CDK2 protein P24941 UNIPROT TPX2 protein Q9ULW0 UNIPROT "down-regulates activity" phosphorylation Thr72 NLQQAIVtPLKPVDN -1 25688093 t lperfetto "In this study, we characterize the phosphorylation of threonine 72 (Thr(72)) in human TPX2, a residue highly conserved across species. We find that Cdk1/2 phosphorylate TPX2 in vitro and in vivo. |Endogenous TPX2 phosphorylated at Thr(72) does not associate with the mitotic spindle. Furthermore, ectopic GFP-TPX2 T72A preferentially concentrates on the spindle" SIGNOR-265099 AXIN2 protein Q9Y2T1 UNIPROT CTNNB1 protein P35222 UNIPROT down-regulates binding 9606 BTO:0000142;BTO:0000671;BTO:0000763 10911903 t gcesareni "It has been found that a multiprotein complex assembled by the cytoplasmic component conductin induces degradation of cytoplasmic beta-catenin. The complex includes apc, the serine/threonine kinase gsk3 beta, and beta-catenin, which bind to conductin at distinct domains." SIGNOR-79947 KDM5B protein Q9UGL1 UNIPROT PAX9 protein P55771 UNIPROT "up-regulates activity" binding 9606 BTO:0000007 12657635 t miannu "Human PLU-1 Has transcriptional repression properties and interacts with the developmental transcription factors BF-1 and PAX9. In a reporter assay system, PLU-1 has potent transcriptional repression activity. BF-1 and PAX9 also represses transcription in the same assay, but co-expression of PLU-1 with BF-1 or PAX9 significantly enhances this repression" SIGNOR-223875 NME1 protein P15531 UNIPROT MMP2 protein P08253 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0001567 17671192 f miannu "To elucidate the molecular mechanism of Nm23-H1 motility suppression, expression microarray analysis of an MDA-MB-435 cancer cell line overexpressing wild-type Nm23-H1 was done and cross-compared with expression profiles from lines expressing the P96S and S120G mutants. Nine genes, MET, PTN, SMO, FZD1, L1CAM, MMP2, NETO2, CTGF, and EDG2, were down-regulated by wild-type but not by mutant Nm23-H1 expression." SIGNOR-255165 TLRs proteinfamily SIGNOR-PF20 SIGNOR TLRs proteinfamily SIGNOR-PF20 SIGNOR "up-regulates activity" binding 9606 24352680 t lperfetto "Upon activation, tlrs hetero- or homodimerize inducing the recruitment of adaptor proteins via the cytoplasmic tir domain" SIGNOR-216301 DDX3X protein O00571 UNIPROT PABPC1 protein P11940 UNIPROT "up-regulates activity" binding 9606 21883093 t miannu "In the present study, we indentified the SG marker PABP1 [poly(A)-binding protein 1] as another direct interaction partner of DDX3. Interestingly, down-regulation of DDX3 interfered with SG assembly, led to nuclear accumulation of PABP1 and reduced cell viability following stress. Conversely, supplementation with a shRNA (short hairpin RNA)-resistant DDX3 restored SG formation, the translocation of PABP1 into SGs and cell survival." SIGNOR-269201 UPF1 protein Q92900 UNIPROT Upf-EJC complex SIGNOR-C367 SIGNOR "form complex" binding 9606 BTO:0000567 17803942 t miannu "The three Up-frameshift (Upf) proteins, Upf1, Upf2, and Upf3 that together form the Upf complex, constitute the conserved core of NMD from yeast to humans. hUpf3b Forms Multiple Contacts with the EJC and Depends on hUpf2 for Complex Formation with hUpf1" SIGNOR-265237 MAOB protein P27338 UNIPROT (R)-noradrenaline smallmolecule CHEBI:18357 ChEBI "up-regulates quantity" "chemical modification" 9606 BTO:0000142 20493079 t Luana "The selective monoamine oxidase inhibitors clorgyline and (−)-deprenyl were used to study the distribution of monoamine oxidase-A and -B (MAO-A, MAO-B) activities towards (−)-noradrenaline and (+),(−)-adrenaline in homogenates from seven different regions of human brain. Noradreanline and adrenaline were substrates for both forms of the enzyme in all regions studied." SIGNOR-269747 LTBP1 protein Q14766 UNIPROT TGFB1 protein P01137 UNIPROT "up-regulates activity" binding 9606 BTO:0003247 8432736 t lperfetto "Together these data form strong support for the hypothesis that the LTBP plays an essential role in the activation of latent TGF-b in heterotypic cultures." SIGNOR-235754 MECP2 protein P51608 UNIPROT Neurogenesis phenotype SIGNOR-PH168 SIGNOR up-regulates 10090 BTO:0002881 19427855 f Luana "Neuronal differentiation of neural precursor cells is promoted by the methyl-CpG-binding protein MeCP2" SIGNOR-264966 AAK1 protein Q2M2I8 UNIPROT NUMB protein P49757 UNIPROT up-regulates phosphorylation Thr102 LRVVDEKtKDLIVDQ 9606 18657069 t llicata "Collectively, these observations demonstrate that numb endocytic activity is regulated by aak1 and that phosphorylation may be a critical step in promoting coated pit maturation." SIGNOR-179606 2-[(9S)-7-(4-Chlorophenyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetrazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12-pentaen-9-yl]-N-[8-[[2-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]oxyacetyl]amino]octyl]acetamide chemical CID:121427831 PUBCHEM BRD4 protein O60885 UNIPROT "down-regulates quantity" "chemical inhibition" 9606 29764999 t Monia "DBET6 induces efficient degradation of BET proteins and inhibits the proliferation of GBM cells" SIGNOR-261094 MAST3 protein O60307 UNIPROT PTEN protein P60484 UNIPROT up-regulates binding 9606 15951562 t miannu "Pten binds to and is phosphorylated by mast kinases./ Pdz domain-mediated binding to pten facilitates its phosphorylation by mast kinases / pdz domain binding increases pten protein stability." SIGNOR-138077 "Factor FVIIa:TF" complex SIGNOR-C319 SIGNOR F8 protein P00451 UNIPROT "down-regulates activity" cleavage Arg759 KNNAIEPrSFSQNSR -1 10350471 t lperfetto "N-Terminal sequencing along with time courses of proteolysis indicated that VIIa-TF/PL cleaved factor VIII first at R740, followed by concomitant cleavage at R336 and R372. |hus, heavy chain cleavage of factor VIII by VIIa-TF/PL produces an inactive factor VIII cofactor no longer capable of activation by thrombin." SIGNOR-263644 RRAGB protein Q5VZM2 UNIPROT RAGBC complex SIGNOR-C115 SIGNOR "form complex" binding 9606 20381137 t gcesareni "Mammals express four Rag proteins€”RagA, RagB, RagC, and RagD€”that form heterodimers consisting of RagA or RagB with RagC or RagD. RagA and RagB, like RagC and RagD, are highly similar to each other and are functionally redundant" SIGNOR-228176 calcium(2+) smallmolecule CHEBI:29108 ChEBI CALM1 protein P0DP23 UNIPROT up-regulates "chemical activation" 9606 10884684 t lperfetto "Calmodulin is the best studied and prototypical example of the e-f-hand family of ca2+-sensing proteins. In the event of a transient rise in Ca2+, the Ca2+ ion is coordinated in each Ca2+-binding loop of Ca2+–CaM by seven, primarily carboxylate, ligands. The binding of Ca2+ leads to substantial alterations in the interhelical angles within the E–F hands in each domain and dramatically changes the two domains of CaM to produce more ‘openÂ’ conformations" SIGNOR-78915 "perfluorooctane-1-sulfonic acid" chemical CHEBI:39421 ChEBI PPARD protein Q03181 UNIPROT "up-regulates activity" "chemical activation" -1 31332417 t miannu "In the present study, we demonstrated PFASs bound to and activated human PPARb/d-LBD directly. The PPARb/d binding potency and transcriptional activity of PFASs were all related to the carbon chain length and the terminal functional group." SIGNOR-268757 TRAF6 protein Q9Y4K3 UNIPROT MALT1 protein Q9UDY8 UNIPROT up-regulates ubiquitination 9606 BTO:0000782 17948050 t gcesareni "Traf6 associates with malt1 in response to t-cell activation and can function as an e3 ligase for malt1 in vitro and in vivo, mediating lysine 63-linked ubiquitination of malt1. Multiple lysine residues in the c-terminus of malt1 serve as acceptor sites for the assembly of polyubiquitin chains. (articolo-abstract)" SIGNOR-158554 LARP4B protein Q92615 UNIPROT Stress_granules phenotype SIGNOR-PH124 SIGNOR up-regulates 9606 20573744 f miannu "Here we show that LARP4B is a cytoplasmic protein that co-sediments with polysomes and accumulates upon stress induction in stress granules." SIGNOR-260939 NUP62 protein P37198 UNIPROT TUBG1 protein P23258 UNIPROT "up-regulates activity" binding 9606 BTO:0000567 24107630 t Simone "Furthermore, we found interactions and co-localization with γ-tubulin and SAS-6. Our results also point to a potential role of Nup62 in targeting gamma-tubulin and SAS-6 to the centrioles." SIGNOR-261257 NDUFA4 protein O00483 UNIPROT "Mitochondrial respiratory chain complex IV" complex SIGNOR-C280 SIGNOR "form complex" binding 30030361 t lperfetto "Complex IV (EC 1.9.31) or cytochrome c oxidase (COX) catalyses the oxidation of cytochrome c and the reduction of oxygen to water, coupled to proton translocation [108]. Mammalian cIV contains 13 or 14 subunits" SIGNOR-267752 TNF protein P01375 UNIPROT AKT1 protein P31749 UNIPROT up-regulates 9606 11287630 f lperfetto "Tumor necrosis factor (tnf) inhibited insulin-promoted tyrosine phosphorylation of irs-1 and activated the akt/protein kinase b serine-threonine kinase, a downstream target for phosphatidylinositol 3-kinase" SIGNOR-106593 THRA protein P10827 UNIPROT RARG protein P13631 UNIPROT up-regulates binding 9606 15650024 t gcesareni "We report that the retinoic acid receptors (rars), a distinct class of nuclear receptors, are also efficient heterodimer partners for trs." SIGNOR-133246 PTPRG protein P23470 UNIPROT ERBB2 protein P04626 UNIPROT "up-regulates activity" dephosphorylation Tyr1248 PTAENPEyLGLDVPV -1 25624455 t miannu "PTPRG activation by the P1-WD peptide affected the tyrosine phosphorylation of several signaling molecules. Data analysis identified 31 molecules whose phosphorylation was modified in a statistically significant manner (Table I). inhibition of ABL1, BMX, BTK, DAB1, ITGB1, JAK2, KDR, KIT, LIMK1, MET, PDGFRB, SHC1, and VCL correlates with tyrosine dephosphorylation. In contrast, SRC inhibition correlates with hyperphosphorylation of the inhibitory Tyr530 residue and with dephosphorylation of the activatory Tyr419. Moreover, CDK2 and CTTN inhibition correlates with a hyperphosphorylation of the inhibitory Tyr15 and Tyr470, respectively. In contrast, a subgroup of 13 proteins, including BLNK, DOK2, ERBB2, GRIN2B, INSR, PDGFRA, PRKCD, PXN, STAT1, STAT2, STAT3, STAT5A, and ZAP70, appears to be activated by PTPRG activity." SIGNOR-254701 UBE3A protein Q05086 UNIPROT RAD23A protein P54725 UNIPROT "down-regulates quantity by destabilization" polyubiquitination 9534 BTO:0000298 10373495 t miannu " Here we report the identification of HHR23A, one of the human homologues of the yeast DNA repair protein Rad23, as an E6-independent target of E6AP.  E6AP-mediated ubiquitination and degradation of HHR23A and HHR23B." SIGNOR-272550 MRPL22 protein Q9NWU5 UNIPROT "39S mitochondrial large ribosomal subunit" complex SIGNOR-C285 SIGNOR "form complex" binding -1 25838379 t lperfetto "We have determined the structure of the intact mitoribosome to 3.5 angstrom resolution by single-particle electron cryo-microscopy. It reveals 80 extensively interconnected proteins, 36 of which are specific to mitochondria, and three rRNA molecules" SIGNOR-262371 MRE11/RAD50/NBS1 complex SIGNOR-C147 SIGNOR "BRCA1-C complex" complex SIGNOR-C299 SIGNOR "form complex" binding 25400280 t lperfetto "The BRCA1–C complex consisting of BRCA1, Mre11:Rad50:Nbs1 (collectively known as the MRN complex) and CtIP plays a role in DSB end resection, a process that also involves EXO1 and DNA2" SIGNOR-263221 STK11 protein Q15831 UNIPROT TP53 protein P04637 UNIPROT up-regulates phosphorylation Ser15 PSVEPPLsQETFSDL 9606 17108107 t gcesareni "We show that lkb1 physically associates with p53 in the nucleus and directly or indirectly phosphorylates p53 ser15 (previously shown to be phosphorylated by amp-dependent kinase) and p53 ser392" SIGNOR-150830 Gbeta proteinfamily SIGNOR-PF4 SIGNOR MKNK2 protein Q9HBH9 UNIPROT up-regulates phosphorylation 9606 9155017 t "inferred from 70% family members" gcesareni "Erk and p38 phosphorylate mnk1 and mnk2, which stimulates their in vitro kinase activity." SIGNOR-270115 PRKCA protein P17252 UNIPROT RRAD protein P55042 UNIPROT unknown phosphorylation Ser299 KMAFRAKsKSCHDLS -1 9677319 t lperfetto "Here we show that Rad serves as a substrate for phosphorylation by CaMKII, cAMP-dependent protein kinase (PKA), protein kinase C (PKC) and casein kinase II (CKII) with stoichiometries in vitro of 0.2-1.3 mol of phosphate/mol of Rad. | PKC and CKII phosphorylate multiple C-terminal serine residues, including Ser214, Ser257, Ser273, Ser290 and Ser299. | However, phosphorylation of Rad by PKC and CKII abolishes the interaction of Rad with calmodulin. These findings suggest that the binding of Rad to calmodulin, as well as its ability to bind GTP, might be regulated by the activation of several serine kinases." SIGNOR-249008 "sorafenib tosylate" chemical CHEBI:50928 ChEBI BRAF protein P15056 UNIPROT "down-regulates activity" "chemical inhibition" -1 16757355 t miannu "This effort culminated in the identification of the clinical candidate BAY 43-9006 (Sorafenib, Nexavar), which has recently been approved by the FDA for advanced renal cell carcinoma in phase III clinical trials. Sorafenib inhibited the kinase activity of both C-RAF and B-RAF (wild type and V600E mutant)." SIGNOR-259220 SRC protein P12931 UNIPROT AKT1 protein P31749 UNIPROT "up-regulates activity" phosphorylation Tyr315 TFCGTPEyLAPEVLE 9606 BTO:0000007 12600984 t lperfetto "We also showed that phosphorylation of Tyr-315 in Akt induced by Src or EGF is dependent on the integrity of this proline-rich motif. Furthermore, the Akt mutant lacking this proline motif fails to block the transcription activity of Forkhead in 293 cells and poorly stimulates the proliferation of Madin-Darby canine kidney cells. Taken together, our data suggest that the interaction between the SH3 domain of Src family kinases and the proline-rich motif in the C-terminal regulatory region of Akt is required for tyrosine phosphorylation of Akt and its subsequent activation." SIGNOR-252621 UBE2I protein P63279 UNIPROT ZHX1 protein Q9UKY1 UNIPROT "up-regulates quantity by stabilization" sumoylation Lys454 VPTSQSVkHETALVN 9606 BTO:0000007 23686912 t miannu "Here, we report that the SUMO-E2 conjugating enzyme Ubc9 was identified to interact with ZHX1 by an interaction screen using a yeast two-hybrid system. This interaction was confirmed by co-immunoprecipitation and co-localization assays. Further study showed that ZHX1 is SUMOylated by Ubc9 with SUMO1 at the sites K159, K454, and K626. Furthermore, we demonstrated that the SUMOylation of ZHX1 regulated the stability, ubiquitination and transcriptional activity of ZHX1. The sumoylation of zinc‐fingers and homeoboxes 1 (ZHX1) by ubc9 regulates its stability and transcriptional repression activity. However, in the current work, we demonstrated that ZHX1 was only SUMOylated by SUMO1." SIGNOR-263900 CDK3 protein Q00526 UNIPROT CABLES1 protein Q8TDN4 UNIPROT unknown phosphorylation Ser313 RCRTLSGsPRPKNFK 9606 11733001 t lperfetto "Here, we report that ser274 of p70ik3-1 is phosphorylated by cdk2 or cdk3 bound to cyclin a and to cyclin e in vitro. Currently, however, the question of how ik3-1 function is modified by its cdk3-mediated phosphorylation of ser274 remains to be adressed." SIGNOR-112418 PSMD14 protein O00487 UNIPROT "26S Proteasome" complex SIGNOR-C307 SIGNOR "form complex" binding 9606 BTO:0000007 29636472 t lperfetto "Here, we report near-atomic resolution cryo-EM structures of the activated human proteasome|The proteasome is composed of a 28-subunit barrel-shaped core particle (CP) and two 19- subunit regulatory particles (RP)5–8 capped at both sides of the CP|Human proteasomes were purified through affinity chromatography on a large scale from a stable HEK293 cell line" SIGNOR-263346 TBK1 protein Q9UHD2 UNIPROT IRF3 protein Q14653 UNIPROT "up-regulates activity" phosphorylation 9606 BTO:0000782 14679297 t lperfetto "We show that purified recombinant ikk-epsilon and tbk1 directly phosphorylate the critical serine residues in irf3 allowing its translocation into the nucleus and production of interferon type i." SIGNOR-120355 JNK proteinfamily SIGNOR-PF15 SIGNOR CTNNB1 protein P35222 UNIPROT down-regulates phosphorylation Ser37 YLDSGIHsGATTTAP 9606 19667122 t lperfetto "Specifically, we provide evidence that jnk binds to e-cadherin/beta-catenin complex and phosphorylates beta-catenin at serine 37 and threonine 41, the sites also phosphorylated by gsk-3beta." SIGNOR-187578 2-oxoglutarate(2-) smallmolecule CHEBI:16810 ChEBI (R)-2-hydroxyglutarate(2-) smallmolecule CHEBI:15801 ChEBI "up-regulates quantity" "precursor of" 25406093 t lperfetto "Here we show that, in addition to catalyzing oxidation of 3-phosphoglycerate, PHGDH catalyzes NADH-dependent reduction of alpha-ketoglutarate (AKG) to the oncometabolite d-2-hydroxyglutarate (d-2HG)." SIGNOR-268573 POU1F1 protein P28069 UNIPROT GH1 protein P01241 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 15998782 f miannu "Such findings are consistent with the existence, in humans, of an LHX4-driven pathway leading to the expression of GH through transcriptional activation of POU1F1." SIGNOR-254559 MAPK14 protein Q16539 UNIPROT BCL2L11 protein O43521 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser69 GPLAPPAsPGPFATR 10116 15486195 t miannu "Ser69 can also be phosphorylated by JNK and p38MAPK at least in vitro. Phosphorylation of BimEL on Ser69 promotes its ubiquitination." SIGNOR-260442 MAPK14 protein Q16539 UNIPROT ELAVL1 protein Q15717 UNIPROT up-regulates phosphorylation 9606 19528229 t gcesareni "P38 mapk phosphorylates the mrna binding protein hur on thr118, which results in cytoplasmic accumulation of hur and its enhanced binding to the p21cip1 mrna." SIGNOR-186138 2-[[2-[[1-[2-(dimethylamino)-1-oxoethyl]-5-methoxy-2,3-dihydroindol-6-yl]amino]-7H-pyrrolo[2,3-d]pyrimidin-4-yl]amino]-6-fluoro-N-methylbenzamide chemical CHEBI:93768 ChEBI IGF1R protein P08069 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-192868 MAPK1 protein P28482 UNIPROT MAPKAPK2 protein P49137 UNIPROT up-regulates phosphorylation Thr334 QSTKVPQtPLHTSRV 9606 8846784 t fstefani "Using novel methodology we demonstrate that activation of mapkap kinase-2 requires the phosphorylation of any two of the three residues thr222, ser272 and thr334. gst-mapkap kinase-2 lacking the n-terminal domain was inactive, but activated fully when phosphorylated at thr222, ser272 and thr334 by p42 mapk or rk." SIGNOR-44347 CYP21A2 protein P08686 UNIPROT 11-deoxycortisol smallmolecule CHEBI:28324 ChEBI "down-regulates quantity" "chemical modification" 9606 BTO:0000050 25855791 t lperfetto "Cytochrome P450 (P450)4 21A2 is the major steroid 21-hydroxylase, which catalyzes the 21-hydroxylation of progesterone and 17alpha-hydroxyprogesterone (17alpha-OH-progesterone) to form 11-deoxycorticosterone and 11-deoxycortisol, respectively" SIGNOR-268644 PTK2 protein Q05397 UNIPROT PXN protein P49023 UNIPROT "up-regulates activity" phosphorylation Tyr31 FLSEETPySYPTGNH 9606 15688067 t miannu "Paxillin is phosphorylated by FAK–Src on Tyr31 and Tyr118, and this can also promote SH2-mediated binding of Crk to paxillin. Overexpressing paxillin that is mutated at these phosphorylation sites inhibits the turnover of focal contacts6 and cell motility, which therefore supports the presence of multiple routes for FAK–Src-mediated signalling in modulating the dynamics of cell adhesion sites." SIGNOR-28247 CSNK2A1 protein P68400 UNIPROT JUN protein P05412 UNIPROT down-regulates phosphorylation Thr231 ALKEEPQtVPEMPGE 9606 1516134 t lperfetto "Casein kinase ii is a negative regulator of c-jun dna binding and ap-1 activitywe show that two of these sites, thr-231 and ser-249, are phosphorylated by casein kinase ii (ckii)." SIGNOR-19607 RASGEF1B protein Q0VAM2 UNIPROT KRAS protein P01116 UNIPROT up-regulates binding 9606 19201597 t gcesareni "Gefs catalyse the transition from gdp-bound, inactive ras to gtp-bound, active ras." SIGNOR-183835 PRKCD protein Q05655 UNIPROT STAT3 protein P40763 UNIPROT up-regulates phosphorylation Ser727 NTIDLPMsPRTLDSL 9606 16418226 t gcesareni "Abrogation of pkcdelta activity inhibited insulin-induced stat3 phosphorylation, pkcdelta-stat3 association and nuclear translocation." SIGNOR-143828 MAPK1 protein P28482 UNIPROT EXOC7 protein Q9UPT5 UNIPROT up-regulates phosphorylation Ser250 SSSGVPYsPAIPNKR 9606 22595671 t lperfetto "Erk1/2 phosphorylation enhances the binding of exo70 to other exocyst components and promotes the assembly of the exocyst complex in response to epidermal growth factor (egf) signaling." SIGNOR-197543 TAF1D protein Q9H5J8 UNIPROT "SL1 complex" complex SIGNOR-C464 SIGNOR "form complex" binding 9606 30693017 t lperfetto "SL1 comprises TBP, TAF1A (also known as TAFI48), TAF1B (also known as TAFI63), TAF1C (also known as TAFI110), and TAF1D (also known as TAFI41) and recruits the RNAP1 complex to induce PIC formation." SIGNOR-269563 SRC_kinase_family proteinfamily SIGNOR-PF32 SIGNOR Degranulation phenotype SIGNOR-PH92 SIGNOR up-regulates 9606 16470226 f "Alessandro Palma" "So, the association of aggregated FcεRI with the preferentially activated LYN in lipid rafts might be sufficient to shift the equilibrium of FcεRI from a nonphosphorylated state to a phosphorylated state, thereby initiating FcεRI-mediated degranulation" SIGNOR-254956 FBXO3 protein Q9UK99 UNIPROT "Cullin 1-RBX1-Skp1" complex SIGNOR-C529 SIGNOR "up-regulates activity" binding 9606 BTO:0004573 18809579 t miannu "O clarify the role of PML in transcription regulation, we purified the PML complex and identified Fbxo3 (Fbx3), Skp1, and Cullin1 as novel components of this complex. Fbx3 formed SCF(Fbx3) ubiquitin ligase and promoted the degradation of HIPK2 and p300 by the ubiquitin-proteasome pathway. " SIGNOR-271743 ARPC3 protein O15145 UNIPROT ARP2/3 complex SIGNOR-C146 SIGNOR "form complex" binding 9606 12479800 t "The subunits in mammalian cells are named Arp3, Arp2, p41-Arc, p34-Arc, p21-Arc, p20-Arc and p16-Arc" SIGNOR-251516 PAK proteinfamily SIGNOR-PF13 SIGNOR SYN1 protein P17600 UNIPROT unknown phosphorylation 10116 12237306 t "inferred from 70% family members" miannu "Recombinant PAK2 could also phosphorylate the Ser9 and Ser551 residues." SIGNOR-269974 FIS1 protein Q9Y3D6 UNIPROT Mitochondrial_fission phenotype SIGNOR-PH143 SIGNOR up-regulates 9606 25486875 f lperfetto "During fission, DRP1 is recruited from the cytosol to the outer mitochondrial membrane, where it assembles with FIS1 to constrict the mitochondrial tubule (2)" SIGNOR-272976 NEK2 protein P51955 UNIPROT NEK2 protein P51955 UNIPROT down-regulates phosphorylation Thr179 FAKTFVGtPYYMSPE 9606 17197699 t gcesareni "Enzymatic activity, inhibited;" SIGNOR-151771 GTF2A1 protein P52655 UNIPROT TFIIA complex SIGNOR-C395 SIGNOR "form complex" binding 9606 BTO:0000567 7724559 t lperfetto "TFIIA purified from HeLa extracts consists of 35-, 19-, and 12-kDa subunits. Here we describe the isolation of a cDNA clone (hTFIIA gamma) encoding the 12-kDa subunit." SIGNOR-266197 succinyl-CoA(5-) smallmolecule CHEBI:57292 ChEBI "coenzyme A(4-)" smallmolecule CHEBI:57287 ChEBI "up-regulates quantity" "precursor of" 33148467 t lperfetto "The acyl-CoA thioesterase (ACOT) family catalyses the hydrolysis of acyl-CoA thioesters to their corresponding non-esterified fatty acid and coenzyme A (CoA)." SIGNOR-271805 ZM447439 chemical CHEBI:91376 ChEBI AURKB protein Q96GD4 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-207923 PRKAA1 protein Q13131 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR "up-regulates activity" phosphorylation Ser588 QTLSDSLsGSSLYST 9606 17711846 t gcesareni "Phosphorylation by AMPK leads to the activtion of FOXO3 transcriptional activity without affecting FOXO3 subcellular localization." SIGNOR-252978 DLG5 protein Q8TDM6 UNIPROT Scribble_complex_DLG5-LLGL2_variant complex SIGNOR-C506 SIGNOR "form complex" binding 9606 23397623 t miannu "The Scribble polarity complex or module is one of the three polarity modules that regulate cell polarity in multiple epithelia including blood-tissue barriers. This protein complex is composed of Scribble, Lethal giant larvae (Lgl) and Discs large (Dlg), which are well conserved across species from fruitflies and worms to mammals." SIGNOR-270893 MAPK3 protein P27361 UNIPROT UBTF protein P17480 UNIPROT down-regulates phosphorylation Thr117 DFPKKPLtPYFRFFM 9606 11741541 t lperfetto "Erk1/2 was found to phosphorylate the architectural transcription factor ubf at amino acids 117 and 201 within hmg boxes 1 and 2, preventing their interaction with dna" SIGNOR-112813 PTPN1 protein P18031 UNIPROT IRS1 protein P35568 UNIPROT down-regulates dephosphorylation -1 10660596 t lperfetto "Tyrosine dephosphorylation and deactivation of insulin receptor substrate-1 by protein-tyrosine phosphatase 1B. Possible facilitation by the formation of a ternary complex with the Grb2 adaptor protein." SIGNOR-74852 HOXA9 protein P31269 UNIPROT MEF2C protein Q06413 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0000661 21261500 f miannu "Overexpression of HOXA9 or HOXA10 in JURKAT cells by lentiviral transduction resulted in decreased expression of MEF2C, indicating repression by these homeodomain proteins. HOXA9/10 inhibits expression of MEF2C via NMYC" SIGNOR-254211 adenosine smallmolecule CHEBI:16335 ChEBI inosine smallmolecule CHEBI:17596 ChEBI "up-regulates quantity" "precursor of" -1 15926889 t Luana "Adenosine deaminase (ADA; EC 3.5.4.4) catalyses the deamination of adenosine and 2′-deoxyadenosine to inosine and deoxyinosine. Two different isoenzymes of ADA designated as ADA1 and ADA2 were found in mammals and lower vertebrates" SIGNOR-269736 ATG16L1 protein Q676U5 UNIPROT CLTCL1 protein P53675 UNIPROT up-regulates binding 9606 20639872 t gcesareni "Clathrin heavy-chain interacts with atg16l1, and is involved in the formation of atg16l1-positive early autophagosome precursors" SIGNOR-166705 HIPK2 protein Q9H2X6 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR up-regulates 9606 BTO:0000452 19820693 f Luana "We show that MeCP2 cooperates with HIPK2 in induction of apoptosis and that Ser 80 phosphorylation is required together with the DNA binding of MeCP2. | We found increased cell death in each of the tested cell lines not only, as expected, when HIPK2 was overexpressed but also with MeCP2 alone. When both proteins were expressed together, the number of dead cells increased in an additive manner." SIGNOR-264551 DTX1 protein Q86Y01 UNIPROT EP300 protein Q09472 UNIPROT up-regulates binding 9606 11564735 t gcesareni "We found that a significant fraction of dtx1 proteins were localized in the nucleus and physically interacted with the transcriptional coactivator p300." SIGNOR-110629 PSMD8 protein P48556 UNIPROT "26S Proteasome" complex SIGNOR-C307 SIGNOR "form complex" binding 9606 BTO:0000007 29636472 t lperfetto "Here, we report near-atomic resolution cryo-EM structures of the activated human proteasome|The proteasome is composed of a 28-subunit barrel-shaped core particle (CP) and two 19- subunit regulatory particles (RP)5–8 capped at both sides of the CP|Human proteasomes were purified through affinity chromatography on a large scale from a stable HEK293 cell line" SIGNOR-263345 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR RPS6K proteinfamily SIGNOR-PF26 SIGNOR "up-regulates activity" phosphorylation Thr573 AENGLLMtPCYTANF 9534 BTO:0004055 9430688 t lperfetto "Several lines of evidence indicate that the mapkap-k1 isoforms are also activated by mapks in vivo via the ras-dependent protein kinase cascade that is triggered by growth factors or tumor-promoting phorbol esters, such as phorbol 12-myristate 13-acetate (pma). here we identify six sites in mapkap-k1a that become phosphorylated in transfected cos-1 cells. The inactive form of mapkap-k1a in unstimulated cells is partially phosphorylated at ser222 and ser733. Stimulation with phorbol 12-myristate 13-acetate induces the phosphorylation of thr360, ser364, thr574, and ser381 and increases the phosphorylation of ser222 and ser733." SIGNOR-252743 MRPS11 protein P82912 UNIPROT "28S mitochondrial small ribosomal subunit" complex SIGNOR-C266 SIGNOR "form complex" binding 9606 25838379 t miannu "The mammalian mitochondrial ribosome (mitoribosome) has a highly protein-rich composition with a small sedimentation coefficient of 55 S, consisting of 39 S large and 28 S small subunits. . We report here the identification of 28 S small subunit proteins." SIGNOR-261458 NAT8L protein Q8N9F0 UNIPROT L-aspartate(1-) smallmolecule CHEBI:29991 ChEBI "down-regulates quantity" "chemical modification" 9606 19524112 t miannu "The biosynthetic enzyme, aspartate-N-acetyltransferase (Asp-NAT; EC 2.3.1.17) is a CNS specific enzyme that catalyzes the transfer of acetate from acetyl-CoA to L-aspartate forming NAA." SIGNOR-267521 AKT2 protein P31751 UNIPROT CASP9 protein P55211 UNIPROT down-regulates phosphorylation Ser196 KLRRRFSsLHFMVEV 9606 9812896 t gcesareni "Akt phosphorylated recombinant casp9 in vitro on serine-196 and inhibited its protease activity" SIGNOR-61561 PTPN6 protein P29350 UNIPROT ROS1 protein P08922 UNIPROT down-regulates dephosphorylation 9606 11266449 t lperfetto "Overexpression of shp-1 results in ros dephosphorylation and effectively downregulates ros-dependent proliferation and transformation. We propose that shp-1 is an important downstream regulator of ros signaling." SIGNOR-105922 creatine smallmolecule CHEBI:16919 ChEBI CKM protein P06732 UNIPROT "up-regulates activity" "chemical activation" 9606 18502307 t miannu "Creatine kinase catalyses the reversible transphosphorylation of creatine by ATP. In the cell, creatine kinase isoenzymes are specifically localized at strategic sites of ATP consumption to efficiently regenerate ATP in situ via phosphocreatine or at sites of ATP generation to build-up a phosphocreatine pool." SIGNOR-265784 PRKCB protein P05771 UNIPROT VTN protein P04004 UNIPROT "up-regulates quantity by stabilization" phosphorylation Ser381 RNRKGYRsQRGHSRG -1 9030777 t lperfetto "Phosphorylation of vitronectin on Ser362 by protein kinase C attenuates its cleavage by plasmin." SIGNOR-248963 AKT proteinfamily SIGNOR-PF24 SIGNOR TP53RK protein Q96S44 UNIPROT up-regulates phosphorylation Ser250 RLRGRKRsMVG 9606 17712528 t gcesareni "Here we show that such an activation of prpk is mediated by another kinase, akt/pkb, which phosphorylates prpk at ser250." SIGNOR-157467 JUN protein P05412 UNIPROT GLS protein O94925 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 28111979 t Luana "The transcription factor c-Jun can directly bind to the GLS gene promoter and enhance expression" SIGNOR-268035 SRC protein P12931 UNIPROT PTK2B protein Q14289 UNIPROT up-regulates phosphorylation Tyr402 CSIESDIyAEIPDET 9606 15695828 t llicata "These data indicate that pyk2 activation via phosphorylation at tyr-402 requires ?V?3 Ligation and src activity." SIGNOR-133870 IL31 protein Q6EBC2 UNIPROT IL31RA protein Q8NI17 UNIPROT up-regulates binding 9606 15184896 t gcesareni "Here we identify a four-helix bundle cytokine we have called interleukin 31 (il-31), which is preferentially produced by t helper type 2 cells. Il-31 signals through a receptor composed of il-31 receptor a and oncostatin m receptor." SIGNOR-125313 SGK1 protein O00141 UNIPROT MAPT protein P10636 UNIPROT down-regulates phosphorylation Ser214 GGKERPGsKEEVDED 9606 16982696 t lperfetto "Second, sgk1 indirectly depolymerized mts through the phosphorylation of tau at ser214" SIGNOR-161288 CTNNB1 protein P35222 UNIPROT SOX2 protein P48431 UNIPROT "down-regulates activity" binding 9606 BTO:0000093 24291232 t flangone "The interaction between Sox2 and _-catenin provides a novel mechanism underlying the functional dichotomy of BC cells, which carries potential therapeutic implications." SIGNOR-241994 (-)-anisomycin chemical CHEBI:338412 ChEBI JUNB protein P17275 UNIPROT up-regulates "chemical activation" 9606 Other t "CellSignaling;phospho-JunB (Thr102/Thr104) (D3C6) Rabbit mAb #8053" gcesareni SIGNOR-189644 MAPK3 protein P27361 UNIPROT JAK2 protein O60674 UNIPROT down-regulates phosphorylation Ser523 GVSDVPTsPTLQRPT 9606 16705159 t "16705160:the phosphorylation of Jak2 on Ser523 inhibits Jak2 activity and represents a novel mechanism for the regulation of Jak2-dependent cytokine signaling." lperfetto "We hypothesize that phosphorylation of ser523 in jak2 by erks 1 and/or 2 or other as-yet-unidentified kinases acts in a negative feedback manner" SIGNOR-146747 CSNK1D protein P48730 UNIPROT MDM2 protein Q00987 UNIPROT down-regulates phosphorylation Ser118 NQQESSDsGTSVSEN 9606 20708156 t gcesareni "Phosphorylation by casein kinase i promotes the turnover of the mdm2 oncoprotein via the scf(beta-trcp) ubiquitin ligase." SIGNOR-167497 Ub:E2 complex SIGNOR-C497 SIGNOR TRIM15 protein Q9C019 UNIPROT "up-regulates activity" ubiquitination 9606 34199813 t miannu "The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t" SIGNOR-271215 HSPA1A protein P0DMV8 UNIPROT MAPK8 protein P45983 UNIPROT down-regulates 9606 16172114 f gcesareni "Hsp70 inhibited stress-induced jnk activation and jnk with sp600125 or by expression of a dominant negative mutant of jnk-blocked bax translocation as effectively as hsp70 overexpression" SIGNOR-140553 GNGT1 protein P63211 UNIPROT PIK3CA protein P42336 UNIPROT up-regulates binding 9606 17419683 t gcesareni "Gbetagamma subunits released from gi can activate pi3k (phosphoinositide 3-kinase), and can be therefore implicated in smo-dependent activation of akt" SIGNOR-154261 PKA proteinfamily SIGNOR-PF17 SIGNOR SLC8B1 protein Q6J4K2 UNIPROT "up-regulates activity" phosphorylation Ser258 YQRQRRGsLFCPMPV 36476859 t "Phosphosite is derived from the graphical abstract" lperfetto "However, the PDE2-inhibitory effect is eliminated when the mitochondrial S258A NCLX mutant that mimics a non-PKA phosphorylated state of NCLX is expressed. Altogether, our findings indicate that NCLX is regulated by the mitochondrial PDE2A2 form.|We show that caffeine, by inhibiting PDE2, enhances PKA phosphorylation leading to mitochondrial NCLX activation, thereby reducing neuronal excitotoxicity and enhancing learning in mice. |Moreover, PDE2 acts by diminishing mitochondrial cAMP, thus promoting NCLX phosphorylation at its PKA site." SIGNOR-275728 PDE2A protein O00408 UNIPROT PRKACA protein P17612 UNIPROT "down-regulates activity" binding 36476859 t lperfetto "We show that caffeine, by inhibiting PDE2, enhances PKA phosphorylation leading to mitochondrial NCLX activation, thereby reducing neuronal excitotoxicity and enhancing learning in mice. " SIGNOR-275730 PDE2A protein O00408 UNIPROT PKA proteinfamily SIGNOR-PF17 SIGNOR "down-regulates activity" binding 36476859 t lperfetto "We show that caffeine, by inhibiting PDE2, enhances PKA phosphorylation leading to mitochondrial NCLX activation, thereby reducing neuronal excitotoxicity and enhancing learning in mice. " SIGNOR-275731 FNTA protein P49354 UNIPROT MRAS protein O14807 UNIPROT "up-regulates activity" 9606 24294527 t lperfetto "Major investments have been made to target Ras through indirect routes. Inhibition of farnesyl transferase to block Ras maturation has failed in large clinical trials." SIGNOR-242553 SLC8B1 protein Q6J4K2 UNIPROT calcium(2+) smallmolecule CHEBI:29108 ChEBI "up-regulates quantity" relocalization 23056385 t lperfetto "This study focuses on NCLX, the recently discovered mitochondrial Na(+)/Ca(2+) exchanger that is linked to Ca(2+) signalling in MIN6 and primary β cells. Suppression either of NCLX expression, using a siRNA construct (siNCLX) or of its activity, by a dominant negative construct (dnNCLX), enhanced mitochondrial Ca(2+) influx and blocked efflux induced by glucose or by cell depolarization." SIGNOR-275732 TBK1 protein Q9UHD2 UNIPROT TNIP1 protein Q15025 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser122 KPPSSGTsSEFEVVT 36574265 t lperfetto "TBK1 phosphorylation activates LIR-dependent degradation of the inflammation repressor TNIP1" SIGNOR-275733 TBK1 protein Q9UHD2 UNIPROT TNIP1 protein Q15025 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser123 PPSSGTSsEFEVVTP 36574265 t lperfetto "TBK1 phosphorylation activates LIR-dependent degradation of the inflammation repressor TNIP1" SIGNOR-275734 TNIP1 protein Q15025 UNIPROT TAX1BP1 protein Q86VP1 UNIPROT "up-regulates activity" relocalization 21885437 t lperfetto "ABIN1 interacted with the A20 regulatory molecule TAX1BP1 and was essential for the recruitment of TAX1BP1 and A20 to the noncanonical IkappaB kinases TBK1 and IKKi in response to poly(I:C) transfection. ABIN1 and TAX1BP1 together disrupted the interactions between the E3 ubiquitin ligase TRAF3 and TBK1/IKKi to attenuate lysine 63-linked polyubiquitination of TBK1/IKKi." SIGNOR-275735 TNIP1 protein Q15025 UNIPROT TRAF3 protein Q13114 UNIPROT "down-regulates activity" binding 21885437 t lperfetto "ABIN1 interacted with the A20 regulatory molecule TAX1BP1 and was essential for the recruitment of TAX1BP1 and A20 to the noncanonical IkappaB kinases TBK1 and IKKi in response to poly(I:C) transfection. ABIN1 and TAX1BP1 together disrupted the interactions between the E3 ubiquitin ligase TRAF3 and TBK1/IKKi to attenuate lysine 63-linked polyubiquitination of TBK1/IKKi." SIGNOR-275736 TAX1BP1 protein Q86VP1 UNIPROT TRAF3 protein Q13114 UNIPROT "down-regulates activity" binding 21885437 t lperfetto "ABIN1 interacted with the A20 regulatory molecule TAX1BP1 and was essential for the recruitment of TAX1BP1 and A20 to the noncanonical IkappaB kinases TBK1 and IKKi in response to poly(I:C) transfection. ABIN1 and TAX1BP1 together disrupted the interactions between the E3 ubiquitin ligase TRAF3 and TBK1/IKKi to attenuate lysine 63-linked polyubiquitination of TBK1/IKKi." SIGNOR-275737 CSNK2A1 protein P68400 UNIPROT FGF14 protein Q92915 UNIPROT "up-regulates activity" phosphorylation Ser228 PGVTPSKsTSASAIM 9606 BTO:0000938 26917740 t lperfetto "Bioluminescence-based screening of small molecule modulators of the FGF14:Nav1.6 complex identified 4,5,6,7 -: tetrabromobenzotriazole (TBB), a potent casein kinase 2 (CK2) inhibitor, as a strong suppressor of FGF14:Nav1.6 interaction. Inhibition of CK2 through TBB reduces the interaction of FGF14 with Nav1.6 and Nav1.2 channels. Mass spectrometry confirmed direct phosphorylation of FGF14 by CK2 at S228 and S230, and mutation to alanine at these sites modified FGF14 modulation of Nav1.6-mediated currents." SIGNOR-275738 CSNK2A1 protein P68400 UNIPROT FGF14 protein Q92915 UNIPROT "up-regulates activity" phosphorylation Ser230 VTPSKSTsASAIMNG 9606 BTO:0000938 26917740 t lperfetto "Bioluminescence-based screening of small molecule modulators of the FGF14:Nav1.6 complex identified 4,5,6,7 -: tetrabromobenzotriazole (TBB), a potent casein kinase 2 (CK2) inhibitor, as a strong suppressor of FGF14:Nav1.6 interaction. Inhibition of CK2 through TBB reduces the interaction of FGF14 with Nav1.6 and Nav1.2 channels. Mass spectrometry confirmed direct phosphorylation of FGF14 by CK2 at S228 and S230, and mutation to alanine at these sites modified FGF14 modulation of Nav1.6-mediated currents." SIGNOR-275739 CSNK2A3 protein Q8NEV1 UNIPROT FGF14 protein Q92915 UNIPROT "up-regulates activity" phosphorylation Ser228 PGVTPSKsTSASAIM 9606 BTO:0000938 26917740 t lperfetto "Bioluminescence-based screening of small molecule modulators of the FGF14:Nav1.6 complex identified 4,5,6,7 -: tetrabromobenzotriazole (TBB), a potent casein kinase 2 (CK2) inhibitor, as a strong suppressor of FGF14:Nav1.6 interaction. Inhibition of CK2 through TBB reduces the interaction of FGF14 with Nav1.6 and Nav1.2 channels. Mass spectrometry confirmed direct phosphorylation of FGF14 by CK2 at S228 and S230, and mutation to alanine at these sites modified FGF14 modulation of Nav1.6-mediated currents." SIGNOR-275742 CSNK2A3 protein Q8NEV1 UNIPROT FGF14 protein Q92915 UNIPROT "up-regulates activity" phosphorylation Ser230 VTPSKSTsASAIMNG 9606 BTO:0000938 26917740 t lperfetto "Bioluminescence-based screening of small molecule modulators of the FGF14:Nav1.6 complex identified 4,5,6,7 -: tetrabromobenzotriazole (TBB), a potent casein kinase 2 (CK2) inhibitor, as a strong suppressor of FGF14:Nav1.6 interaction. Inhibition of CK2 through TBB reduces the interaction of FGF14 with Nav1.6 and Nav1.2 channels. Mass spectrometry confirmed direct phosphorylation of FGF14 by CK2 at S228 and S230, and mutation to alanine at these sites modified FGF14 modulation of Nav1.6-mediated currents." SIGNOR-275743 CDK2 protein P24941 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR down-regulates phosphorylation Ser249 EGGKSGKsPRRRAAS 9606 17038621 t lperfetto "Cdk2 specifically phosphorylated foxo1 at serine-249 (ser249) in vitro and in vivo. Phosphorylation of ser249 resulted in cytoplasmic localization and inhibition of foxo1." SIGNOR-252892 CSNK2B protein P67870 UNIPROT FGF14 protein Q92915 UNIPROT "up-regulates activity" phosphorylation Ser228 PGVTPSKsTSASAIM 9606 BTO:0000938 26917740 t lperfetto "Bioluminescence-based screening of small molecule modulators of the FGF14:Nav1.6 complex identified 4,5,6,7 -: tetrabromobenzotriazole (TBB), a potent casein kinase 2 (CK2) inhibitor, as a strong suppressor of FGF14:Nav1.6 interaction. Inhibition of CK2 through TBB reduces the interaction of FGF14 with Nav1.6 and Nav1.2 channels. Mass spectrometry confirmed direct phosphorylation of FGF14 by CK2 at S228 and S230, and mutation to alanine at these sites modified FGF14 modulation of Nav1.6-mediated currents." SIGNOR-275744 CSNK2B protein P67870 UNIPROT FGF14 protein Q92915 UNIPROT "up-regulates activity" phosphorylation Ser230 VTPSKSTsASAIMNG 9606 BTO:0000938 26917740 t lperfetto "Bioluminescence-based screening of small molecule modulators of the FGF14:Nav1.6 complex identified 4,5,6,7 -: tetrabromobenzotriazole (TBB), a potent casein kinase 2 (CK2) inhibitor, as a strong suppressor of FGF14:Nav1.6 interaction. Inhibition of CK2 through TBB reduces the interaction of FGF14 with Nav1.6 and Nav1.2 channels. Mass spectrometry confirmed direct phosphorylation of FGF14 by CK2 at S228 and S230, and mutation to alanine at these sites modified FGF14 modulation of Nav1.6-mediated currents." SIGNOR-275745 CSNK2B protein P67870 UNIPROT SCN2A protein Q99250 UNIPROT "up-regulates activity" phosphorylation Ser1112 VPIAVGEsDFENLNT 9606 BTO:0000938 19064667 t lperfetto "We found that the ankyrin-binding motif of Na(v)1.2 that determines channel concentration at the AIS depends on a glutamate residue (E1111), but also on several serine residues (S1112, S1124, and S1126). We showed that phosphorylation of these residues by protein kinase CK2 (CK2) regulates Na(v) channel interaction with ankyrins. | inhibition of CK2 activity reduced sodium channel accumulation at the AIS of neurons. In conclusion, CK2 contributes to sodium channel organization by regulating their interaction with ankyrin G." SIGNOR-275752 CSNK2A1 protein P68400 UNIPROT SCN2A protein Q99250 UNIPROT "up-regulates activity" phosphorylation Ser1112 VPIAVGEsDFENLNT 9606 BTO:0000938 19064667 t lperfetto "We found that the ankyrin-binding motif of Na(v)1.2 that determines channel concentration at the AIS depends on a glutamate residue (E1111), but also on several serine residues (S1112, S1124, and S1126). We showed that phosphorylation of these residues by protein kinase CK2 (CK2) regulates Na(v) channel interaction with ankyrins. | inhibition of CK2 activity reduced sodium channel accumulation at the AIS of neurons. In conclusion, CK2 contributes to sodium channel organization by regulating their interaction with ankyrin G." SIGNOR-275753 CSNK2A2 protein P19784 UNIPROT SCN2A protein Q99250 UNIPROT "up-regulates activity" phosphorylation Ser1112 VPIAVGEsDFENLNT 9606 BTO:0000938 19064667 t lperfetto "We found that the ankyrin-binding motif of Na(v)1.2 that determines channel concentration at the AIS depends on a glutamate residue (E1111), but also on several serine residues (S1112, S1124, and S1126). We showed that phosphorylation of these residues by protein kinase CK2 (CK2) regulates Na(v) channel interaction with ankyrins. | inhibition of CK2 activity reduced sodium channel accumulation at the AIS of neurons. In conclusion, CK2 contributes to sodium channel organization by regulating their interaction with ankyrin G." SIGNOR-275754 CSNK2A3 protein Q8NEV1 UNIPROT SCN2A protein Q99250 UNIPROT "up-regulates activity" phosphorylation Ser1124 LNTEEFSsESDMEES 9606 BTO:0000938 19064667 t lperfetto "We found that the ankyrin-binding motif of Na(v)1.2 that determines channel concentration at the AIS depends on a glutamate residue (E1111), but also on several serine residues (S1112, S1124, and S1126). We showed that phosphorylation of these residues by protein kinase CK2 (CK2) regulates Na(v) channel interaction with ankyrins. | inhibition of CK2 activity reduced sodium channel accumulation at the AIS of neurons. In conclusion, CK2 contributes to sodium channel organization by regulating their interaction with ankyrin G." SIGNOR-275755 CSNK2B protein P67870 UNIPROT SCN2A protein Q99250 UNIPROT "up-regulates activity" phosphorylation Ser1124 LNTEEFSsESDMEES 9606 BTO:0000938 19064667 t lperfetto "We found that the ankyrin-binding motif of Na(v)1.2 that determines channel concentration at the AIS depends on a glutamate residue (E1111), but also on several serine residues (S1112, S1124, and S1126). We showed that phosphorylation of these residues by protein kinase CK2 (CK2) regulates Na(v) channel interaction with ankyrins. | inhibition of CK2 activity reduced sodium channel accumulation at the AIS of neurons. In conclusion, CK2 contributes to sodium channel organization by regulating their interaction with ankyrin G." SIGNOR-275756 CSNK2A1 protein P68400 UNIPROT SCN2A protein Q99250 UNIPROT "up-regulates activity" phosphorylation Ser1124 LNTEEFSsESDMEES 9606 BTO:0000938 19064667 t lperfetto "We found that the ankyrin-binding motif of Na(v)1.2 that determines channel concentration at the AIS depends on a glutamate residue (E1111), but also on several serine residues (S1112, S1124, and S1126). We showed that phosphorylation of these residues by protein kinase CK2 (CK2) regulates Na(v) channel interaction with ankyrins. | inhibition of CK2 activity reduced sodium channel accumulation at the AIS of neurons. In conclusion, CK2 contributes to sodium channel organization by regulating their interaction with ankyrin G." SIGNOR-275757 CSNK2A2 protein P19784 UNIPROT SCN2A protein Q99250 UNIPROT "up-regulates activity" phosphorylation Ser1124 LNTEEFSsESDMEES 9606 BTO:0000938 19064667 t lperfetto "We found that the ankyrin-binding motif of Na(v)1.2 that determines channel concentration at the AIS depends on a glutamate residue (E1111), but also on several serine residues (S1112, S1124, and S1126). We showed that phosphorylation of these residues by protein kinase CK2 (CK2) regulates Na(v) channel interaction with ankyrins. | inhibition of CK2 activity reduced sodium channel accumulation at the AIS of neurons. In conclusion, CK2 contributes to sodium channel organization by regulating their interaction with ankyrin G." SIGNOR-275758 CSNK2A3 protein Q8NEV1 UNIPROT SCN2A protein Q99250 UNIPROT "up-regulates activity" phosphorylation Ser1126 TEEFSSEsDMEESKE 9606 BTO:0000938 19064667 t lperfetto "We found that the ankyrin-binding motif of Na(v)1.2 that determines channel concentration at the AIS depends on a glutamate residue (E1111), but also on several serine residues (S1112, S1124, and S1126). We showed that phosphorylation of these residues by protein kinase CK2 (CK2) regulates Na(v) channel interaction with ankyrins. | inhibition of CK2 activity reduced sodium channel accumulation at the AIS of neurons. In conclusion, CK2 contributes to sodium channel organization by regulating their interaction with ankyrin G." SIGNOR-275759 CSNK2B protein P67870 UNIPROT SCN2A protein Q99250 UNIPROT "up-regulates activity" phosphorylation Ser1126 TEEFSSEsDMEESKE 9606 BTO:0000938 19064667 t lperfetto "We found that the ankyrin-binding motif of Na(v)1.2 that determines channel concentration at the AIS depends on a glutamate residue (E1111), but also on several serine residues (S1112, S1124, and S1126). We showed that phosphorylation of these residues by protein kinase CK2 (CK2) regulates Na(v) channel interaction with ankyrins. | inhibition of CK2 activity reduced sodium channel accumulation at the AIS of neurons. In conclusion, CK2 contributes to sodium channel organization by regulating their interaction with ankyrin G." SIGNOR-275760 CSNK2A1 protein P68400 UNIPROT SCN2A protein Q99250 UNIPROT "up-regulates activity" phosphorylation Ser1126 TEEFSSEsDMEESKE 9606 BTO:0000938 19064667 t lperfetto "We found that the ankyrin-binding motif of Na(v)1.2 that determines channel concentration at the AIS depends on a glutamate residue (E1111), but also on several serine residues (S1112, S1124, and S1126). We showed that phosphorylation of these residues by protein kinase CK2 (CK2) regulates Na(v) channel interaction with ankyrins. | inhibition of CK2 activity reduced sodium channel accumulation at the AIS of neurons. In conclusion, CK2 contributes to sodium channel organization by regulating their interaction with ankyrin G." SIGNOR-275761 CSNK2A2 protein P19784 UNIPROT SCN2A protein Q99250 UNIPROT "up-regulates activity" phosphorylation Ser1126 TEEFSSEsDMEESKE 9606 BTO:0000938 19064667 t lperfetto "We found that the ankyrin-binding motif of Na(v)1.2 that determines channel concentration at the AIS depends on a glutamate residue (E1111), but also on several serine residues (S1112, S1124, and S1126). We showed that phosphorylation of these residues by protein kinase CK2 (CK2) regulates Na(v) channel interaction with ankyrins. | inhibition of CK2 activity reduced sodium channel accumulation at the AIS of neurons. In conclusion, CK2 contributes to sodium channel organization by regulating their interaction with ankyrin G." SIGNOR-275762 GSK3B protein P49841 UNIPROT SCN8A protein Q9UQD0 UNIPROT "up-regulates activity" phosphorylation Thr1938 HREKKEStPSTASLP 10116 BTO:0000938 29642012 t lperfetto "In vivo genetic manipulations demonstrate that GSK3β and Nav1.6 are molecular determinants of MSN excitability and that silencing of GSK3β prevents maladaptive plasticity of IC MSNs. In vitro studies reveal direct interaction of GSK3β with Nav1.6 and phosphorylation at Nav1.6T1936 by GSK3β. A GSK3β-Nav1.6T1936 competing peptide reduces MSNs excitability in IC, but not EC rats. These results identify GSK3β regulation of Nav1.6 as a biosignature of MSNs maladaptive plasticity." SIGNOR-275763 PKA proteinfamily SIGNOR-PF17 SIGNOR SCN5A protein Q14524 UNIPROT "up-regulates activity" phosphorylation Ser528 KPRSSRGsIFTFRRR 9606 BTO:0000938 33410863 t lperfetto "Among the sites identified, only six were previously suggested to be the targets for specific kinases using in silico and/or in vitro analyses: S36 and S525 were attributed to the regulation by PKA; S484 and S664 were assigned to the serum- and glucocorticoid-inducible kinase 3 (SGK3); and S516 and S571 were ascribed to CaMKII (reviewed in Marionneau and Abriel, 2015). In marked contrast, several previously described phosphorylation sites were not detected in the present study, including the PKA-dependent S528, the CaMKII-associated T594, the PKC-dependent S1506, the adenosine monophosphate–activated protein kinase (AMPK)–dependent T101 (Liu et al., 2019), and the six Fyn-dependent tyrosines (Ahern et al., 2005; Iqbal et al., 2018).|The simplest interpretation of these findings is that these three phosphorylation clusters, at positions S457-S460, S483-T486, and S664-S671, are likely involved in regulating the basal and/or gating properties of native cardiac NaV1.5 channels. Conversely, the other phosphorylation sites, with lower stoichiometries, may play spatially or temporally distinct roles in the physiological or more pathophysiological regulation of channel expression or gating. | Remarkably, this MS analysis also revealed that the vast majority of identified phosphorylation sites (at least 26) are clustered, suggesting concomitant phosphorylation and roles in regulating channel expression and/or function. Unexpectedly, however, except for S664, S667, and S671, no apparent effects of phosphomimetic or phosphosilent mutations were observed on heterologously expressed (in HEK-293 cells) NaV1.5" SIGNOR-275764 PKA proteinfamily SIGNOR-PF17 SIGNOR SCN5A protein Q14524 UNIPROT "up-regulates activity" phosphorylation Ser36 AEKQARGsTTLQESR 9606 BTO:0000938 33410863 t lperfetto "Among the sites identified, only six were previously suggested to be the targets for specific kinases using in silico and/or in vitro analyses: S36 and S525 were attributed to the regulation by PKA; S484 and S664 were assigned to the serum- and glucocorticoid-inducible kinase 3 (SGK3); and S516 and S571 were ascribed to CaMKII (reviewed in Marionneau and Abriel, 2015). In marked contrast, several previously described phosphorylation sites were not detected in the present study, including the PKA-dependent S528, the CaMKII-associated T594, the PKC-dependent S1506, the adenosine monophosphate–activated protein kinase (AMPK)–dependent T101 (Liu et al., 2019), and the six Fyn-dependent tyrosines (Ahern et al., 2005; Iqbal et al., 2018).|The simplest interpretation of these findings is that these three phosphorylation clusters, at positions S457-S460, S483-T486, and S664-S671, are likely involved in regulating the basal and/or gating properties of native cardiac NaV1.5 channels. Conversely, the other phosphorylation sites, with lower stoichiometries, may play spatially or temporally distinct roles in the physiological or more pathophysiological regulation of channel expression or gating. | Remarkably, this MS analysis also revealed that the vast majority of identified phosphorylation sites (at least 26) are clustered, suggesting concomitant phosphorylation and roles in regulating channel expression and/or function. Unexpectedly, however, except for S664, S667, and S671, no apparent effects of phosphomimetic or phosphosilent mutations were observed on heterologously expressed (in HEK-293 cells) NaV1.5" SIGNOR-275765 PKA proteinfamily SIGNOR-PF17 SIGNOR SCN5A protein Q14524 UNIPROT "up-regulates activity" phosphorylation Ser525 TSMKPRSsRGSIFTF 9606 BTO:0000938 33410863 t lperfetto "Among the sites identified, only six were previously suggested to be the targets for specific kinases using in silico and/or in vitro analyses: S36 and S525 were attributed to the regulation by PKA; S484 and S664 were assigned to the serum- and glucocorticoid-inducible kinase 3 (SGK3); and S516 and S571 were ascribed to CaMKII (reviewed in Marionneau and Abriel, 2015). In marked contrast, several previously described phosphorylation sites were not detected in the present study, including the PKA-dependent S528, the CaMKII-associated T594, the PKC-dependent S1506, the adenosine monophosphate–activated protein kinase (AMPK)–dependent T101 (Liu et al., 2019), and the six Fyn-dependent tyrosines (Ahern et al., 2005; Iqbal et al., 2018).|The simplest interpretation of these findings is that these three phosphorylation clusters, at positions S457-S460, S483-T486, and S664-S671, are likely involved in regulating the basal and/or gating properties of native cardiac NaV1.5 channels. Conversely, the other phosphorylation sites, with lower stoichiometries, may play spatially or temporally distinct roles in the physiological or more pathophysiological regulation of channel expression or gating. | Remarkably, this MS analysis also revealed that the vast majority of identified phosphorylation sites (at least 26) are clustered, suggesting concomitant phosphorylation and roles in regulating channel expression and/or function. Unexpectedly, however, except for S664, S667, and S671, no apparent effects of phosphomimetic or phosphosilent mutations were observed on heterologously expressed (in HEK-293 cells) NaV1.5" SIGNOR-275766 SGK3 protein Q96BR1 UNIPROT SCN5A protein Q14524 UNIPROT "up-regulates activity" phosphorylation Ser484 KRRKRMSsGTEECGE 9606 BTO:0000938 33410863 t lperfetto "Among the sites identified, only six were previously suggested to be the targets for specific kinases using in silico and/or in vitro analyses: S36 and S525 were attributed to the regulation by PKA; S484 and S664 were assigned to the serum- and glucocorticoid-inducible kinase 3 (SGK3); and S516 and S571 were ascribed to CaMKII (reviewed in Marionneau and Abriel, 2015). In marked contrast, several previously described phosphorylation sites were not detected in the present study, including the PKA-dependent S528, the CaMKII-associated T594, the PKC-dependent S1506, the adenosine monophosphate–activated protein kinase (AMPK)–dependent T101 (Liu et al., 2019), and the six Fyn-dependent tyrosines (Ahern et al., 2005; Iqbal et al., 2018).|The simplest interpretation of these findings is that these three phosphorylation clusters, at positions S457-S460, S483-T486, and S664-S671, are likely involved in regulating the basal and/or gating properties of native cardiac NaV1.5 channels. Conversely, the other phosphorylation sites, with lower stoichiometries, may play spatially or temporally distinct roles in the physiological or more pathophysiological regulation of channel expression or gating. | Remarkably, this MS analysis also revealed that the vast majority of identified phosphorylation sites (at least 26) are clustered, suggesting concomitant phosphorylation and roles in regulating channel expression and/or function. Unexpectedly, however, except for S664, S667, and S671, no apparent effects of phosphomimetic or phosphosilent mutations were observed on heterologously expressed (in HEK-293 cells) NaV1.5" SIGNOR-275767 RNF167 protein Q9H6Y7 UNIPROT VAMP3 protein Q15836 UNIPROT "down-regulates quantity by destabilization" ubiquitination Lys66 QFETSAAkLKRKYWW 9606 BTO:0000007 23353890 t miannu "Here, we show that Godzilla/RNF167 regulates endosome recycling by the ubiquitylation of VAMP3 on Lys66, Lys68 and Lys77; namely, two adjacent Lys residues on the both sides of the critical interface of SNARE complex are ubiquitylated. In agreement with VAMP3 being a target for Goliath family ubiquitin ligases, we show that recycling endosome trafficking is abrogated in response to their activity. While we observed ubiquitylation of VAMP3 by Godzilla, we are unable to describe the nature of this ubiquitination, be it mono-ubiquitin or extended ubiquitin chains." SIGNOR-272093 HMOX1 protein P09601 UNIPROT BCL2 protein P10415 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 26722274 f irozzo "The results of the present study indicated that knockdown of HMOX-1 significantly enhanced doxorubicin-induced apoptosis and downregulated the expression of Bcl-2 and Bcl-xL in breast cancer cells." SIGNOR-256303 SACM1L protein Q9NTJ5 UNIPROT "Receptor_mediated_ endocytosis" phenotype SIGNOR-PH121 SIGNOR down-regulates 9534 BTO:0001444 22253445 f lperfetto "Ectopic Expression of Sac1 Phosphatase Inhibits SARS-CoV S-mediated Entry" SIGNOR-260735 SGK3 protein Q96BR1 UNIPROT SCN5A protein Q14524 UNIPROT "up-regulates activity" phosphorylation Ser664 GARQRALsAVSVLTS 9606 BTO:0000938 33410863 t lperfetto "Among the sites identified, only six were previously suggested to be the targets for specific kinases using in silico and/or in vitro analyses: S36 and S525 were attributed to the regulation by PKA; S484 and S664 were assigned to the serum- and glucocorticoid-inducible kinase 3 (SGK3); and S516 and S571 were ascribed to CaMKII (reviewed in Marionneau and Abriel, 2015). In marked contrast, several previously described phosphorylation sites were not detected in the present study, including the PKA-dependent S528, the CaMKII-associated T594, the PKC-dependent S1506, the adenosine monophosphate–activated protein kinase (AMPK)–dependent T101 (Liu et al., 2019), and the six Fyn-dependent tyrosines (Ahern et al., 2005; Iqbal et al., 2018).|The simplest interpretation of these findings is that these three phosphorylation clusters, at positions S457-S460, S483-T486, and S664-S671, are likely involved in regulating the basal and/or gating properties of native cardiac NaV1.5 channels. Conversely, the other phosphorylation sites, with lower stoichiometries, may play spatially or temporally distinct roles in the physiological or more pathophysiological regulation of channel expression or gating. | Remarkably, this MS analysis also revealed that the vast majority of identified phosphorylation sites (at least 26) are clustered, suggesting concomitant phosphorylation and roles in regulating channel expression and/or function. Unexpectedly, however, except for S664, S667, and S671, no apparent effects of phosphomimetic or phosphosilent mutations were observed on heterologously expressed (in HEK-293 cells) NaV1.5" SIGNOR-275768 AMPK complex SIGNOR-C15 SIGNOR SCN5A protein Q14524 UNIPROT "up-regulates activity" phosphorylation Thr101 IVLNKGKtIFRFSAT 9606 BTO:0000938 33410863 t lperfetto "Among the sites identified, only six were previously suggested to be the targets for specific kinases using in silico and/or in vitro analyses: S36 and S525 were attributed to the regulation by PKA; S484 and S664 were assigned to the serum- and glucocorticoid-inducible kinase 3 (SGK3); and S516 and S571 were ascribed to CaMKII (reviewed in Marionneau and Abriel, 2015). In marked contrast, several previously described phosphorylation sites were not detected in the present study, including the PKA-dependent S528, the CaMKII-associated T594, the PKC-dependent S1506, the adenosine monophosphate–activated protein kinase (AMPK)–dependent T101 (Liu et al., 2019), and the six Fyn-dependent tyrosines (Ahern et al., 2005; Iqbal et al., 2018).|The simplest interpretation of these findings is that these three phosphorylation clusters, at positions S457-S460, S483-T486, and S664-S671, are likely involved in regulating the basal and/or gating properties of native cardiac NaV1.5 channels. Conversely, the other phosphorylation sites, with lower stoichiometries, may play spatially or temporally distinct roles in the physiological or more pathophysiological regulation of channel expression or gating. | Remarkably, this MS analysis also revealed that the vast majority of identified phosphorylation sites (at least 26) are clustered, suggesting concomitant phosphorylation and roles in regulating channel expression and/or function. Unexpectedly, however, except for S664, S667, and S671, no apparent effects of phosphomimetic or phosphosilent mutations were observed on heterologously expressed (in HEK-293 cells) NaV1.5" SIGNOR-275769 MAPK1 protein P28482 UNIPROT DUSP1 protein P28562 UNIPROT down-regulates phosphorylation Ser323 HCSAEAGsPAMAVLD 9606 16286470 t lperfetto "The dual-specificity mapk phosphatase mkp-1/cl100/dusp1 is an inducible nuclear protein controlled by p44/42 mapk (erk1/2) in a negative feedback mechanism to inhibit kinase activity. Here, we report on the molecular basis for a novel positive feedback mechanism to sustain erk activation by triggering mkp-1 proteolysis. Active erk2 docking to the def motif (fxfp, residues 339-342) of n-terminally truncated mkp-1 in vitro initiated phosphorylation at the ser(296)/ser(323) domain" SIGNOR-141601 CAMK2A protein Q9UQM7 UNIPROT SCN5A protein Q14524 UNIPROT "up-regulates activity" phosphorylation Ser571 PWPLRRTsAQGQPSP 9606 BTO:0000938 33410863 t lperfetto "Among the sites identified, only six were previously suggested to be the targets for specific kinases using in silico and/or in vitro analyses: S36 and S525 were attributed to the regulation by PKA; S484 and S664 were assigned to the serum- and glucocorticoid-inducible kinase 3 (SGK3); and S516 and S571 were ascribed to CaMKII (reviewed in Marionneau and Abriel, 2015). In marked contrast, several previously described phosphorylation sites were not detected in the present study, including the PKA-dependent S528, the CaMKII-associated T594, the PKC-dependent S1506, the adenosine monophosphate–activated protein kinase (AMPK)–dependent T101 (Liu et al., 2019), and the six Fyn-dependent tyrosines (Ahern et al., 2005; Iqbal et al., 2018).|The simplest interpretation of these findings is that these three phosphorylation clusters, at positions S457-S460, S483-T486, and S664-S671, are likely involved in regulating the basal and/or gating properties of native cardiac NaV1.5 channels. Conversely, the other phosphorylation sites, with lower stoichiometries, may play spatially or temporally distinct roles in the physiological or more pathophysiological regulation of channel expression or gating. | Remarkably, this MS analysis also revealed that the vast majority of identified phosphorylation sites (at least 26) are clustered, suggesting concomitant phosphorylation and roles in regulating channel expression and/or function. Unexpectedly, however, except for S664, S667, and S671, no apparent effects of phosphomimetic or phosphosilent mutations were observed on heterologously expressed (in HEK-293 cells) NaV1.5" SIGNOR-275771 PP2CA_R1A_R2A complex SIGNOR-C132 SIGNOR DCK protein P27707 UNIPROT "down-regulates activity" dephosphorylation Ser74 EFEELTMsQKNGGNV 24462681 t lperfetto "Protein phosphatase 2A regulates deoxycytidine kinase activity via Ser-74 dephosphorylation|Deoxycytidine kinase (dCK) is a critical enzyme for activation of anticancer nucleoside analogs. Its activity is controlled via Ser-74 phosphorylation. Here, we investigated which Ser/Thr phosphatase dephosphorylates Ser-74. In cells, the PP1/PP2A inhibitor okadaic acid increased both dCK activity and Ser-74 phosphorylation" SIGNOR-275804 DCK protein P27707 UNIPROT CDK1 protein P06493 UNIPROT "down-regulates activity" binding 22850745 t lperfetto "We demonstrate that dCK interacts with cyclin-dependent kinase 1 (Cdk1) after IR and that the interaction inhibits Cdk1 activity both in vitro and in vivo." SIGNOR-275805 CAMK2B protein Q13554 UNIPROT SCN5A protein Q14524 UNIPROT "up-regulates activity" phosphorylation Ser571 PWPLRRTsAQGQPSP 9606 BTO:0000938 33410863 t lperfetto "Among the sites identified, only six were previously suggested to be the targets for specific kinases using in silico and/or in vitro analyses: S36 and S525 were attributed to the regulation by PKA; S484 and S664 were assigned to the serum- and glucocorticoid-inducible kinase 3 (SGK3); and S516 and S571 were ascribed to CaMKII (reviewed in Marionneau and Abriel, 2015). In marked contrast, several previously described phosphorylation sites were not detected in the present study, including the PKA-dependent S528, the CaMKII-associated T594, the PKC-dependent S1506, the adenosine monophosphate–activated protein kinase (AMPK)–dependent T101 (Liu et al., 2019), and the six Fyn-dependent tyrosines (Ahern et al., 2005; Iqbal et al., 2018).|The simplest interpretation of these findings is that these three phosphorylation clusters, at positions S457-S460, S483-T486, and S664-S671, are likely involved in regulating the basal and/or gating properties of native cardiac NaV1.5 channels. Conversely, the other phosphorylation sites, with lower stoichiometries, may play spatially or temporally distinct roles in the physiological or more pathophysiological regulation of channel expression or gating. | Remarkably, this MS analysis also revealed that the vast majority of identified phosphorylation sites (at least 26) are clustered, suggesting concomitant phosphorylation and roles in regulating channel expression and/or function. Unexpectedly, however, except for S664, S667, and S671, no apparent effects of phosphomimetic or phosphosilent mutations were observed on heterologously expressed (in HEK-293 cells) NaV1.5" SIGNOR-275774 MAFA protein Q8NHW3 UNIPROT PCSK1 protein P29120 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 17149590 f miannu "the expression of important beta cell genes, e.g. those encoding solute carrier family 2 (facilitated glucose transporter), member 2 (formerly known as GLUT2), pancreatic and duodenal homeobox factor 1 (PDX1), NK6 transcription factor-related, locus 1 (NKX6-1), glucagon-like peptide 1 receptor (GLP1R), prohormone convertase 1/3 (PCSK1) and pyruvate carboxylase (PC), was regulated positively by MAFA and negatively by DN-MAFA." SIGNOR-254566 CAMK2D protein Q13557 UNIPROT SCN5A protein Q14524 UNIPROT "up-regulates activity" phosphorylation Ser516 LSLTRGLsRTSMKPR 9606 BTO:0000938 33410863 t lperfetto "Among the sites identified, only six were previously suggested to be the targets for specific kinases using in silico and/or in vitro analyses: S36 and S525 were attributed to the regulation by PKA; S484 and S664 were assigned to the serum- and glucocorticoid-inducible kinase 3 (SGK3); and S516 and S571 were ascribed to CaMKII (reviewed in Marionneau and Abriel, 2015). In marked contrast, several previously described phosphorylation sites were not detected in the present study, including the PKA-dependent S528, the CaMKII-associated T594, the PKC-dependent S1506, the adenosine monophosphate–activated protein kinase (AMPK)–dependent T101 (Liu et al., 2019), and the six Fyn-dependent tyrosines (Ahern et al., 2005; Iqbal et al., 2018).|The simplest interpretation of these findings is that these three phosphorylation clusters, at positions S457-S460, S483-T486, and S664-S671, are likely involved in regulating the basal and/or gating properties of native cardiac NaV1.5 channels. Conversely, the other phosphorylation sites, with lower stoichiometries, may play spatially or temporally distinct roles in the physiological or more pathophysiological regulation of channel expression or gating. | Remarkably, this MS analysis also revealed that the vast majority of identified phosphorylation sites (at least 26) are clustered, suggesting concomitant phosphorylation and roles in regulating channel expression and/or function. Unexpectedly, however, except for S664, S667, and S671, no apparent effects of phosphomimetic or phosphosilent mutations were observed on heterologously expressed (in HEK-293 cells) NaV1.5" SIGNOR-275776 CAMK2D protein Q13557 UNIPROT SCN5A protein Q14524 UNIPROT "up-regulates activity" phosphorylation Ser571 PWPLRRTsAQGQPSP 9606 BTO:0000938 33410863 t lperfetto "Among the sites identified, only six were previously suggested to be the targets for specific kinases using in silico and/or in vitro analyses: S36 and S525 were attributed to the regulation by PKA; S484 and S664 were assigned to the serum- and glucocorticoid-inducible kinase 3 (SGK3); and S516 and S571 were ascribed to CaMKII (reviewed in Marionneau and Abriel, 2015). In marked contrast, several previously described phosphorylation sites were not detected in the present study, including the PKA-dependent S528, the CaMKII-associated T594, the PKC-dependent S1506, the adenosine monophosphate–activated protein kinase (AMPK)–dependent T101 (Liu et al., 2019), and the six Fyn-dependent tyrosines (Ahern et al., 2005; Iqbal et al., 2018).|The simplest interpretation of these findings is that these three phosphorylation clusters, at positions S457-S460, S483-T486, and S664-S671, are likely involved in regulating the basal and/or gating properties of native cardiac NaV1.5 channels. Conversely, the other phosphorylation sites, with lower stoichiometries, may play spatially or temporally distinct roles in the physiological or more pathophysiological regulation of channel expression or gating. | Remarkably, this MS analysis also revealed that the vast majority of identified phosphorylation sites (at least 26) are clustered, suggesting concomitant phosphorylation and roles in regulating channel expression and/or function. Unexpectedly, however, except for S664, S667, and S671, no apparent effects of phosphomimetic or phosphosilent mutations were observed on heterologously expressed (in HEK-293 cells) NaV1.5" SIGNOR-275777 CAMK2G protein Q13555 UNIPROT SCN5A protein Q14524 UNIPROT "up-regulates activity" phosphorylation Ser516 LSLTRGLsRTSMKPR 9606 BTO:0000938 33410863 t lperfetto "Among the sites identified, only six were previously suggested to be the targets for specific kinases using in silico and/or in vitro analyses: S36 and S525 were attributed to the regulation by PKA; S484 and S664 were assigned to the serum- and glucocorticoid-inducible kinase 3 (SGK3); and S516 and S571 were ascribed to CaMKII (reviewed in Marionneau and Abriel, 2015). In marked contrast, several previously described phosphorylation sites were not detected in the present study, including the PKA-dependent S528, the CaMKII-associated T594, the PKC-dependent S1506, the adenosine monophosphate–activated protein kinase (AMPK)–dependent T101 (Liu et al., 2019), and the six Fyn-dependent tyrosines (Ahern et al., 2005; Iqbal et al., 2018).|The simplest interpretation of these findings is that these three phosphorylation clusters, at positions S457-S460, S483-T486, and S664-S671, are likely involved in regulating the basal and/or gating properties of native cardiac NaV1.5 channels. Conversely, the other phosphorylation sites, with lower stoichiometries, may play spatially or temporally distinct roles in the physiological or more pathophysiological regulation of channel expression or gating. | Remarkably, this MS analysis also revealed that the vast majority of identified phosphorylation sites (at least 26) are clustered, suggesting concomitant phosphorylation and roles in regulating channel expression and/or function. Unexpectedly, however, except for S664, S667, and S671, no apparent effects of phosphomimetic or phosphosilent mutations were observed on heterologously expressed (in HEK-293 cells) NaV1.5" SIGNOR-275779 CAMK2G protein Q13555 UNIPROT SCN5A protein Q14524 UNIPROT "up-regulates activity" phosphorylation Ser571 PWPLRRTsAQGQPSP 9606 BTO:0000938 33410863 t lperfetto "Among the sites identified, only six were previously suggested to be the targets for specific kinases using in silico and/or in vitro analyses: S36 and S525 were attributed to the regulation by PKA; S484 and S664 were assigned to the serum- and glucocorticoid-inducible kinase 3 (SGK3); and S516 and S571 were ascribed to CaMKII (reviewed in Marionneau and Abriel, 2015). In marked contrast, several previously described phosphorylation sites were not detected in the present study, including the PKA-dependent S528, the CaMKII-associated T594, the PKC-dependent S1506, the adenosine monophosphate–activated protein kinase (AMPK)–dependent T101 (Liu et al., 2019), and the six Fyn-dependent tyrosines (Ahern et al., 2005; Iqbal et al., 2018).|The simplest interpretation of these findings is that these three phosphorylation clusters, at positions S457-S460, S483-T486, and S664-S671, are likely involved in regulating the basal and/or gating properties of native cardiac NaV1.5 channels. Conversely, the other phosphorylation sites, with lower stoichiometries, may play spatially or temporally distinct roles in the physiological or more pathophysiological regulation of channel expression or gating. | Remarkably, this MS analysis also revealed that the vast majority of identified phosphorylation sites (at least 26) are clustered, suggesting concomitant phosphorylation and roles in regulating channel expression and/or function. Unexpectedly, however, except for S664, S667, and S671, no apparent effects of phosphomimetic or phosphosilent mutations were observed on heterologously expressed (in HEK-293 cells) NaV1.5" SIGNOR-275780 CAMK2A protein Q9UQM7 UNIPROT SCN8A protein Q9UQD0 UNIPROT "up-regulates activity" phosphorylation Ser641 RRSVKRNsTVDCNGV 9606 BTO:0000938 32611770 t lperfetto "CaMKII enhances voltage-gated sodium channel Nav1.6 activity and neuronal excitability|mmobilized peptide arrays and nanoflow LC-electrospray ionization/MS of Nav1.6 reveal potential sites of CaMKII phosphorylation, specifically Ser-561 and Ser-641/Thr-642 within the first intracellular loop of the channel." SIGNOR-275785 CAMK2A protein Q9UQM7 UNIPROT SCN8A protein Q9UQD0 UNIPROT "up-regulates activity" phosphorylation Thr642 RSVKRNStVDCNGVV 9606 BTO:0000938 32611770 t lperfetto "CaMKII enhances voltage-gated sodium channel Nav1.6 activity and neuronal excitability|mmobilized peptide arrays and nanoflow LC-electrospray ionization/MS of Nav1.6 reveal potential sites of CaMKII phosphorylation, specifically Ser-561 and Ser-641/Thr-642 within the first intracellular loop of the channel." SIGNOR-275786 CAMK2B protein Q13554 UNIPROT SCN8A protein Q9UQD0 UNIPROT "up-regulates activity" phosphorylation Ser561 PFLSRHNsKSSIFSF 9606 BTO:0000938 32611770 t lperfetto "CaMKII enhances voltage-gated sodium channel Nav1.6 activity and neuronal excitability|mmobilized peptide arrays and nanoflow LC-electrospray ionization/MS of Nav1.6 reveal potential sites of CaMKII phosphorylation, specifically Ser-561 and Ser-641/Thr-642 within the first intracellular loop of the channel." SIGNOR-275787 CAMK2B protein Q13554 UNIPROT SCN8A protein Q9UQD0 UNIPROT "up-regulates activity" phosphorylation Ser641 RRSVKRNsTVDCNGV 9606 BTO:0000938 32611770 t lperfetto "CaMKII enhances voltage-gated sodium channel Nav1.6 activity and neuronal excitability|mmobilized peptide arrays and nanoflow LC-electrospray ionization/MS of Nav1.6 reveal potential sites of CaMKII phosphorylation, specifically Ser-561 and Ser-641/Thr-642 within the first intracellular loop of the channel." SIGNOR-275788 CAMK2B protein Q13554 UNIPROT SCN8A protein Q9UQD0 UNIPROT "up-regulates activity" phosphorylation Thr642 RSVKRNStVDCNGVV 9606 BTO:0000938 32611770 t lperfetto "CaMKII enhances voltage-gated sodium channel Nav1.6 activity and neuronal excitability|mmobilized peptide arrays and nanoflow LC-electrospray ionization/MS of Nav1.6 reveal potential sites of CaMKII phosphorylation, specifically Ser-561 and Ser-641/Thr-642 within the first intracellular loop of the channel." SIGNOR-275789 CAMK2D protein Q13557 UNIPROT SCN8A protein Q9UQD0 UNIPROT "up-regulates activity" phosphorylation Ser561 PFLSRHNsKSSIFSF 9606 BTO:0000938 32611770 t lperfetto "CaMKII enhances voltage-gated sodium channel Nav1.6 activity and neuronal excitability|mmobilized peptide arrays and nanoflow LC-electrospray ionization/MS of Nav1.6 reveal potential sites of CaMKII phosphorylation, specifically Ser-561 and Ser-641/Thr-642 within the first intracellular loop of the channel." SIGNOR-275790 CAMK2D protein Q13557 UNIPROT SCN8A protein Q9UQD0 UNIPROT "up-regulates activity" phosphorylation Ser641 RRSVKRNsTVDCNGV 9606 BTO:0000938 32611770 t lperfetto "CaMKII enhances voltage-gated sodium channel Nav1.6 activity and neuronal excitability|mmobilized peptide arrays and nanoflow LC-electrospray ionization/MS of Nav1.6 reveal potential sites of CaMKII phosphorylation, specifically Ser-561 and Ser-641/Thr-642 within the first intracellular loop of the channel." SIGNOR-275791 PRKCA protein P17252 UNIPROT MYL9 protein P24844 UNIPROT down-regulates phosphorylation Thr10 SKRAKAKtTKKRPQR 9606 22136066 t lperfetto "Rlc can also be phosphorylated at ser1/ser2/thr9 by protein kinase c (pkc). Biophysical studies show that phosphorylation at these sites leads to an increase in the km of myosin light chain kinase (mlck) for rlc, thereby indirectly inhibiting myosin ii activity" SIGNOR-191536 CDK4 protein P11802 UNIPROT SMAD3 protein P84022 UNIPROT down-regulates phosphorylation Thr8 MSSILPFtPPIVKRL 9606 19114991 t lpetrilli "In the nucleus cdk2/4-mediated phosphorylation of smad3 occurs mostly at thr8, thr179, and ser213. Cdk-dependent phosphorylation of smad3 inhibits its transcriptional activity" SIGNOR-182983 leucine smallmolecule CHEBI:25017 ChEBI Glutaminolysis phenotype SIGNOR-PH119 SIGNOR "up-regulates activity" 9606 BTO:0000567 22749528 f Luana "Leucine and Glutamine Activate Glutaminolysis and mTORC1" SIGNOR-268011 CAMK2A protein Q9UQM7 UNIPROT SCN5A protein Q14524 UNIPROT "up-regulates activity" phosphorylation Thr594 LHGKKNStVDCNGVV 9606 33410863 t lperfetto "Among the sites identified, only six were previously suggested to be the targets for specific kinases using in silico and/or in vitro analyses: S36 and S525 were attributed to the regulation by PKA; S484 and S664 were assigned to the serum- and glucocorticoid-inducible kinase 3 (SGK3); and S516 and S571 were ascribed to CaMKII (reviewed in Marionneau and Abriel, 2015). In marked contrast, several previously described phosphorylation sites were not detected in the present study, including the PKA-dependent S528, the CaMKII-associated T594, the PKC-dependent S1506, the adenosine monophosphate‚Äìactivated protein kinase (AMPK)‚Äìdependent T101 (Liu et al., 2019), and the six Fyn-dependent tyrosines (Ahern et al., 2005; Iqbal et al., 2018).|The simplest interpretation of these findings is that these three phosphorylation clusters, at positions S457-S460, S483-T486, and S664-S671, are likely involved in regulating the basal and/or gating properties of native cardiac NaV1.5 channels. Conversely, the other phosphorylation sites, with lower stoichiometries, may play spatially or temporally distinct roles in the physiological or more pathophysiological regulation of channel expression or gating. | Remarkably, this MS analysis also revealed that the vast majority of identified phosphorylation sites (at least 26) are clustered, suggesting concomitant phosphorylation and roles in regulating channel expression and/or function. Unexpectedly, however, except for S664, S667, and S671, no apparent effects of phosphomimetic or phosphosilent mutations were observed on heterologously expressed (in HEK-293 cells) NaV1.5" SIGNOR-275772 CAMK2B protein Q13554 UNIPROT SCN5A protein Q14524 UNIPROT "up-regulates activity" phosphorylation Thr594 LHGKKNStVDCNGVV 9606 33410863 t lperfetto "Among the sites identified, only six were previously suggested to be the targets for specific kinases using in silico and/or in vitro analyses: S36 and S525 were attributed to the regulation by PKA; S484 and S664 were assigned to the serum- and glucocorticoid-inducible kinase 3 (SGK3); and S516 and S571 were ascribed to CaMKII (reviewed in Marionneau and Abriel, 2015). In marked contrast, several previously described phosphorylation sites were not detected in the present study, including the PKA-dependent S528, the CaMKII-associated T594, the PKC-dependent S1506, the adenosine monophosphate‚Äìactivated protein kinase (AMPK)‚Äìdependent T101 (Liu et al., 2019), and the six Fyn-dependent tyrosines (Ahern et al., 2005; Iqbal et al., 2018).|The simplest interpretation of these findings is that these three phosphorylation clusters, at positions S457-S460, S483-T486, and S664-S671, are likely involved in regulating the basal and/or gating properties of native cardiac NaV1.5 channels. Conversely, the other phosphorylation sites, with lower stoichiometries, may play spatially or temporally distinct roles in the physiological or more pathophysiological regulation of channel expression or gating. | Remarkably, this MS analysis also revealed that the vast majority of identified phosphorylation sites (at least 26) are clustered, suggesting concomitant phosphorylation and roles in regulating channel expression and/or function. Unexpectedly, however, except for S664, S667, and S671, no apparent effects of phosphomimetic or phosphosilent mutations were observed on heterologously expressed (in HEK-293 cells) NaV1.5" SIGNOR-275775 WNT5A protein P41221 UNIPROT AXIN1 protein O15169 UNIPROT down-regulates 9606 SIGNOR-C110 21078818 f gcesareni "We demonstrate here that prototype canonical wnt3a and noncanonical wnt5a ligands specifically trigger completely unrelated endogenous coreceptors-lrp5/6 and ror1/2, respectively-through a common mechanism that involves their wnt-dependent coupling to the frizzled (fzd) coreceptor and recruitment of shared components, including dishevelled (dvl), axin, and glycogen synthase kinase 3 (gsk3)." SIGNOR-169663 VEGFA protein P15692 UNIPROT DLL4 protein Q9NR61 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 22426001 f gcesareni "Activation triggered by vegf-a (also known as vegf) has been shown to induce expression of thenotchligand dll4 in angiogenic vessels." SIGNOR-196736 CAMK2D protein Q13557 UNIPROT SCN5A protein Q14524 UNIPROT "up-regulates activity" phosphorylation Thr594 LHGKKNStVDCNGVV 9606 33410863 t lperfetto "Among the sites identified, only six were previously suggested to be the targets for specific kinases using in silico and/or in vitro analyses: S36 and S525 were attributed to the regulation by PKA; S484 and S664 were assigned to the serum- and glucocorticoid-inducible kinase 3 (SGK3); and S516 and S571 were ascribed to CaMKII (reviewed in Marionneau and Abriel, 2015). In marked contrast, several previously described phosphorylation sites were not detected in the present study, including the PKA-dependent S528, the CaMKII-associated T594, the PKC-dependent S1506, the adenosine monophosphate‚Äìactivated protein kinase (AMPK)‚Äìdependent T101 (Liu et al., 2019), and the six Fyn-dependent tyrosines (Ahern et al., 2005; Iqbal et al., 2018).|The simplest interpretation of these findings is that these three phosphorylation clusters, at positions S457-S460, S483-T486, and S664-S671, are likely involved in regulating the basal and/or gating properties of native cardiac NaV1.5 channels. Conversely, the other phosphorylation sites, with lower stoichiometries, may play spatially or temporally distinct roles in the physiological or more pathophysiological regulation of channel expression or gating. | Remarkably, this MS analysis also revealed that the vast majority of identified phosphorylation sites (at least 26) are clustered, suggesting concomitant phosphorylation and roles in regulating channel expression and/or function. Unexpectedly, however, except for S664, S667, and S671, no apparent effects of phosphomimetic or phosphosilent mutations were observed on heterologously expressed (in HEK-293 cells) NaV1.5" SIGNOR-275778 CAMK2G protein Q13555 UNIPROT SCN5A protein Q14524 UNIPROT "up-regulates activity" phosphorylation Thr594 LHGKKNStVDCNGVV 9606 33410863 t lperfetto "Among the sites identified, only six were previously suggested to be the targets for specific kinases using in silico and/or in vitro analyses: S36 and S525 were attributed to the regulation by PKA; S484 and S664 were assigned to the serum- and glucocorticoid-inducible kinase 3 (SGK3); and S516 and S571 were ascribed to CaMKII (reviewed in Marionneau and Abriel, 2015). In marked contrast, several previously described phosphorylation sites were not detected in the present study, including the PKA-dependent S528, the CaMKII-associated T594, the PKC-dependent S1506, the adenosine monophosphate‚Äìactivated protein kinase (AMPK)‚Äìdependent T101 (Liu et al., 2019), and the six Fyn-dependent tyrosines (Ahern et al., 2005; Iqbal et al., 2018).|The simplest interpretation of these findings is that these three phosphorylation clusters, at positions S457-S460, S483-T486, and S664-S671, are likely involved in regulating the basal and/or gating properties of native cardiac NaV1.5 channels. Conversely, the other phosphorylation sites, with lower stoichiometries, may play spatially or temporally distinct roles in the physiological or more pathophysiological regulation of channel expression or gating. | Remarkably, this MS analysis also revealed that the vast majority of identified phosphorylation sites (at least 26) are clustered, suggesting concomitant phosphorylation and roles in regulating channel expression and/or function. Unexpectedly, however, except for S664, S667, and S671, no apparent effects of phosphomimetic or phosphosilent mutations were observed on heterologously expressed (in HEK-293 cells) NaV1.5" SIGNOR-275781 2'-deoxycytidine smallmolecule CHEBI:15698 ChEBI "2'-deoxycytosine 5'-monophosphate(2-)" smallmolecule CHEBI:57566 ChEBI "up-regulates quantity" "precursor of" 20637175 t lperfetto "Human deoxycytidine kinase (dCK4; EC 2.7.1.74) catalyzes the phosphorylation of 2′-deoxycytidine (dCyd), 2′-deoxyadenosine and 2′-deoxyguanosine to their corresponding monophosphate forms, using ATP or UTP as phosphoryl donors. This reaction is the first and rate-limiting step of the deoxyribonucleoside salvage pathway, which provides deoxynucleoside triphosphates for DNA replication and repair as an alternative to de novo nucleotide synthesis" SIGNOR-275810 2'-deoxyadenosine smallmolecule CHEBI:17256 ChEBI "2'-deoxyadenosine 5'-monophosphate(2-)" smallmolecule CHEBI:58245 ChEBI "up-regulates quantity" "precursor of" 20637175 t lperfetto "Human deoxycytidine kinase (dCK4; EC 2.7.1.74) catalyzes the phosphorylation of 2′-deoxycytidine (dCyd), 2′-deoxyadenosine and 2′-deoxyguanosine to their corresponding monophosphate forms, using ATP or UTP as phosphoryl donors. This reaction is the first and rate-limiting step of the deoxyribonucleoside salvage pathway, which provides deoxynucleoside triphosphates for DNA replication and repair as an alternative to de novo nucleotide synthesis" SIGNOR-275811 2'-deoxyguanosine smallmolecule CHEBI:17172 ChEBI "2'-deoxyguanosine 5'-monophosphate(2-)" smallmolecule CHEBI:57673 ChEBI "up-regulates quantity" "precursor of" 20637175 t lperfetto "Human deoxycytidine kinase (dCK4; EC 2.7.1.74) catalyzes the phosphorylation of 2′-deoxycytidine (dCyd), 2′-deoxyadenosine and 2′-deoxyguanosine to their corresponding monophosphate forms, using ATP or UTP as phosphoryl donors. This reaction is the first and rate-limiting step of the deoxyribonucleoside salvage pathway, which provides deoxynucleoside triphosphates for DNA replication and repair as an alternative to de novo nucleotide synthesis" SIGNOR-275812 "L-cystathionine dizwitterion" smallmolecule CHEBI:58161 ChEBI "L-cysteine zwitterion" smallmolecule CHEBI:35235 ChEBI "up-regulates quantity" "precursor of" 9606 BTO:0000671;BTO:0000759;BTO:0002688 19961860 t lperfetto "the role of CSE in this reaction pathway is to convert l-cystathionine into l-cysteine whilst generating α-ketobutyrate and ammonia (Fig. 1). The reaction proceeds via an α,γ-elimination mechanism where the C–γ–S bond of l-cystathionine is specifically cleaved to yield l-cysteine.12 Defects in this metabolic pathway are associated with cystathioninuria, l-cysteine deficiency and subsequent impairment of glutathione metabolism, as well as higher plasma homocysteine concentrations.13, 14, 15, 16, 17 Besides its role in the conversion of l-cystathionine into l-cysteine, studies have also shown that CSE can utilize l-cysteine as a substrate for producing H2S via an α,β-elimination reaction (Fig. 1).18, 19, 20 However, to date, no reports have clearly demonstrated the residues that affect CSE-mediated H2S production." SIGNOR-275813 "L-cysteine zwitterion" smallmolecule CHEBI:35235 ChEBI hydrosulfide smallmolecule CHEBI:29919 ChEBI "up-regulates quantity" "precursor of" 9606 BTO:0000671;BTO:0000759;BTO:0002688 19961860 t lperfetto "the role of CSE in this reaction pathway is to convert l-cystathionine into l-cysteine whilst generating α-ketobutyrate and ammonia (Fig. 1). The reaction proceeds via an α,γ-elimination mechanism where the C–γ–S bond of l-cystathionine is specifically cleaved to yield l-cysteine.12 Defects in this metabolic pathway are associated with cystathioninuria, l-cysteine deficiency and subsequent impairment of glutathione metabolism, as well as higher plasma homocysteine concentrations.13, 14, 15, 16, 17 Besides its role in the conversion of l-cystathionine into l-cysteine, studies have also shown that CSE can utilize l-cysteine as a substrate for producing H2S via an α,β-elimination reaction (Fig. 1).18, 19, 20 However, to date, no reports have clearly demonstrated the residues that affect CSE-mediated H2S production." SIGNOR-275814 "L-cysteine zwitterion" smallmolecule CHEBI:35235 ChEBI pyruvate smallmolecule CHEBI:15361 ChEBI "up-regulates quantity" "precursor of" 9606 BTO:0000671;BTO:0000759;BTO:0002688 19961860 t lperfetto "the role of CSE in this reaction pathway is to convert l-cystathionine into l-cysteine whilst generating α-ketobutyrate and ammonia (Fig. 1). The reaction proceeds via an α,γ-elimination mechanism where the C–γ–S bond of l-cystathionine is specifically cleaved to yield l-cysteine.12 Defects in this metabolic pathway are associated with cystathioninuria, l-cysteine deficiency and subsequent impairment of glutathione metabolism, as well as higher plasma homocysteine concentrations.13, 14, 15, 16, 17 Besides its role in the conversion of l-cystathionine into l-cysteine, studies have also shown that CSE can utilize l-cysteine as a substrate for producing H2S via an α,β-elimination reaction (Fig. 1).18, 19, 20 However, to date, no reports have clearly demonstrated the residues that affect CSE-mediated H2S production." SIGNOR-275815 "L-homocysteine zwitterion" smallmolecule CHEBI:58199 ChEBI hydrosulfide smallmolecule CHEBI:29919 ChEBI "up-regulates quantity" "precursor of" 9606 BTO:0000671;BTO:0000759;BTO:0002688 19961860 t lperfetto "the role of CSE in this reaction pathway is to convert l-cystathionine into l-cysteine whilst generating α-ketobutyrate and ammonia (Fig. 1). The reaction proceeds via an α,γ-elimination mechanism where the C–γ–S bond of l-cystathionine is specifically cleaved to yield l-cysteine.12 Defects in this metabolic pathway are associated with cystathioninuria, l-cysteine deficiency and subsequent impairment of glutathione metabolism, as well as higher plasma homocysteine concentrations.13, 14, 15, 16, 17 Besides its role in the conversion of l-cystathionine into l-cysteine, studies have also shown that CSE can utilize l-cysteine as a substrate for producing H2S via an α,β-elimination reaction (Fig. 1).18, 19, 20 However, to date, no reports have clearly demonstrated the residues that affect CSE-mediated H2S production." SIGNOR-275816 "L-selenocystathionine zwitterion" smallmolecule CHEBI:62226 ChEBI "L-selenocysteine zwitterion" smallmolecule CHEBI:57843 ChEBI "up-regulates quantity" "precursor of" 9606 BTO:0000671;BTO:0000759;BTO:0002688 19961860 t lperfetto "the role of CSE in this reaction pathway is to convert l-cystathionine into l-cysteine whilst generating α-ketobutyrate and ammonia (Fig. 1). The reaction proceeds via an α,γ-elimination mechanism where the C–γ–S bond of l-cystathionine is specifically cleaved to yield l-cysteine.12 Defects in this metabolic pathway are associated with cystathioninuria, l-cysteine deficiency and subsequent impairment of glutathione metabolism, as well as higher plasma homocysteine concentrations.13, 14, 15, 16, 17 Besides its role in the conversion of l-cystathionine into l-cysteine, studies have also shown that CSE can utilize l-cysteine as a substrate for producing H2S via an α,β-elimination reaction (Fig. 1).18, 19, 20 However, to date, no reports have clearly demonstrated the residues that affect CSE-mediated H2S production." SIGNOR-275817 CTH protein P32929 UNIPROT "L-cysteine zwitterion" smallmolecule CHEBI:35235 ChEBI "up-regulates quantity" "chemical modification" 9606 BTO:0000671;BTO:0000759;BTO:0002688 19961860 t lperfetto "the role of CSE in this reaction pathway is to convert l-cystathionine into l-cysteine whilst generating α-ketobutyrate and ammonia (Fig. 1). The reaction proceeds via an α,γ-elimination mechanism where the C–γ–S bond of l-cystathionine is specifically cleaved to yield l-cysteine.12 Defects in this metabolic pathway are associated with cystathioninuria, l-cysteine deficiency and subsequent impairment of glutathione metabolism, as well as higher plasma homocysteine concentrations.13, 14, 15, 16, 17 Besides its role in the conversion of l-cystathionine into l-cysteine, studies have also shown that CSE can utilize l-cysteine as a substrate for producing H2S via an α,β-elimination reaction (Fig. 1).18, 19, 20 However, to date, no reports have clearly demonstrated the residues that affect CSE-mediated H2S production." SIGNOR-275818 CTH protein P32929 UNIPROT hydrosulfide smallmolecule CHEBI:29919 ChEBI "up-regulates quantity" "chemical modification" 9606 BTO:0000671;BTO:0000759;BTO:0002688 19961860 t lperfetto "the role of CSE in this reaction pathway is to convert l-cystathionine into l-cysteine whilst generating α-ketobutyrate and ammonia (Fig. 1). The reaction proceeds via an α,γ-elimination mechanism where the C–γ–S bond of l-cystathionine is specifically cleaved to yield l-cysteine.12 Defects in this metabolic pathway are associated with cystathioninuria, l-cysteine deficiency and subsequent impairment of glutathione metabolism, as well as higher plasma homocysteine concentrations.13, 14, 15, 16, 17 Besides its role in the conversion of l-cystathionine into l-cysteine, studies have also shown that CSE can utilize l-cysteine as a substrate for producing H2S via an α,β-elimination reaction (Fig. 1).18, 19, 20 However, to date, no reports have clearly demonstrated the residues that affect CSE-mediated H2S production." SIGNOR-275819 CTH protein P32929 UNIPROT pyruvate smallmolecule CHEBI:15361 ChEBI "up-regulates quantity" "chemical modification" 9606 BTO:0000671;BTO:0000759;BTO:0002688 19961860 t lperfetto "the role of CSE in this reaction pathway is to convert l-cystathionine into l-cysteine whilst generating α-ketobutyrate and ammonia (Fig. 1). The reaction proceeds via an α,γ-elimination mechanism where the C–γ–S bond of l-cystathionine is specifically cleaved to yield l-cysteine.12 Defects in this metabolic pathway are associated with cystathioninuria, l-cysteine deficiency and subsequent impairment of glutathione metabolism, as well as higher plasma homocysteine concentrations.13, 14, 15, 16, 17 Besides its role in the conversion of l-cystathionine into l-cysteine, studies have also shown that CSE can utilize l-cysteine as a substrate for producing H2S via an α,β-elimination reaction (Fig. 1).18, 19, 20 However, to date, no reports have clearly demonstrated the residues that affect CSE-mediated H2S production." SIGNOR-275820 CTH protein P32929 UNIPROT "L-selenocysteine zwitterion" smallmolecule CHEBI:57843 ChEBI "up-regulates quantity" "chemical modification" 9606 BTO:0000671;BTO:0000759;BTO:0002688 19961860 t lperfetto "the role of CSE in this reaction pathway is to convert l-cystathionine into l-cysteine whilst generating α-ketobutyrate and ammonia (Fig. 1). The reaction proceeds via an α,γ-elimination mechanism where the C–γ–S bond of l-cystathionine is specifically cleaved to yield l-cysteine.12 Defects in this metabolic pathway are associated with cystathioninuria, l-cysteine deficiency and subsequent impairment of glutathione metabolism, as well as higher plasma homocysteine concentrations.13, 14, 15, 16, 17 Besides its role in the conversion of l-cystathionine into l-cysteine, studies have also shown that CSE can utilize l-cysteine as a substrate for producing H2S via an α,β-elimination reaction (Fig. 1).18, 19, 20 However, to date, no reports have clearly demonstrated the residues that affect CSE-mediated H2S production." SIGNOR-275821 Oxytocin protein P01178-PRO_0000020495 UNIPROT "GABA-A (a2-b1-g2) receptor" complex SIGNOR-C331 SIGNOR up-regulates 9606 33536967 f lperfetto "OT inhibits corticotropin-releasing factor (CRF) mRNA expression at the hypothalamus, resulting in antistress and anti-anxiety effects| It has been demonstrated that the inhibitory effect of OT on CRF mRNA expression is not a direct one on CRF neurons. GABAergic neurons are present in the surroundings of the PVN (peri-PVN). These GABA-projecting neurons into the PVN inhibits CRF expression via GABAA receptors" SIGNOR-268580 MMP21 protein Q8N119 UNIPROT ECM_disassembly phenotype SIGNOR-PH80 SIGNOR up-regulates 17318226 f lperfetto "Historically, MMPs were thought to function mainly as enzymes that degrade structural components of the ECM." SIGNOR-272366 Dinaciclib chemical CID:46926350 PUBCHEM CDK1 protein P06493 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-191322 CTH protein P32929 UNIPROT "L-cystathionine dizwitterion" smallmolecule CHEBI:58161 ChEBI "down-regulates quantity" "chemical modification" 9606 BTO:0000671;BTO:0000759;BTO:0002688 19961860 t lperfetto "the role of CSE in this reaction pathway is to convert l-cystathionine into l-cysteine whilst generating α-ketobutyrate and ammonia (Fig. 1). The reaction proceeds via an α,γ-elimination mechanism where the C–γ–S bond of l-cystathionine is specifically cleaved to yield l-cysteine.12 Defects in this metabolic pathway are associated with cystathioninuria, l-cysteine deficiency and subsequent impairment of glutathione metabolism, as well as higher plasma homocysteine concentrations.13, 14, 15, 16, 17 Besides its role in the conversion of l-cystathionine into l-cysteine, studies have also shown that CSE can utilize l-cysteine as a substrate for producing H2S via an α,β-elimination reaction (Fig. 1).18, 19, 20 However, to date, no reports have clearly demonstrated the residues that affect CSE-mediated H2S production." SIGNOR-275822 CTH protein P32929 UNIPROT "L-selenocystathionine zwitterion" smallmolecule CHEBI:62226 ChEBI "down-regulates quantity" "chemical modification" 9606 BTO:0000671;BTO:0000759;BTO:0002688 19961860 t lperfetto "the role of CSE in this reaction pathway is to convert l-cystathionine into l-cysteine whilst generating α-ketobutyrate and ammonia (Fig. 1). The reaction proceeds via an α,γ-elimination mechanism where the C–γ–S bond of l-cystathionine is specifically cleaved to yield l-cysteine.12 Defects in this metabolic pathway are associated with cystathioninuria, l-cysteine deficiency and subsequent impairment of glutathione metabolism, as well as higher plasma homocysteine concentrations.13, 14, 15, 16, 17 Besides its role in the conversion of l-cystathionine into l-cysteine, studies have also shown that CSE can utilize l-cysteine as a substrate for producing H2S via an α,β-elimination reaction (Fig. 1).18, 19, 20 However, to date, no reports have clearly demonstrated the residues that affect CSE-mediated H2S production." SIGNOR-275823 PGAM5 protein Q96HS1 UNIPROT ME1 protein P48163 UNIPROT "up-regulates activity" dephosphorylation Ser336 KKIWLVDsKGLIVKG 31735643 t lperfetto "PGAM5-mediated dephosphorylation of malic enzyme 1 (ME1) at S336 allows increased ACAT1-mediated K337 acetylation, leading to ME1 dimerization and activation, both of which are reversed by NEK1 kinase-mediated S336 phosphorylation. SIRT6 deacetylase antagonizes ACAT1 function in a manner that involves mutually exclusive ME1 S336 phosphorylation and K337 acetylation." SIGNOR-275569 PLK1 protein P53350 UNIPROT LRRK1 protein Q38SD2 UNIPROT "up-regulates activity" phosphorylation Ser1817 GDSIADVsIMYSEEL 9606 BTO:0000567 26192437 t "phosphosite is derived from Fig 2" lperfetto "Here we show that LRRK1 is a PLK1 substrate that is phosphorylated on Ser 1790. PLK1 phosphorylation is required for CDK1-mediated activation of LRRK1 at the centrosomes" SIGNOR-275467 LRRK1 protein Q38SD2 UNIPROT CDK5RAP2 protein Q96SN8 UNIPROT "up-regulates activity" phosphorylation Ser140 SLAEAGGsEIQRVKE 9606 BTO:0000567 26192437 t lperfetto "Interestingly, LRRK1 in turn phosphorylates CDK5RAP2(Cep215), a human homologue of Drosophila Centrosomin (Cnn), in its gamma-tubulin-binding motif, thus promoting the interaction of CDK5RAP2 with gamma-tubulin. LRRK1 phosphorylation of CDK5RAP2 Ser 140 is necessary for CDK5RAP2-dependent microtubule nucleation." SIGNOR-275468 CDK1 protein P06493 UNIPROT CLIP1 protein P30622 UNIPROT "up-regulates activity" phosphorylation Thr287 KIGFPSTtPAKAKAN 19687009 t lperfetto "Cdc2 phosphorylates T287|CLIP-170, the founding member of microtubule “plus ends tracking” proteins, is involved in many critical microtubule-related functions, including recruitment of dynactin to the microtubule plus ends and formation of kinetochore-microtubule attachments during metaphase. |These results demonstrate that Cdc2-mediated phosphorylation of CLIP-170 is essential for the normal function of this protein during cell cycle progression." SIGNOR-275470 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR CLIP1 protein P30622 UNIPROT "up-regulates activity" phosphorylation Thr287 KIGFPSTtPAKAKAN 19687009 t lperfetto "Cdc2 phosphorylates T287|CLIP-170, the founding member of microtubule “plus ends tracking” proteins, is involved in many critical microtubule-related functions, including recruitment of dynactin to the microtubule plus ends and formation of kinetochore-microtubule attachments during metaphase. |These results demonstrate that Cdc2-mediated phosphorylation of CLIP-170 is essential for the normal function of this protein during cell cycle progression." SIGNOR-275471 LRRK1 protein Q38SD2 UNIPROT CLIP1 protein P30622 UNIPROT "up-regulates activity" phosphorylation Thr1430 EMFGHWAtNCNDDET 25413345 t "Phosphosite positions are derived from Figure 1" lperfetto "LRRK1 phosphorylates CLIP-170 at Thr1384, located in its C-terminal zinc knuckle motif, and this promotes the association of CLIP-170 with dynein-dynactin complexes." SIGNOR-275469 PHKG1 protein Q16816 UNIPROT PYG proteinfamily SIGNOR-PF96 SIGNOR "up-regulates activity" phosphorylation 9606 BTO:0002049 22225877 t "It is well-characterized that GP is activated by PhK-mediated serine phosphorylation at Ser-15" SIGNOR-267960 NEK1 protein Q96PY6 UNIPROT ME1 protein P48163 UNIPROT "down-regulates activity" phosphorylation Ser336 KKIWLVDsKGLIVKG 31735643 t lperfetto "PGAM5-mediated dephosphorylation of malic enzyme 1 (ME1) at S336 allows increased ACAT1-mediated K337 acetylation, leading to ME1 dimerization and activation, both of which are reversed by NEK1 kinase-mediated S336 phosphorylation. SIRT6 deacetylase antagonizes ACAT1 function in a manner that involves mutually exclusive ME1 S336 phosphorylation and K337 acetylation." SIGNOR-275570 ACAT1 protein P24752 UNIPROT ME1 protein P48163 UNIPROT "up-regulates activity" acetylation Lys337 KIWLVDSkGLIVKGR 31735643 t lperfetto "PGAM5-mediated dephosphorylation of malic enzyme 1 (ME1) at S336 allows increased ACAT1-mediated K337 acetylation, leading to ME1 dimerization and activation, both of which are reversed by NEK1 kinase-mediated S336 phosphorylation. SIRT6 deacetylase antagonizes ACAT1 function in a manner that involves mutually exclusive ME1 S336 phosphorylation and K337 acetylation." SIGNOR-275571 SIRT6 protein Q8N6T7 UNIPROT ME1 protein P48163 UNIPROT "down-regulates activity" deacetylation Lys337 KIWLVDSkGLIVKGR 31735643 t lperfetto "PGAM5-mediated dephosphorylation of malic enzyme 1 (ME1) at S336 allows increased ACAT1-mediated K337 acetylation, leading to ME1 dimerization and activation, both of which are reversed by NEK1 kinase-mediated S336 phosphorylation. SIRT6 deacetylase antagonizes ACAT1 function in a manner that involves mutually exclusive ME1 S336 phosphorylation and K337 acetylation." SIGNOR-275572 PAK5 protein Q9P286 UNIPROT DNPEP protein Q9ULA0 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser119 VKRRSRRsQVGFQQV 9606 BTO:0000150 31219614 t lperfetto "We show that PAK5 interacts with and phosphorylates DNPEP at serine 119. | PAK5 decreases DNPEP abundance via the ubiquitin-proteasome pathway." SIGNOR-275651 P4HB protein P07237 UNIPROT ERN1 protein O75460 UNIPROT "down-regulates activity" binding 32149426 t lperfetto "The secretory pathway kinase Fam20C phosphorylates Ser357 of PDI and responds rapidly to various ER stressors. Phosphorylation of Ser357 induces an open conformation of PDI and turns it from a ""foldase"" into a ""holdase"", which is critical for preventing protein misfolding in the ER. Phosphorylated PDI also binds to the lumenal domain of IRE1α, a major UPR signal transducer, and attenuates excessive IRE1α activity." SIGNOR-275573 FAM20C protein Q8IXL6 UNIPROT P4HB protein P07237 UNIPROT "up-regulates activity" phosphorylation Ser357 KIKPHLMsQELPEDW 32149426 t lperfetto "The secretory pathway kinase Fam20C phosphorylates Ser357 of PDI and responds rapidly to various ER stressors. Phosphorylation of Ser357 induces an open conformation of PDI and turns it from a ""foldase"" into a ""holdase"", which is critical for preventing protein misfolding in the ER. Phosphorylated PDI also binds to the lumenal domain of IRE1α, a major UPR signal transducer, and attenuates excessive IRE1α activity." SIGNOR-275574 AREL1 protein O15033 UNIPROT PIAS4 protein Q8N2W9 UNIPROT "down-regulates quantity by destabilization" ubiquitination phosphorylation:Ser18;Thr783 MVMSFRVsDLQMLLG;T>782 27162139 t lperfetto "In this study, we discovered a new protein isoform encoded by KIAA0317, termed fibrosis-inducing E3 ligase 1 (FIEL1), which potently stimulates the TGFβ signaling pathway through the site-specific ubiquitination of PIAS4.FIEL1 targets PIAS4 using a double locking mechanism that is facilitated by the kinases PKCζ and GSK3β. Specifically, PKCζ phosphorylation of PIAS4 and GSK3β phosphorylation of FIEL1 are both essential for the degradation of PIAS4." SIGNOR-275575 ATM protein Q13315 UNIPROT DYRK2 protein Q92630 UNIPROT "up-regulates quantity by stabilization" phosphorylation Thr106 NKRTVLTtQPNGLTT 19965871 t "Phosphosites were derived from Figure 3" lperfetto "ATM augments nuclear stabilization of DYRK2 by inhibiting MDM2 in the apoptotic response to DNA damage|Upon exposure to genotoxic stress, ATM phosphorylates DYRK2 at Thr-33 and Ser-369, which enables DYRK2 to escape from degradation by dissociation from MDM2 and to induce the kinase activity toward p53 at Ser-46 in the nucleus." SIGNOR-275576 AKT1 protein P31749 UNIPROT CASP9 protein P55211 UNIPROT "down-regulates activity" phosphorylation Ser196 KLRRRFSsLHFMVEV -1 9812896 t lperfetto "Akt phosphorylated recombinant casp9 in vitro on serine-196 and inhibited its protease activity" SIGNOR-252581 PLK1 protein P53350 UNIPROT MDM2 protein Q00987 UNIPROT up-regulates phosphorylation Ser260 SLDSEDYsLSEEGQE 9606 12383858 t gcesareni "Here we show that the oncogenic and cell cycle-regulatory protein kinase, polo-like kinase-1 (plk1), phosphorylates mdm2 at one of these residues, ser260, and stimulates mdm2-mediated turnover of p53. These data are consistent with the idea that deregulation of plk1 during tumourigenesis may help suppress p53 function." SIGNOR-94272 PLK4 protein O00444 UNIPROT FBXW5 protein Q969U6 UNIPROT "down-regulates activity" phosphorylation Ser151 SQFNKDDsLLLASGV 21725316 t lperfetto "The activity of SCF-FBXW5 is in turn negatively regulated by Polo-like kinase 4 (PLK4), which phosphorylates FBXW5 at Ser 151 to suppress its ability to ubiquitylate HsSAS-6." SIGNOR-275476 CAMK2D protein Q13557 UNIPROT KCNQ1 protein P51787 UNIPROT "down-regulates activity" phosphorylation Ser484 PHFMRTNsFAEDLDL 29410121 t lperfetto "CaMKII regulates KCNQ1 at S484 during sustained β-AR stimulation to inhibit IKs. The ability of CaMKII to inhibit IKs may contribute to arrhythmogenicity during HF." SIGNOR-275479 PRKAA2 protein P54646 UNIPROT HIPK2 protein Q9H2X6 UNIPROT "down-regulates activity" phosphorylation Thr1116 AALGSTGtVAHLVAS 23871434 t "Phosphosite positions are derived from Figure S5" lperfetto "AMPKalpha2-mediated inhibition of WIP1 phosphorylation by HIPK2|Site-directed mutagenesis of Thr112 and Ser114 in the N terminus, and Thr1107 in the C terminus markedly reduced HIPK2 phosphorylation by AMPKalpha2 in vitro" SIGNOR-275487 GRK2 protein P25098 UNIPROT SLC9A5 protein Q14940 UNIPROT "down-regulates activity" phosphorylation Ser712 EEEESDSsETEKEDD 21296876 t lperfetto "Simultaneous mutation of five Ser/Thr residues within 702-714 to Ala ((702)ST/AA(714)) abolished phosphorylation and binding of beta-arrestin2. In transfected cells, the CK2 catalytic alpha subunit formed a complex with NHE5 and decreased wild-type but not (702)ST/AA(714) NHE5 activity, further supporting a regulatory role for this kinase. The rate of internalization of (702)ST/AA(714) was also diminished and relatively insensitive to overexpression of beta-arrestin2." SIGNOR-275500 GRK2 protein P25098 UNIPROT SLC9A5 protein Q14940 UNIPROT "down-regulates activity" phosphorylation Ser711 EEEEESDsSETEKED 21296876 t lperfetto "Simultaneous mutation of five Ser/Thr residues within 702-714 to Ala ((702)ST/AA(714)) abolished phosphorylation and binding of beta-arrestin2. In transfected cells, the CK2 catalytic alpha subunit formed a complex with NHE5 and decreased wild-type but not (702)ST/AA(714) NHE5 activity, further supporting a regulatory role for this kinase. The rate of internalization of (702)ST/AA(714) was also diminished and relatively insensitive to overexpression of beta-arrestin2." SIGNOR-275501 PRKAA2 protein P54646 UNIPROT HIPK2 protein Q9H2X6 UNIPROT "down-regulates activity" phosphorylation Ser121 LMRRSTVsLLDTYQK 23871434 t "Phosphosite positions are derived from Figure S5" lperfetto "AMPKalpha2-mediated inhibition of WIP1 phosphorylation by HIPK2|Site-directed mutagenesis of Thr112 and Ser114 in the N terminus, and Thr1107 in the C terminus markedly reduced HIPK2 phosphorylation by AMPKalpha2 in vitro" SIGNOR-275486 PRKD1 protein Q15139 UNIPROT RTKN protein Q9BST9 UNIPROT "up-regulates activity" phosphorylation Ser448 QALAKQGsLYHEMAI 22228765 t "Phosphosite positions are derived from Figure 2" lperfetto "Here, we show that rhotekin, an effector of RhoA GTPase, is a novel substrate of PKD. We identified Ser-435 in rhotekin as the potential site targeted by PKD in vivo. Expression of a phosphomimetic S435E rhotekin mutant resulted in an increase of endogenous active RhoA GTPase levels. Phosphorylation of rhotekin by PKD2 modulates the anchoring of the RhoA in the plasma membrane." SIGNOR-275511 MYC protein P01106 UNIPROT CDKN1B protein P46527 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0000150;BTO:0000782 BTO:0000887;BTO:0001260 11313917 f amattioni "P27(kip1) gene is a target of transcriptional repression by c-myc." SIGNOR-107032 ATM protein Q13315 UNIPROT DYRK2 protein Q92630 UNIPROT "up-regulates quantity by stabilization" phosphorylation Ser442 IELLGMPsQKLLDAS 19965871 t "Phosphosites were derived from Figure 3" lperfetto "ATM augments nuclear stabilization of DYRK2 by inhibiting MDM2 in the apoptotic response to DNA damage|Upon exposure to genotoxic stress, ATM phosphorylates DYRK2 at Thr-33 and Ser-369, which enables DYRK2 to escape from degradation by dissociation from MDM2 and to induce the kinase activity toward p53 at Ser-46 in the nucleus." SIGNOR-275577 DYRK2 protein Q92630 UNIPROT TP53 protein P04637 UNIPROT "up-regulates activity" phosphorylation Ser46 AMDDLMLsPDDIEQW 19965871 t lperfetto "Phosphorylation of p53 at Ser-46 is indispensable for the commitment to apoptotic cell death. |Upon exposure to genotoxic stress, ATM phosphorylates DYRK2 at Thr-33 and Ser-369, which enables DYRK2 to escape from degradation by dissociation from MDM2 and to induce the kinase activity toward p53 at Ser-46 in the nucleus." SIGNOR-275578 MDM2 protein Q00987 UNIPROT DYRK2 protein Q92630 UNIPROT "down-regulates quantity by destabilization" ubiquitination 19965871 t lperfetto "Under normal conditions, nuclear and not cytoplasmic DYRK2 is ubiquitinated by MDM2, resulting in its constitutive degradation.|Upon exposure to genotoxic stress, ATM phosphorylates DYRK2 at Thr-33 and Ser-369, which enables DYRK2 to escape from degradation by dissociation from MDM2 and to induce the kinase activity toward p53 at Ser-46 in the nucleus." SIGNOR-275579 "BRCA1-BARD1 complex" complex SIGNOR-C297 SIGNOR LARP7 protein Q4G0J3 UNIPROT "down-regulates quantity by destabilization" ubiquitination 32726637 t lperfetto "Here, we demonstrate that upon genotoxic stress, BRCA1 together with BARD1 catalyzes the K48 polyubiquitination on LARP7, a 7SK RNA binding protein known to control RNAPII pausing, and thereby degrades it through the 26S ubiquitin-proteasome pathway." SIGNOR-275581 AKT1 protein P31749 UNIPROT PARK7 protein Q99497 UNIPROT "up-regulates activity" phosphorylation Thr125 GFGSKVTtHPLAKDK 32858971 t lperfetto "Using a proteomic approach, we identified on DJ-1 a novel threonine phosphorylation (T125) that was found, by the in-silico tool scansite 4, as part of a putative Akt consensus. |Deglycase activity of DJ-1 on histones proteins, investigated by coupling 2D tau gel with LC-MS/MS and 2D-TAU (Triton-Acid-Urea)-Western blot, was found correlated with its phosphorylation status that, in turn, depends from Akt activation." SIGNOR-275582 PDPK1 protein O15530 UNIPROT AKT1 protein P31749 UNIPROT "up-regulates activity" phosphorylation Thr308 KDGATMKtFCGTPEY 9606 BTO:0000567 15718470 t gcesareni "Akt/PKB activation requires the phosphorylation of Thr308 in the activation loop by the phosphoinositide-dependent kinase 1 (PDK1) and Ser473 within the carboxyl-terminal hydrophobic motif by an unknown kinase." SIGNOR-252612 SRC protein P12931 UNIPROT BCKDK protein O14874 UNIPROT "up-regulates activity" phosphorylation Tyr246 RRLCEHKyGNAPRVR 9606 BTO:0001615 32238881 t lperfetto "Src phosphorylated BCKDK at the tyrosine 246 (Y246) site in vitro and ex vivo. Knockdown and knockout of Src downregulated the phosphorylation of BCKDK. Importantly, phosphorylation of BCKDK by Src enhanced the activity and stability of BCKDK, thereby promoting the migration, invasion, and EMT of CRC cells." SIGNOR-275583 SRC protein P12931 UNIPROT BCKDK protein O14874 UNIPROT "up-regulates quantity by stabilization" phosphorylation Tyr246 RRLCEHKyGNAPRVR 9606 BTO:0001615 32238881 t lperfetto "Src phosphorylated BCKDK at the tyrosine 246 (Y246) site in vitro and ex vivo. Knockdown and knockout of Src downregulated the phosphorylation of BCKDK. Importantly, phosphorylation of BCKDK by Src enhanced the activity and stability of BCKDK, thereby promoting the migration, invasion, and EMT of CRC cells." SIGNOR-275584 SRC protein P12931 UNIPROT FXN protein Q16595 UNIPROT "down-regulates quantity by destabilization" phosphorylation Tyr118 EDLADKPyTFEDYDV 9606 BTO:0000007 25948553 t lperfetto "We found that frataxin can be phosphorylated by Src. Phosphorylation occurs primarily on Y118 and promotes frataxin ubiquitination, a signal for degradation." SIGNOR-275585 DNPEP protein Q9ULA0 UNIPROT USP4 protein Q13107 UNIPROT "down-regulates quantity by destabilization" cleavage 31219614 t lperfetto "A further analysis showed that the hydrolysis pathway contributes to DNPEP-mediated degradation of USP4 (Supporting Information Figs. S3A–S3F). The interaction between USP4 and DNPEP was confirmed by coIP assays" SIGNOR-275652 KLHL2 protein O95198 UNIPROT WNK1 protein Q9H4A3 UNIPROT "down-regulates quantity by destabilization" binding 9606 BTO:0000007 23838290 t miannu "We found that KLHL2, as well as KLHL3, was co-immunoprecipitated with all four WNK isoforms. The direct interaction of KLHL2 with WNKs was confirmed on fluorescence correlation spectroscopy. Co-expression of KLHL2 and Cullin3 decreased the abundance of WNK1, WNK3 and WNK4 within HEK293T cells, and a significant increase of WNK4 ubiquitination by KLHL2 and Cullin3 was observed both in HEK293T cells and in an in vitro ubiquitination assay. These results suggest that KLHL2-Cullin3 also functions as an E3-ligase for WNK isoforms within the body." SIGNOR-272119 DUSP26 protein Q9BV47 UNIPROT TP53 protein P04637 UNIPROT down-regulates dephosphorylation Ser20 PLSQETFsDLWKLLP 9606 20562916 t miannu "We found that dusp26 promotes the resistance of human neuroblastoma to doxorubicin-induced apoptosis by acting as a p53 phosphatase to downregulate p53 tumor suppressor function in neuroblastoma cells. / we found that dusp26 binds to p53 and dephosphorylates p53 at ser20 and ser37." SIGNOR-166258 "GABA-A (a3-b1-g2) receptor" complex SIGNOR-C332 SIGNOR CRHR2 protein Q13324 UNIPROT down-regulates 9606 BTO:0000614 33536967 f lperfetto "OT inhibits corticotropin-releasing factor (CRF) mRNA expression at the hypothalamus, resulting in antistress and anti-anxiety effects| It has been demonstrated that the inhibitory effect of OT on CRF mRNA expression is not a direct one on CRF neurons. GABAergic neurons are present in the surroundings of the PVN (peri-PVN). These GABA-projecting neurons into the PVN inhibits CRF expression via GABAA receptors" SIGNOR-268591 MSH2 protein P43246 UNIPROT BLM protein P54132 UNIPROT up-regulates binding 9606 SIGNOR-C60 15064730 t miannu "We show that the recombinant hmsh2/6 protein complex stimulated the ability of the bloom's syndrome gene product, blm, to process holliday junctions in vitro" SIGNOR-123699 PRKACA protein P17612 UNIPROT NF2 protein P35240 UNIPROT down-regulates phosphorylation Ser518 DTDMKRLsMEIEKEK 9606 18071304 t lperfetto "Merlin localizes to the cell membrane where it links the actin cytoskeleton to membrane proteins.we identify a novel pka phosphorylation site, serine 10, in the n terminus of merlin. s10a reduces the amount of cellular f-actin and merlin s10d stabilizes f-actin filaments." SIGNOR-159844 PLK1 protein P53350 UNIPROT CHEK2 protein O96017 UNIPROT up-regulates phosphorylation Thr68 SSLETVStQELYSIP 9606 12493754 t gcesareni "Plk1 overexpression enhances phosphorylation of chk2 at thr-68." SIGNOR-96637 AXIN1 protein O15169 UNIPROT AXIN1 protein O15169 UNIPROT "up-regulates activity" binding 9606 17529994 t amattioni "The axin dix domain has a novel structural fold largely composed of beta-strands that engage in head-to-tail self-interaction to form filaments in the crystal" SIGNOR-155218 RET protein P07949 UNIPROT MAPK14 protein Q16539 UNIPROT up-regulates phosphorylation Tyr182 TDDEMTGyVATRWYR 9606 8622669 t gcesareni "Dually phosphorylated on thr-180 and tyr-182 by the map2ks map2k3/mkk3, map2k4/mkk4 and map2k6/mkk6 in response to inflammatory citokines, environmental stress or growth factors, which activates the enzyme." SIGNOR-40497 BIRC3 protein Q13489 UNIPROT PACS2 protein Q86VP3 UNIPROT "down-regulates quantity by destabilization" polyubiquitination -1 24633224 t miannu "Under basal conditions, PACS-2 underwent K48-linked poly-ubiquitination, resulting in PACS-2 proteasomal degradation. Biochemical assays showed cIAP-1 and cIAP-2 interacted with PACS-2 in vitro and co-immunoprecipitation studies demonstrated that the two cIAPs bound PACS-2 in vivo. More importantly, both cIAP-1 and cIAP-2 directly mediated PACS-2 ubiquitination in a cell-free assay." SIGNOR-272852 MRPS33 protein Q9Y291 UNIPROT "28S mitochondrial small ribosomal subunit" complex SIGNOR-C266 SIGNOR "form complex" binding 9606 25838379 t miannu "The mammalian mitochondrial ribosome (mitoribosome) has a highly protein-rich composition with a small sedimentation coefficient of 55 S, consisting of 39 S large and 28 S small subunits. . We report here the identification of 28 S small subunit proteins." SIGNOR-261444 PRKCA protein P17252 UNIPROT TNNI3 protein P19429 UNIPROT "up-regulates activity" phosphorylation Ser23 PAPIRRRsSNYRAYA -1 11121119 t lperfetto "In addition to the established phosphorylation sites (S22 and S23) we found that S38 and S165 were the other two main sites of phosphorylation. | Phosphorylation of S22/23A also decreased its affinity for troponin C indicating that phosphorylation of S38 and/or S165 impedes binding of troponin I to troponin C. Formation of a troponin I/troponin C complex prior to cAMP-dependent protein kinase treatment did not prevent overphosphorylation." SIGNOR-249066 ITGB1BP1 protein O14713 UNIPROT "A4/b1 integrin" complex SIGNOR-C162 SIGNOR "down-regulates activity" binding 9606 19118207 t miannu "Integrins also bind to many PTBdomain-containing proteins (Calderwood et al., 2003) – including Dok1 and integrincytoplasmic-domain-associated protein 1 (ICAP1) – and these can compete with talin for binding to integrin and so can impair activation" SIGNOR-257642 STAT5A protein P42229 UNIPROT MEF2C protein Q06413 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 21261500 f miannu "STAT5 binds directly to the promoter region and potently mediates repression of MEF2C, probably via HDAC recruitment." SIGNOR-254207 PTPN2 protein P17706 UNIPROT INSR protein P06213 UNIPROT down-regulates dephosphorylation Tyr1185 FGMTRDIyETDYYRK 9606 10734133 t flangone "Finally, we have tested the set of ptps for their ability to dephosphorylate a phosphopeptide corresponding to the irk autophosphorylation site. tc-ptp, sap-1, and ptp-1b all tested positive, but ptp-? Showed no activity, although the same gst-ptp preparation could efficiently convert pnpp (tablei). Interestingly, many other ptps showed activity, namely dep-1, glepp-1, lar, ptp-?, -?, -?, And shp-1." SIGNOR-75910 MAPK13 protein O15264 UNIPROT STMN1 protein P16949 UNIPROT down-regulates phosphorylation Ser25 QAFELILsPRSKESV 9606 BTO:0000782;BTO:0001271 8125092 t gcesareni "Serine 25 of oncoprotein 18 is a major cytosolic target for the mitogen-activated protein kinase." SIGNOR-36362 INSR protein P06213 UNIPROT PIK3R1 protein P27986 UNIPROT "up-regulates activity" phosphorylation Tyr607 NENTEDQySLVEDDE 9534 8385099 t "The alpha-type 85-kDa subunit of phosphatidylinositol 3-kinase is phosphorylated at tyrosines 368, 580, and 607 by the insulin receptor." SIGNOR-251322 GSK3B protein P49841 UNIPROT FGF14 protein Q92915 UNIPROT "up-regulates activity" phosphorylation Ser226 PKPGVTPsKSTSASA 9606 BTO:0000938 32599005 t lperfetto "Our laboratory has also demonstrated that FGF14 is a key accessory protein that binds to the intracellular Nav1.6 C-terminal tail, and that GSK3β can phosphorylate FGF14 both in vitro and in vivo at S226 [20] in an experimental model of Alzheimer's disease" SIGNOR-275746 SLBP protein Q14493 UNIPROT H2BC15 protein Q99877 UNIPROT "up-regulates quantity by expression" "translation regulation" 9606 BTO:0001938 19155325 t lperfetto "Synthesis of mature histone mRNA requires only a single processing reaction: an endonucleolytic cleavage between a conserved stem-loop and a purine-rich downstream element to form the 3' end. The stem-loop binding protein (SLBP) is required for processing, and following processing, histone mRNA is transported to the cytoplasm, where SLBP participates in translation of the histone mRNA|We used radiolabeled probes generated by PCR targeting the open reading frame (ORF) to detect histones H2A, H2B, H3, H4, and H1 and used 7SK snRNA as a loading control (Fig. 2A). The abundance of histone H2A, H2B, H3, and H4 mRNAs is reduced to 37% to 70% of control levels in the SLBP knockdown cells when compared to the C2 control." SIGNOR-265392 FADD protein Q13158 UNIPROT CASP8 protein Q14790 UNIPROT "up-regulates activity" binding 9606 11717445 t amattioni "Fadd recruits caspase-8 through homotypic interactions of death-effector domains (deds), leading to caspase-8 activation and apoptosis. In turn, fadd recruits the zymogen form of the apoptosis-initiating protease caspase-8, through homophilic interaction of death effector domains." SIGNOR-112061 CDK13 protein Q14004 UNIPROT POLR2A protein P24928 UNIPROT "up-regulates activity" phosphorylation Ser1665 SPTSPSYsPTSPSYS 9606 BTO:0006413 32917631 t "Ser2 in CTD of PolII" lperfetto "Together, these studies demonstrate the important, yet largely redundant, role for CDK12 and CDK13 for the regulation of POLII CTD phosphorylation at multiple residues, as well as the global role for both of these kinases in regulating POLII occupancy across the genome.|CDK12 and CDK13 are thus evolutionarily related and structurally similar kinases, and biochemical assays have demonstrated that both have POLII C-terminal domain (CTD) kinase activity and the ability to phosphorylate the Ser2 residue of the repetitive CTD heptad sequence" SIGNOR-273041 PKA proteinfamily SIGNOR-PF17 SIGNOR TRPV4 protein Q9HBA0 UNIPROT "up-regulates activity" phosphorylation Ser189 DEEFREPsTGKTCLP 9606 19661060 t Manara "We conclude that the serine/threonine kinases PKC and PKA enhance activation of the TRPV4 ion channel by phosphorylation at specific sites and that phosphorylation depends on assembly of PKC and PKA by AKAP79 into a signaling complex with TRPV4." SIGNOR-260883 AXIN2 protein Q9Y2T1 UNIPROT GSK3B protein P49841 UNIPROT "up-regulates activity" binding 9606 BTO:0000142;BTO:0000671;BTO:0000763 SIGNOR-C110 10911903 t gcesareni "It has been found that a multiprotein complex assembled by the cytoplasmic component conductin induces degradation of cytoplasmic beta-catenin. The complex includes apc, the serine/threonine kinase gsk3 beta, and beta-catenin, which bind to conductin at distinct domains." SIGNOR-79950 FASN protein P49327 UNIPROT NADP(3-) smallmolecule CHEBI:58349 ChEBI "up-regulates quantity" "chemical modification" 9606 15507492 t miannu "Human fatty acid synthase (FAS) is a complex homodimeric (552-kDa) enzyme that regulates the¬†de novo¬†biosynthesis of long-chain fatty acids. This cytosolic enzyme catalyzes the formation of 16 carbon (C16) palmitate, from acetyl-coenzyme A (acetyl-CoA) and malonyl-coenzyme A (malonyl-CoA) in the presence of NADPH.¬†" SIGNOR-268087 PRKCB protein P05771 UNIPROT NOS3 protein P29474 UNIPROT "down-regulates activity" phosphorylation Thr495 TGITRKKtFKEVANA 9606 BTO:0001853 24379783 t lperfetto "The phosphorylation of both S617 and S635 have also been shown to promote increased eNOS-derived NO release (Michell et al., 2002). The phosphorylaiton of S617 can be induced by PKA or Akt activity, and may serve to sensitize eNOS to calmodulin binding and modulate the phosphorylation of other eNOS sites" SIGNOR-251630 Gbeta proteinfamily SIGNOR-PF4 SIGNOR JAK2 protein O60674 UNIPROT down-regulates phosphorylation 9606 16705159 t "16705160:the phosphorylation of Jak2 on Ser523 inhibits Jak2 activity and represents a novel mechanism for the regulation of Jak2-dependent cytokine signaling." lperfetto "We hypothesize that phosphorylation of ser523 in jak2 by erks 1 and/or 2 or other as-yet-unidentified kinases acts in a negative feedback manner" SIGNOR-270046 ESR1 protein P03372 UNIPROT KDM4B protein O94953 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0001248 20682797 f miannu "Here, we show the histone demethylase JMJD2B is regulated by both ERalpha and HIF-1alpha, drives breast cancer cell proliferation in normoxia and hypoxia, and epigenetically regulates the expression of cell cycle genes such as CCND1, CCNA1, and WEE1. these data indicate that JMJD2B is a bona fide target of ERα and its expression in ER-positive breast cancer cells is mainly dependent on ERα." SIGNOR-263737 "Succinyl-CoA GTP variant" complex SIGNOR-C399 SIGNOR succinyl-CoA(5-) smallmolecule CHEBI:57292 ChEBI "down-regulates quantity" "chemical modification" 9606 27487822 t miannu "In the citric acid cycle, succinyl-CoA synthetase (SCS) catalyzes the only step that provides substrate-level phosphorylation: succinyl-CoA + NDP + Pi = succinate + CoA + NTP, where N is adenosine or guanosine and the reaction requires magnesium ions." SIGNOR-266268 PIP3 smallmolecule CHEBI:16618 ChEBI PDPK1 protein O15530 UNIPROT "up-regulates activity" relocalization 9606 21798082 t lperfetto "Pip3 acts in turn as a docking site for two kinases, phosphoinositide-dependent kinase 1 (PDK1) and AKT, and the subsequent phosphorylation of AKT at serine 308 by PDK1, leading to AKT activation." SIGNOR-175253 DNMT3A protein Q9Y6K1 UNIPROT DNMT1/DNMT3A complex SIGNOR-C42 SIGNOR "form complex" binding 9606 12145218 t miannu "We show that the human de novo enzymes hdnmt3a and hdnmt3b form complexes with the major maintenance enzyme hdnmt1 /in vivo co-expression of hdnmt1 and hdnmt3a or hdnmt3b leads to methylation spreading in the genome, suggesting co-operation between de novo and maintenance enzymes during dna methylation" SIGNOR-90842 ZBED1 protein O96006 UNIPROT RPS12 protein P25398 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000567 17220279 t Luana "HDRE-like sequences act as positive regulatory elements for RP gene promoter activities in vivo. | Cotransfection of a plasmid expressing hDREF increased luciferase expression directed by each RP gene promoter more than 30% compared with the values obtained without the hDREF-expressing plasmid." SIGNOR-266084 NFYA protein P23511 UNIPROT PHGDH protein O43175 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 18378410 f miannu "Positive regulation of promoter activity of human 3-phosphoglycerate dehydrogenase (PHGDH) gene is mediated by transcription factors Sp1 and NF-Y." SIGNOR-255209 SRC_kinase_family proteinfamily SIGNOR-PF32 SIGNOR KLF16 protein Q9BXK1 UNIPROT "up-regulates activity" phosphorylation Tyr10 AAVACVDyFAADVLM 22203677 t lperfetto "Phosphorylation of KLF16 was confirmed by in vivo (32)P incorporation and controlled by a Y10F site-directed mutant. Inhibition of Src-type tyrosine kinase signaling as well as the nonphosphorylatable Y10F mutation disrupted KLF16-mediated gene silencing, demonstrating that its function is regulatable rather than constitutive." SIGNOR-275586 AKT2 protein P31751 UNIPROT CHUK protein O15111 UNIPROT up-regulates phosphorylation Thr23 EMRERLGtGGFGNVC 9606 SIGNOR-C14 19609947 t gcesareni "Although there are likely to be multiple levels of crosstalk between the pi3k-akt and nf-kb pathways, one mechanism has been attributed to direct phosphorylation of the amino acid residue t23 on ikb kinase alfa (ikkalfa) by akt, thereby leading to activation of this kinase upstream of nf-kb akt mediates ikkalpha phosphorylation at threonine 23 akt transiently associates in vivo with ikk and induces ikk activation. Akt mediates ikkalfa phosphorylation at threonine 23.Akt phosphorylates ikkalpha on t23, and this phosphorylation event is a prerequisite for the phosphorylation of p65 at s534 by ikkalpha and beta" SIGNOR-187010 CDK13 protein Q14004 UNIPROT POLR2A protein P24928 UNIPROT "up-regulates activity" phosphorylation Ser1644 SPTSPSYsPTSPSYS 9606 BTO:0006413 32917631 t "Ser2 in CTD of PolII" lperfetto "Together, these studies demonstrate the important, yet largely redundant, role for CDK12 and CDK13 for the regulation of POLII CTD phosphorylation at multiple residues, as well as the global role for both of these kinases in regulating POLII occupancy across the genome.|CDK12 and CDK13 are thus evolutionarily related and structurally similar kinases, and biochemical assays have demonstrated that both have POLII C-terminal domain (CTD) kinase activity and the ability to phosphorylate the Ser2 residue of the repetitive CTD heptad sequence" SIGNOR-273042 PRKACA protein P17612 UNIPROT PIN1 protein Q13526 UNIPROT "down-regulates activity" phosphorylation Ser16 PGWEKRMsRSSGRVY 9606 11723108 t llicata "Pka and pkc readily phosphorylated pin1 and its ww domain in summary, we have demonstrated that phosphorylation of the pin1 ww domain on ser16 regulates its ability to function as a pser/thr-binding module. |To examine the importance of Ser16 of Pin1, it was mutated to Glu to mimic pSer, and the mutant Pin1S16E failed to bind mitotic phosphoproteins" SIGNOR-112164 UBE3A protein Q05086 UNIPROT ALDH1A2 protein O94788 UNIPROT "down-regulates quantity by destabilization" ubiquitination 9606 BTO:0000007 29076503 t lperfetto "Hyperactivity of E3 ubiquitin (Ub) ligase UBE3A, stemming from 15q11-q13 copy number variations, accounts for 1%-3% of ASD cases worldwide, but the underlying mechanisms remain incompletely characterized. Here we report that the functionality of ALDH1A2, the rate-limiting enzyme of retinoic acid (RA) synthesis, is negatively regulated by UBE3A in a ubiquitylation-dependent manner." SIGNOR-265135 TGFB1 protein P01137 UNIPROT ENG protein P17813 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0002741 21146604 f miannu "In hepatic stellate cells, TGF-β1 upregulates endoglin expression most likely via the ALK5 pathway and requires the SP1 transcription factor." SIGNOR-255202 CAMKK2 protein Q96RR4 UNIPROT PRKAA1 protein Q13131 UNIPROT up-regulates phosphorylation Thr183 SDGEFLRtSCGSPNY 9606 21918180 t gcesareni "Ampka1 activators increased phosphorylation level and cytoplasmic localization (reduced nuclear/cytoplasmic ratio). Ampka1 activators reduced rna synthesis in the nucleoli." SIGNOR-176602 ABL1 protein P00519 UNIPROT RBM39 protein Q14498 UNIPROT "up-regulates activity" phosphorylation Tyr99 RGRYRSPySGPKFNS 9606 BTO:0000007 27018250 t miannu "In this paper, we report that RBM39 interacts with the nonreceptor tyrosine kinase c-Abl. Both the Src homology (SH) 2 and SH3 domains of c-Abl interact with RBM39. The major tyrosine phosphorylation sites on RBM39 that are phosphorylated by c-Abl are Y95 and Y99, as demonstrated by liquid chromatography coupled with tandem mass spectrometry (LC/MS/MS) and mutational analysis. c-Abl was shown boost the transcriptional coactivation activity of RBM39 for ERα and PRβ in a tyrosine kinase-dependent manner." SIGNOR-262610 mir-133a1 mirna URS00005EB596_9606 RNAcentral IGF1R protein P08069 UNIPROT "down-regulates quantity" "post transcriptional regulation" 9606 17996649 f miannu "Here, we show that miR-223 is a direct transcriptional target of AML1/ETO. By recruiting chromatin remodeling enzymes at an AML1-binding site on the pre-miR-223 gene, AML1/ETO induces heterochromatic silencing of miR-223. Ectopic miR-223 expression, RNAi against AML1/ETO, or demethylating treatment enhances miR-223 levels and restores cell differentiation." SIGNOR-261973 PRKDC protein P78527 UNIPROT LIG4 protein P49917 UNIPROT down-regulates phosphorylation Thr650 HLKAPNLtNVNKISN 9606 15194694 t lperfetto "Using tandem mass spectrometry, we identified a dna-pk phosphorylation site at thr-650 in human lig4 and a potential second phosphorylation site at ser-668 or ser-672. Phosphorylation of lig4 per se was not required for lig4 dna end joining activity. Substitution of these amino acids with alanine, individually or in combination, led to changes in lig4 protein stability of mouse lig4. The phosphomimetic mutation s650d returned lig4 stability to that of the wild-type protein. Furthermore dna-pk was found to negatively regulate lig4 protein stability." SIGNOR-125877 ROCK2 protein O75116 UNIPROT MYL9 protein P24844 UNIPROT "up-regulates activity" phosphorylation Ser20 KRPQRATsNVFAMFD 9606 8702756 t miannu "Here we found that Rho-kinase stoichiometrically phosphorylated myosin light chain (MLC). Peptide mapping and phosphoamino acid analyses revealed that the primary phosphorylation site of MLC by Rho-kinase was Ser-19, which is the site phosphorylated by MLC kinase. Rho-kinase phosphorylated recombinant MLC, whereas it failed to phosphorylate recombinant MLC, which contained Ala substituted for both Thr-18 and Ser-19. We also found that the phosphorylation of MLC by Rho-kinase resulted in the facilitation of the actin activation of myosin ATPase." SIGNOR-261709 PPP2CA protein P67775 UNIPROT STK3 protein Q13188 UNIPROT down-regulates dephosphorylation Thr180 DTMAKRNtVIGTPFW 9606 23431053 t gcesareni "Rassf1a apparently protects mst1/2 against inactivation by pp2a, the phosphatases that dephosphorylate the stimulatory thr-183 and thr-180 of mst1 andmst2, respectively." SIGNOR-201266 ETS1 protein P14921 UNIPROT TBXAS1 protein P24557 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 14586398 f miannu "We demonstrate that p53 and ets-1 coregulate TXSA in an antagonistic and inter-related manner, with ets-1 being a potent transcriptional activator and p53 inhibiting ets-1-dependent transcription." SIGNOR-254088 NAD(1-) smallmolecule CHEBI:57540 ChEBI NADH smallmolecule CHEBI:16908 ChEBI "up-regulates quantity" "precursor of" 9606 28139779 t miannu "Human NAD-dependent isocitrate dehydrogenase existing as the Œ±2Œ≤Œ≥ heterotetramer, catalyzes the decarboxylation of isocitrate into Œ±-ketoglutarate in the Krebs cycle, and is allosterically regulated by citrate, ADP and ATP." SIGNOR-268113 CHRM5 protein P08912 UNIPROT GNA14 protein O95837 UNIPROT "up-regulates activity" binding 9606 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257291 ASXL1 protein Q8IXJ9 UNIPROT CDKN2A protein P42771 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 29967380 t miannu "Modeling ASXL1 mutation revealed impaired hematopoiesis caused by derepression of p16Ink4a through aberrant PRC1-mediated histone modification. These results indicated that loss of protein interaction between Asxl1 mutant and Bmi1 affected the activity of PRC1, and subsequent derepression of p16Ink4a by aberrant histone ubiquitination could induce cellular senescence, resulting in low-risk MDS-like phenotypes in Asxl1G643fs/+ mice." SIGNOR-260119 staurosporine chemical CHEBI:15738 ChEBI PRKCH protein P24723 UNIPROT "down-regulates activity" "chemical inhibition" -1 22037378 t Luana "Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here." SIGNOR-258286 RBBP4 protein Q09028 UNIPROT "MBD3/NuRD complex" complex SIGNOR-C338 SIGNOR "form complex" binding 9606 27098840 t miannu "The NuRD complex is a multi-protein transcriptional corepressor that couples histone deacetylase and ATP-dependent chromatin remodelling activities.In humans, an assembly of proteins called the NuRD complex makes chromatin more compact by removing acetyl groups from nucleosomes. This complex is important for early development and for the stability and repair of our genes. Three proteins make up its core: HDAC1, which removes the acetyl group from the nucleosome; MTA1, which acts as a scaffold to hold the complex together; and RBBP4, which enables the complex to interact with nucleosomes. MBD2 and MBD3 are members of the methyl cytosine-guanosine (CpG)-binding domain (MBD) family of proteins42; 43. Of the five MBD members, only MBD2 and MBD3 associate with NuRD and are required for the complex formation and gene repression." SIGNOR-263849 GPER1 protein Q99527 UNIPROT GNAS protein P63092 UNIPROT "up-regulates activity" binding 10696571 t "GPCRs transduce their signal via G-protein heterotrimers (αβγ) that dissociate in free Gα-subunit protein and Gβγ-subunit protein complexes following ligand stimulation; the activated receptor induces a conformational change in the associated G protein α-subunit leading to release of GDP followed by binding of GTP and α-subunit dissociation from the receptor." SIGNOR-251102 SMAD2 protein Q15796 UNIPROT MEF2A protein Q02078 UNIPROT up-regulates binding 10090 BTO:0000165 BTO:0001760 SIGNOR-C8 11160896 t lperfetto "Our studies indicate that smad2 and 4 (smad2/4) complexes cooperate with mef2 regulatory proteins in a gal4-based one-hybrid reporter gene assay." SIGNOR-235846 FOXO proteinfamily SIGNOR-PF27 SIGNOR RBL2 protein Q08999 UNIPROT "up-regulates quantity" "transcriptional regulation" 9606 BTO:0000944 11884591 t gcesareni "Here we show that the Forkheads AFX (FOXO4) and FKHR-L1 (FOXO3a) also directly control transcription of the retinoblastoma-like p130 protein and cause upregulation of p130 protein expression." SIGNOR-252934 PRKACA protein P17612 UNIPROT SUFU protein Q9UMX1 UNIPROT up-regulates phosphorylation Ser346 RAPSRKDsLESDSST 9606 21317289 t gcesareni "We report that Sufu is phosphorylated at Ser-342 and Ser-346 by GSK3? and cAMP-dependent protein kinase A (PKA), respectively, and phosphorylation at this dual site stabilizes Sufu against Shh signaling-induced degradation" SIGNOR-200496 AHR protein P35869 UNIPROT CYP1B1 protein Q16678 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0001033 16115918 f miannu "Expressions of CYP1B1 mRNA and protein were increased in prostate cancer. The aryl hydrocarbon receptor (AhR)/AhR nuclear translocator (ARNT) heterodimer complex activates gene transcription by binding to the DREs of CYP1B1." SIGNOR-253733 ASTN2 protein O75129 UNIPROT ASTN1 protein O14525 UNIPROT "down-regulates quantity" binding 9606 BTO:0000007 20573900 t miannu "Biochemical and flow cytometry experiments show that ASTN2 forms a complex with ASTN1 and regulates surface expression of ASTN1. Coexpression with ASTN2 reduces the cell surface localization of ASTN1." SIGNOR-269813 FFAR2 protein O15552 UNIPROT GNAL protein P38405 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-256946 DNA_damage stimulus SIGNOR-ST1 SIGNOR TAOK1 protein Q7L7X3 UNIPROT up-regulates 9606 17396146 f lperfetto "These findings indicate that TAO kinases are regulators of p38-mediated responses to DNA damage and are intermediates in the activation of p38 by ATM." SIGNOR-226599 NUP42 protein O15504 UNIPROT NPC complex SIGNOR-C263 SIGNOR "form complex" binding 27016207 t lperfetto "The protein inventory of the NPC has been studied for a very diverse set of eukaryotes, including trypanosomes, fungi, plants, animals, and humans [4], [5], [6], [7], [8], [9]. In all cases, about 30 different Nups were found (Fig. 2)." SIGNOR-262097 "HIF-1 complex" complex SIGNOR-C418 SIGNOR PDK1 protein Q15118 UNIPROT "up-regulates quantity" "transcriptional regulation" 10090 16517405 t "We found that HIF-1 also actively suppresses metabolism through the tricarboxylic acid cycle (TCA) by directly trans-activating the gene encoding pyruvate dehydrogenase kinase 1 (PDK1). PDK1 inactivates the TCA cycle enzyme, pyruvate dehydrogenase (PDH), which converts pyruvate to acetyl-CoA." SIGNOR-267480 MAPK9 protein P45984 UNIPROT JUN protein P05412 UNIPROT up-regulates binding 9606 9405416 t "Inactive c-Jun NH2-terminal kinase (JNK)." gcesareni "C-jun is targeted for ubiquitination by its association with inactive c-jun nh2-terminal kinase (jnk).Phosphorylation By activated jnk protects c-jun from ubiquitination." SIGNOR-53791 ATM protein Q13315 UNIPROT NABP2 protein Q9BQ15 UNIPROT "up-regulates activity" phosphorylation Thr117 EPNPEYStQQAPNKA 10090 BTO:0002245 18449195 t miannu "Ataxia telangiectasia mutated (ATM) kinase phosphorylates hSSB1 in response to DNA double-strand breaks (DSBs). This phosphorylation event is required for DNA damage-induced stabilization of hSSB1." SIGNOR-262639 CDK1 protein P06493 UNIPROT LMNA protein P02545 UNIPROT up-regulates phosphorylation Ser392 ERLRLSPsPTSQRSR 9606 18815303 t gcesareni "Phosphorylation by mitotic cdc2 kinase at ser-22, ser-390, and ser-392 residues on lamin a/c, or by protein kinase c (pkc) during apoptosis, leads to the depolymerization of lamin (disassembly of the nuclear lamina), which may lead to their release from the inm" SIGNOR-181318 CDK5 protein Q00535 UNIPROT LMTK2 protein Q8IWU2 UNIPROT down-regulates phosphorylation 9606 12832520 t gcesareni "Cprk displays catalytic activity in in vitro kinase assays and is itself phosphorylated by cdk5/p35. Cdk5/p35 inhibits cprk activity." SIGNOR-102717 3-(1-methyl-3-indolyl)-4-[1-[1-(2-pyridinylmethyl)-4-piperidinyl]-3-indolyl]pyrrole-2,5-dione chemical CHEBI:91368 ChEBI PRKACB protein P22694 UNIPROT "down-regulates activity" "chemical inhibition" -1 22037378 t Luana "Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here." SIGNOR-258211 nalbuphine chemical CHEBI:7454 ChEBI OPRK1 protein P41145 UNIPROT "up-regulates activity" "chemical activation" 10029 9262330 t miannu "We recently cloned a human kappa opioid receptor and stably expressed it in Chinese hamster ovary (CHO) cells. In this study, the effects of activation of the human kappa receptor by agonists on [35S]GTPgammaS binding to CHO cell membranes were examined.. The rank order of potencies of opioid ligands tested in stimulating [35S]GTPgammaS binding was dynorphin A 1-17 > (+/-)-ethylketocyclazocine > beta-funaltrexamine, (-)-U50,488H, tifluadom > nalorphine > pentazocine, nalbuphine > buprenorphine." SIGNOR-258658 EGFR protein P00533 UNIPROT SHC3 protein Q92529 UNIPROT up-regulates binding 9606 BTO:0000938 BTO:0000142 24212772 t "GRB2 recruit indirectly through PTB domain-mediated binding of the Shc adaptor" gcesareni "Several tyrosine-based motifs recruit a number of signal transducers to the phosphorylated form of erbb1 such as the adaptor proteins growth-factor-receptor bound-2 (grb2) and src-homology-2-containing (shc)." SIGNOR-55861 "Exon junction complex" complex SIGNOR-C369 SIGNOR mRNA-nucleus_export phenotype SIGNOR-PH127 SIGNOR up-regulates 9606 11532962 f lperfetto "The exon–exon junction complex provides a binding platform for factors involved in mRNA export and nonsense-mediated mRNA decay" SIGNOR-268313 PRKCA protein P17252 UNIPROT HABP4 protein Q5JVS0 UNIPROT "down-regulates activity" phosphorylation Thr375 GRGARGGtRGGRGRI 9606 BTO:0004974 14699138 t lperfetto "We found a strong phosphorylation of Ki-1/57 by PKCalphabeta, PKCdelta, PKClambda/zeta, and especially by PKCsigma, however not by PKCmi. These data show that Ki-1/57 can serve in principal as a substrate for a wide variety of different PKC isoforms but also that its phosphorylation is strongest with PKCsigma. | This suggests that the two threonine residues present in this fragment (Thr354 and Thr375) might be the main target residues for phosphorylation by PKC in vitro. | Ki-1/57 Exits the Nucleus upon PMA Activation" SIGNOR-249252 STAT1 protein P42224 UNIPROT IL12A protein P29459 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000801 19029990 f lperfetto "STAT1 binds as a homodimer to cis elements known as gammaactivated sequences in the promoters of the genes encoding NOS2, the MHC class II transactivator (CIITA) and IL-12, among others." SIGNOR-249499 Amyloid_fibril_formation phenotype SIGNOR-PH59 SIGNOR Apoptosis phenotype SIGNOR-PH2 SIGNOR up-regulates 9606 BTO:0000590 11578751 f lperfetto "Alzheimer's disease, the cause of one of the most common types of dementia, is a brain disorder affecting the elderly and is characterized by the formation of two main protein aggregates: senile plaques and neurofibrillary tangles, which are involved in the process leading to progressive neuronal degeneration and death" SIGNOR-251640 ROS stimulus SIGNOR-ST2 SIGNOR GSTA4 protein O15217 UNIPROT up-regulates 9534 BTO:0004055 12646569 f lperfetto "We have also provided evidence that the mitochondrial GSTA4-4 level markedly increases in COS cells under oxidative stress conditions, suggesting its critical role in maintaining the GSH homeostasis under conditions of chemical and oxidative stress" SIGNOR-264797 NOTCH1 protein P46531 UNIPROT RBPJ/NOTCH complex SIGNOR-C97 SIGNOR "form complex" binding 9606 7566092 t "Here we show that activated forms of mNotch associate with the human analogue of Su(H), KBF2/RBP-Jk and act as transcriptional activators through the KBF2-binding sites of the HES-1 promoter." SIGNOR-254381 ECM stimulus SIGNOR-ST20 SIGNOR "A6/b1 integrin" complex SIGNOR-C164 SIGNOR up-regulates 9606 30889378 t miannu "Upon binding to the extracellular matrix (ECM), the integrins organize the cytoskeleton and activate intracellular signaling, regulating complex cellular behaviors, including survival, proliferation, migration, and various cell fate transitions" SIGNOR-259037 CDK13 protein Q14004 UNIPROT POLR2A protein P24928 UNIPROT "up-regulates activity" phosphorylation Ser1735 SPTSPSYsPTSPSYS 9606 BTO:0006413 32917631 t "Ser2 in CTD of PolII" lperfetto "Together, these studies demonstrate the important, yet largely redundant, role for CDK12 and CDK13 for the regulation of POLII CTD phosphorylation at multiple residues, as well as the global role for both of these kinases in regulating POLII occupancy across the genome.|CDK12 and CDK13 are thus evolutionarily related and structurally similar kinases, and biochemical assays have demonstrated that both have POLII C-terminal domain (CTD) kinase activity and the ability to phosphorylate the Ser2 residue of the repetitive CTD heptad sequence" SIGNOR-273043 "L-serine zwitterion" smallmolecule CHEBI:33384 ChEBI "L-cystathionine dizwitterion" smallmolecule CHEBI:58161 ChEBI "up-regulates quantity" "precursor of" 9606 23981774 t lperfetto "Cystathionine β-synthase (CBS) is a pyridoxal 5'-phosphate (PLP)-dependent enzyme that catalyzes the condensation of homocysteine with serine to generate cystathionine." SIGNOR-275827 BCOR protein Q6W2J9 UNIPROT HOXA7 protein P31268 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 10090 26847029 f irozzo "Importantly, our results showed that BCOR is a repressor of HoxA cluster of genes (HoxA5, HoxA7 and HoxA9) in myeloid cells. Knock-down of HoxA5, HoxA7 and HoxA9 significantly decreased the clonogenic growth of Bcor mutant and wild type cells, demonstrating the Hox genes, as targets of BCOR, played an important role in mediating BCOR’s function in regulating myeloid cell proliferation." SIGNOR-256013 CEP41 protein Q9BYV8 UNIPROT HIF1A protein Q16665 UNIPROT "up-regulates activity" binding 9606 BTO:0000007 31885126 t miannu "We performed these assays in HEK 293T cells and observed CEP41 binds HIF1α under both normoxic and hypoxic conditions. Of note, we found hypoxia induces more expression of HIF1α and increases its binding to CEP41 (Fig 8B and C). Hence, these results suggest CEP41 modulates the activation of HIF1α via a physical interaction" SIGNOR-269662 STXBP2 protein Q15833 UNIPROT STX11 protein O75558 UNIPROT "up-regulates activity" binding 9606 BTO:0000782 28265073 t lperfetto "Strikingly, addition of Munc18-2 substantially and selectively facilitates complete fusion mediated by lipid-anchored STX11 by promoting and stabilizing the assembly of SNARE complexes." SIGNOR-261898 FZD3 protein Q9NPG1 UNIPROT DVL1 protein O14640 UNIPROT "up-regulates activity" binding 9606 22944199 t amattioni "When canonical wnts bind to their respective fzd receptors, heterotrimeric g-proteins and dsh get activated and lead to the recruitment of axin to the fzd co-receptor lrp." SIGNOR-134288 "Elongin E3-Cul-5" complex SIGNOR-C531 SIGNOR SIGLEC7 protein Q9Y286 UNIPROT "down-regulates quantity by destabilization" polyubiquitination 10090 BTO:0001516 17138568 t miannu "SOCS proteins can act as E3 ligases by forming a complex with Elongin B/C and Cul5/Rbx1/2.SOCS3 targets Siglec 7 for degradation" SIGNOR-272644 KDM6A protein O15550 UNIPROT SPI1 protein P17947 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 29736013 t miannu "Our findings reveal a dual role for UTX in suppressing acute myeloid leukaemia via repression of oncogenic ETS and upregulation of tumor suppressive GATA programs. several ETS transcription factors, including Elf4, Etv6, Erg, Fli1, Ets2, Spi1 and Elk3 were upregulated immediately after Utx loss in the preleukaemic phase" SIGNOR-260036 ITSN1 protein Q15811 UNIPROT "AP-2/clathrin vescicle" complex SIGNOR-C249 SIGNOR "up-regulates quantity by stabilization" binding 24789820 t lperfetto "Early recruitment of FCHo1/2, Eps15, epsin, and intersectin to the rims of assembling coated pits is essential for their stability and further growth" SIGNOR-260714 RET protein P07949 UNIPROT MAPK14 protein Q16539 UNIPROT up-regulates phosphorylation Tyr182 TDDEMTGyVATRWYR 9606 17548358 t gcesareni "Dually phosphorylated on thr-180 and tyr-182 by the map2ks map2k3/mkk3, map2k4/mkk4 and map2k6/mkk6 in response to inflammatory citokines, environmental stress or growth factors, which activates the enzyme." SIGNOR-155381 EGFR protein P00533 UNIPROT VAV2 protein P52735 UNIPROT up-regulates phosphorylation Tyr159 HDLGEDIyDCVPCED 9606 12454019 t miannu "To understand the mechanism of egf-dependent vav2 activation, we examined first the egf-dependent phosphorylation sites on vav2 and the nature of interaction of vav2 with the activated egf receptor. Based on our in vitro and in vivo data all three tyrosine residues (142, 159, and 172) in the n-terminal domain of vav2 can be phosphorylated by the egf receptor." SIGNOR-95976 N-[2-hydroxy-5-(1-hydroxy-2-{[1-(4-methoxyphenyl)propan-2-yl]amino}ethyl)phenyl]formamide chemical CHEBI:63082 ChEBI ADRB1 protein P08588 UNIPROT "up-regulates activity" "chemical activation" 10030 BTO:0000457 20590599 t Luana "Thus, overall, salmeterol is a highly selective β2-adrenoceptor agonist because of its higher β2-affinity and not because of higher β2-intrinsic efficacy. A similar reasoning can be applied to formoterol, although this agonist has higher intrinsic efficacy at all three receptors (rank 6, 8 and 5 at β1, β2 and β3)." SIGNOR-257854 CDK1 protein P06493 UNIPROT MASTL protein Q96GX5 UNIPROT "up-regulates activity" phosphorylation Thr194 NMMDILTtPSMAKPR 8355 22354989 t gcesareni "We propose a model in which the initiating event for Gwl activation is phosphorylation by MPF of the proline-directed sites T193 and T206 in the presumptive activation loop" SIGNOR-243414 AKT1 protein P31749 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR down-regulates phosphorylation Thr24 LPRPRSCtWPLPRPE -1 BTO:0000318 10377430 t lperfetto "Here we show that the activation of phosphatidylinositol 3 (PI3) kinase by extracellular growth factors induces phosphorylation, nuclear export, and transcriptional inactivation of FKHR1, a member of the FKHR subclass of the forkhead family of transcription factors. Protein kinase B (PKB)/Akt, a key mediator of PI3 kinase signal transduction, phosphorylated recombinant FKHR1 in vitro at threonine-24 and serine-253. Mutants FKHR1(T24A), FKHR1(S253A), and FKHR1(T24A/S253A) were resistant to both PKB/Akt-mediated phosphorylation and PI3 kinase-stimulated nuclear export." SIGNOR-252857 HCK protein P08631 UNIPROT BCR-ABL "fusion protein" SIGNOR-FP6 SIGNOR "up-regulates activity" phosphorylation Tyr798 VSRNAAEyLLSSGIN 9606 16912036 t Manara "Src family kinases phosphorylate the Bcr-Abl SH3-SH2 region and modulate Bcr-Abl transforming activity. | Tyrosine phosphorylation of the SH3-SH2 region is essential for full Bcr-Abl biological activity." SIGNOR-260812 HNF4G protein Q14541 UNIPROT HAS2 protein Q92819 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0003723 23896584 t Luana "Transcription was activated by HNF4G in reporter assays using the promoter/enhancer region of the HAS2 gene. The endogenous expression of the HAS2 gene was suppressed by knockdown of HNF4G." SIGNOR-261626 WNT1 protein P04628 UNIPROT CTNNB1 protein P35222 UNIPROT up-regulates 10116 11149923 f gcesareni "Wnt-1 signaling inhibited the cytochrome c release and the subsequent caspase-9 activation induced by chemotherapeutic drugs, including both vincristine and vinblastine. Furthermore, we found that wnt-1-mediated cell survival was dependent on the activation of beta-catenin/t cell factor (tcf) transcription" SIGNOR-85760 CHAF1A protein Q13111 UNIPROT MGMT protein P16455 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0000567 15657354 f miannu "Chromatin immunoprecipitation analysis of methyl-CpG binding domain containing proteins detected a greater amount of MeCP2, MBD1, and CAF-1 bound to the MGMT promoter in MGMT-silenced cells. Our findings implicate specific MBD proteins in methylation-mediated transcriptional silencing of MGMT." SIGNOR-254569 PKM protein P14618 UNIPROT phosphonatoenolpyruvate smallmolecule CHEBI:58702 ChEBI "down-regulates quantity" "chemical modification" 9606 15996096 t miannu "Pyruvate kinase (PK)1 is an important regulatory enzyme that is able to generate ATP under hypoxic conditions as well as regulate glucose consumption. Pyruvate kinase catalyzes the last step in glycolysis converting the substrate phosphoenolpyruvate (PEP) into pyruvate, while producing one molecule of ATP per reaction per cycle (Figure 1A)." SIGNOR-266534 HABP4 protein Q5JVS0 UNIPROT MEF2C protein Q06413 UNIPROT "down-regulates activity" binding 10116 15862299 t llicata "MEF2C DNA-binding activity is inhibited through its interaction with the regulatory protein Ki-1/57." SIGNOR-238283 MMP16 protein P51512 UNIPROT ECM stimulus SIGNOR-ST20 SIGNOR down-regulates 17318226 f lperfetto "Historically, MMPs were thought to function mainly as enzymes that degrade structural components of the ECM." SIGNOR-272384 CDK2 protein P24941 UNIPROT CDC6 protein Q99741 UNIPROT "down-regulates activity" phosphorylation Ser74 TPHLPPCsPPKQGKK 9606 SIGNOR-C83 10339564 t lperfetto "Hscdc6 is an excellent substrate for cdk2 in vitro and is phosphorylated in vivo at three sites (ser-54, ser-74, and ser-106)|An HsCdc6A1A2A3 mutant, which mimics unphosphorylated HsCdc6, is exclusively nuclear, and its expression inhibits initiation of DNA replication. An HsCdc6E1E2E3 mutant, which mimics phosphorylated HsCdc6, is exclusively cytoplasmic and is not associated with the chromatin/nuclear matrix fraction." SIGNOR-67548 MAPK8 protein P45983 UNIPROT MFN2 protein O95140 UNIPROT "down-regulates quantity" phosphorylation Ser27 HMAEVNASPLKHFVT 9606 BTO:0001938 22748923 t Barakat "We demonstrate that a critical component of the mitochondrial fusion apparatus, the mitofusin Mfn2, is a target for phosphorylation in response to a variety of cellular stresses. We provide direct evidence that JNK mediates this phosphorylation." SIGNOR-274138 ZBTB32 protein Q9Y2Y4 UNIPROT ZBTB16/ZBTB32 complex SIGNOR-C80 SIGNOR "form complex" binding 9606 10572087 t miannu "We show that fazf is a transcriptional repressor and it readily forms heterodimers with plzf." SIGNOR-72380 CyclinE/CDK2 complex SIGNOR-C16 SIGNOR Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 21524151 f miannu "In its hypophosphorylated state, pRb binds transcription factors of the E2F family which are required for cell cycle progression. As the level of CyclinD/Cdk4/6 complexes increases, pRb becomes phosphorylated and progression through G1 occurs. At a critical level of phosphorylation, E2F is released from pRb. This activates the transcription of CyclinE which complexes with Cdk2 to fully release pRb repression by further phosphorylation, establishing a positive feedback loop. E2F further promotes the transcription of S-phase genes. Thus, CyclinD/Cdk4/6 and CyclinE/Cdk2 together regulate S-phase entry via phosphorylating pRb, which controls pRb binding to E2F" SIGNOR-262532 PAICS protein P22234 UNIPROT 5-amino-1-(5-phosphonato-beta-D-ribosyl)imidazol-3-ium smallmolecule CHEBI:137981 ChEBI "down-regulates quantity" "chemical modification" 9606 33179964 t miannu "The next two reactions (steps 6 and 7) involve carb oxylation of AIR to 4-carboxy-5-aminoimidazole ribonu cleotide (CAIR) and ligation of the carboxy group of CAIR with an amide group derived from Asp in an ATP dependent reaction forming 4-(N-succinylcarboxamide)- 5-aminoimidazole ribonucleotide (SAICAR). These reac tions are catalyzed by the bifunctional enzyme phosphoribosylaminoimidazole carboxylase/phosphori bosylaminoimidazole succinocarboxamide synthetase (PAICS)." SIGNOR-267317 PHKG1 protein Q16816 UNIPROT PHKG1 protein Q16816 UNIPROT unknown phosphorylation Ser31 EILGRGVsSVVRRCI -1 7935360 t miannu "Phosphopeptides correspond to sequences occurring in the gamma-subunit of phosphorylase kinase […] undergoes autophosphorylation. phosphorylation occurs primarily at Ser30 while in the latter an additional reaction takes place at Ser81." SIGNOR-250388 FGG protein P02679 UNIPROT Platelet_aggregation phenotype SIGNOR-PH81 SIGNOR up-regulates 16418530 f lperfetto "In response to agonist stimulation, the αIIbβ3 integrin on platelets is converted to an active conformation that binds fibrinogen and mediates platelet aggregation." SIGNOR-253373 JUN protein P05412 UNIPROT RCAN1 protein P53805 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 18641051 f lperfetto "Taken together, our findings suggest that c-Jun, a transcription factor downstream of the JNK signaling pathway, up-regulates Adapt78 expression in response to TG-induced ER stress and contributes to protection against TG-induced cell death." SIGNOR-253148 FBXO32 protein Q969P5 UNIPROT MYOD1 protein P15172 UNIPROT "down-regulates quantity by destabilization" ubiquitination 9606 BTO:0001103 19319192 t gcesareni "Here we present evidence that mafbx targets myod for degradation in several models of skeletal muscle atrophy." SIGNOR-184861 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR mTORC1 complex SIGNOR-C3 SIGNOR unknown phosphorylation 9606 21071439 t "inferred from 70% family members" lperfetto "We found three proline-directed residues within raptor, ser(8), ser(696), and ser(863), which are directly phosphorylated by erk1/2. Expression of phosphorylation-deficient alleles of raptor revealed that phosphorylation of these sites by erk1/2 normally promotes mtorc1 activity and signaling to downstream substrates, such as 4e-bp1." SIGNOR-270150 YBX1 protein P67809 UNIPROT MMP13 protein P45452 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 17822788 f miannu "YB-1 binds to the MMP-13 promoter sequence and represses MMP-13 transactivation via the AP-1 site." SIGNOR-255615 DAPK3 protein O43293 UNIPROT MYL12B protein O14950 UNIPROT up-regulates phosphorylation Thr19 KKRPQRAtSNVFAMF 9606 1178183 t gcesareni "Hzipk phosphorylated the regulatory light chain of myosin ii (mrlc) at both ser19 and thr18 in vitro. Phosphorylation of mrlc is required to generate the driving force in the migration of the cells but not necessary for localization of myosin ii at the leading edge." SIGNOR-16047 EGFR protein P00533 UNIPROT SHC3 protein Q92529-2 UNIPROT "up-regulates activity" phosphorylation Tyr218 GDGSDHPyYNSIPSK -1 11791173 t done miannu "We also obtained tryptic phosphopeptide maps of N-Shc protein phosphorylated in vitro by other tyrosine kinases, TrkB, v-Src and EGFR. The overall patterns of the phosphopeptide maps generated by these tyrosine kinases were similar, although there were some differences among these maps (Figure 4a–d).We performed phosphopeptide mapping analysis using GST-fused N-Shc protein, and found that N-Shc phosphorylated by TrkA in vitro was resolved into at least seven phosphopeptides (Y1 through Y7, Figure 4a). Phosphopeptide mapping revealed that N-Shc has novel tyrosine-phosphorylation sites at Y259/Y260 and Y286; in vivo-phosphorylation of these tyrosines was demonstrated by site-specific anti-pTyr antibodies. Phosphorylated Y286 bound to several proteins, of which one was Crk. The pY221/pY222 site, corresponding to one of the Grb2-binding sites of Shc, also preferentially bound to Crk. The phosphorylation-dependent interaction between N-Shc and Crk was demonstrated in vitro and in vivo." SIGNOR-273910 EGFR protein P00533 UNIPROT SHC3 protein Q92529-2 UNIPROT "up-regulates activity" phosphorylation Tyr283 RQGSSDIySTPEGKL -1 11791173 t done miannu "We also obtained tryptic phosphopeptide maps of N-Shc protein phosphorylated in vitro by other tyrosine kinases, TrkB, v-Src and EGFR. The overall patterns of the phosphopeptide maps generated by these tyrosine kinases were similar, although there were some differences among these maps (Figure 4a–d).We performed phosphopeptide mapping analysis using GST-fused N-Shc protein, and found that N-Shc phosphorylated by TrkA in vitro was resolved into at least seven phosphopeptides (Y1 through Y7, Figure 4a). Phosphopeptide mapping revealed that N-Shc has novel tyrosine-phosphorylation sites at Y259/Y260 and Y286; in vivo-phosphorylation of these tyrosines was demonstrated by site-specific anti-pTyr antibodies. Phosphorylated Y286 bound to several proteins, of which one was Crk. The pY221/pY222 site, corresponding to one of the Grb2-binding sites of Shc, also preferentially bound to Crk. The phosphorylation-dependent interaction between N-Shc and Crk was demonstrated in vitro and in vivo." SIGNOR-273911 EGFR protein P00533 UNIPROT SHC3 protein Q92529-2 UNIPROT "up-regulates activity" phosphorylation Tyr219 DGSDHPYyNSIPSKM -1 11791173 t done miannu "We also obtained tryptic phosphopeptide maps of N-Shc protein phosphorylated in vitro by other tyrosine kinases, TrkB, v-Src and EGFR. The overall patterns of the phosphopeptide maps generated by these tyrosine kinases were similar, although there were some differences among these maps (Figure 4a–d).We performed phosphopeptide mapping analysis using GST-fused N-Shc protein, and found that N-Shc phosphorylated by TrkA in vitro was resolved into at least seven phosphopeptides (Y1 through Y7, Figure 4a). Phosphopeptide mapping revealed that N-Shc has novel tyrosine-phosphorylation sites at Y259/Y260 and Y286; in vivo-phosphorylation of these tyrosines was demonstrated by site-specific anti-pTyr antibodies. Phosphorylated Y286 bound to several proteins, of which one was Crk. The pY221/pY222 site, corresponding to one of the Grb2-binding sites of Shc, also preferentially bound to Crk. The phosphorylation-dependent interaction between N-Shc and Crk was demonstrated in vitro and in vivo." SIGNOR-273912 NTRK1 protein P04629 UNIPROT SHC3 protein Q92529-2 UNIPROT "up-regulates activity" phosphorylation Tyr218 GDGSDHPyYNSIPSK -1 11791173 t done miannu "We also obtained tryptic phosphopeptide maps of N-Shc protein phosphorylated in vitro by other tyrosine kinases, TrkB, v-Src and EGFR. The overall patterns of the phosphopeptide maps generated by these tyrosine kinases were similar, although there were some differences among these maps (Figure 4a–d).We performed phosphopeptide mapping analysis using GST-fused N-Shc protein, and found that N-Shc phosphorylated by TrkA in vitro was resolved into at least seven phosphopeptides (Y1 through Y7, Figure 4a). Phosphopeptide mapping revealed that N-Shc has novel tyrosine-phosphorylation sites at Y259/Y260 and Y286; in vivo-phosphorylation of these tyrosines was demonstrated by site-specific anti-pTyr antibodies. Phosphorylated Y286 bound to several proteins, of which one was Crk. The pY221/pY222 site, corresponding to one of the Grb2-binding sites of Shc, also preferentially bound to Crk. The phosphorylation-dependent interaction between N-Shc and Crk was demonstrated in vitro and in vivo." SIGNOR-273913 NTRK1 protein P04629 UNIPROT SHC3 protein Q92529-2 UNIPROT "up-regulates activity" phosphorylation Tyr283 RQGSSDIySTPEGKL -1 11791173 t done miannu "We also obtained tryptic phosphopeptide maps of N-Shc protein phosphorylated in vitro by other tyrosine kinases, TrkB, v-Src and EGFR. The overall patterns of the phosphopeptide maps generated by these tyrosine kinases were similar, although there were some differences among these maps (Figure 4a–d).We performed phosphopeptide mapping analysis using GST-fused N-Shc protein, and found that N-Shc phosphorylated by TrkA in vitro was resolved into at least seven phosphopeptides (Y1 through Y7, Figure 4a). Phosphopeptide mapping revealed that N-Shc has novel tyrosine-phosphorylation sites at Y259/Y260 and Y286; in vivo-phosphorylation of these tyrosines was demonstrated by site-specific anti-pTyr antibodies. Phosphorylated Y286 bound to several proteins, of which one was Crk. The pY221/pY222 site, corresponding to one of the Grb2-binding sites of Shc, also preferentially bound to Crk. The phosphorylation-dependent interaction between N-Shc and Crk was demonstrated in vitro and in vivo." SIGNOR-273914 NTRK1 protein P04629 UNIPROT SHC3 protein Q92529-2 UNIPROT "up-regulates activity" phosphorylation Tyr219 DGSDHPYyNSIPSKM -1 11791173 t done miannu "We also obtained tryptic phosphopeptide maps of N-Shc protein phosphorylated in vitro by other tyrosine kinases, TrkB, v-Src and EGFR. The overall patterns of the phosphopeptide maps generated by these tyrosine kinases were similar, although there were some differences among these maps (Figure 4a–d).We performed phosphopeptide mapping analysis using GST-fused N-Shc protein, and found that N-Shc phosphorylated by TrkA in vitro was resolved into at least seven phosphopeptides (Y1 through Y7, Figure 4a). Phosphopeptide mapping revealed that N-Shc has novel tyrosine-phosphorylation sites at Y259/Y260 and Y286; in vivo-phosphorylation of these tyrosines was demonstrated by site-specific anti-pTyr antibodies. Phosphorylated Y286 bound to several proteins, of which one was Crk. The pY221/pY222 site, corresponding to one of the Grb2-binding sites of Shc, also preferentially bound to Crk. The phosphorylation-dependent interaction between N-Shc and Crk was demonstrated in vitro and in vivo." SIGNOR-273915 SSU72 protein Q9NP77 UNIPROT POLR2A protein P24928 UNIPROT "up-regulates activity" dephosphorylation Ser1623 SPTSPSYsPTSPSYS -1 15125841 t "Phosphorylation of serine-2 (S2) and serine-5 (S5) of the C-terminal domain (CTD) of RNA polymerase II (RNAP II) is a dynamic process that regulates the transcription cycle and coordinates recruitment of RNA processing factors. The Fcp1 CTD phosphatase catalyzes dephosphorylation of S2-P.| Depletion of Ssu72 impairs transcription in vitro" SIGNOR-248816 SH3GLB2 protein Q9NR46 UNIPROT Endocytosis phenotype SIGNOR-PH123 SIGNOR up-regulates 9606 25517094 f miannu "Endocytosis is required for internalization of micronutrients and turnover of membrane components. Endophilin has been assigned as a component of clathrin-mediated endocytosis." SIGNOR-263887 NTRK2 protein Q16620 UNIPROT SHC3 protein Q92529-2 UNIPROT "up-regulates activity" phosphorylation Tyr218 GDGSDHPyYNSIPSK -1 11791173 t done miannu "We also obtained tryptic phosphopeptide maps of N-Shc protein phosphorylated in vitro by other tyrosine kinases, TrkB, v-Src and EGFR. The overall patterns of the phosphopeptide maps generated by these tyrosine kinases were similar, although there were some differences among these maps (Figure 4a–d).We performed phosphopeptide mapping analysis using GST-fused N-Shc protein, and found that N-Shc phosphorylated by TrkA in vitro was resolved into at least seven phosphopeptides (Y1 through Y7, Figure 4a). Phosphopeptide mapping revealed that N-Shc has novel tyrosine-phosphorylation sites at Y259/Y260 and Y286; in vivo-phosphorylation of these tyrosines was demonstrated by site-specific anti-pTyr antibodies. Phosphorylated Y286 bound to several proteins, of which one was Crk. The pY221/pY222 site, corresponding to one of the Grb2-binding sites of Shc, also preferentially bound to Crk. The phosphorylation-dependent interaction between N-Shc and Crk was demonstrated in vitro and in vivo." SIGNOR-273916 NTRK2 protein Q16620 UNIPROT SHC3 protein Q92529-2 UNIPROT "up-regulates activity" phosphorylation Tyr283 RQGSSDIySTPEGKL -1 11791173 t done miannu "We also obtained tryptic phosphopeptide maps of N-Shc protein phosphorylated in vitro by other tyrosine kinases, TrkB, v-Src and EGFR. The overall patterns of the phosphopeptide maps generated by these tyrosine kinases were similar, although there were some differences among these maps (Figure 4a–d).We performed phosphopeptide mapping analysis using GST-fused N-Shc protein, and found that N-Shc phosphorylated by TrkA in vitro was resolved into at least seven phosphopeptides (Y1 through Y7, Figure 4a). Phosphopeptide mapping revealed that N-Shc has novel tyrosine-phosphorylation sites at Y259/Y260 and Y286; in vivo-phosphorylation of these tyrosines was demonstrated by site-specific anti-pTyr antibodies. Phosphorylated Y286 bound to several proteins, of which one was Crk. The pY221/pY222 site, corresponding to one of the Grb2-binding sites of Shc, also preferentially bound to Crk. The phosphorylation-dependent interaction between N-Shc and Crk was demonstrated in vitro and in vivo." SIGNOR-273917 NTRK2 protein Q16620 UNIPROT SHC3 protein Q92529-2 UNIPROT "up-regulates activity" phosphorylation Tyr219 DGSDHPYyNSIPSKM -1 11791173 t done miannu "We also obtained tryptic phosphopeptide maps of N-Shc protein phosphorylated in vitro by other tyrosine kinases, TrkB, v-Src and EGFR. The overall patterns of the phosphopeptide maps generated by these tyrosine kinases were similar, although there were some differences among these maps (Figure 4a–d).We performed phosphopeptide mapping analysis using GST-fused N-Shc protein, and found that N-Shc phosphorylated by TrkA in vitro was resolved into at least seven phosphopeptides (Y1 through Y7, Figure 4a). Phosphopeptide mapping revealed that N-Shc has novel tyrosine-phosphorylation sites at Y259/Y260 and Y286; in vivo-phosphorylation of these tyrosines was demonstrated by site-specific anti-pTyr antibodies. Phosphorylated Y286 bound to several proteins, of which one was Crk. The pY221/pY222 site, corresponding to one of the Grb2-binding sites of Shc, also preferentially bound to Crk. The phosphorylation-dependent interaction between N-Shc and Crk was demonstrated in vitro and in vivo." SIGNOR-273918 SRC protein P12931 UNIPROT SHC3 protein Q92529-2 UNIPROT "up-regulates activity" phosphorylation Tyr218 GDGSDHPyYNSIPSK -1 11791173 t done miannu "We also obtained tryptic phosphopeptide maps of N-Shc protein phosphorylated in vitro by other tyrosine kinases, TrkB, v-Src and EGFR. The overall patterns of the phosphopeptide maps generated by these tyrosine kinases were similar, although there were some differences among these maps (Figure 4a–d).We performed phosphopeptide mapping analysis using GST-fused N-Shc protein, and found that N-Shc phosphorylated by TrkA in vitro was resolved into at least seven phosphopeptides (Y1 through Y7, Figure 4a). Phosphopeptide mapping revealed that N-Shc has novel tyrosine-phosphorylation sites at Y259/Y260 and Y286; in vivo-phosphorylation of these tyrosines was demonstrated by site-specific anti-pTyr antibodies. Phosphorylated Y286 bound to several proteins, of which one was Crk. The pY221/pY222 site, corresponding to one of the Grb2-binding sites of Shc, also preferentially bound to Crk. The phosphorylation-dependent interaction between N-Shc and Crk was demonstrated in vitro and in vivo." SIGNOR-273919 SRC protein P12931 UNIPROT SHC3 protein Q92529-2 UNIPROT "up-regulates activity" phosphorylation Tyr283 RQGSSDIySTPEGKL -1 11791173 t done miannu "We also obtained tryptic phosphopeptide maps of N-Shc protein phosphorylated in vitro by other tyrosine kinases, TrkB, v-Src and EGFR. The overall patterns of the phosphopeptide maps generated by these tyrosine kinases were similar, although there were some differences among these maps (Figure 4a–d).We performed phosphopeptide mapping analysis using GST-fused N-Shc protein, and found that N-Shc phosphorylated by TrkA in vitro was resolved into at least seven phosphopeptides (Y1 through Y7, Figure 4a). Phosphopeptide mapping revealed that N-Shc has novel tyrosine-phosphorylation sites at Y259/Y260 and Y286; in vivo-phosphorylation of these tyrosines was demonstrated by site-specific anti-pTyr antibodies. Phosphorylated Y286 bound to several proteins, of which one was Crk. The pY221/pY222 site, corresponding to one of the Grb2-binding sites of Shc, also preferentially bound to Crk. The phosphorylation-dependent interaction between N-Shc and Crk was demonstrated in vitro and in vivo." SIGNOR-273920 MAPK1 protein P28482 UNIPROT CyclinE/CDK2 complex SIGNOR-C16 SIGNOR up-regulates phosphorylation 9606 12359725 t lperfetto "In addition to its role in stimulating cyclin d1 expression and nuclear translocation of cdk2, erk regulates thr-160 phosphorylation of cdk2-cyclin e." SIGNOR-217499 SRC protein P12931 UNIPROT SHC3 protein Q92529-2 UNIPROT "up-regulates activity" phosphorylation Tyr219 DGSDHPYyNSIPSKM -1 11791173 t done miannu "We also obtained tryptic phosphopeptide maps of N-Shc protein phosphorylated in vitro by other tyrosine kinases, TrkB, v-Src and EGFR. The overall patterns of the phosphopeptide maps generated by these tyrosine kinases were similar, although there were some differences among these maps (Figure 4a–d).We performed phosphopeptide mapping analysis using GST-fused N-Shc protein, and found that N-Shc phosphorylated by TrkA in vitro was resolved into at least seven phosphopeptides (Y1 through Y7, Figure 4a). Phosphopeptide mapping revealed that N-Shc has novel tyrosine-phosphorylation sites at Y259/Y260 and Y286; in vivo-phosphorylation of these tyrosines was demonstrated by site-specific anti-pTyr antibodies. Phosphorylated Y286 bound to several proteins, of which one was Crk. The pY221/pY222 site, corresponding to one of the Grb2-binding sites of Shc, also preferentially bound to Crk. The phosphorylation-dependent interaction between N-Shc and Crk was demonstrated in vitro and in vivo." SIGNOR-273921 EGFR protein P00533 UNIPROT SHC3 protein Q92529-2 UNIPROT "up-regulates activity" phosphorylation Tyr301 PTGEAPTyVNTQQIP -1 11791173 t done miannu "We also obtained tryptic phosphopeptide maps of N-Shc protein phosphorylated in vitro by other tyrosine kinases, TrkB, v-Src and EGFR. The overall patterns of the phosphopeptide maps generated by these tyrosine kinases were similar, although there were some differences among these maps (Figure 4a–d).We performed phosphopeptide mapping analysis using GST-fused N-Shc protein, and found that N-Shc phosphorylated by TrkA in vitro was resolved into at least seven phosphopeptides (Y1 through Y7, Figure 4a). Phosphopeptide mapping revealed that N-Shc has novel tyrosine-phosphorylation sites at Y259/Y260 and Y286; in vivo-phosphorylation of these tyrosines was demonstrated by site-specific anti-pTyr antibodies. Phosphorylated Y286 bound to several proteins, of which one was Crk. The pY221/pY222 site, corresponding to one of the Grb2-binding sites of Shc, also preferentially bound to Crk. The phosphorylation-dependent interaction between N-Shc and Crk was demonstrated in vitro and in vivo." SIGNOR-273922 NTRK1 protein P04629 UNIPROT SHC3 protein Q92529-2 UNIPROT "up-regulates activity" phosphorylation Tyr301 PTGEAPTyVNTQQIP -1 11791173 t done miannu "We also obtained tryptic phosphopeptide maps of N-Shc protein phosphorylated in vitro by other tyrosine kinases, TrkB, v-Src and EGFR. The overall patterns of the phosphopeptide maps generated by these tyrosine kinases were similar, although there were some differences among these maps (Figure 4a–d).We performed phosphopeptide mapping analysis using GST-fused N-Shc protein, and found that N-Shc phosphorylated by TrkA in vitro was resolved into at least seven phosphopeptides (Y1 through Y7, Figure 4a). Phosphopeptide mapping revealed that N-Shc has novel tyrosine-phosphorylation sites at Y259/Y260 and Y286; in vivo-phosphorylation of these tyrosines was demonstrated by site-specific anti-pTyr antibodies. Phosphorylated Y286 bound to several proteins, of which one was Crk. The pY221/pY222 site, corresponding to one of the Grb2-binding sites of Shc, also preferentially bound to Crk. The phosphorylation-dependent interaction between N-Shc and Crk was demonstrated in vitro and in vivo." SIGNOR-273923 NTRK2 protein Q16620 UNIPROT SHC3 protein Q92529-2 UNIPROT "up-regulates activity" phosphorylation Tyr301 PTGEAPTyVNTQQIP -1 11791173 t done miannu "We also obtained tryptic phosphopeptide maps of N-Shc protein phosphorylated in vitro by other tyrosine kinases, TrkB, v-Src and EGFR. The overall patterns of the phosphopeptide maps generated by these tyrosine kinases were similar, although there were some differences among these maps (Figure 4a–d).We performed phosphopeptide mapping analysis using GST-fused N-Shc protein, and found that N-Shc phosphorylated by TrkA in vitro was resolved into at least seven phosphopeptides (Y1 through Y7, Figure 4a). Phosphopeptide mapping revealed that N-Shc has novel tyrosine-phosphorylation sites at Y259/Y260 and Y286; in vivo-phosphorylation of these tyrosines was demonstrated by site-specific anti-pTyr antibodies. Phosphorylated Y286 bound to several proteins, of which one was Crk. The pY221/pY222 site, corresponding to one of the Grb2-binding sites of Shc, also preferentially bound to Crk. The phosphorylation-dependent interaction between N-Shc and Crk was demonstrated in vitro and in vivo." SIGNOR-273924 SRC protein P12931 UNIPROT SHC3 protein Q92529-2 UNIPROT "up-regulates activity" phosphorylation Tyr301 PTGEAPTyVNTQQIP -1 11791173 t done miannu "We also obtained tryptic phosphopeptide maps of N-Shc protein phosphorylated in vitro by other tyrosine kinases, TrkB, v-Src and EGFR. The overall patterns of the phosphopeptide maps generated by these tyrosine kinases were similar, although there were some differences among these maps (Figure 4a–d).We performed phosphopeptide mapping analysis using GST-fused N-Shc protein, and found that N-Shc phosphorylated by TrkA in vitro was resolved into at least seven phosphopeptides (Y1 through Y7, Figure 4a). Phosphopeptide mapping revealed that N-Shc has novel tyrosine-phosphorylation sites at Y259/Y260 and Y286; in vivo-phosphorylation of these tyrosines was demonstrated by site-specific anti-pTyr antibodies. Phosphorylated Y286 bound to several proteins, of which one was Crk. The pY221/pY222 site, corresponding to one of the Grb2-binding sites of Shc, also preferentially bound to Crk. The phosphorylation-dependent interaction between N-Shc and Crk was demonstrated in vitro and in vivo." SIGNOR-273925 PTPN6 protein P29350 UNIPROT SH3BP2 protein P78314 UNIPROT down-regulates dephosphorylation 9606 16649996 t gcesareni "Shp-1 dephosphorylates 3bp2 and potentially downregulates 3bp2-mediated t cell antigen receptor signaling" SIGNOR-146508 SPOP protein O43791 UNIPROT BMI1 protein P35226 UNIPROT "up-regulates activity" binding 9606 BTO:0000007 15897469 t miannu "Here, we describe an E3 ubiquitin ligase consisting of SPOP and CULLIN3 that is able to ubiquitinate the PcG protein BMI1 and the variant histone MACROH2A1. To investigate whether BMI1 can form a complex with SPOP and CULLIN3 in vivo, we reconstituted the complex in 293HEK cells. We find that BMI1 readily immunoprecipitates both hemagglutinin (HA)-SPOP and CULLIN3, and, conversely, CULLIN3 immunoprecipitates BMI1 (Fig. 2a). Complex formation depends on the presence of SPOP, in accordance with BMI1 binding to the MATH domain of SPOP (Fig. 1b) and previously published data showing SPOP–CULLIN interaction by means of the BTB/POZ domain of SPOP (30)." SIGNOR-272658 CSNK2A1 protein P68400 UNIPROT CALM1 protein P0DP23 UNIPROT "down-regulates activity" phosphorylation Ser82 RKMKDTDsEEEIREA -1 26675311 t miannu "Phosphorylation of CaM at four sites by CK2 was found to follow a sequential order, with Ser81 as the first, Thr79 as the second, and Ser101 or Thr117 as the third. We found that in the complex between CaM and CaMKII, residue E115 of CaM is strongly interacting with K299 of the kinase through forming a salt-bridge (PDB entry 1WEL), it is quite likely that the phosphorylation induced structural change can disrupt this interaction and negatively affect the binding between the two proteins" SIGNOR-266353 Ub:E2 complex SIGNOR-C497 SIGNOR TRIM64B protein A6NI03 UNIPROT "up-regulates activity" ubiquitination 9606 34199813 t miannu "The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t" SIGNOR-271271 NTF4 protein P34130 UNIPROT NTRK1 protein P04629 UNIPROT up-regulates binding 9606 11114882 t gcesareni "Ngf is the preferred ligand for trka, bdnf and nt4/5 are preferred for trkb, and nt3 for trkc (barbacid 1994). These specificities are not absolute, and nt3 is also a ligand for trka and trkb." SIGNOR-85117 PTPRJ protein Q12913 UNIPROT KDR protein P35968 UNIPROT down-regulates dephosphorylation Tyr1054 FGLARDIyKDPDYVR 9606 18936167 t gcesareni "The autoactivation residues y1054 and y1059 are targeted by dep-1 and this results in the inhibition of kinase activity and the consequent general dephosphorylation of vegfr2." SIGNOR-181672 GGCX protein P38435 UNIPROT F9 protein P00740 UNIPROT "up-regulates activity" carboxylation Glu86 ENTERTTeFWKQYVD 10090 BTO:0001103 11133752 t lperfetto "The direct gamma-carboxyglutamic acid analysis and the N-terminal sequence analysis of the myotube-synthesized F.IX demonstrate efficient carboxylation at 11 of 12 γ-carboxyglutamic acid residues. |In previous work54 we have demonstrated that the γ-glutamyl carboxylase is present in skeletal muscle, but at a level only 5% to 10% of that found in the liver. This level of enzyme appears to be sufficient to provide full carboxylation of F.IX synthesized in myotubes|Glu 7, 8, 15, 17, 20, 21, 26, 27, 30, 33, and 36 are each less than 10% of the yield at the previous and subsequent cycles. Only a single γ-carboxylated residue, Gla 40, was not assessed by N-terminal sequencing." SIGNOR-263696 PML-RARalpha "fusion protein" SIGNOR-FP2 SIGNOR SP1 protein P08047 UNIPROT "up-regulates activity" binding 9606 BTO:0001412 18025157 t "We show that the ID1 and ID2 promoters are activated by PML-RARalpha but, unexpectedly, not by wild-type RARalpha/RXR. Our data support a model in which the PML-RARalpha fusion protein regulates a novel class of target genes by interaction with the Sp1 and NF-Y transcription factors, without directly binding to the DNA, defining a gain-of-function for the oncoprotein." SIGNOR-255749 PTK2 protein Q05397 UNIPROT ACTN4 protein O43707 UNIPROT down-regulates phosphorylation Tyr31 GGGSMGDyMAQEDDW 9606 23454549 t lperfetto "Phosphorylation at y12 by fak reduces _-actinin1's affinity for actin [25] and [27]. _-actinin4 is phosphorylated at y4, y31, and y265. Phosphorylation at y4 or y31 decreases its binding to actin [28] while phosphorylation of y265 increases its affinity for actin" SIGNOR-192195 propan-2-ol smallmolecule CHEBI:17824 ChEBI TLCD3B protein Q71RH2 UNIPROT "up-regulates activity" binding 9606 BTO:0000140 30010626 t lperfetto "Optimal bone fracture repair requires 24R,25-dihydroxyvitamin D3 and its effector molecule FAM57B2" SIGNOR-270575 DNA_damage stimulus SIGNOR-ST1 SIGNOR PARP1 protein P09874 UNIPROT up-regulates 9606 17891139 f miannu "We identify the major poly(ADP-ribosyl)ated sites of p53 by PARP-1 and find that PARP-1-mediated poly(ADP-ribosyl)ation blocks the interaction between p53 and the nuclear export receptor Crm1, resulting in nuclear accumulation of p53. These findings molecularly link PARP-1 and p53 in the DNA-damage response, providing the mechanism for how p53 accumulates in the nucleus in response to DNA damage.|PARP-1 is super-activated by binding to damaged DNA, and poly(ADP-ribosyl)ates p53. Poly(ADP-ribosyl)ation probably induces a structural change that mask the NES, and thus Crm1 can no longer target p53 to the nuclear export machinery, resulting in accumulation of p53 in the nucleus." SIGNOR-260065 SP1 protein P08047 UNIPROT CHGA protein P10645 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 12456801 t "Recently, binding of specific protein 1 (Sp1) and cAMP response element binding protein (CREB) to a GC-rich element at -92/-62 has been identified as a critical step in gastrin-dependent regulation of the chromogranin A (CgA) gene in gastric epithelial cells. Here we demonstrate that binding of early growth response protein 1 (Egr-1) to the distal part of the -92/-62 site is also required for gastrin-dependent CgA transactivation." SIGNOR-254273 "CID 132010322" chemical CID:132010322 PUBCHEM BRD3 protein Q15059 UNIPROT "down-regulates activity" "chemical inhibition" 9606 31969702 t Luana "ABBV-744 potently inhibited the BD2 domain of BET family proteins with more than 290× selectivity relative to the BD1 domains of BRD2, BRD3 and BRD4" SIGNOR-261104 Pac-1 chemical CID:135421197 PUBCHEM CASP3 protein P42574 UNIPROT "up-regulates activity" "chemical activation" -1 16936720 t lperfetto "Here we report the identification of a small molecule (PAC-1) that directly activates procaspase-3 to caspase-3 in vitro and induces apoptosis in cancerous cells isolated from primary colon tumors in a manner directly proportional to the concentration of procaspase-3 inside these cells. W" SIGNOR-262016 4-[4-[[2-(4-chlorophenyl)-5,5-dimethyl-1-cyclohexenyl]methyl]-1-piperazinyl]-N-[4-[[(2R)-4-(4-morpholinyl)-1-(phenylthio)butan-2-yl]amino]-3-(trifluoromethylsulfonyl)phenyl]sulfonylbenzamide chemical CHEBI:94128 ChEBI BCL2 protein P10415 UNIPROT down-regulates "chemical inhibition" 9606 23336025 t gcesareni "Bcl-2 inhibitors physically antagonize their anti-apoptotic actions to create a synergistic effect. Numerous compounds have been specifically developed or identified as bcl-2 inhibitors. These compounds include abt-737 and abt-263, obatoclax, gossypol." SIGNOR-200460 PAX7 protein P23759 UNIPROT KMT2A protein Q03164 UNIPROT up-regulates binding 9606 SIGNOR-C89 22863532 t miannu "Carm1 specifically methylates multiple arginines in the n-terminus of pax7. Methylated pax7 directly binds the c-terminal cleavage forms of the trithorax proteins mll1/2 resulting in the recruitment of the ash2l:mll1/2:wdr5:rbbp5 histone h3k4 methyltransferase complex to regulatory enhancers and the proximal promoter of myf5." SIGNOR-198626 MIB2 protein Q96AX9 UNIPROT RIPK1 protein Q13546 UNIPROT "down-regulates activity" polyubiquitination Lys634 KVYQMLQkWVMREGI 9606 BTO:0000815 29642005 t miannu "Here, we show that the E3 ubiquitin ligase Mind Bomb-2 (MIB2) regulates TNF-induced cell death by inactivating RIPK1 via inhibitory ubiquitylation.  We find that MIB2 represses the cytotoxic potential of RIPK1 by ubiquitylating lysine residues in the C-terminal portion of RIPK1. Our data suggest that ubiquitin conjugation of RIPK1 interferes with RIPK1 oligomerization and RIPK1-FADD association. MIB2 Ubiquitylates RIPK1 at Lysines K377 and K634" SIGNOR-272663 PI3K complex SIGNOR-C156 SIGNOR superoxide smallmolecule CHEBI:18421 ChEBI "up-regulates quantity" 23994464 f apalma "The PI3Kγ pathway (but not PLCβ2/3) is required for chemotaxis of the cells while both pathways are required for GPCR-induced superoxide release" SIGNOR-255011 PRKACA protein P17612 UNIPROT CCND1 protein P24385 UNIPROT unknown phosphorylation Ser234 YRLTRFLsRVIKCDP -1 8058338 t miannu "PKA phosphorylates three distinct serine residues in cyclin D1 at positions 90, 197 and 234." SIGNOR-250346 PAK1 protein Q13153 UNIPROT ARHGDIA protein P52565 UNIPROT down-regulates phosphorylation Ser174 KGMLARGsYSIKSRF 9606 15225553 t lperfetto "Pak1 binds and phosphorylates rhogdi both in vitro and in vivo at ser101 and ser174. This resulted in dissociation of rac1-rhogdi, but not rhoa-rhogdi, complexes, as determined by in vitro assays of complexation and in vivo by coimmunoprecipitation analysis. We observed that cdc42-induced rac1 activation is inhibited by expression of pak1 autoinhibitory domain. The dissociation of rac1 from rhogdi and its subsequent activation stimulated by pdgf or egf is also attenuated by pak1 autoinhibitory domain, and this is dependent on the ability of rhogdi to be phosphorylated at ser101/174." SIGNOR-126654 TJP2 protein Q9UDY2 UNIPROT ARVCF protein O00192 UNIPROT "down-regulates activity" relocalization 9615 15456900 t "Regulation of binding" miannu "We identified ARVCF as a binding partner of ZO-1 and ZO-2 and characterized the role of PDZ-domain proteins in plasma membrane and nuclear localization of ARVCF. ZO-2, in contrast, relocated to the nucleus with ARVCF, and, given the interaction between the ZO-2 PDZ domains and ARVCF, raised the possibility that ZO-2 may play a role in nuclear localization of ARVCF. Such a role for ZO-2 is indeed supported by the ability of the ZO-2 PDZ domain to efficiently relocate ARVCF from the plasma membrane to the nucleus in a process that required the ability of the two proteins to interact and the presence of a functional NLS in the ZO-2 PDZ domains. Thus, ZO-2 could be involved in nuclear translocation and/or retention of ARVCF and play a role in regulating postulated functions of ARVCF in gene expression" SIGNOR-252122 PRKAA1 protein Q13131 UNIPROT GLI1 protein P08151 UNIPROT "down-regulates activity" phosphorylation Thr1074 QRGSSGHtPPPSGPP 9606 26190112 t Luana "AMPK phosphorylates GLI1 at serines 102 and 408 and threonine 1074. Mutation of these three sites into alanine prevents phosphorylation by AMPK. This in turn leads to increased GLI1 protein stability, transcriptional activity, and oncogenic potency." SIGNOR-259862 STAT3 protein P40763 UNIPROT IL1RN protein P18510 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000130;BTO:0000876 20032313 f miannu "The interleukin 1 receptor antagonist (IL-1ra) is an important negative regulator of the inflammatory response, whose genetic deficiency has been recently shown to cause a severe autoinflammatory syndrome in humans. In this study we characterized the molecular mechanisms whereby interleukin 10 (IL-10) potentiates IL-1ra transcription in LPS-stimulated monocytes and neutrophils. our findings uncover a novel mechanism whereby IL-10-activated STAT3 modulates IL-1ra transcription in LPS-treated phagocytes by making IL-1ra promoter accessible to readily available nuclear NF-kappaB." SIGNOR-254795 TAF13 protein Q15543 UNIPROT TFIID complex SIGNOR-C343 SIGNOR "form complex" binding 9606 27096372 t miannu "The general transcription factor IID (TFIID) plays a central role in the initiation of RNA polymerase II (Pol II)-dependent transcription by nucleating pre-initiation complex (PIC) assembly at the core promoter. TFIID comprises the TATA-binding protein (TBP) and 13 TBP-associated factors (TAF1-13), which specifically interact with a variety of core promoter DNA sequences." SIGNOR-263923 CDK13 protein Q14004 UNIPROT POLR2A protein P24928 UNIPROT "up-regulates activity" phosphorylation Ser1672 SPTSPSYsPTSPSYS 9606 BTO:0006413 32917631 t "Ser2 in CTD of PolII" lperfetto "Together, these studies demonstrate the important, yet largely redundant, role for CDK12 and CDK13 for the regulation of POLII CTD phosphorylation at multiple residues, as well as the global role for both of these kinases in regulating POLII occupancy across the genome.|CDK12 and CDK13 are thus evolutionarily related and structurally similar kinases, and biochemical assays have demonstrated that both have POLII C-terminal domain (CTD) kinase activity and the ability to phosphorylate the Ser2 residue of the repetitive CTD heptad sequence" SIGNOR-273046 AAK1 protein Q2M2I8 UNIPROT AP1M1 protein Q9BXS5 UNIPROT up-regulates phosphorylation Thr144 QEGHKLEtGAPRPPA 9606 BTO:0000938 11877461 t lperfetto "Aak1 is enriched at presynaptic terminals, whereas in nonneuronal cells it colocalizes with clathrin and ap2 in clathrin-coated pits and at the leading edge of migrating cells. Aak1 specifically phosphorylates the mu subunit in vitro, and stage-specific assays for endocytosis show that mu phosphorylation by aak1 results in a decrease in ap2-stimulated transferrin internalization. Together, these results provide strong evidence that aak1 is the endogenous mu 2 kinase and plays a regulatory role in clathrin-mediated endocytosis." SIGNOR-115589 TRIM25 protein Q14258 UNIPROT DDX58 protein O95786 UNIPROT "up-regulates activity" polyubiquitination 9606 BTO:0000007 17392790 t lys63 miannu "The carboxy-terminal SPRY domain of TRIM25 interacts with the N-terminal CARDs of RIG-I; this interaction effectively delivers the Lys 63-linked ubiquitin moiety to the N-terminal CARDs of RIG-I, resulting in a marked increase in RIG-I downstream signalling activity.  Thus, we demonstrate that TRIM25 E3 ubiquitin ligase induces the Lys 63-linked ubiquitination of RIG-I, which is crucial for the cytosolic RIG-I signalling pathway to elicit host antiviral innate immunity." SIGNOR-271645 NEDD4L protein Q96PU5 UNIPROT TTYH3 protein Q9C0H2 UNIPROT "down-regulates quantity by destabilization" polyubiquitination 9606 BTO:0000007 18577513 t miannu "Our data indicate that Nedd4-2 binds to two family members, TTYH2 and TTYH3, which contain consensus PY ((L/P)PXY) binding sites for HECT type E3 ubiquitin ligases, but not to TTYH1, which lacks this motif. Consistently, Nedd4-2 ubiquitinates both TTYH2 and TTYH3. Importantly, we have shown that endogenous TTYH2 and Nedd4-2 are binding partners and demonstrated that the TTYH2 PY motif is essential for these interactions. We have also shown that Nedd4-2-mediated ubiquitination of TTYH2 is a critical regulator of cell surface and total cellular levels of this protein. " SIGNOR-272633 PTPRG protein P23470 UNIPROT EGFR protein P00533 UNIPROT "up-regulates activity" dephosphorylation Tyr1172 ISLDNPDyQQDFFPK -1 25624455 t miannu "PTPRG activation by the P1-WD peptide affected the tyrosine phosphorylation of several signaling molecules. Data analysis identified 31 molecules whose phosphorylation was modified in a statistically significant manner (Table I). inhibition of ABL1, BMX, BTK, DAB1, ITGB1, JAK2, KDR, KIT, LIMK1, MET, PDGFRB, SHC1, and VCL correlates with tyrosine dephosphorylation. In contrast, SRC inhibition correlates with hyperphosphorylation of the inhibitory Tyr530 residue and with dephosphorylation of the activatory Tyr419. Moreover, CDK2 and CTTN inhibition correlates with a hyperphosphorylation of the inhibitory Tyr15 and Tyr470, respectively. In contrast, a subgroup of 13 proteins, including BLNK, DOK2, ERBB2, GRIN2B, INSR, PDGFRA, PRKCD, PXN, STAT1, STAT2, STAT3, STAT5A, and ZAP70, appears to be activated by PTPRG activity." SIGNOR-254700 SLBP protein Q14493 UNIPROT "Histone H2B" proteinfamily SIGNOR-PF68 SIGNOR "up-regulates quantity by expression" "translation regulation" 9606 BTO:0001938 19155325 t lperfetto "Synthesis of mature histone mRNA requires only a single processing reaction: an endonucleolytic cleavage between a conserved stem-loop and a purine-rich downstream element to form the 3' end. The stem-loop binding protein (SLBP) is required for processing, and following processing, histone mRNA is transported to the cytoplasm, where SLBP participates in translation of the histone mRNA|We used radiolabeled probes generated by PCR targeting the open reading frame (ORF) to detect histones H2A, H2B, H3, H4, and H1 and used 7SK snRNA as a loading control (Fig. 2A). The abundance of histone H2A, H2B, H3, and H4 mRNAs is reduced to 37% to 70% of control levels in the SLBP knockdown cells when compared to the C2 control." SIGNOR-265375 PPARGC1A protein Q9UBK2 UNIPROT APOC3 protein P02656 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000599 16891307 f miannu "Overexpression of SRC1 and PGC1alpha by recombinant adenoviruses led to a significant up-regulation of well characterized HNF4alpha-dependent genes (ApoCIII, ApoAV, PEPCK, AldoB, OTC, and CYP7A1) and forced HepG2 cells toward a more differentiated phenotype as demonstrated by increased ureogenic rate." SIGNOR-255059 MAP3K1 protein Q13233 UNIPROT MAP2K7 protein O14733 UNIPROT "up-regulates activity" phosphorylation 9606 BTO:0000007 17110930 t Barakat "Upon TNFα stimulation, MEKK1, ASK1, and TAK1 phosphorylate and activate MKK7, which in turn activates JNK" SIGNOR-274147 PRKCD protein Q05655 UNIPROT GNAZ protein P19086 UNIPROT unknown phosphorylation Ser27 DRHLRSEsQRQRREI 9606 8429024 t lperfetto "Gz alpha variants containing selected substitutions of alanine for serine residues were expressed in human kidney 293 cells, and the ability of each to be phosphorylated in response to phorbol 12-myristate 13-acetate was examined. A focus was placed on Ser25 and Ser27, the 2 serine residues within a sequence of Gz alpha used to obtain a phosphorylation-sensitive antibody. The results demonstrate that Ser27 is the primary site of phosphorylation. Conversion of Ser27 to an alanine resulted in a 65% decrease in incorporation of [32P] phosphate; conversion of Ser25 had no effect." SIGNOR-248932 LMTK2 protein Q8IWU2 UNIPROT PPP1CA protein P62136 UNIPROT "down-regulates activity" phosphorylation Thr320 NPGGRPItPPRNSAK 9606 12393858 t gcesareni "Kpi-2 kinase domain phosphorylated protein phosphatase-1 (pp1c) at thr(320), which attenuated pp1c activity." SIGNOR-94631 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR PPARA protein Q07869 UNIPROT "up-regulates activity" phosphorylation 9606 BTO:0000599 10187842 t "inferred from 70% family members" lperfetto "We now demonstrate that amino acids 1-92 of hPPARalpha contain an activation function (AF)-1-like domain, which is further activated by insulin through a pathway involving the mitogen-activated protein kinases p42 and p44. Further analysis of the amino-terminal region of PPARalpha revealed that the insulin-induced trans-activation occurs through the phosphorylation of two mitogen-activated protein kinase sites at positions 12 and 21, both of which are conserved across evolution." SIGNOR-270180 Ub:E2 complex SIGNOR-C497 SIGNOR TRIM7 protein Q9C029 UNIPROT "up-regulates activity" ubiquitination 9606 34199813 t miannu "The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t" SIGNOR-271216 MAPK1 protein P28482 UNIPROT FOXO3 protein O43524 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser344 QDDDAPLsPMLYSSS 9606 18204439 t lperfetto "Here, we show that erk downregulates forkhead box o 3a (foxo3a) by directly interacting with and phosphorylating foxo3a at ser 294, ser 344 and ser 425, which consequently promotes cell proliferation and tumorigenesisMDM2 is required for ERk-mediated FOXO3a degradation." SIGNOR-160411 AGT protein P01019 UNIPROT AGTR1 protein P30556 UNIPROT "up-regulates activity" binding 10116 BTO:0004578 17346243 t "AT(1) receptor (AngII type-1 receptor), a G-protein-coupled receptor, mediates most of the physiological and pathophysiological actions of AngII, and this receptor is predominantly expressed in cardiovascular cells, such as VSMCs (vascular smooth muscle cells)" SIGNOR-252293 LRRK2 protein Q5S007 UNIPROT DVL3 protein Q92997 UNIPROT up-regulates binding 9606 23754980 t gcesareni "Subsequent assays confirmed a direct interaction between the lrrk2 roccor domain and all three human dvl proteins, these data are consistent with a role for lrrk2 in the activation of canonical wnt signaling bringing dvl proteins to cellular membranes." SIGNOR-202187 MYC protein P01106 UNIPROT DHODH protein Q02127 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0003291 18628958 t miannu "PPAT, catalyzing the first step of purine synthesis, and DHODH, an enzyme generating uridine in the middle of the pyrimidine synthesis pathway, were validated as direct c-MYC target genes by all criteria." SIGNOR-267382 ADORA2B protein P29275 UNIPROT GNAZ protein P19086 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257307 CDC20 protein Q12834 UNIPROT MCC complex SIGNOR-C382 SIGNOR "form complex" binding 9606 BTO:0000567 25092294 t miannu "The mitotic (or spindle assembly) checkpoint system delays anaphase until all chromosomes are correctly attached to the mitotic spindle. When the checkpoint is active, a Mitotic Checkpoint Complex (MCC) assembles and inhibits the ubiquitin ligase Anaphase-Promoting Complex/Cyclosome (APC/C). MCC is composed of the checkpoint proteins Mad2, BubR1, and Bub3 associated with the APC/C activator Cdc20." SIGNOR-265976 CSNK2A1 protein P68400 UNIPROT EGR1 protein P18146 UNIPROT "down-regulates activity" phosphorylation Thr391 TTHIRTHtGEKPFAC 10090 BTO:0000944 8662759 t llicata "Casein kinase II associates with Egr-1 and acts as a negative modulator of its DNA binding and transcription activities in NIH 3T3 cells. | There are three CKII recognition sites (S376XXD, T389XE, and T516XXXD) in fragment 10." SIGNOR-250857 SL-327 chemical CHEBI:92211 ChEBI MAP2K5 protein Q13163 UNIPROT down-regulates "chemical inhibition" 9606 BTO:0000938 BTO:0000142 11160424 t gcesareni "The mek1/2 inhibitors pd98059, sl327, and u0126 have been extensively used to implicate erk1/2 in neuroplasticity." SIGNOR-104933 AKT1 protein P31749 UNIPROT METTL1 protein Q9UBP6 UNIPROT down-regulates phosphorylation Ser27 YYRQRAHsNPMADHT 9606 3627513 t lperfetto "The trna methylase mettl1 is phosphorylated and inactivated by pkb and rsk in vitro and in cells" SIGNOR-24994 "trichostatin A" chemical CHEBI:46024 ChEBI HDAC8 protein Q9BY41 UNIPROT "down-regulates activity" "chemical inhibition" -1 20139990 t Luana "Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1)." SIGNOR-258013 MAPK3 protein P27361 UNIPROT GRK2 protein P25098 UNIPROT down-regulates phosphorylation Ser670 KMKNKPRsPVVELSK 9606 BTO:0000007 10574913 t gcesareni "Erk1 phosphorylates grk2 at ser(670). Inhibition of erk activity in hek293 cells potentiates grk2 activity, whereas, conversely, erk activation inhibits grk2 activity." SIGNOR-72582 KAT2B protein Q92831 UNIPROT H3-4 protein Q16695 UNIPROT "down-regulates activity" acetylation Lys10 RTKQTARkSTGGKAP 9606 SIGNOR-C465 34811519 t "Acetlyation of H3 causes transcriptional activation, thus has an inhibitory role on H3" lperfetto "The HAT module within the SAGA and ADA complexes acetylates histone H3, mainly on residues K9 and K14." SIGNOR-269613 BAK1 protein Q16611 UNIPROT AIFM1 protein O95831 UNIPROT up-regulates relocalization 9606 23003569 t gcesareni "First, bax/bak-mediated momp leads to the release of a significant part of the cyt c, smac/diablo and htra2/omi proteins. in a third step, cyt c, smac/diablo and htra2/omi, which were released into the cytosol, trigger caspase activation. This is necessary to alter the physical association of aif and endog with the im to enable their relocation to the cytosol." SIGNOR-192092 NOG protein Q13253 UNIPROT GDF5 protein P43026 UNIPROT "down-regulates activity" binding 9606 21976273 t miannu "Growth and differentiation factor 5 (GDF5), a member of the bone morphogenetic protein (BMP) family, is essential for cartilage, bone, and joint formation. Antagonists such as noggin counteract BMP signaling by covering the ligand's BMP type I (BMPRI) and type II (BMPRII, ActRII, ActRIIB) interaction sites. The mutation GDF5-S94N is located within the BMPRII interaction site, the so-called knuckle epitope, and was identified in patients suffering from multiple synostoses syndrome (SYNS)." SIGNOR-252420 CBS protein P35520 UNIPROT "L-homocysteine zwitterion" smallmolecule CHEBI:58199 ChEBI "down-regulates quantity" "chemical modification" 9606 23981774 t lperfetto "Cystathionine β-synthase (CBS) is a pyridoxal 5'-phosphate (PLP)-dependent enzyme that catalyzes the condensation of homocysteine with serine to generate cystathionine." SIGNOR-275828 CAMK2A protein Q9UQM7 UNIPROT GFAP protein P14136 UNIPROT "down-regulates activity" phosphorylation Ser13 ITSAARRsYVSSGEM -1 7822264 t llicata "On the other hand, GFAP was phosphorylated to approximately 1.9 mol of phosphate/mol of GFAP by Ca(2+)-CaM-dependent protein kinase II, and this phosphorylation did induce disassembly of the filament. Sequential analysis of the purified phosphopeptides revealed that only Ser8 on GFAP was phosphorylated by cdc2 kinase, whereas Ser13, Ser17, Ser34, and Ser389 on GFAP were phosphorylated by Ca(2+)-CaM-dependent protein kinase II." SIGNOR-250626 MYC protein P01106 UNIPROT SFRP1 protein Q8N474 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 "BTO:0004896; BTO:0004300" 17485441 f gcesareni "c-Myc suppresses the Wnt inhibitors DKK1 and SFRP1, and derepression of DKK1 or SFRP1 reduces Myc-dependent transforming activity" SIGNOR-245360 FAS protein P25445 UNIPROT RASSF1 protein Q9NS23 UNIPROT up-regulates 9606 22830020 f gcesareni "It was also shown that the fas active receptor induces rassf1a to compete with raf1 in binding to mst2, thus promoting the formation of a lats1 complex." SIGNOR-198435 ATM protein Q13315 UNIPROT CCDC6 protein Q16204 UNIPROT up-regulates phosphorylation Thr434 TPPPSPNtQTPVQPP 9606 BTO:0000551 23108047 t miannu "Phosphorylation of ccdc6 at thr434 by atm during dna damage response prevents fbxw7-mediated ccdc6 degradation." SIGNOR-199276 NR4A3 protein Q92570 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR down-regulates 9606 BTO:0000815;BTO:0002552 30455429 f miannu "NR4A3 exhibits p53-independent anti-proliferative functions. Ectopic expression of NR4A3 inhibits the growth of MDA-MB-231 and H1299 cancer cell lines." SIGNOR-256201 CHUK protein O15111 UNIPROT IRF7 protein Q92985 UNIPROT up-regulates phosphorylation 9606 16612387 t gcesareni "Ikkalfa associated with and phosphorylated and activate interferon regulatory factor-7 (irf7), which is required for interferon-alfa (ifnalfa) production." SIGNOR-146116 SMAD4 protein Q13485 UNIPROT SMAD4/JUN complex SIGNOR-C10 SIGNOR "form complex" binding 9606 9312063 t gcesareni "Our analysis of the regulation of dpc4 transcriptional activity by c-jun was consistent with the possibility that c-jun and dpc4 could interact and produce trans-activation of the 3tp-lux reporter." SIGNOR-50589 hydrogencarbonate smallmolecule CHEBI:17544 ChEBI "GABA-A (a3-b1-g2) receptor" complex SIGNOR-C332 SIGNOR "up-regulates activity" "chemical activation" 9606 BTO:0000938 26136660 t miannu "The raise in the intracellular bicarbonate concentration may augment the depolarizing efflux of bicarbonate upon activation of GABAA receptors; however, both transporters also extrude chloride and thereby increase the gradient for a hyperpolarizing chloride current." SIGNOR-264922 NEDD4 protein P46934 UNIPROT AP1G2 protein O75843 UNIPROT "up-regulates activity" polyubiquitination 9606 BTO:0001950 18772139 t miannu "Gamma2-Adaptin is a putative member of the clathrin adaptor protein family with unknown physiological function. We previously reported that gamma2-adaptin acts as a ubiquitin receptor by virtue of its ubiquitin-interacting motif. Here we demonstrate that this motif mediates a specific physical interaction with the ubiquitin ligase Nedd4 and promotes ubiquitination of gamma2-adaptin. These antibodies clearly recognized the 96 kDa form, thus demonstrating that a fraction of γ2-adaptin is modified by monoubiquitination (Fig. 1C). Thus, binding of γ2-adaptin to Nedd4 is not necessary for its membrane association.Accordingly, one possible function of γ2-adaptin may be to act as an adaptor for Nedd4, recruiting it to membrane compartments for subsequent ubiquitination." SIGNOR-272635 PTPRG protein P23470 UNIPROT BMX protein P51813 UNIPROT "down-regulates activity" dephosphorylation Tyr40 LTKTNLSyYEYDKMK -1 25624455 t miannu "PTPRG activation by the P1-WD peptide affected the tyrosine phosphorylation of several signaling molecules. Data analysis identified 31 molecules whose phosphorylation was modified in a statistically significant manner (Table I). inhibition of ABL1, BMX, BTK, DAB1, ITGB1, JAK2, KDR, KIT, LIMK1, MET, PDGFRB, SHC1, and VCL correlates with tyrosine dephosphorylation. In contrast, SRC inhibition correlates with hyperphosphorylation of the inhibitory Tyr530 residue and with dephosphorylation of the activatory Tyr419. Moreover, CDK2 and CTTN inhibition correlates with a hyperphosphorylation of the inhibitory Tyr15 and Tyr470, respectively. In contrast, a subgroup of 13 proteins, including BLNK, DOK2, ERBB2, GRIN2B, INSR, PDGFRA, PRKCD, PXN, STAT1, STAT2, STAT3, STAT5A, and ZAP70, appears to be activated by PTPRG activity." SIGNOR-254693 BIRC2 protein Q13490 UNIPROT RIPK1 protein Q13546 UNIPROT "down-regulates quantity by destabilization" polyubiquitination 9606 BTO:0000815 18570872 t miannu " In this report, we show that cIAP1 and cIAP2 promote cancer cell survival by functioning as E3 ubiquitin ligases that maintain constitutive ubiquitination of the RIP1 adaptor protein. We demonstrate that AEG40730, a compound modeled on BIR-binding tetrapeptides, binds to cIAP1 and cIAP2, facilitates their autoubiquitination and proteosomal degradation, and causes a dramatic reduction in RIP1 ubiquitination. We show that cIAP1 and cIAP2 directly ubiquitinate RIP1 and induce constitutive RIP1 ubiquitination in cancer cells and demonstrate that constitutively ubiquitinated RIP1 associates with the prosurvival kinase TAK1." SIGNOR-272638 CSNK2A1 protein P68400 UNIPROT PPP1R1B protein Q9UD71 UNIPROT "up-regulates activity" phosphorylation Ser45 LFRLSEHsSPEEEAS -1 2557337 t llicata "Study of [Plphosphate release during manual Edman degradation confirmed that the phosphorylated residues in rat DARPP-32 were Ser45 and Ser102. | Phosphorylation by casein kinase II did not affect the potency of DARPP-32 as an inhibitor of protein phosphatase-1, which depended only on phosphorylation of Thr34 by cAMP-dependent protein kinase. However, phosphorylation of DARPP-32 by casein kinase II facilitated phosphorylation of Thr34 by cAMP-dependent protein kinase" SIGNOR-250928 TFIIH complex SIGNOR-C457 SIGNOR POLR2A protein P24928 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser1724 SPSYSPTsPSYSPTS 9606 14662762 t lperfetto "Although there is some inconsistency in the literature, it is generally thought that cdk7, a component of the transcription factor (tf) iih, is a major ser-5 kinase, whereas cdk9, a component of positive transcription elongation factor (p-tef) b, is a major ser-2 kinase within cells. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination." SIGNOR-269334 FYN protein P06241 UNIPROT CD300LF protein Q8TDQ1 UNIPROT "up-regulates activity" phosphorylation Tyr263 AEDQEPTyCNMGHLS 17202342 t lperfetto "Y236 (YVTM) and Y263 (YCNM) fit with the consensus motif reported to bind the p85α regulatory subunit of PI3K (16). |The association between IREM-1 and p85α was only perceived in the presence of c-Fyn, suggesting that tyrosine phosphorylation of IREM-1 cytoplasmic tail of IREM-1 was required for the interaction." SIGNOR-275620 PRKCZ protein Q05513 UNIPROT NCF1 protein P14598 UNIPROT up-regulates phosphorylation Ser379 DLILNRCsESTKRKL 9606 BTO:0000130 12056906 t lperfetto "Phosphopeptide mapping of p47(phox) showed that, as opposed to pkc zeta, pkc alpha, beta ii, and delta are able to phosphorylate all the major pkc sites. The use of p47(phox) mutants identified serines 303, 304, 315, 320, 328, 359, 370, and 379 as targets of pkc alpha, beta ii, and delta.Taken together, these results suggest that pkc alpha, beta ii, delta, and zeta expressed in human neutrophils can individually phosphorylate p47(phox) and induce both its translocation and nadph oxidase activation." SIGNOR-89288 OTUD7B protein Q6GQQ9 UNIPROT RIPK1 protein Q13546 UNIPROT "down-regulates activity" deubiquitination 9606 BTO:0000007 18178551 t lperfetto "NF-kappaB Suppression by the Deubiquitinating Enzyme Cezanne|Our study provides several lines of evidence to suggest that Cezanne suppresses TNFR signaling to NF-κB by targeting RIP1 for deubiquitination." SIGNOR-268411 RPS6K proteinfamily SIGNOR-PF26 SIGNOR CDC25B protein P30305 UNIPROT up-regulates phosphorylation Ser353 VQNKRRRsVTPPEEQ 9606 23708659 t lperfetto "Rsk promotes g2/m transition through activating phosphorylation of cdc25a and cdc25b rsk is likely to be more active in mitotic cells than in interphase cells, as evidenced by the phosphorylation status of t359/s363 in rsk. Together, these findings indicate that rsk promotes g2/m transition in mammalian cells through activating phosphorylation of cdc25a and cdc25b." SIGNOR-252781 MAPK14 protein Q16539 UNIPROT "Histone H3" proteinfamily SIGNOR-PF69 SIGNOR unknown phosphorylation 9606 10806218 t gcesareni "More importantly, incubation of active erk2 or p38 kinase with h3 protein resulted in phosphorylation of h3 at serine 10 in vitro. These results suggest that erk and p38 kinase are at least two important mediators of phosphorylation of h3 at serine 10." SIGNOR-265338 MYC protein P01106 UNIPROT FUT3 protein P21217 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 22547830 f miannu "We provide evidence that ST3GAL1/3/4 and FUT3 are transcriptionally up-regulated by c-Myc with probable involvement of Ser62 phosphorylation, and that FUT2 is transcriptionally down-regulated through the attenuation of CDX2." SIGNOR-254612 CDK6 protein Q00534 UNIPROT RUNX1 protein Q01196 UNIPROT up-regulates phosphorylation Ser266 QYLGSIAsPSVHPAT 9606 BTO:0002181 16046550 t "The effect has been demonstrated using Q01196-8." gcesareni "We have identified four phosphorylation sites on aml1c that are necessary for transcriptional activity of aml1c in k562 and 293t cells (27).4 mutation of these four sites (serine 276, serine 293, serine 303, and threonine 300) to alanine abolishes transcriptional activation, whereas mutation of these sites to aspartic acid (which mimics phosphorylation) results in a hyperactive protein." SIGNOR-138957 RRAGB protein Q5VZM2 UNIPROT RAGBD complex SIGNOR-C116 SIGNOR "form complex" binding 9606 20381137 t gcesareni "Mammals express four Rag proteins€”RagA, RagB, RagC, and RagD€”that form heterodimers consisting of RagA or RagB with RagC or RagD. RagA and RagB, like RagC and RagD, are highly similar to each other and are functionally redundant" SIGNOR-228179 CASP7 protein P55210 UNIPROT PSEN1 protein P49768 UNIPROT "up-regulates activity" cleavage Asp345 EEWEAQRdSHLGPHR -1 10069390 t lperfetto "Remarkably, the caspases acting on PS1 could be subdivided in two groups. One group, containing caspase-8, -6 and -11, cleaved PS1 after residues ENDD329 and to a lesser extent after residues AQRD341. A second group consisting of caspase-3, -7 and -1 acted uniquely on AQRD341. Importantly, these two cleavage sites were also recognized by caspases in the C-terminal PS1 fragment produced by constitutive proteolysis." SIGNOR-261757 UBA6 protein A0AVT1 UNIPROT "Ub:E1 (UBA6 substrate)" complex SIGNOR-C496 SIGNOR "form complex" binding 9606 24816100 t miannu "The activation of ubiquitin by the ubiquitin-activating enzyme Uba1 (E1) constitutes the first step in the covalent modification of target proteins with ubiquitin. This activation is a three-step process in which ubiquitin is adenylated at its C-terminal glycine, followed by the covalent attachment of ubiquitin to a catalytic cysteine residue of Uba1 and the subsequent adenylation of a second ubiquitin." SIGNOR-270835 SND1 protein Q7KZF4 UNIPROT IGFBP3 protein P17936 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 23878061 f irozzo "Therefore, we concluded that SND1 could affect SMMC-7721 cells proliferation by regulating IGFBP3 expression and IGF signaling pathway." SIGNOR-259140 CDK13 protein Q14004 UNIPROT POLR2A protein P24928 UNIPROT "up-regulates activity" phosphorylation Ser1721 SPTSPSYsPTSPSYS 9606 BTO:0006413 32917631 t "Ser2 in CTD of PolII" lperfetto "Together, these studies demonstrate the important, yet largely redundant, role for CDK12 and CDK13 for the regulation of POLII CTD phosphorylation at multiple residues, as well as the global role for both of these kinases in regulating POLII occupancy across the genome.|CDK12 and CDK13 are thus evolutionarily related and structurally similar kinases, and biochemical assays have demonstrated that both have POLII C-terminal domain (CTD) kinase activity and the ability to phosphorylate the Ser2 residue of the repetitive CTD heptad sequence" SIGNOR-273048 PTK6 protein Q13882 UNIPROT KHDRBS1 protein Q07666 UNIPROT up-regulates phosphorylation 9606 BTO:0000150 10913193 t gcesareni "Sik/brk is the first identified tyrosine kinase that can phosphorylate sam68 and regulate its activity within the nucleus, where it resides during most of the cell cycle" SIGNOR-80020 BZW2 protein Q9Y6E2 UNIPROT ATF4 protein P18848 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 31643092 f miannu "Subsequent research reveals that BZW2 induces ATF4 translation which is a pro‐oncogenic transcription factor" SIGNOR-261222 phenformin chemical CHEBI:8064 ChEBI KCNJ11 protein Q14654 UNIPROT "down-regulates activity" "chemical inhibition" 9606 20188727 t lperfetto "Phenformin has a direct inhibitory effect on the ATP-sensitive potassium channel |Phenformin but not metformin inhibits a number of variants of K(ATP) including the cloned equivalents of currents present in vascular and non-vascular smooth muscle (Kir6.1/SUR2B and Kir6.2/SUR2B) and pancreatic beta-cells (Kir6.2/SUR1)." SIGNOR-262031 PI3K complex SIGNOR-C156 SIGNOR AKT1 protein P31749 UNIPROT "up-regulates activity" phosphorylation 9606 BTO:0001103 15829723 t apalma "IGF-I binding to its receptor activates the kinase activity of the receptor, which then recruits the insulin response substrate-1, causing activation of phosphatidyl-inositol-3 kinase (PI3K) to phosphorylate Akt." SIGNOR-255106 STUB1 protein Q9UNE7 UNIPROT ATCAY protein Q86WG3 UNIPROT "down-regulates quantity by destabilization" polyubiquitination -1 16275660 t miannu "CHIP e.g. was found to efficiently polyubiquitinate caytaxin in vitro, suggesting that it might influence caytaxin degradation in vivo." SIGNOR-272651 MAPK8 protein P45983 UNIPROT ELK1 protein P19419 UNIPROT "up-regulates activity" phosphorylation Ser389 LSPIAPRsPAKLSFQ 9606 BTO:0000567 7651411 t lperfetto "However, both of these stimuli strongly activate two other mapks, jnk1 and jnk2, and stimulate elk-1 transcriptional activity and phosphorylation jnk phosphorylation sites include ser383 and ser389, the major residues whose phosphorylation is responsible for enhancement of elk-1 trascriptional activity." SIGNOR-236432 SMAD1 protein Q15797 UNIPROT PPARG protein P37231 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 BTO:0004058 12589053 f lperfetto "Overexpression of smad6, a natural antagonist for smad1, blocked ppargamma expression and adipocytic differentiation induced by bmp2" SIGNOR-236227 STUB1 protein Q9UNE7 UNIPROT SMAD1 protein Q15797 UNIPROT down-regulates ubiquitination 9606 14701756 t gcesareni "These results suggest that chip can interact with the smad1/smad4 proteins and block bmp signal transduction through the ubiquitin-mediated degradation of smad proteins." SIGNOR-120731 "mono(2-ethylhexyl) phthalate" chemical CHEBI:17243 ChEBI PPARG protein P37231 UNIPROT "up-regulates activity" "chemical activation" 9534 BTO:0001538 27551952 t miannu "MEHP and MiNP exhibit potent activation of hCAR2 and hPXR with higher affinities for these receptors than for the hPPARs. The rank order potency for MEHP and MiNP was hCAR2 > hPXR > hPPARs." SIGNOR-268785 MAPK14 protein Q16539 UNIPROT SLC9A1 protein P19634 UNIPROT up-regulates phosphorylation Ser729 ASPQSPEsVDLVNEE 9606 11604491 t llicata "Trophic factor withdrawal: p38 mitogen-activated protein kinase activates nhe1, which induces intracellular alkalinization. activated p38 mapk directly phosphorylated the c terminus of nhe1 within a 40-amino-acid region. Analysis by mass spectroscopy identified four phosphorylation sites on nhe1, thr 717, ser 722, ser 725, and ser 728." SIGNOR-111047 ALDOC protein P09972 UNIPROT "D-glyceraldehyde 3-phosphate(2-)" smallmolecule CHEBI:59776 ChEBI "up-regulates quantity" "chemical modification" 9606 16051738 t miannu "Aldolase catalyzes the reversible conversion of FBP to glyceraldehyde-3-phosphate and dihydroxyacetone phosphate (DHAP; Figure 1). Aldolase is a tetramer of identical subunits of 40 kDa each, and 3 distinct isoenzymes have been identified: aldolase A, B, and C." SIGNOR-266481 GSK3B protein P49841 UNIPROT CAP1 protein Q01518 UNIPROT "up-regulates activity" phosphorylation Ser310 PKPQTSPsPKRATKK 9606 BTO:0000763 30123351 t lperfetto "We found that GSK3 phosphorylates S307 and S309 by using inhibitors LiCl. Inhibition of GSK3beta can cause loss of cell polarity as well as accumulation of stress fibers. We propose that GSK3 regulates CAP1 through at least two mechanisms. First, GSK3 (and potentially other kinases) phosphorylate CAP1 at S309 and promote CAP1 localization to the cytosol. Second, phosphorylation at S309 affects protein-protein interactions with actin and cofilin. The loss of this phospho-regulation by GSK3 inhibition is expected to disrupt CAP1 function and actin dynamics." SIGNOR-264823 SMDT1 protein Q9H4I9 UNIPROT MCU_MICU2_variant complex SIGNOR-C502 SIGNOR "form complex" binding 9606 32315830 t miannu "MCU is a Ca2+-selective channel that mediates mitochondrial Ca2+ influx. The human channel contains tetrameric pore-forming MCU, regulatory subunits MICU1/2, and EMRE that is required both for channel function and MICU1/2-mediated Ca2+ regulation." SIGNOR-270875 MAPK1 protein P28482 UNIPROT RORA protein P35398 UNIPROT down-regulates phosphorylation Thr183 PGEAEPLtPTYNISA 9606 17512500 t "The effect has been demonstrated using P35398-4" gcesareni "We identified the extracellular signal-regulated kinase 2 (erk-2) as roralpha4 phosphorylating kinase in vitro. The primary sequence of roralpha4 contains an erk-2 recognition motif (p-l-t(128)-p) within the hinge domain, and mutation of thr-128 to ala prevents roralpha4 phosphorylation by erk. The roralpha4-t128a mutant exhibits an increased dna-binding affinity, an increased transcriptional activity" SIGNOR-154914 MET-enkephalin smallmolecule CHEBI:6618 ChEBI OPRD1 protein P41143 UNIPROT "up-regulates activity" "chemical activation" 9606 BTO:0002524 31160049 t "Ligand-GPCR dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257551 17alpha-hydroxypregnenolone smallmolecule CHEBI:28750 ChEBI 17alpha-hydroxyprogesterone smallmolecule CHEBI:17252 ChEBI "up-regulates quantity" "precursor of" 9606 BTO:0000050 2139411 t lperfetto "The isolation, cloning, and expression of a cDNA insert complementary to mRNA encoding human 3 beta-hydroxysteroid dehydrogenase/delta 5----4isomerase is reported. |The expressed protein was similar in size to human placental microsomal 3 beta-hydroxysteroid dehydrogenase/delta 5----4isomerase, as detected by immunoblot analysis, and catalyzed the conversion of 17 alpha-hydroxypregnenolone to 17 alpha-hydroxyprogesterone, pregnenolone to progesterone, and dehydroepiandrosterone to androstenedione." SIGNOR-268639 ILK protein Q13418 UNIPROT PPP1R12A protein O14974 UNIPROT "down-regulates activity" phosphorylation Thr710 DLQEAEKtIGRSRST -1 12030846 t miannu "MYPT1 was phosphorylated by ILK and phosphorylation sites in the N- and C-terminal fragments of MYPT1 were detected. From sequence analyses, three sites were identified: a primary site at Thr(709), and two other sites at Thr(695) and Thr(495). ILK produced an intermediate level of inhibition" SIGNOR-262885 PTPRB protein P23467 UNIPROT GHR protein P10912 UNIPROT down-regulates dephosphorylation 9606 12907755 t gcesareni "Inally, mrna tissue distribution of these ptps by rt-pcr analysis and coexpression of the wild-type ptps to test their ability to dephosphorylate ligand-activated ghr suggest ptp-h1 and ptp1b as potential candidates involved in ghr signaling." SIGNOR-104580 TTBK1 protein Q5TCY1 UNIPROT MAPT protein P10636 UNIPROT down-regulates phosphorylation Ser515 SGDRSGYsSPGSPGT 9606 BTO:0000938 16923168 t "The effect has been demonstrated using P10636-8" lperfetto "Direct tau phosphorylation by ttbk1 at ser198, ser199, ser202 and ser422, which are also phosphorylated in phfs. Ttbk1 also induces tau aggregation in human neuronal cells in a dose-dependent manner. We conclude that ttbk1 is a neuron-specific dual kinase involved in tau phosphorylation at ad-related sites and is also associated with tau aggregation." SIGNOR-148966 ECM stimulus SIGNOR-ST20 SIGNOR "A3/b1 integrin" complex SIGNOR-C161 SIGNOR up-regulates 9606 30889378 t miannu "Upon binding to the extracellular matrix (ECM), the integrins organize the cytoskeleton and activate intracellular signaling, regulating complex cellular behaviors, including survival, proliferation, migration, and various cell fate transitions" SIGNOR-259044 SIRT1 protein Q96EB6 UNIPROT Cell_cycle_progress phenotype SIGNOR-PH42 SIGNOR down-regulates 9606 BTO:0000007 14976264 f lperfetto "Sirt1 increased foxo3's ability to induce cell cycle arrest and resistance to oxidative stress" SIGNOR-267285 SMURF1 protein Q9HCE7 UNIPROT ANKRD13D protein Q6ZTN6 UNIPROT unknown ubiquitination -1 20804422 t miannu "Recombinant proteins were used to profile substrate ubiquitination by the Smurf1 ubiquitin ligase on a global scale using protein microarrays. T Proteins ubiquitinated on the protein microarray were confirmed as potential substrates of the Smurf1 activity using an off chip in vitro ubiquitination assay." SIGNOR-272677 PPARG protein P37231 UNIPROT GLS protein O94925 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0005871 33754076 f Luana "Furthermore, the protein level of the rate-limiting enzyme GLS1 but not GLUD1, GOT1, or GPT2 was consistently reduced by PPARγ agonists" SIGNOR-268043 ADAM10 protein O14672 UNIPROT ERBB2 protein P04626 UNIPROT "up-regulates activity" cleavage 9606 26284334 t miannu "The ADAM proteases are best known for their role in shedding the extracellular domain of transmembrane proteins. Among the transmembrane proteins shed by ADAM10 are notch, HER2, E-cadherin, CD44, L1 and the EGFR ligands, EGF and betacellulin." SIGNOR-259845 IGF1R protein P08069 UNIPROT IGF1R protein P08069 UNIPROT "up-regulates activity" phosphorylation Tyr1161 FGMTRDIyETDYYRK -1 8940173 t miannu "The insulin-like growth factor type I (IGF-I) receptor can become tyrosine phosphorylated and enzymatically activated either in response to ligand or because of the activity of the Src tyrosine kinaseWe mapped the sites of IGF-I receptor autophosphorylation to peptides representing three different receptor domains: tyrosines 943 and 950 in the juxtamembrane region; tyrosines 1131, 1135, and 1136 within the kinase domain; and tyrosine 1316 in the carboxyl-terminal domain." SIGNOR-246248 SMURF1 protein Q9HCE7 UNIPROT ANKS4B protein Q8N8V4 UNIPROT unknown ubiquitination -1 20804422 t miannu "Recombinant proteins were used to profile substrate ubiquitination by the Smurf1 ubiquitin ligase on a global scale using protein microarrays. T Proteins ubiquitinated on the protein microarray were confirmed as potential substrates of the Smurf1 activity using an off chip in vitro ubiquitination assay." SIGNOR-272678 sirolimus chemical CHEBI:9168 ChEBI MTOR protein P42345 UNIPROT "down-regulates activity" "chemical inhibition" 9606 7566123 t Monia "Consistent with an essential role for FRAP kinase activity in vivo, autophosphorylation of FRAP is inhibited by FKBP12-rapamycin." SIGNOR-261074 SMURF1 protein Q9HCE7 UNIPROT TOM1 protein O60784 UNIPROT unknown ubiquitination -1 20804422 t miannu "Recombinant proteins were used to profile substrate ubiquitination by the Smurf1 ubiquitin ligase on a global scale using protein microarrays. T Proteins ubiquitinated on the protein microarray were confirmed as potential substrates of the Smurf1 activity using an off chip in vitro ubiquitination assay." SIGNOR-272679 ASXL1 protein Q8IXJ9 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR down-regulates 10090 26470845 f lperfetto "Consistently, our results show that ASXL1 mutations are associated with lower expression levels of p15INK4B and a proliferative advantage of hematopoietic progenitors in primary bone marrow cells, and that depletion of ASXL1 in multiple cell lines results in resistance to growth inhibitory signals." SIGNOR-241614 GSK3B/Axin/APC complex SIGNOR-C110 SIGNOR CTNNB1 protein P35222 UNIPROT "down-regulates activity" phosphorylation Thr41 GIHSGATtTAPSLSG 9606 11955436 t lperfetto "Wnt regulation of beta-catenin degradation is essential for development and carcinogenesis. beta-catenin degradation is initiated upon amino-terminal serine/threonine phosphorylation, which is believed to be performed by glycogen synthase kinase-3 (GSK-3) in complex with tumor suppressor proteins Axin and adnomatous polyposis coli (APC)." SIGNOR-227905 TGFBI protein Q15582 UNIPROT "A3/b1 integrin" complex SIGNOR-C161 SIGNOR "up-regulates activity" binding 10090 BTO:0001175 10906123 t lperfetto "In addition, we demonstrated the functional receptor for betaig-h3 is alpha(3)beta(1) integrin. These results, therefore, establish the essential motifs within the 2nd and the 4th domains of betaig-h3, which interact with alpha(3)beta(1) integrin to mediate HCE cell adhesion to betaig-h3 and suggest that other proteins containing Asp-Ile in their fas-1 domains could possibly function as cell adhesion molecules." SIGNOR-253211 DNMT3A protein Q9Y6K1 UNIPROT Differentiation phenotype SIGNOR-PH37 SIGNOR up-regulates 9606 27639498 f irozzo "The DNA methyltransferase 3 genes (DNMT3A and DNMT3B) encode methyltransferases that catalyze the addition of a methyl group to the cytosine residue of CpG dinucleotide; therefore they play an essential role in DNA methylation and gene silencing regulatory processes. DNMT3A function is involved in hematopoietic stem cells (HSCs) renewal and myeloid differentiation." SIGNOR-255714 GATA6 protein Q92908 UNIPROT CYP11A1 protein P05108 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0002850 15284005 f miannu "The transcription factor GATA6, which regulates the promoter activity of CYP17 and CYP11A, was increased in the PCOS compared to normal theca cells." SIGNOR-254197 CDK13 protein Q14004 UNIPROT POLR2A protein P24928 UNIPROT "up-regulates activity" phosphorylation Ser1931 SPTSPTYsPTSPKGS 9606 BTO:0006413 32917631 t "Ser2 in CTD of PolII" lperfetto "Together, these studies demonstrate the important, yet largely redundant, role for CDK12 and CDK13 for the regulation of POLII CTD phosphorylation at multiple residues, as well as the global role for both of these kinases in regulating POLII occupancy across the genome.|CDK12 and CDK13 are thus evolutionarily related and structurally similar kinases, and biochemical assays have demonstrated that both have POLII C-terminal domain (CTD) kinase activity and the ability to phosphorylate the Ser2 residue of the repetitive CTD heptad sequence" SIGNOR-273049 PRKACA protein P17612 UNIPROT PLN protein P26678 UNIPROT "up-regulates activity" phosphorylation Ser16 RSAIRRAsTIEMPQQ 10090 10988285 t miannu "Phospholamban (PLB) can be phosphorylated at Ser(16) by cyclic AMP-dependent protein kinase. phosphorylation of Ser(16) is sufficient for mediating the maximal cardiac responses to beta-adrenergic stimulation." SIGNOR-250030 PRKACA protein P17612 UNIPROT RGS10 protein O43665 UNIPROT "down-regulates activity" phosphorylation Ser176 QTAAKRAsRIYNT 9606 11443111 t lperfetto "We report in this study the acute functional regulation of rgs10 thru the specific and inducible phosphorylation of rgs10 protein at serine 168 by camp-dependent kinase a. This phosphorylation nullifies the rgs10 activity at the plasma membrane, which controls the g protein-dependent activation of the inwardly rectifying potassium channel." SIGNOR-109173 CDK2 protein P24941 UNIPROT CDKN2D protein P55273 UNIPROT up-regulates phosphorylation Thr141 RRDARGLtPLELALQ 9606 22558186 t lperfetto "Cdk2 and pka were found to participate in p19ink4d phosphorylation process and that they would mediate serine 76 and threonine 141 modifications respectively.we propose a sequential phosphorylation model for p19 in which modification at s76 would enable a second phosphorylation event at t141. The phosphorylation-induced structural changes could have functional implicancies for p19 in the dna damage response" SIGNOR-197274 PRKACA protein P17612 UNIPROT STK11 protein Q15831 UNIPROT "up-regulates activity" phosphorylation Ser428 SSKIRRLsACKQQ 10116 11297520 t miannu "Phosphorylation of the protein kinase mutated in Peutz-Jeghers cancer syndrome, LKB1/STK11, at Ser431 by p90(RSK) and cAMP-dependent protein kinase, but not its farnesylation at Cys(433), is essential for LKB1 to suppress cell growth." SIGNOR-250055 LCK protein P06239 UNIPROT ESR1 protein P03372 UNIPROT up-regulates phosphorylation Tyr537 CKNVVPLyDLLLEML 9606 10571988 t gcesareni "On the basis of these data and other reports describing the structure and activity of y537 mutations, as well as knowledge of the three-dimensional structure of the her ligand binding domain, we propose an alternate model wherein y537f mutation favors an open pocket conformation, affecting the estrogen binding kinetics and stability of the hormone-bound, transcriptionally active closed pocket conformation." SIGNOR-72373 MAPK3 protein P27361 UNIPROT GRB10 protein Q13322 UNIPROT up-regulates phosphorylation Ser150 PELCGPGsPPVLTPG 9606 15952796 t lperfetto "Phosphorylation of grb10 by mitogen-activated protein kinase: identification of ser150 and ser476 of human grb10zeta as major phosphorylation sitesreplacing ser(150) and ser(476) with alanines reduced the inhibitory effect of human grb10zeta on insulin-stimulated irs1 tyrosine phosphorylation" SIGNOR-138171 CDK3 protein Q00526 UNIPROT TFCP2 protein Q12800 UNIPROT down-regulates phosphorylation Ser309 SLGEGNGsPNHQPEP 9606 19237534 t lperfetto "In vitro, lsf is phosphorylated by cyclin e/cyclin-dependent kinase 2 (cdk2), cyclin c/cdk2, and cyclin c/cdk3, predominantly on s309. Phosphorylation by cyclin c/cyclin-dependent kinase 2 following mitogenic stimulation of murine fibroblasts inhibits transcriptional activity of lsf during g1 progression" SIGNOR-184164 CDK2 protein P24941 UNIPROT CDC25A protein P30304 UNIPROT down-regulates phosphorylation Ser263 CKLFDSPsLCSSSTR 9606 17110335 t gcesareni "We show here that dna-responsive checkpoints activate pp2a/b56delta phosphatase complexes to dephosphorylate cdc25 at a site distinct from ser287 (t138), the phosphorylation of which is required for 14-3-3 release." SIGNOR-150839 MFN2 protein O95140 UNIPROT Mitochondrial_fusion phenotype SIGNOR-PH218 SIGNOR up-regulates 9606 25486875 f lperfetto "OPA1, MFN1 and MFN2 are essential mediators of the sequential fusion of the outer and inner membranes of adjacent mitochondria" SIGNOR-272985 PDPK1 protein O15530 UNIPROT RPS6KB1 protein P23443 UNIPROT up-regulates phosphorylation Thr252 HDGTVTHtFCGTIEY 9606 9445476 t gcesareni "A regulatory link between p70s6k and pkb was demonstrated, as pdk1 was found to selectively phosphorylate p70s6k at thr229. More importantly, pdk1 activated p70s6k in vitro and in vivo, whereas the catalytically inactive pdk1 blocked insulin-induced activation of p70s6k. one of the most studied signalling events controlled by ptdins(3,4,5)p3, comprises the activation of a group of agc family protein kinases, including isoforms of protein kinase b (pkb)/akt, p70 ribosomal s6 kinase (s6k), serum- and glucocorticoid-induced protein kinase (sgk) and protein kinase c (pkc), which play crucial roles in regulating physiological processes relevant to metabolism, growth, proliferation and survival. Here, we review recent biochemical, genetic and structural studies on the 3-phosphoinositide-dependent protein kinase-1 (pdk1), which phosphorylates and activates the agc kinase members regulated by pi 3-kinase. We also discuss whether inhibitors of pdk1 might have chemotherapeutic potential in the treatment of cancers in which the pdk1-regulated agc kinases are constitutively activated." SIGNOR-55306 FZD3 protein Q9NPG1 UNIPROT CXCL1 protein P09341 UNIPROT up-regulates binding 9606 17251915 t gcesareni "In the non-canonical wnt pathway, frizzled uses galfaq or galfai and gbetagamma dimers to activate phospholipase c (plc), resulting in protein kinase c (pkc) activation and calcium mobilization that regulates the transcription factor nfat, and frizzled also signals through the small gtpases rho and rac to c-jun n-terminal kinase (jnk), which activates the ap1 transcription factor gpcrs signal through four relatively small families of galfa proteins (galfas, galfai/o, galfaq, and galfa12/13), and if fzd receptors are classic gpcrs, they should signal through one of these four galfa families." SIGNOR-152597 PRKCB protein P05771 UNIPROT PRKCB protein P05771 UNIPROT "up-regulates activity" phosphorylation Ser661 QNEFAGFsYTNPEFV 9606 17115692 t lperfetto "The catalytic or kinase domain requires phosphorylation at three sites for full activation (24, 25): ? Phosphorylation of threonine 500 (thr-500) in the activation loop by the upstream kinase pdk-1 is a prerequisite for the maturation of the enzyme (26), which subsequently leads to autophosphorylation at threonine 641 (thr-641) in the turn motif and serine 660 (ser-660) in the hydrophobic motif" SIGNOR-150861 S1PR2 protein O95136 UNIPROT GNA14 protein O95837 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257289 TAOK3 protein Q9H2K8 UNIPROT STK3/4 proteinfamily SIGNOR-PF41 SIGNOR up-regulates phosphorylation 9606 23431053 t "inferred from 70% of family members" gcesareni "In addition, the thousand-and-one (tao) amino acids kinase or taok1 3 has been shown to directly phosphorylate and activate hpo or mst1/2" SIGNOR-269949 KCNC4 protein Q03721 UNIPROT potassium(1+) smallmolecule CHEBI:29103 ChEBI "down-regulates quantity" relocalization 9606 11506885 t miannu "Kv3 currents are activated specifically during action potential repolarization. Analysis of the Kv3 subfamily of K+ channel subunits has lead to the discovery of a new class of neuronal voltage-gated K+ channels characterized by positively shifted voltage dependencies and very fast deactivation rates. These properties are adaptations that allow these channels to produce currents that can specifically enable fast repolarization of action potentials without compromising spike initiation or height" SIGNOR-265588 MMP2 protein P08253 UNIPROT A2M protein P01023 UNIPROT "down-regulates quantity by destabilization" cleavage Arg719 VMGRGHArLVHVEEP -1 9344465 t lperfetto "The complex formation was confirmed by the use of 125I-labeled matrix metalloproteinase-2. The cleavage sites in the ""bait"" regions following formation of high-molecular-weight complexes of matrix metalloproteinases with the alpha-macroglobulins were determined by protein sequence analysis. Pregnancy zone protein was cleaved at Thr693-Tyr694 and alpha2-macroglobulin at Gly679-Leu680 and Arg696-Leu697 by matrix metalloproteinase-2. Matrix metalloproteinase-9 cleaved alpha2-macroglobulin at the same site as matrix metalloproteinase-2, but cleavage of pregnancy zone protein was at Leu753-Ser754.|MMP-2 and MMP-9 cause a significant degradation of these bands and the background, a degradation which is prevented by both a2M and PZP." SIGNOR-261739 ATM protein Q13315 UNIPROT BLM protein P54132 UNIPROT up-regulates phosphorylation Thr99 NAPAGQEtQRGGSKS 9606 12034743 t lperfetto "Mitotic phosphorylation of blm was partially dependent on atm, and phosphorylation sites on blm were identified. A phosphospecific antibody against one of these sites (thr-99) revealed radiation-induced phosphorylation, which was defective in ataxia-telangiectasia cells. These data suggest that atm and blm function together in recognizing abnormal dna structures by direct interaction and that these phosphorylation sites in blm are important for radiosensitivity status but not for sce frequency." SIGNOR-88010 MAPK3 protein P27361 UNIPROT ATF2 protein P15336 UNIPROT up-regulates phosphorylation Thr69 SVIVADQtPTPTRFL 9606 12110590 t gcesareni "Here, we show that in fibroblasts, insulin, epidermal growth factor (egf) and serum activate atf2 via a so far unknown two-step mechanism involving two distinct ras effector pathways: the raf-mek-erk pathway induces phosphorylation of atf2 thr71, whereas subsequent atf2 thr69 phosphorylation requires the ral-ralgds-src-p38 pathway." SIGNOR-90529 SGK2 protein Q9HBY8 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR "down-regulates activity" phosphorylation Ser253 APRRRAVsMDNSNKY 9606 BTO:0000007 11154281 t lperfetto "Protein kinase SGK mediates survival signals by phosphorylating the forkhead transcription factor FKHRL1 (FOXO3a)|However, SGK and Akt display differences with respect to the efficacy with which they phosphorylate the three regulatory sites on FKHRL1. While both kinases can phosphorylate Thr-32, SGK displays a marked preference for Ser-315 whereas Akt favors Ser-253. These findings suggest that SGK and Akt may coordinately regulate the function of FKHRL1 by phosphorylating this transcription factor at distinct sites. The efficient phosphorylation of these three sites on FKHRL1 by SGK and Akt appears to be critical to the ability of growth factors to suppress FKHRL1-dependent transcription, thereby preventing FKHRL1 from inducing cell cycle arrest and apoptosis." SIGNOR-252990 (S)-duloxetine chemical CHEBI:36795 ChEBI SLC6A2 protein P23975 UNIPROT "down-regulates activity" "chemical inhibition" -1 18387300 t Luana "Selective inhibition of serotonin (5-HT) and noradrenaline (NA) reuptake (SNRI) has been shown to be an attractive dual pharmacology approach for the treatment of a number of diseases.1,2 For example, dual 5- HT/NA reuptake inhibitor duloxetine (1) has shown clinical efficacy in the treatment of depression, pain, and urinary incontinence." SIGNOR-257775 MMP1 protein P03956 UNIPROT COL1A1 protein P02452 UNIPROT "down-regulates quantity by destabilization" cleavage Gly776 IGPPGPAgAPGDKGE -1 17318226 t lperfetto "In vitro, MMP1 initiates degradation of native fibrillar collagens, crucial components of vertebrate extracellular matrix (ECM), by cleaving the peptide bond between Gly775–Ile776 or Gly775–Lys776 in native type I, II or III collagen molecules3,4. " SIGNOR-272336 PTPN9 protein P43378 UNIPROT GHR protein P10912 UNIPROT "down-regulates activity" dephosphorylation 10029 BTO:0000246 12907755 t "Protein tyrosine phosphatases (PTPs) play key roles in switching off tyrosine phosphorylation cascades, such as initiated by cytokine receptors. We have used substrate-trapping mutants of a large set of PTPs to identify members of the PTP family that have substrate specificity for the phosphorylated human GH receptor (GHR) intracellular domain. Among 31 PTPs tested, T cell (TC)-PTP, PTP-beta, PTP1B, stomach cancer-associated PTP 1 (SAP-1), Pyst-2, Meg-2, and PTP-H1 showed specificity for phosphorylated GHR" SIGNOR-248505 FYN protein P06241 UNIPROT BSG protein P35613-2 UNIPROT "up-regulates activity" phosphorylation Tyr140 PVTDWAWyKITDSED 9606 BTO:0000849 32291412 t miannu "Our findings demonstrated that Fyn directly phosphorylates CD147 at Y140 and Y183. Moreover, the CD147-FF (Y140F/Y183F) mutation impaired the interaction between CD147 and GnT-V, leading to decreased CD147 glycosylation and membrane recruitment." SIGNOR-273999 FYN protein P06241 UNIPROT BSG protein P35613-2 UNIPROT "up-regulates activity" phosphorylation Tyr183 MEADPGQyRCNGTSS 9606 BTO:0000849 32291412 t miannu "Our findings demonstrated that Fyn directly phosphorylates CD147 at Y140 and Y183. Moreover, the CD147-FF (Y140F/Y183F) mutation impaired the interaction between CD147 and GnT-V, leading to decreased CD147 glycosylation and membrane recruitment." SIGNOR-274000 SMURF1 protein Q9HCE7 UNIPROT TPM4 protein P67936 UNIPROT unknown ubiquitination -1 20804422 t miannu "Recombinant proteins were used to profile substrate ubiquitination by the Smurf1 ubiquitin ligase on a global scale using protein microarrays. T Proteins ubiquitinated on the protein microarray were confirmed as potential substrates of the Smurf1 activity using an off chip in vitro ubiquitination assay." SIGNOR-272684 PRKACA protein P17612 UNIPROT CDK18 protein Q07002 UNIPROT "up-regulates activity" phosphorylation Ser14 KNFKRRFsLSVPRTE 28361970 t lperfetto "We previously revealed that PCTK3 is activated by two pathways: interaction with cytoplasmic cyclin A and phosphorylation at Ser-12 by protein kinase A (PKA)12. Activated PCTK3 phosphorylates retinoblastoma protein (Rb) in vitro. " SIGNOR-264560 WNT11 protein O96014 UNIPROT CHRNA1 protein P02708 UNIPROT up-regulates 9606 BTO:0000938 BTO:0000887 22309736 f gcesareni "We identified five wnts (wnt9a, wnt9b, wnt10b, wnt11, and wnt16) that are able to stimulate achr clustering, of which wnt9a and wnt11 are expressed abundantly in developing muscles." SIGNOR-195963 ERBB4 protein Q15303 UNIPROT STAT5A protein P42229 UNIPROT up-regulates binding 9606 16729043 t gcesareni "We identified stat5 as a direct binding partner to egfr and erbb4 and discovered new recognition motifs for shc and stat5." SIGNOR-146894 MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR MAPK1 protein P28482 UNIPROT "up-regulates activity" phosphorylation Thr185 HDHTGFLtEYVATRW 9606 BTO:0003807 11971971 t lperfetto "Mapk1 is phosphorylated by map2k1/mek1 and map2k2/mek2 on thr-185 and tyr-187 in response to external stimuli like insulin or ngf. Both phosphorylations are required for activity." SIGNOR-244792 NLRX1 protein Q86UT6 UNIPROT PCBP2 protein Q15366 UNIPROT "up-regulates activity" binding 9606 28956771 t Giorgia "Moreover, poly(rC) binding protein 2 (PCBP2) interacts with NLRX1 to participate in the NLRX1-induced degradation of MAVS and the inhibition of antiviral responses during HCV infection." SIGNOR-260359 Ub:E2 complex SIGNOR-C497 SIGNOR TRAF4 protein Q9BUZ4 UNIPROT "up-regulates activity" ubiquitination 9606 34199813 t miannu "The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t" SIGNOR-271081 CRYAB protein P02511 UNIPROT CRYGS protein P22914 UNIPROT "up-regulates activity" binding -1 20621668 t miannu "Human gamma-crystallins are long-lived, unusually stable proteins of the eye lens exhibiting duplicated, double Greek key domains. The lens also contains high concentrations of the small heat shock chaperone alpha-crystallin, which suppresses aggregation of model substrates in vitro. Mature-onset cataract is believed to represent an aggregated state of partially unfolded and covalently damaged crystallins. The alphaB-crystallin oligomers formed long-lived stable complexes with their gammaD-crystallin substrates. These in vitro results provide support for protein unfolding/protein aggregation models for cataract, with alpha-crystallin suppressing aggregation of damaged or unfolded proteins through early adulthood but becoming saturated with advancing age." SIGNOR-253623 CAST protein P20810 UNIPROT CAPN2 protein P17655 UNIPROT "down-regulates activity" binding 9606 BTO:0000590 25969760 t lperfetto "In addition to Ca2+, calpastatin has a key role in the regulation of calpain. Calpastatin, a heat-stable protein ranging from ~70 to ~140 kDa of apparent molecular weight depending on the cell type, is considered a specific endogenous inhibitor of calpains|The calpastatin molecule contains four inhibitory units [75–77]. Each of these units binds to one calpain molecule [75–77]. Therefore, the ratio calpain/calpastatin plays a key role in the regulation of calpain activity [78–80]. The inhibitory effect of calpastatin requires Ca2+-dependent high-affinity binding to three sites of calpain" SIGNOR-251609 SMURF1 protein Q9HCE7 UNIPROT PADI4 protein Q9UM07 UNIPROT unknown ubiquitination -1 20804422 t miannu "Recombinant proteins were used to profile substrate ubiquitination by the Smurf1 ubiquitin ligase on a global scale using protein microarrays. T Proteins ubiquitinated on the protein microarray were confirmed as potential substrates of the Smurf1 activity using an off chip in vitro ubiquitination assay." SIGNOR-272689 IFNG protein P01579 UNIPROT LPL protein P06858 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0000801 2114181 f Regulation miannu "Interferon-gamma inhibits lipoprotein lipase in human monocyte-derived macrophages. The data indicate that IFN-gamma is inhibiting macrophage LPL at least in part via a reduction of LPL synthesis" SIGNOR-251848 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR ESR1 protein P03372 UNIPROT up-regulates phosphorylation Ser106 PLNSVSPsPLMLLHP 9606 BTO:0000567 17615152 t lperfetto "In several estrogen response element-containing genes, the s118a mutation strongly reduced induction by e(2), and u0126 did not further reduce expression. Here, we show that serines 104 (s104) and 106 (s106) are also phosphorylated by mapk in vitro and upon stimulation of mapk activity in vivo.Phosphorylation at serines 104 and 106 by erk1/2 mapk is important for estrogen receptor-alpha activity" SIGNOR-244651 LDB1 protein Q86U70 UNIPROT LHX2 protein P50458 UNIPROT "up-regulates activity" binding 9606 BTO:0000007 17005264 t miannu "Cofactor CLIM2 promotes the repressive action of LIM homeodomain transcription factor Lhx2 in the expression of porcine pituitary glycoprotein hormone alpha subunit gene." SIGNOR-223962 PP1 proteinfamily SIGNOR-PF54 SIGNOR AHCYL1 protein O43865 UNIPROT unknown dephosphorylation Ser68 RSLSRSIsQSSTDSY 10090 17635105 t lperfetto "Moreover, IRBIT-associated PP1 specifically dephosphorylated Ser68 of IRBIT. Phosphorylation of Ser68 was required for subsequent phosphorylation of Ser71 and Ser74, but the latter two sites were not targeted by PP1. We found that phosphorylation of Ser71 and Ser74 were sufficient to enable inhibition of IP3 binding to the IP3R|Given the importance of phosphorylation for the function of IRBIT in suppressing IP3R activity [7,10], in the present study, we searched for a protein phosphatase involved in the dephosphorylation and, hence, inactivation of IRBIT. We found that IRBIT contains a specific well-conserved binding site for PP1." SIGNOR-264657 AKT1 protein P31749 UNIPROT FOXO1 protein Q12778 UNIPROT down-regulates phosphorylation 9606 21798082 t lperfetto "Akt inactivates protein degradation by phosphorylating and thus repressing the transcription factors of the FoxO family, and stimulates protein synthesis via the mammalian target of rapamycin (mTOR) and glycogen synthase kinase 3b (GSK3B)." SIGNOR-175285 LRP6 protein O75581 UNIPROT AXIN1 protein O15169 UNIPROT "down-regulates activity" relocalization 9606 16890161 t amattioni "The phosphorylation of lrp6 generates a docking site for axin and recruits it to the plasma membrane, where axin is inactivated and/or targeted for degradation by an unknown mechanism." SIGNOR-148668 CDC25A protein P30304 UNIPROT CDK6 protein Q00534 UNIPROT "up-regulates activity" dephosphorylation Tyr24 AEIGEGAyGKVFKAR 9606 BTO:0000007 23429262 t lperfetto "Invalidation of CDK4 has no impact by itself on the cell proliferation, but invalidation of CDC25A prevents the dephosphorylation of CDK6 (Y24) and CDK4 (Y17) residues, and impedes their association with CCNDs." SIGNOR-267569 CDK2 protein P24941 UNIPROT MYBL2 protein P10244 UNIPROT "up-regulates activity" phosphorylation Thr518 SMDNTPHtPTPFKNA 10593981 t llicata "Ten phosphorylation sites carboxyl-terminal to the DNA-binding domain were identified by this method: threonines at positions 267, 408, 497, 519, 522, and 524 and serines at positions 283, 396, 455, and 581. | Our results indicate that B-Myb can be phosphorylated in a cell-free system by both cyclin A-Cdk2 and cyclin E-Cdk2 complexes. | These data suggest that B-Myb is a target for phosphorylation by cyclin-Cdk2 and that phosphorylation of B-Myb regulates its transcriptional activity." SIGNOR-250740 SMURF1 protein Q9HCE7 UNIPROT ILRUN protein Q9H6K1 UNIPROT unknown ubiquitination -1 20804422 t miannu "Recombinant proteins were used to profile substrate ubiquitination by the Smurf1 ubiquitin ligase on a global scale using protein microarrays. T Proteins ubiquitinated on the protein microarray were confirmed as potential substrates of the Smurf1 activity using an off chip in vitro ubiquitination assay." SIGNOR-272697 SMURF1 protein Q9HCE7 UNIPROT UBQLN1 protein Q9UMX0 UNIPROT unknown ubiquitination -1 20804422 t miannu "Recombinant proteins were used to profile substrate ubiquitination by the Smurf1 ubiquitin ligase on a global scale using protein microarrays. T Proteins ubiquitinated on the protein microarray were confirmed as potential substrates of the Smurf1 activity using an off chip in vitro ubiquitination assay." SIGNOR-272701 PSMB2 protein P49721 UNIPROT "26S Proteasome" complex SIGNOR-C307 SIGNOR "form complex" binding 9606 BTO:0000007 29636472 t lperfetto "Here, we report near-atomic resolution cryo-EM structures of the activated human proteasome|The proteasome is composed of a 28-subunit barrel-shaped core particle (CP) and two 19- subunit regulatory particles (RP)5–8 capped at both sides of the CP|Human proteasomes were purified through affinity chromatography on a large scale from a stable HEK293 cell line" SIGNOR-263358 S1PR2 protein O95136 UNIPROT GNA13 protein Q14344 UNIPROT up-regulates binding 9606 22863277 t gcesareni "Serum-borne lysophosphatidic acid (lpa) and sphingosine 1-phosphophate (s1p) act through g12/13-coupled receptors to inhibit the hippo pathway kinases lats1/2 thereby activating yap and taz transcription co-activators, which are oncoproteins repressed by lats1/2." SIGNOR-198559 PRKCA protein P17252 UNIPROT MBP protein P02686 UNIPROT unknown phosphorylation Ser190 RGAPKRGsGKDSHHP -1 2413024 t lperfetto "MBP was phosphorylated by either protein kinase A or C | Subsequent amino acid analysis and/or sequential Edman degradation of the purified phosphopeptides, together with the known primary sequence of this protein, revealed that Ser-46 and Ser-151 were specifically phosphorylated by protein kinase C, whereas Thr-34 and Ser-115 were phosphorylated preferentially by protein kinase A. Both kinases reacted with Ser-8, Ser-11, Ser-55, Ser-110, Ser-132, and Ser-161 at various reaction velocities." SIGNOR-248871 SMURF1 protein Q9HCE7 UNIPROT BMPR2 protein Q13873 UNIPROT down-regulates ubiquitination 9606 22298955 t gcesareni "Smurf1 and smurf2 are e3 ubiquitin ligases known to suppress tgf-beta signaling through degradation of smads and receptors for tgf-beta and bmps." SIGNOR-195654 PTPN12 protein Q05209 UNIPROT INSR protein P06213 UNIPROT down-regulates dephosphorylation Tyr1190 DIYETDYyRKGGKGL 9606 10734133 t gcesareni "Autophosphorylated on tyrosine residues in response to insulin. Dephosphorylated by ptpreand ptpn1 at tyr-999, tyr-1185, tyr-1189 and tyr-1190." SIGNOR-75902 BMS-599626 chemical CID:10437018 PUBCHEM EGFR protein P00533 UNIPROT down-regulates "chemical inhibition" 9606 17062696 t "AC480 significantly enhanced the radiosensitivity of HN-5 cells, expressing both EGFR and Her2." gcesareni "The studies described here are intended to characterize the ability of bms-599626, a small-molecule inhibitor of the human epidermal growth factor receptor (her) kinase family, to modulate signaling and growth of tumor cells that depend on her1 and/or her2." SIGNOR-150190 OPHN1 protein O60890 UNIPROT RAC1 protein P63000 UNIPROT "up-regulates activity" "gtpase-activating protein" 9606 BTO:0000938 12932438 t miannu "OPHN-1 colocalized with the actin cytoskeleton in neuronal and glial cells. We have previously shown that OPHN1 stimulates GTPases activity of RhoA, Cdc42, and Rac1 in vitro" SIGNOR-268399 TMED10 protein P49755 UNIPROT PSEN1 protein P49768 UNIPROT up-regulates binding 9606 16641999 t gcesareni "Here we report that tmp21, a member of the p24 cargo protein family, is a component of presenilin complexes and differentially regulates gamma-secretase cleavage" SIGNOR-146364 CDK1 protein P06493 UNIPROT CDC25C protein P30307 UNIPROT up-regulates phosphorylation Thr48 VCPDVPRtPVGKFLG 9606 8119945 t gcesareni "Phosphorylation at thr-48, thr-67, ser-122, thr-130, ser-168 and ser-214 occurs at g2 and g2-m transition and is catalyzed by cdk1. Ser-168 phosphorylation levels are lower than those at the other 5 cdk1 sites. Phosphorylation by cdk1 leads to increased activity." SIGNOR-36271 MAP2K6 protein P52564 UNIPROT MAPK13 protein O15264 UNIPROT up-regulates phosphorylation 9606 8663074 t gcesareni "Mapkk6 was shown to phosphorylate and specifically activate the p38/mpk2 sub of the mitogen-activated protein kinase superfamily." SIGNOR-42390 "Ub:E1 (UBA6 substrate)" complex SIGNOR-C496 SIGNOR UBE2Z protein Q9H832 UNIPROT "up-regulates activity" ubiquitination 9606 34199813 t miannu "The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t" SIGNOR-271347 "A6/b1 integrin" complex SIGNOR-C164 SIGNOR SOX2 protein P48431 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 BTO:0001086 18757303 f lperfetto "Recombinant human LN-511 alone was suffi- cient to enable self-renewal of mouse ES cells for up to 169 days (31 passages). Cells cultured on LN-511 maintained expression of pluripotency markers, such as Oct4, Sox2, Tert, UTF1, and Nanog|ES cells interacted with LN-511 via 􏰇1-integrins, mostly a6b1 and aVb1." SIGNOR-253279 PPP4C protein P60510 UNIPROT TP53BP1 protein Q12888 UNIPROT "up-regulates activity" dephosphorylation Ser1618 LTKAADIsLDNLVEG -1 24703952 t lperfetto "Here we show that 53BP1 is phosphorylated during mitosis on two residues, T1609 and S1618, located in its well-conserved ubiquitination-dependent recruitment (UDR) motif.|Dephosphorylation enables the recruitment of 53BP1 to double-strand DNA breaks |Depletion of PP4C, or PP4R3beta, causes persistence of phospho-T1609 and phospho-S1618" SIGNOR-264451 RBBP7 protein Q16576 UNIPROT "MBD2/NuRD complex" complex SIGNOR-C337 SIGNOR "form complex" binding 9606 27098840 t miannu "The NuRD complex is a multi-protein transcriptional corepressor that couples histone deacetylase and ATP-dependent chromatin remodelling activities.In humans, an assembly of proteins called the NuRD complex makes chromatin more compact by removing acetyl groups from nucleosomes. This complex is important for early development and for the stability and repair of our genes. Three proteins make up its core: HDAC1, which removes the acetyl group from the nucleosome; MTA1, which acts as a scaffold to hold the complex together; and RBBP4, which enables the complex to interact with nucleosomes. MBD2 and MBD3 are members of the methyl cytosine-guanosine (CpG)-binding domain (MBD) family of proteins42; 43. Of the five MBD members, only MBD2 and MBD3 associate with NuRD and are required for the complex formation and gene repression." SIGNOR-263836 ARHGAP11A protein Q6P4F7 UNIPROT RHOA protein P61586 UNIPROT "down-regulates activity" "gtpase-activating protein" 9606 BTO:0000007 32203420 t Luana "We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2)." SIGNOR-260466 KCTD17 protein Q8N5Z5 UNIPROT TCHP protein Q9BT92 UNIPROT "down-regulates quantity by destabilization" binding 9606 BTO:0004910 25270598 t miannu "We have identified KCTD17 as a substrate-adaptor for Cul3-RING E3 ligases (CRL3s) that polyubiquitylates trichoplein. Depletion of KCTD17 specifically arrests ciliogenesis at the initial step of axoneme extension through aberrant trichoplein-Aurora-A activity. Thus, CRL3-KCTD17 targets trichoplein to proteolysis to initiate the axoneme extension during ciliogenesis." SIGNOR-272463 CDK14 protein O94921 UNIPROT LRP6 protein O75581 UNIPROT up-regulates phosphorylation Ser1490 AILNPPPsPATERSH 9606 20059949 t gcesareni "Low-density lipoprotein receptor related proteins 5 and 6 (lrp5/6) are transmembrane receptors that initiate wnt/beta-catenin signaling. Phosphorylation of pppsp motifs in the lrp6 cytoplasmic domain is crucial for signal transduction. Using a kinome-wide rnai screen, we show that pppsp phosphorylation requires the drosophila cyclin-dependent kinase (cdk) l63. L63 and its vertebrate homolog pftk are regulated by the membrane tethered g2/m cyclin, cyclin y, which mediates binding to and phosphorylation of lrp6." SIGNOR-162924 PRKDC protein P78527 UNIPROT PNKP protein Q96T60 UNIPROT up-regulates phosphorylation Ser114 EETRTPEsQPDTPPG 9606 21824916 t lperfetto "We demonstrate that pnkp is phosphorylated by the dna-dependent protein kinase (dna-pk) and ataxia-telangiectasia mutated (atm) in vitro. The major phosphorylation site for both kinases was serine 114, with serine 126 being a minor site. Purified pnkp protein with mutation of serines 114 and 126 had decreased dna kinase and dna phosphatase activities and reduced affinity for dna in vitro." SIGNOR-176016 PRKG1 protein Q13976 UNIPROT CFTR protein P13569 UNIPROT up-regulates phosphorylation Ser660 FSAERRNsILTETLH 9606 10581361 t lperfetto "Direct amino acid sequencing and peptide mapping of cf-2 revealed that serines 660, 700, 737, and 813 as well as serine 768, serine 795, or both were phosphorylated by pka and pkgcftr possesses a large cluster of strict dibasic consensus sites for phosphorylation by protein kinase a (pka) in the r-domain and an obligatory dependence on phosphorylation is a hallmark of cftr cl(-) channel function" SIGNOR-72712 SCN3A protein Q9NY46 UNIPROT sodium(1+) chemical CHEBI:29101 ChEBI "up-regulates quantity" relocalization 9606 27262167 t miannu "Voltage-gated Na1 channels (NaV channels) drive the rapid upstroke of action potentials in cardiac and skeletal muscle and in most neurons, thereby serving as initiators of electrical activity in excitable tissue. Nine genes encode a family of homologous of NaV channel pore-forming a subunits. While channels are open, Na1 ions flux through the central pore down an electrochemical gradient, further depolarizing the membrane and triggering an action potential." SIGNOR-253409 PDGFRB protein P09619 UNIPROT PDGFRB protein P09619 UNIPROT up-regulates phosphorylation Tyr1021 PNEGDNDyIIPLPDP 9606 1396585 t llicata "These data show that tyrosine phosphorylation of plc-gamma is dependent on autophosphorylation of the pdgf beta-receptor at tyr1009 and tyr1021." SIGNOR-18579 CDK8 protein P49336 UNIPROT CCNH protein P51946 UNIPROT down-regulates phosphorylation Ser5 sSQKRHWT 9606 10993082 t gcesareni "Here we show that cdk8/cyclin c can regulate transcription by targeting the cdk7/cyclin h subunits of the general transcription initiation factor iih (tfiih). cdk8 phosphorylates mammalian cyclin h in the vicinity of its functionally unique amino-terminal and carboxy-terminal alpha-helical domains. This phosphorylation represses both the ability of tfiih to activate transcription and its ctd kinase activity. In addition, mimicking cdk8 phosphorylation of cyclin h in vivo has a dominant-negative effect on cell growth." SIGNOR-82037 BIRC3 protein Q13489 UNIPROT RIPK4 protein P57078 UNIPROT "up-regulates activity" polyubiquitination lys145 9606 BTO:0000007 21931591 t miannu "CIAP1/2 are direct E3 ligases conjugating diverse types of ubiquitin chains to receptor interacting proteins kinases 1 to 4 (RIP1-4).Together, our results demonstrate that depleting cIAP1/2 inhibits RIP1-4 mediated NF-kB activation without affecting RIP auto-phosphorylation.Lysine residues K51 and K145 of RIP4 are critical for cIAP1-mediated ubiquitination and NF-kB activation." SIGNOR-272709 CAV1 protein Q03135 UNIPROT SLC1A3 protein P43003 UNIPROT "down-regulates activity" binding 9606 BTO:0000938 26690923 t miannu "EAAT3 has previously been shown to form complexes with caveolin-1, a major component of caveolae, which participate in the regulation of transport proteins. The present study explored the impact of caveolin-1 on electrogenic transport by excitatory amino acid transporter isoforms EAAT1-4. caveolin-1 is a powerful negative regulator of the excitatory glutamate transporters EAAT1, EAAT2, EAAT3, and EAAT4. Caveolin-1 has been shown to form complexes with the excitatory amino acid transporter EAAT3 (EAAC1) (Gonzalez et al. 2007) and may thus modify the EAAT isoforms by direct interaction with the carriers." SIGNOR-264808 SSTR1 protein P30872 UNIPROT GNAI1 protein P63096 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-256679 MAP2K7 protein O14733 UNIPROT IRS1 protein P35568 UNIPROT "down-regulates activity" phosphorylation Ser312 TESITATsPASMVGG 9606 BTO:0000975 17360977 t lperfetto "Tyrosine phosphorylation of IRS-1 initiates insulin signaling, whereas serine/threonine phosphorylation alters the ability of IRS-1 to transduce the insulin signalInsulin increased the phosphorylation of Ser312, Ser616, Ser636, Ser892, Ser1101, and Ser1223 Ser312 can be phosphorylated by kinases, such as c-jun NH2-terminal kinase and inhibitor of _B kinase" SIGNOR-217920 NMBR protein P28336 UNIPROT GNA14 protein O95837 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257422 SUPT3H protein O75486 UNIPROT "SAGA complex" complex SIGNOR-C465 SIGNOR "form complex" binding 9606 34811519 t lperfetto "Here we present the cryogenic-electron microscopy (cryo-EM) structure of human SAGA (hSAGA)|Human SAGA is a 20-subunit, 1.4-MDa complex with five functional modules (Fig. ​(Fig.1a):1a): a scaffolding core that includes TBP-associated factors (TAFs); a TRRAP (Transformation/Transcription domain Associated Protein) containing a phosphoinositide-3-kinase (PI3K)-related pseudoprotein kinase (ΨPIKK); a histone acetyltransferase (HAT); a deubiquitinase (DUB) and a metazoan-specific splicing (SPL) module" SIGNOR-269590 MITF protein O75030 UNIPROT MLANA protein Q16655 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000848 12819038 f miannu "The results of the present work demonstrate that the essential melanocyte-specific transcription factor MITF regulates expression of the genes encoding the melanoma tumor markers MLANA and SILV. MITF up- or down-regulation is seen to correspondingly modulate expression of MLANA and SILV in parallel directions, at both mRNA and protein levels." SIGNOR-254590 CREB1 protein P16220 UNIPROT G6P proteinfamily SIGNOR-PF81 SIGNOR "up-regulates quantity" "transcriptional regulation" 9600 BTO:0000567 26652733 t "inferred from family member" "Further, CRTC2 is required for the glucocorticoid-associated cooperative mRNA expression of the glucose-6-phosphatase, a rate-limiting enzyme for hepatic gluconeogenesis, by facilitating the attraction of GR and itself to its promoter region already occupied by CREB" SIGNOR-270250 CDK13 protein Q14004 UNIPROT POLR2A protein P24928 UNIPROT "up-regulates activity" phosphorylation Ser1917 SPTSPTYsPTSPKYS 9606 BTO:0006413 32917631 t "Ser2 in CTD of PolII" lperfetto "Together, these studies demonstrate the important, yet largely redundant, role for CDK12 and CDK13 for the regulation of POLII CTD phosphorylation at multiple residues, as well as the global role for both of these kinases in regulating POLII occupancy across the genome.|CDK12 and CDK13 are thus evolutionarily related and structurally similar kinases, and biochemical assays have demonstrated that both have POLII C-terminal domain (CTD) kinase activity and the ability to phosphorylate the Ser2 residue of the repetitive CTD heptad sequence" SIGNOR-273050 RPS6K proteinfamily SIGNOR-PF26 SIGNOR ESR1 protein P03372 UNIPROT up-regulates phosphorylation Ser167 GGRERLAsTNDKGSM 9606 BTO:0000150 7838153 t gcesareni "Serine 167 is the major phosphorylation site on the human estrogen receptor. Phosphorylation is mediated by casein kinase ii." SIGNOR-252807 PPP1CC protein P36873 UNIPROT AHCYL1 protein O43865 UNIPROT unknown dephosphorylation Ser68 RSLSRSIsQSSTDSY 10090 17635105 t "Moreover, IRBIT-associated PP1 specifically dephosphorylated Ser68 of IRBIT. Phosphorylation of Ser68 was required for subsequent phosphorylation of Ser71 and Ser74, but the latter two sites were not targeted by PP1. We found that phosphorylation of Ser71 and Ser74 were sufficient to enable inhibition of IP3 binding to the IP3R|Given the importance of phosphorylation for the function of IRBIT in suppressing IP3R activity [7,10], in the present study, we searched for a protein phosphatase involved in the dephosphorylation and, hence, inactivation of IRBIT. We found that IRBIT contains a specific well-conserved binding site for PP1." SIGNOR-248498 Corticotropin protein P01189-PRO_0000024969 UNIPROT MC4R protein P32245 UNIPROT "up-regulates activity" binding 9606 BTO:0000142 20371771 t lperfetto "The melanocortin (MC) receptor family consists of five Gs-coupled receptors that control various physiological functions in response to four distinct agonists, adrenocorticotropic hormone (ACTH, also known as corticotrophin) and alpha, beta, and gamma melanocyte-stimulating hormone (MSH), which are derived from the proopiomelanocortin precursor protein, and two inverse agonists, agouti and agouti-related proteins" SIGNOR-268711 ERAP1 protein Q9NZ08 UNIPROT "peptide antigen" smallmolecule CHEBI:166824 ChEBI "up-regulates quantity" "chemical modification" 9606 31810556 t scontino "While peptides loaded onto MHC class I molecules are 8‚Äì11 amino acid residues long (a restriction based on the size and conformation of the peptide-binding groove of MHC class I molecules), peptides translocated by TAP can be significantly longer. These peptides will be trimmed to the correct length by ERAP-1." SIGNOR-267772 trastuzumab antibody DB00072 DRUGBANK ERBB2 protein P04626 UNIPROT "down-regulates activity" binding 9606 29017563 t miannu "HER2+ breast cancer is associated with poor prognosis and high mortality rates, but the development of HER2-targeted therapies, such as originator trastuzumab (Herceptin®), has substantially improved patient survival." SIGNOR-259904 oxymetazoline chemical CHEBI:7862 ChEBI ADRA2B protein P18089 UNIPROT "up-regulates activity" "chemical activation" 9606 BTO:0000007 9605427 t miannu "AR agonists stimulated binding of [35S]GTPgS to HEK 293 cell membranes containing the human a2a, a2b, or a2c ARs (Fig. 6). EPI and NE were full agonists; clonidine and oxymetazoline were partial agonists, while antagonists (e.g. rauwolscine, 5 mM) did not stimulate [35S]GTPgS incorporation (Table 3). Although a few agonists showed a great deal of selectivity for a single receptor subtype, the rank order of agonist potency for selected compounds at the human receptors (Table 3) was: a2a: Dexmedetomidine . guanabenz . UK-14304 .clonidine . ST-91 . NE a2b: Dexmedetomidine . clonidine . guanabenz . NE .ST-91 . UK-14304 a2c: Dexmedetomidine . NE . UK-14304 . ST-91 $ clonidine .. guanabenz" SIGNOR-258916 PPARD protein Q03181 UNIPROT TXN protein P10599 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0001950 18048767 f miannu "Activation of PPAR-delta upregulated the expression of antioxidant genes superoxide dismutase 1, catalase, and thioredoxin and decreased reactive oxygen species production in ECs." SIGNOR-255052 SRC protein P12931 UNIPROT KCNB1 protein Q14721 UNIPROT up-regulates phosphorylation Tyr128 YWGIDEIyLESCCQA 9606 BTO:0000938 19622611 t flangone "In the present study we show that an n-terminal tyrosine of kv2.1 (y124), which is a known target of src kinase, is critical for the apoptotic current surge..Kv2.1-mediated k+ currents are also enhanced during non-injurious conditions through direct phosphorylation of intracellular n-terminal residue tyrosine 124 (y124) by src kinase" SIGNOR-187201 CDK13 protein Q14004 UNIPROT POLR2A protein P24928 UNIPROT "up-regulates activity" phosphorylation Ser1882 SPTSPTYsPTTPKYS 9606 BTO:0006413 32917631 t "Ser2 in CTD of PolII" lperfetto "Together, these studies demonstrate the important, yet largely redundant, role for CDK12 and CDK13 for the regulation of POLII CTD phosphorylation at multiple residues, as well as the global role for both of these kinases in regulating POLII occupancy across the genome.|CDK12 and CDK13 are thus evolutionarily related and structurally similar kinases, and biochemical assays have demonstrated that both have POLII C-terminal domain (CTD) kinase activity and the ability to phosphorylate the Ser2 residue of the repetitive CTD heptad sequence" SIGNOR-273052 WWP1 protein Q9H0M0 UNIPROT TGFBR1 protein P36897 UNIPROT down-regulates ubiquitination 9606 15221015 t gcesareni "Similar to smurfs, wwp1 associated with smad7 and induced its nuclear export, and enhanced binding of smad7 to tgf-beta type i receptor to cause ubiquitination and degradation of the receptor. Consistent with these results, wwp1 inhibited phosphorylation of smad2 induced by tgf-beta. Wwp1 thus negatively regulates tgf-beta signaling in cooperation with smad7" SIGNOR-126581 CSNK2A1 protein P68400 UNIPROT LEF1 protein Q9UJU2 UNIPROT up-regulates phosphorylation 9606 15747065 t gcesareni "Here, we identify ck1 and ck2 as major kinases that directly bind to and phosphorylate lef-1 inducing distinct, kinase-specific changes in the lef-1/dna complex. Ck1-dependent phosphorylation inhibits, whereas ck2 activates lef-1/beta-catenin transcriptional activity in reporter gene assays." SIGNOR-134500 "Noncanonical PRC1" complex SIGNOR-C151 SIGNOR UHRF1 protein Q96T88 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 10090 BTO:0000011 25533466 f miannu "We concluded that FBXL10 recruits the noncanonical PRC1 complex to directly repress Cdk1, Uhrf1, and Pparg that may account for the FBXL10-mediated inhibition of adipogenesis." SIGNOR-252250 AMBRA1 protein Q9C0C7 UNIPROT BECN1 protein Q14457 UNIPROT "up-regulates activity" binding 9606 17589504 t lperfetto "Here we show that Ambra1 (activating molecule in Beclin1-regulated autophagy), a large, previously unknown protein bearing a WD40 domain at its amino terminus, regulates autophagy and has a crucial role in embryogenesis. We found that Ambra1 is a positive regulator of the Becn1-dependent programme of autophagy" SIGNOR-156409 XIAP protein P98170 UNIPROT RIPK4 protein P57078 UNIPROT "up-regulates activity" polyubiquitination 9606 BTO:0000007 21931591 t miannu "In this study, we report that in addition to RIP1 and RIP2, also RIP3 and RIP4 directly interact with XIAP, cIAP1 and cIAP2. When comparing the ability of these IAPs to directly conjugate RIP1–RIP4 with ubiquitin chains, we found that cIAP1 was the most effective E3 and was capable of ubiquitinating all four RIPs in the presence of the E2 component UbcH5a. On the contrary, XIAP was only capable of inducing weak ubiquitination of RIP4." SIGNOR-272716 EIF2AK3 protein Q9NZJ5 UNIPROT EIF2S1 protein P05198 UNIPROT "down-regulates activity" phosphorylation Ser52 MILLSELsRRRIRSI 9606 30070006 t gcesareni "The integrated stress response is characterized by the phosphorylation of eukaryotic initiation factor-2α (eIF2α) on serine 51 by one out of four specific kinases (EIF2AK1 to 4)" SIGNOR-246153 PRKCE protein Q02156 UNIPROT FGFR1 protein P11362 UNIPROT up-regulates phosphorylation Ser779 PLDQYSPsFPDTRSS 9606 BTO:0000938 23564461 t lperfetto "Phosphorylation of serine 779 in fibroblast growth factor receptor 1 and 2 by protein kinase c(epsilon) regulates ras/mitogen-activated protein kinase signaling and neuronal differentiationour findings show that in addition to fgfr tyrosine phosphorylation, the phosphorylation of a conserved serine residue, ser(779), can quantitatively control ras/mapk signaling to promote specific cellular responses." SIGNOR-201671 "perfluorooctane-1-sulfonic acid" chemical CHEBI:39421 ChEBI PPARA protein Q07869 UNIPROT "up-regulates activity" "chemical activation" 10090 BTO:0000759 34861291 t miannu "Perfluorooctane sulfonate (PFOS) is a stable environmental contaminant that can activate peroxisome proliferator-activated receptor alpha (PPARα). These results indicate that mouse PPARα can be activated in the liver by PFOS causing increased expression of Acox1, Cyp4a10 and histopathological changes in the liver." SIGNOR-268754 BCR-ABL "fusion protein" SIGNOR-FP6 SIGNOR BCR protein P11274 UNIPROT down-regulates phosphorylation Tyr283 YQPYQSIyVGGMMEG 9606 BTO:0001271 8622703 t lperfetto "We have previously demonstrated that the bcr protein is tyrosine phosphorylated within first-exon sequences by the bcr-abl oncoprotein. Here we report that in addition to tyrose 177 (y-177), y-360 and y283 are phosphorylated in bcr-abl proteins in vitro. Tyrosine-phosphorylated bcr, phosphorylated in vitro by bcr-abl, was greatly inhibited in its serine/threonine kinase activity, impairing both auto- and transkinase activities of bcr." SIGNOR-40615 HES1 protein Q14469 UNIPROT E2F1 protein Q01094 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 19891787 f gcesareni "We earlier identified e2f-1 as a crucial transcription factor directly inhibited by hes-1." SIGNOR-189061 PAX7 protein P23759 UNIPROT Quiescence phenotype SIGNOR-PH25 SIGNOR up-regulates BTO:0001103 15501225 f svumbaca "Our work presented here provides a possible mechanism involving Pax-7 that allow satellite cells to exit the cell cycle, down-regulate MyoD, and prevent myogenin induction, phenotypes characteristic of the quiescent satellite cell." SIGNOR-255366 PRMT5 protein O14744 UNIPROT HOXA9 protein P31269 UNIPROT "up-regulates activity" methylation Arg140 KPEPLSArRGDCPTL 9606 BTO:0000007 22269951 t lperfetto "Hoxa9 methylation by prmt5 is essential for endothelial cell expression of leukocyte adhesion molecules. / prmt5 is a critical coactivator component in a newly defined, hoxa9-containing transcription complex./ Hoxa9 is methylated on arg140 by prmt5." SIGNOR-195526 PRKCZ protein Q05513 UNIPROT NR1H4 protein Q96RI1 UNIPROT up-regulates phosphorylation Thr456 GRLTELRtFNHHHAE 9606 BTO:0000195 18668687 t "The effect has been demonstrated using Q96RI1-2" gcesareni "The effect of fic1 on fxr phosphorylation and nuclear localization and its effects on bsep promoter activity could be blocked with protein kinase c zeta (pkc zeta) inhibitors (pseudosubstrate or small interfering rna silencing). Recombinant pkc zeta directly phosphorylated immunoprecipitated fxr. The mutation of threonine 442 of fxr to alanine yielded a dominant negative protein," SIGNOR-179771 ISYNA1 protein Q9NPH2 UNIPROT "1D-myo-inositol 1-phosphate" smallmolecule CHEBI:18297 ChEBI "up-regulates quantity" "chemical modification" 9606 15464731 t lperfetto "Human myo-inositol 1-phosphate synthase (IP synthase; E.C. 5.5.1.4), encoded by ISYNA1, catalyzes the de novo synthesis of inositol 1-phosphate from glucose 6-phosphate." SIGNOR-254131 CCKAR protein P32238 UNIPROT GNAQ protein P50148 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257303 SMARCD3 protein Q6STE5 UNIPROT "Muscle cell-specific SWI/SNF ARID1A variant" complex SIGNOR-C481 SIGNOR "form complex" binding 9606 BTO:0000887 11073988 t miannu "The SWI/SNF family of chromatin-remodeling complexes facilitates gene activation by assisting transcription machinery to gain access to targets in chromatin. Our data suggest that BAF250 confers specificity to the human BAF complex and may recruit the complex to its targets through either protein-DNA or protein-protein interactions." SIGNOR-270692 CEBPA protein P49715 UNIPROT Differentiation phenotype SIGNOR-PH37 SIGNOR up-regulates 9606 BTO:0004730 16319681 f lperfetto "The transcription factor C/EBPalpha controls differentiation and proliferation in normal granulopoiesis in a stage-specific manner. Loss of C/EBPalpha function in myeloid cells in vitro and in vivo leads to a block to myeloid differentiation similar to that which is observed in malignant cells from patients with acute myeloid leukemia. The finding of C/EBPalpha alterations in subgroups of acute myeloid leukemia patients suggests a direct link between critically decreased C/EBPalpha function and the development of the disorder." SIGNOR-249632 CDK13 protein Q14004 UNIPROT POLR2A protein P24928 UNIPROT "up-regulates activity" phosphorylation Ser1889 SPTTPKYsPTSPTYS 9606 BTO:0006413 32917631 t "Ser2 in CTD of PolII" lperfetto "Together, these studies demonstrate the important, yet largely redundant, role for CDK12 and CDK13 for the regulation of POLII CTD phosphorylation at multiple residues, as well as the global role for both of these kinases in regulating POLII occupancy across the genome.|CDK12 and CDK13 are thus evolutionarily related and structurally similar kinases, and biochemical assays have demonstrated that both have POLII C-terminal domain (CTD) kinase activity and the ability to phosphorylate the Ser2 residue of the repetitive CTD heptad sequence" SIGNOR-273053 PRKCD protein Q05655 UNIPROT YWHAB protein P31946 UNIPROT down-regulates phosphorylation Ser60 VVGARRSsWRVISSI 9606 16024783 t gcesareni "We provide a mechanism for these observations through the phosphorylation of 14-3-3 by ikk and pkc on serine residues ser132 and ser60, respectively, which interferes with its binding to ttp and hence the retention of ttp in the cytoplasm." SIGNOR-138612 Ub:E2 complex SIGNOR-C497 SIGNOR TTC3 protein P53804 UNIPROT "up-regulates activity" ubiquitination 9606 34199813 t miannu "The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t" SIGNOR-271087 GRK5 protein P34947 UNIPROT BDKRB2 protein P30411 UNIPROT "down-regulates activity" phosphorylation Ser375 GTLRTSIsVERQIHK 9606 BTO:0000007 11517230 t "Ligand-induced phosphorylation is found at Ser339 and Ser346/Ser348 that could be executed by several G protein-coupled receptor kinases. 32P labeling of peptide 3 containing pS346/pS348 was enhanced 1.5–3-fold as compared with mock-transfected cells in the order GRK6 < GRK5 < GRK2 < GRK4α < GRK3. several endogenous GRKs may phosphorylate the B2R and that the various GRKs, even without apparent effect on total GPCR phosphorylation levels, may induce distinct phosphorylation patterns with possible functional consequences for receptor desensitization and sequestration." SIGNOR-251209 CBL protein P22681 UNIPROT PIK3R1 protein P27986 UNIPROT down-regulates ubiquitination 9606 BTO:0000782 11526404 t lperfetto "Cbl-b, a ring-type e3 ubiquitin protein ligase, is implicated in setting the threshold of t lymphocyte activation. The p85 regulatory subunit of phosphatidylinositol 3 kinase (pi3k) was identified as a substrate for cbl-b. We have shown that cbl-b negatively regulated p85 in a proteolysis-independent manner." SIGNOR-110060 RBPJ protein Q06330 UNIPROT MAML2 protein Q8IZL2 UNIPROT up-regulates binding 9606 21873209 t gcesareni "When bound to the active intracellular domain of notch (nicd), rbpj recruits a coactivator complex, including a mastermind homologue (maml1-3 in mammals), and drives a complex transcriptional program with pervasive phenotypic effects" SIGNOR-176197 PRKCG protein P05129 UNIPROT KIR3DL1 protein P43629 UNIPROT down-regulates phosphorylation Ser415 QRKITRPsQRPKTPP 9606 17911614 t gcesareni "Functional studies of the wild-type receptor and serine/threonine mutants indicated that phosphorylation of ser(394) by protein kinase c slightly suppresses kir3dl1 inhibitory function, and reduces receptor internalization and turnover." SIGNOR-158133 PIN1 protein Q13526 UNIPROT IRS1 protein P35568 UNIPROT "up-regulates activity" isomerization 9606 BTO:0000599 23720771 t lperfetto "In this study, the association of Par14 with insulin receptor substrate 1 (IRS-1) was demonstrated in HepG2 cells|Therefore, although Pin1 and Par14 associate with different portions of IRS-1, the prolyl cis/trans isomerization in multiple sites of IRS-1 by these isomerases appears to be critical for efficient insulin receptor-induced IRS-1 phosphorylation|Par14 overexpression in HepG2 markedly enhanced insulin-induced IRS-1 phosphorylation and its downstream events" SIGNOR-265757 TMLHE protein Q9NVH6 UNIPROT succinate(2-) smallmolecule CHEBI:30031 ChEBI "up-regulates quantity" "chemical modification" 9606 11431483 t miannu "Epsilon-N-Trimethyllysine hydroxylase (EC ) is the first enzyme in the biosynthetic pathway of l-carnitine and catalyzes the formation of beta-hydroxy-N-epsilon-trimethyllysine from epsilon-N-trimethyllysine, a reaction dependent on alpha-ketoglutarate, Fe(2+), and oxygen." SIGNOR-269683 GSC protein P56915 UNIPROT EPHA7 protein Q15375 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 10090 BTO:0000596 9417125 t Luana "We demonstrate that Goosecoid can act as a repressor of its own promoter activity in transient co-transfection experiments in mouse P19 cells and in Xenopus embryos. Autorepression depends on the presence of the homeodomain and is mediated through the prd element more proximal to the transcriptional start site." SIGNOR-261613 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR GTF2I protein P78347 UNIPROT up-regulates phosphorylation 9606 10648599 t "inferred from 70% family members" lperfetto "Tfii-i can be phosphorylated in vitro by erk and mutation of consensus map kinase substrate sites at serines 627 and 633 impairs the phosphorylation of tfii-i by erk and its activity on the c-fos promoter. These results suggest that erk regulates the activity of tfii-i by direct phosphorylation." SIGNOR-270169 RET protein P07949 UNIPROT PTK2 protein Q05397 UNIPROT up-regulates phosphorylation Tyr925 DRSNDKVyENVTGLV 9606 21454698 t gcesareni "Strikingly, when fak and ret kinases were co-incubated in the presence of atp, a marked increased in fak tyr-576/577 and tyr-925 phosphorylation was observed together with a shift in mobility of fak, indicating conversion to an activated state" SIGNOR-173021 L-thyroxine smallmolecule CHEBI:18332 ChEBI THRA protein P10827 UNIPROT "up-regulates activity" "chemical activation" 10116 BTO:0000759 2158622 t miannu "We determined the affinity for T3 and analog binding characteristics of the translational products of c-erbA a- and /3-probes together with hepatic nuclear extracts." SIGNOR-258382 AKT proteinfamily SIGNOR-PF24 SIGNOR DLX5 protein P56178 UNIPROT up-regulates phosphorylation 9606 22298955 t lperfetto "Akt, a member of the ser-ine/threonine-specific protein kinase, was found to phosphorylate osx and dlx5. akt interacts with and phosphorylates dlx5. In addition, we provide evidences that akt kinase activity is important for akt to enhance the protein stability and transcriptional activity of dlx5." SIGNOR-244228 PRKCZ protein Q05513 UNIPROT SP1 protein P08047 UNIPROT up-regulates phosphorylation Ser670 CGKRFTRsDELQRHK 9606 BTO:0000887;BTO:0001260 18258854 t llicata "Here we have used a variety of approaches to identify 3 amino acids (thr668, ser670, and thr681) in the zinc finger domain of sp1 that are modified by pkc-zeta angiotensin ii, which activates pkc-? Phosphorylation (at thr410) via the angiotensin ii type 1 receptor, stimulates sp1 phosphorylation and increases sp1 binding to the platelet-derived growth factor-d promoter." SIGNOR-160766 KAT2A protein Q92830 UNIPROT H3-3A protein P84243 UNIPROT "down-regulates activity" acetylation Lys10 RTKQTARkSTGGKAP 9606 SIGNOR-C465 34811519 t "Acetlyation of H3 causes transcriptional activation, thus has an inhibitory role on H3" lperfetto "The HAT module within the SAGA and ADA complexes acetylates histone H3, mainly on residues K9 and K14." SIGNOR-269595 calcium(2+) smallmolecule CHEBI:29108 ChEBI KCNMA1 protein Q12791 UNIPROT "up-regulates activity" "chemical activation" 9606 BTO:0000938 31152168 t miannu "The large-conductance Ca2+- and voltage-activated K+ (BK) channel is a tetramer consisting of four α-subunits encoded by the KCNMA1 gene on chromosome 10q22.3. The BK channel can be allosterically activated by both changes in the membrane voltage (voltage-dependent activation pathway) and intracellular [Ca2+] concentration (calcium-dependent activation pathway)" SIGNOR-269192 JAK2 protein O60674 UNIPROT JAK2 protein O60674 UNIPROT "down-regulates activity" phosphorylation Ser523 GVSDVPTsPTLQRPT 9606 21841788 t lperfetto "The jak2 jh2 domain functions as a negative regulator and is presumed to be a catalytically inactive pseudokinase, but the mechanism(s) for its inhibition of jak2 remains unknown. Here we show that jh2 is a dual-specificity protein kinase that phosphorylates two negative regulatory sites in jak2: ser523 and tyr570." SIGNOR-176054 CDK13 protein Q14004 UNIPROT POLR2A protein P24928 UNIPROT "up-regulates activity" phosphorylation Ser1616 TPQSPSYsPTSPSYS 9606 BTO:0006413 32917631 t "Ser2 in CTD of PolII" lperfetto "Together, these studies demonstrate the important, yet largely redundant, role for CDK12 and CDK13 for the regulation of POLII CTD phosphorylation at multiple residues, as well as the global role for both of these kinases in regulating POLII occupancy across the genome.|CDK12 and CDK13 are thus evolutionarily related and structurally similar kinases, and biochemical assays have demonstrated that both have POLII C-terminal domain (CTD) kinase activity and the ability to phosphorylate the Ser2 residue of the repetitive CTD heptad sequence" SIGNOR-273054 AKT proteinfamily SIGNOR-PF24 SIGNOR Survival phenotype SIGNOR-PH13 SIGNOR up-regulates 9606 BTO:0000830 15526160 f miannu "c-Kit promotes survival via PI3-kinase-dependent activation of Akt and phosphorylation of Bad, a pro-apoptotic molecule, at S136 in vivo." SIGNOR-254952 FZR1 protein Q9UM11 UNIPROT APC-c complex SIGNOR-C150 SIGNOR "up-regulates activity" binding 9534 BTO:0004055 12023018 t miannu "We previously showed that human Aurora-A is turned over through the anaphase promoting complex/cyclosome (APC/C)–ubiquitin–proteasome pathway. The association of two distinct WD40 repeat proteins known as Cdc20 and Cdh1, respectively, sequentially activates the APC/C. The present study shows that Aurora-A degradation is dependent on hCdh1 in vivo, not on hCdc20, and that Aurora-A is targeted for proteolysis through distinct structural features of the destruction box, the KEN box motifs and its kinase activity." SIGNOR-272611 NEDD4L protein Q96PU5 UNIPROT SCN11A protein Q9UI33 UNIPROT "down-regulates quantity by destabilization" ubiquitination 10090 BTO:0000938 23778145 t miannu "The control of Nav density at the cell membrane is crucial to ensuring normal neuronal excitability. Navs are subject to posttranslational modifications that may influence their cell membrane availability. Ubiquitylation is a key process that orchestrates the internalization and subsequent degradation or recycling of Navs. This is accomplished by ubiquitin protein ligases, such as NEDD4-2 (neuronal precursor cell expressed developmentally downregulated-4 type 2)." SIGNOR-253462 WNK1 protein Q9H4A3 UNIPROT WNK1 protein Q9H4A3 UNIPROT up-regulates phosphorylation Ser382 KRASFAKsVIGTPEF 9606 17190791 t gcesareni "We finally establish that full-length wnk1, wnk2 and wnk3, but not wnk4, are capable of directly phosphorylating ser382 of wnk1 in vitro. This supports the notion that t-loop phosphorylation of wnk isoforms is controlled by trans-autophosphorylation." SIGNOR-151675 NCOA1 protein Q15788 UNIPROT APOA5 protein Q6Q788 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000599 16891307 f miannu "Overexpression of SRC1 and PGC1alpha by recombinant adenoviruses led to a significant up-regulation of well characterized HNF4alpha-dependent genes (ApoCIII, ApoAV, PEPCK, AldoB, OTC, and CYP7A1) and forced HepG2 cells toward a more differentiated phenotype as demonstrated by increased ureogenic rate." SIGNOR-255064 CDK13 protein Q14004 UNIPROT POLR2A protein P24928 UNIPROT "up-regulates activity" phosphorylation Ser1861 TPTSPKYsPTSPKYS 9606 BTO:0006413 32917631 t "Ser2 in CTD of PolII" lperfetto "Together, these studies demonstrate the important, yet largely redundant, role for CDK12 and CDK13 for the regulation of POLII CTD phosphorylation at multiple residues, as well as the global role for both of these kinases in regulating POLII occupancy across the genome.|CDK12 and CDK13 are thus evolutionarily related and structurally similar kinases, and biochemical assays have demonstrated that both have POLII C-terminal domain (CTD) kinase activity and the ability to phosphorylate the Ser2 residue of the repetitive CTD heptad sequence" SIGNOR-273055 GRK6 protein P43250 UNIPROT BDKRB2 protein P30411 UNIPROT "down-regulates activity" phosphorylation Ser366 EPIQMENsMGTLRTS 9606 BTO:0000007 11517230 t "Ligand-induced phosphorylation is found at Ser339 and Ser346/Ser348 that could be executed by several G protein-coupled receptor kinases. 32P labeling of peptide 3 containing pS346/pS348 was enhanced 1.5–3-fold as compared with mock-transfected cells in the order GRK6 < GRK5 < GRK2 < GRK4α < GRK3. several endogenous GRKs may phosphorylate the B2R and that the various GRKs, even without apparent effect on total GPCR phosphorylation levels, may induce distinct phosphorylation patterns with possible functional consequences for receptor desensitization and sequestration." SIGNOR-251207 PDPK1 protein O15530 UNIPROT PRKCB protein P05771 UNIPROT up-regulates phosphorylation 9606 15209375 t gcesareni "One of the most studied events controlled by ptdins(3,4,5)p3, comprises the activation of a of agc family protein kinases, including isoforms of protein kinase b (pkb)/akt, p70 ribosomal s6 kinase (s6k), serum and glucocorticoid-induced protein kinase (sgk) and protein kinase c (pkc), which play crucial roles in regulating physiological processes relevant to metabolism, growth, proliferation and survival. Here, we review recent biochemical, genetic and structural studies on the 3-phosphoinositide-dependent protein kinase-1 (pdk1), which phosphorylates and activates the agc kinase members regulated by pi 3-kinase. We also discuss whether inhibitors of pdk1 might have chemotherapeutic potential in the treatment of cancers in which the pdk1-regulated agc kinases are constitutively activated." SIGNOR-126069 POU4F1 protein Q01851 UNIPROT ESR1 protein P03372 UNIPROT "up-regulates activity" binding 9606 9448000 t 2 miannu "The POU domain of Brn-3a and Brn-3b was shown to interact with the DNA-binding domain of the ER. Brn-3-ER interactions also affect transcriptional activity of an ERE-containing promoter, such that in estradiol-stimulated cells, Brn-3b strongly activated the promoter via the ERE, while Brn-3a had a mild inhibitory effect." SIGNOR-241275 tolazoline chemical CHEBI:28502 ChEBI ADRA2B protein P18089 UNIPROT "down-regulates activity" "chemical inhibition" 9606 9605427 t miannu "AR agonists stimulated binding of [35S]GTPgS to HEK 293 cell membranes containing the human a2a, a2b, or a2c ARs (Fig. 6). EPI and NE were full agonists; clonidine and oxymetazoline were partial agonists, while antagonists (e.g. rauwolscine, 5 mM) did not stimulate [35S]GTPgS incorporation (Table 3). Although a few agonists showed a great deal of selectivity for a single receptor subtype, the rank order of agonist potency for selected compounds at the human receptors (Table 3) was: a2a: Dexmedetomidine . guanabenz . UK-14304 .clonidine . ST-91 . NE a2b: Dexmedetomidine . clonidine . guanabenz . NE .ST-91 . UK-14304 a2c: Dexmedetomidine . NE . UK-14304 . ST-91 $ clonidine .. guanabenz" SIGNOR-258913 CRYBB2 protein P43320 UNIPROT CRYBB3 protein P26998 UNIPROT "up-regulates activity" binding 9606 16319073 t miannu "At high concentrations or in the lens, βB2-crystallin forms hetero-oligomers with other β-crystallins. These oligomeric β-crystallins further participate in the formation of a supramolecular assembly that is important in lens function-lens transparency." SIGNOR-252152 CSNK2A1 protein P68400 UNIPROT PML protein P29590 UNIPROT down-regulates phosphorylation Ser565 VISSSEDsDAENSSS 9606 BTO:0000551 16873060 t llicata "Here we show that ck2 regulates pml protein levels by promoting its ubiquitin-mediated degradation dependent on direct phosphorylation at ser517." SIGNOR-148310 PPP2R2A protein P63151 UNIPROT TGFBR1 protein P36897 UNIPROT up-regulates binding 9606 9774674 t lperfetto "In this report, we show that another WD-40 repeat protein, the B_ subunit of protein phosphatase 2A, associates with the cytoplasmic domain of type I TGF-_ receptors. [...] We therefore conclude that B_ specifically and directly associates with the type I receptor cytoplasmic domain in vitro." SIGNOR-227517 MOB1A protein Q9H8S9 UNIPROT LATS1 protein O95835 UNIPROT up-regulates binding 9606 21084559 t "Lats1 and Lats2 are nuclear Dbf2-related (NDR) family protein kinases." gcesareni "Lats1/2 are activated by association with the highly homologous scaffold proteins mps one binder kinase activator-like 1a (mobkl1a) and 1b (mobkl1b), which are collectively referred to as mob1" SIGNOR-169752 CDK13 protein Q14004 UNIPROT POLR2A protein P24928 UNIPROT "up-regulates activity" phosphorylation Ser1910 TPTSPKYsPTSPTYS 9606 BTO:0006413 32917631 t "Ser2 in CTD of PolII" lperfetto "Together, these studies demonstrate the important, yet largely redundant, role for CDK12 and CDK13 for the regulation of POLII CTD phosphorylation at multiple residues, as well as the global role for both of these kinases in regulating POLII occupancy across the genome.|CDK12 and CDK13 are thus evolutionarily related and structurally similar kinases, and biochemical assays have demonstrated that both have POLII C-terminal domain (CTD) kinase activity and the ability to phosphorylate the Ser2 residue of the repetitive CTD heptad sequence" SIGNOR-273056 BRSK1 protein Q8TDC3 UNIPROT CDC25B protein P30305 UNIPROT down-regulates phosphorylation Ser375 ARVLRSKsLCHDEIE 9606 BTO:0000567;BTO:0000938 BTO:0000142 15150265 t lperfetto "Hssad1 specifically phosphorylated wee1a, cdc25-c, and -b on ser-642, ser-216, and ser-361 in vitro, respectivelyphosphorylation of cdc25 triggers cell-cycle arrest by the sequestration of cdc25 by 14-3-3" SIGNOR-124839 SIRT2 protein Q8IXJ6 UNIPROT PCK1 protein P35558 UNIPROT "up-regulates quantity by stabilization" deacetylation Lys70 EGILRRLkKYDNCWL 9606 BTO:0000007 21726808 t lperfetto "Conversely, SIRT2 deacetylates and stabilizes PEPCK1.|Furthermore, coexpression of P300 increased acetylation levels of wild-type PEPCK1, but not PEPCK13K/R, indicating that P300 acts on these lysine residues of PEPCK1" SIGNOR-267599 ITCH protein Q96J02 UNIPROT ERBB4 protein Q15303 UNIPROT "down-regulates quantity by destabilization" polyubiquitination 9606 BTO:0000007 17463226 t miannu "Interaction with the ErbB-4 receptors occurs via the WW domains of AIP4/Itch. Functional analyses demonstrate that AIP4/Itch is recruited to the ErbB-4 receptor to promote its polyubiquitination and degradation, thereby regulating stability of the receptor and access of receptor intracellular domains to the nuclear compartment. " SIGNOR-272618 ASB3 protein Q9Y575 UNIPROT TNFRSF1B protein P20333 UNIPROT "down-regulates quantity by destabilization" binding 9606 BTO:0000007 15899873 t miannu "While the ankyrin repeats of ASB3 interact with the C-terminal 37 amino acids of TNF-R2, the SOCS box of ASB3 is responsible for recruiting the E3 ubiquitin ligase adaptors Elongins-B/C, leading to TNF-R2 ubiquitination on multiple lysine residues within its C-terminal region. Downregulation of ASB3 expression by a small interfering RNA inhibited TNF-R2 degradation and potentiated TNF-R2-mediated cytotoxicity. The data presented here implicate ASB3 as a negative regulator of TNF-R2-mediated cellular responses to TNF-alpha by direct targeting of TNF-R2 for ubiquitination and proteasome-mediated degradation" SIGNOR-271546 PRKCB protein P05771 UNIPROT STXBP1 protein P61764 UNIPROT "down-regulates activity" phosphorylation Ser313 SLKDFSSsKRMNTGE 9913 BTO:0000259 12519779 t lperfetto "Munc18a is essential for neurotransmitter release by exocytosis and can be phosphorylated by PKC in vitro on Ser-306 and Ser-313. We demonstrate that it is phosphorylated on Ser-313 in response to phorbol ester treatment in adrenal chromaffin cells. Mutation of both phosphorylation sites to glutamate reduces its affinity for syntaxin and so acts as a phosphomimetic mutation." SIGNOR-249186 GARS1 protein P41250 UNIPROT ATP(4-) smallmolecule CHEBI:30616 ChEBI "down-regulates quantity" "chemical modification" 9606 24898252 t miannu "Aminoacyl-tRNA synthetases are an ancient enzyme family that specifically charges tRNA molecules with cognate amino acids for protein synthesis. Glycyl- tRNA synthetase (GlyRS) is one of the most intriguing aminoacyl-tRNA synthetases due to its divergent quaternary structure and abnormal charging properties. . In this study we report crystal structures of wild type and mutant hGlyRS in complex with tRNA and with small substrates and describe the molecular details of enzymatic recognition of the key tRNA identity elements in the acceptor stem and the anticodon loop." SIGNOR-270479 ITCH protein Q96J02 UNIPROT JUNB protein P17275 UNIPROT "down-regulates quantity by destabilization" polyubiquitination 10090 BTO:0001045 11828324 t miannu "Itch promotes Ub conjugation to JunB Molecularly, Itch associated with and induced ubiquitination of JunB, a transcription factor that is involved in TH2 differentiation. However, in Itch−/− T cells under the same conditions, degradation of JunB was markedly delayed." SIGNOR-272619 ELP5 protein Q8TE02 UNIPROT "Elongator complex" complex SIGNOR-C466 SIGNOR "form complex" binding 9606 28601220 t miannu "Elongator is a highly conserved eukaryotic protein complex consisting of two sets of six Elp proteins, while homologues of its catalytic subunit Elp3 are found in all the kingdoms of life. Although it was originally described as a transcription elongation factor, cumulating evidence suggests that its primary function is catalyzing tRNA modifications. In humans, defects in Elongator subunits are associated with neurological disorders and cancer." SIGNOR-269712 DTX1 protein Q86Y01 UNIPROT ASCL1 protein P50553 UNIPROT down-regulates binding 9606 11564735 t gcesareni "Through its binding to p300, dtx1 inhibited transcriptional activation by the neural-specific helix-loop-helix-type transcription factor mash1" SIGNOR-110626 Naltriben chemical CID:5486827 PUBCHEM OPRK1 protein P41145 UNIPROT "down-regulates activity" "chemical inhibition" 10029 BTO:0000246 9686407 t miannu "Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors." SIGNOR-258426 NHLRC1 protein Q6VVB1 UNIPROT DVL2 protein O14641 UNIPROT "down-regulates quantity by destabilization" polyubiquitination 9606 BTO:0000007 22223637 t miannu "We have also found that malin enhances K48- and K63-linked ubiquitination of dishevelled2 that could lead to its degradation through both proteasome and autophagy. Altogether, our results indicate that malin regulates Wnt signaling pathway through the degradation of dishevelled2 and suggest possible deregulation of Wnt signaling in Lafora disease." SIGNOR-272005 RPS6KB1 protein P23443 UNIPROT GLI1 protein P08151 UNIPROT up-regulates phosphorylation Ser84 LTKKRALsISPLSDA 9606 22439934 t gcesareni "In this study, we found that an activated mtor/s6k1 pathway promotes gli1 transcriptional activity and oncogenic function through s6k1-mediated gli1 phosphorylation at ser84, which releases gli1 from its endogenous inhibitor, sufu." SIGNOR-196756 PPP2CA protein P67775 UNIPROT TP53 protein P04637 UNIPROT "up-regulates quantity by stabilization" dephosphorylation Thr55 DDIEQWFtEDPGPDE 9606 17245430 t "A specific PP2A regulatory subunit, B56gamma, mediates DNA damage-induced dephosphorylation of p53 at Thr55| In this study, we reported that the specific B regulatory subunits of PP2A B56gamma1 and B56gamma3 mediate dephosphorylation of p53 at Thr55. Ablation of the B56gamma protein by RNAi, which abolishes the Thr55 dephosphorylation in response to DNA damage, reduces p53 stabilization, Bax expression and cell apoptosis" SIGNOR-248618 MAPK3 protein P27361 UNIPROT SP1 protein P08047 UNIPROT up-regulates phosphorylation Thr739 SEGSGTAtPSALITT 9606 BTO:0000887;BTO:0001260 14593115 t gcesareni "We showed that perifosine activates the mitogen-activated protein/extracellular signal-regulated kinase pathway, and this activation promotes the phosphorylation of sp1 in known mitogen-activated protein kinase residues (threonine 453 and 739), thereby leading to increased sp1 binding and enhanced p21(waf1/cip1) transcription." SIGNOR-118936 PRKCA protein P17252 UNIPROT ADD1 protein P35611 UNIPROT up-regulates phosphorylation Ser726 KKKFRTPsFLKKSKK 9606 8810272 t gcesareni "These data demonstrate that adducin is a significant in vivo substrate for pkc or other pma-activated kinases in a variety of cells, and that phosphorylation of adducin occurs in dendritic spines that are believed to respond to external signals by changes in morphology and reorganization of cytoskeletal structures. Ser-726 and ser-713 in the c-terminal marcks-related domains of alpha- and beta-adducin, respectively, were identified as the major phosphorylation sites common for pka and pkc." SIGNOR-43744 DDHD1 protein Q8NEL9 UNIPROT "long-chain fatty acid anion" smallmolecule CHEBI:57560 ChEBI "up-regulates quantity" "chemical modification" 9606 22922100 t miannu "Members of the intracellular phospholipase A1 family of proteins have been implicated in organelle biogenesis and membrane trafficking. The mammalian family comprises three members: phosphatidic acid-preferring phospholipase A1 (PA-PIA1)/DDHD1, p125/Sec23ip and KIAA0725p/DDHD2, all of which have a DDHD domain." SIGNOR-269653 DUSP7 protein Q16829 UNIPROT GHR protein P10912 UNIPROT "down-regulates activity" dephosphorylation 10029 BTO:0000246 12907755 t "Protein tyrosine phosphatases (PTPs) play key roles in switching off tyrosine phosphorylation cascades, such as initiated by cytokine receptors. We have used substrate-trapping mutants of a large set of PTPs to identify members of the PTP family that have substrate specificity for the phosphorylated human GH receptor (GHR) intracellular domain. Among 31 PTPs tested, T cell (TC)-PTP, PTP-beta, PTP1B, stomach cancer-associated PTP 1 (SAP-1), Pyst-2, Meg-2, and PTP-H1 showed specificity for phosphorylated GHR" SIGNOR-248726 ruxolitinib chemical CHEBI:66919 ChEBI JAK2 protein O60674 UNIPROT "down-regulates activity" "chemical inhibition" -1 22037378 t Luana "Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here." SIGNOR-258277 CNOT1 protein A5YKK6 UNIPROT "CCR4-NOT complex" complex SIGNOR-C439 SIGNOR "form complex" binding 9606 19558367 t lperfetto "In the present study, we examine the composition of the human Ccr4-Not complex in an in-depth proteomic approach using stable cell lines expressing tagged CNOT proteins. We find at least four different variants of the human complex, consisting of seven stable core proteins and mutually exclusive associated mRNA deadenylase subunits. Interestingly, human CNOT4 is in a separate approximately 200 kDa complex. Furthermore, analyses of associated proteins indicate involvement of Ccr4-Not complexes in splicing, transport and localization of RNA molecules." SIGNOR-268300 CSNK2A1 protein P68400 UNIPROT G3BP1 protein Q13283 UNIPROT "down-regulates activity" phosphorylation Ser149 VTEPQEEsEEEVEEP 9606 BTO:0001938 27920254 t miannu "We also show that casein kinase 2 phosphorylates G3BP1 at serine 149 in vitro and in cells. These data support a role for casein kinase 2 in regulation of protein synthesis by downregulating stress granule formation through G3BP1.CK2 regulates SG disassembly during stress recovery.G3BP1 is among the strongest SG nucleating proteins, and previous work indicated that G3BP1 phosphorylation at S149 restricts stress granule assembly by partly inhibiting G3BP1 oligomerization" SIGNOR-260748 PTMS protein P20962 UNIPROT NCOA1 protein Q15788 UNIPROT "up-regulates activity" binding 9606 BTO:0000567 16150697 t miannu "Macromolecular translocation inhibitor II (MTI-II), which was first identified as an in vitro inhibitor of binding between the highly purified glucocorticoid receptor (GR) and isolated nuclei, is an 11.5-kDa Zn2+-binding protein that is also known as ZnBP or parathymosin. MTI-II Enhances GR-dependent Transcription through Its Acidic Domain. MTI-II Enhances GR-dependent Transcription in Cooperation with SRC-1 and p300 in Vivo. CBP and p300 Coprecipitate with MTI-II in a Glucocorticoid Hormone-dependent Manner. Immunoprecipitation analysis showed that in the presence of glucocorticoid hormone, p300 and CREB-binding protein are coprecipitated with MTI-II. Furthermore, the knockdown of endogenous MTI-II by RNAi reduces the transcriptional activity of GR in cells." SIGNOR-268462 DAGLB protein Q8NCG7 UNIPROT 1,2-diacyl-sn-glycerol smallmolecule CHEBI:17815 ChEBI "down-regulates quantity" "chemical modification" 9606 26787883 t miannu "Diacylglycerol lipases (DAGL√鬱 and DAGL√é¬≤) convert diacylglycerol to the endocannabinoid 2-arachidonoylglycerol." SIGNOR-264263 TAOK2 protein Q9UL54 UNIPROT STK3 protein Q13188 UNIPROT up-regulates phosphorylation 9606 23431053 t gcesareni "In addition, the thousand-and-one (tao) amino acids kinase or taok13 has been shown to directly phosphorylate and activate hpo or mst1/2." SIGNOR-201327 TGFBR1 protein P36897 UNIPROT TRAF6 protein Q9Y4K3 UNIPROT "up-regulates activity" binding 9606 BTO:0000007 18922473 t gcesareni "We report here that TRAF6 is specifically required for the Smad-independent activation of JNK and p38 and its carboxyl TRAF homology domain physically interacts with TGF-² receptors" SIGNOR-241918 TGFB2 protein P61812 UNIPROT Angiogenesis phenotype SIGNOR-PH46 SIGNOR up-regulates 17326328 f lperfetto "More than a dozen different proteins have been identified as angiogenic activators, including vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), angiogenin, transforming growth factor (TGF)-α, TGF-β, tumor necrosis factor (TNF)-α, platelet-derived endothelial growth factor, granulocyte colony-stimulating factor, placental growth factor, interleukin-8, hepatocyte growth factor, and epidermal growth factor" SIGNOR-252283 IER3 protein P46695 UNIPROT PPP2R5C protein Q13362 UNIPROT down-regulates binding 9606 16456541 t gcesareni "Iex-1 binds to b56 subunits and perk independently, enhances b56 phosphorylation by erk at a conserved ser/pro site in this complex and triggers dissociation from the catalytic subunit." SIGNOR-144309 UBXN8 protein O00124 UNIPROT VCP protein P55072 UNIPROT "down-regulates quantity" relocalization 9606 21949850 t SARA "The human protein named Rep8 or Ubxd6 as a new cofactor of p97. Rep8 tethers p97 to the ER membrane for efficient ER-associated degradation." SIGNOR-261002 CYP2D6 protein P10635 UNIPROT dopamine smallmolecule CHEBI:18243 ChEBI "up-regulates quantity" "chemical modification" 9606 NBK536726 t brain lperfetto "Under specific conditions, dopamine can also be synthesized by a minor pathway, in which L-tyrosine is converted into p-tyramine (mediated by AADC), with subsequent hydroxylation to dopamine by the enzyme CYP2D6 (Cytochrome P450 2D6) which is found in the substantia nigra of human brain¬†" SIGNOR-263996 MAPK14 protein Q16539 UNIPROT HBB protein P68871 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 20162623 f Indirect:regulation miannu "Our results demonstrate that activin A induced Hb synthesis and promoter activation of the specific erythroid gene, ζ-globin, through p38α and p38β isoforms and their activator, MKK6 (mitogen-activated protein kinase kinase 6)." SIGNOR-251837 SLC12A5 protein Q9H2X9 UNIPROT chloride smallmolecule CHEBI:17996 ChEBI "down-regulates activity" relocalization 9606 26951057 t miannu "As shown in Fig. 2, the intracellular Cl− concentration is regulated mainly by two cation-chloride cotransporters, NKCC1 and KCC2 [32]. NKCC1 imports Cl− whereas KCC2 extrudes intracellular Cl−." SIGNOR-264987 SMURF1 protein Q9HCE7 UNIPROT BMPR2 protein Q13873 UNIPROT down-regulates ubiquitination 9606 17317136 t gcesareni "Smurf1 and smurf2 are e3 ubiquitin ligases known to suppress tgf-beta signaling through degradation of smads and receptors for tgf-beta and bmps." SIGNOR-153402 AKT1 protein P31749 UNIPROT RPS3 protein P23396 UNIPROT "up-regulates activity" phosphorylation Thr70 GRRIRELtAVVQKRF 10116 BTO:0003060 20605787 t miannu "Here, we show that human RPS3 is a physiological target of Akt kinase and a novel mediator of neuronal apoptosis. NGF stimulation resulted in phosphorylation of threonine 70 of RPS3 by Akt, and this phosphorylation was required for Akt binding to RPS3.our experiment demonstrated that Akt up-regulates the endonuclease activity of RPS3 via phosphorylation and led us to believe that Akt phosphorylation of RPS3 after DNA damage is an antiapoptotic signal or a molecular switch that extends the life of a cell after DNA damage." SIGNOR-259815 DUSP4 protein Q13115 UNIPROT MAPK3 protein P27361 UNIPROT "down-regulates activity" dephosphorylation Thr202 HDHTGFLtEYVATRW 10116 7535768 t "Dephosphorylation and Inactivation of ERKs|ERK1 phosphorylated on either threonine (ERK1*Y204F) or tyrosine alone (ERK1*T202A) was utilized as a substrate for HVH2. Threonine 202 and tyrosine 204 in ERK1 (53) correspond to threonine 183 and tyrosine 185 in ERK2 which are the activation-phosphorylation sites by MEK(14, 15, 16). ERK1*, a kinase-deficient mutant, was phosphorylated on both threonine and tyrosine by MEK2 (Fig. 3B). ERK1*T202A, having threonine 202 substituted by an alanine, was phosphorylated only on tyrosine while ERK1*Y204F, having tyrosine 204 substituted by a phenylalanine, was phosphorylated only on threonine (Fig. 3B). GST-HVH2 dephosphorylated all three ERK1* mutants (Fig. 3A), suggesting that double phosphorylations of adjacent threonine and tyrosine were not a prerequisite for HVH2 recognition. However, HVH2 dephosphorylated ERK1* and ERK1*T202A more efficiently than ERK1*Y204F (Fig. 3A), indicating that HVH2 preferred phosphotyrosine over phosphothreonine. Interestingly, MEK also phosphorylated tyrosine residues more efficiently than threonine residues of ERK" SIGNOR-248715 Guanfacine chemical CHEBI:5558 ChEBI ADRA2B protein P18089 UNIPROT "up-regulates activity" "chemical activation" 9606 BTO:0000007 9605427 t miannu "AR agonists stimulated binding of [35S]GTPgS to HEK 293 cell membranes containing the human a2a, a2b, or a2c ARs (Fig. 6). EPI and NE were full agonists; clonidine and oxymetazoline were partial agonists, while antagonists (e.g. rauwolscine, 5 mM) did not stimulate [35S]GTPgS incorporation (Table 3). Although a few agonists showed a great deal of selectivity for a single receptor subtype, the rank order of agonist potency for selected compounds at the human receptors (Table 3) was: a2a: Dexmedetomidine . guanabenz . UK-14304 .clonidine . ST-91 . NE a2b: Dexmedetomidine . clonidine . guanabenz . NE .ST-91 . UK-14304 a2c: Dexmedetomidine . NE . UK-14304 . ST-91 $ clonidine .. guanabenz" SIGNOR-258920 PPP1R9A protein Q9ULJ8 UNIPROT ARHGEF2 protein Q92974 UNIPROT "up-regulates activity" binding 10090 BTO:0001976 15996550 t miannu "The Rho Family GEF Lfc Interacts with Neurabin and Spinophilin. Neurabin and spinophilin are homologous protein phosphatase 1 and actin binding proteins that regulate dendritic spine function. The results obtained in the present study suggest a mechanism by which neurabin or spinophilin contributes to the organization of the F-actin cytoskeleton in dendritic spines, and in turn to the regulation of spine morphology, via the activity-dependent recruitment of the Rho-specific GEF Lfc" SIGNOR-269177 "trichostatin A" chemical CHEBI:46024 ChEBI HDAC7 protein Q8WUI4 UNIPROT "down-regulates activity" "chemical inhibition" -1 20139990 t Luana "Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1)." SIGNOR-258014 OXTR protein P30559 UNIPROT GNAS protein Q5JWF2 UNIPROT "up-regulates activity" binding 9606 30739093 t miannu "OT binds to its cognate G protein–coupled receptor (OTR) and exerts diverse effects, including stimulation (Gs) or inhibition (Gi/o) of adenylyl cyclase, stimulation of potassium channel currents (Gi), and activation of phospholipase C (Gq)." SIGNOR-270331 IFNGR1 protein P15260 UNIPROT JAK1 protein P23458 UNIPROT up-regulates binding 9606 17063185 t flangone "Interferon- (ifn;type ii ifn) induces reorganization of the ifn-receptor subunits, ifngr1 and ifngr2, activating the janus kinases jak1 and jak2, which are constitutively associated with each subunit, respectively" SIGNOR-150194 sapitinib chemical CHEBI:132986 ChEBI "ErbB receptor family" proteinfamily SIGNOR-PF36 SIGNOR down-regulates "chemical inhibition" 9606 BTO:0000551 20145185 t "AZD8931 has a unique pharmacologic profile providing equipotent EGFR, erbB2, and erbB3 signaling and showing greater antitumor activity than agents with a narrower spectrum of erbB receptor inhibition in specific preclinical models." gcesareni "In vivo, azd8931 inhibited xenograft growth in a range of models while significantly affecting egfr, erbb2, and erbb3 phosphorylation and downstream signaling pathways, apoptosis, and proliferation." SIGNOR-269874 IGF1R protein P08069 UNIPROT IGF1R protein P08069 UNIPROT "up-regulates activity" phosphorylation Tyr1166 DIYETDYyRKGGKGL -1 8940173 t miannu "The insulin-like growth factor type I (IGF-I) receptor can become tyrosine phosphorylated and enzymatically activated either in response to ligand or because of the activity of the Src tyrosine kinaseWe mapped the sites of IGF-I receptor autophosphorylation to peptides representing three different receptor domains: tyrosines 943 and 950 in the juxtamembrane region; tyrosines 1131, 1135, and 1136 within the kinase domain; and tyrosine 1316 in the carboxyl-terminal domain." SIGNOR-246244 Ub:E2 complex SIGNOR-C497 SIGNOR SH3RF3 protein Q8TEJ3 UNIPROT "up-regulates activity" ubiquitination 9606 34199813 t miannu "The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t" SIGNOR-271039 MMP3 protein P08254 UNIPROT DCN protein P07585 UNIPROT "down-regulates quantity by destabilization" cleavage Ser240 ISRVDAAsLKGLNNL -1 9148753 t miannu "Degradation of decorin by matrix metalloproteinases. These data indicate proteolytic degradation of DCN by MMP-2, MMP-3 and MMP-7, and suggest the possibility that, under pathophysiological conditions, the digestion by the MMPs may induce tissue reactions mediated by TGF-beta1 released from DCN in the connective tissues." SIGNOR-256353 MAPK8IP3 protein Q9UPT6 UNIPROT MAPK9 protein P45984 UNIPROT up-regulates binding 9606 15767678 t gcesareni "The c-jun nh2-terminal kinase (jnk)-interacting protein (jip) group of scaffold proteins (jip1, jip2, and jip3) can interact with components of the jnk signaling pathway and potently activate jnk." SIGNOR-134561 CBX3 protein Q13185 UNIPROT ChAHP complex SIGNOR-C407 SIGNOR "form complex" binding 10090 BTO:0002896 29795351 t miannu "Here we show that ADNP interacts with the chromatin remodeller CHD4 and the chromatin architectural protein HP1 to form a stable complex, which we refer to as ChAHP. Besides mediating complex assembly, ADNP recognizes DNA motifs that specify binding of ChAHP to euchromatin. In conclusion, CHD4, ADNP and HP1β/γ form a stable protein complex, which we refer to as ChAHP." SIGNOR-266753 "Ub:E1 (UBA1 substrate)" complex SIGNOR-C495 SIGNOR UBE2V2 protein Q15819 UNIPROT "up-regulates activity" ubiquitination 9606 34199813 t miannu "The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t" SIGNOR-271335 EXOC8 protein Q8IYI6 UNIPROT "Exocyst_EXOC6 variant" complex SIGNOR-C492 SIGNOR "form complex" binding 9606 26240175 t miannu "The exocyst is an octameric protein complex that is implicated in the tethering of secretory vesicles to the plasma membrane prior to SNARE-mediated fusion." SIGNOR-270791 p38 proteinfamily SIGNOR-PF16 SIGNOR HNF4A protein P41235 UNIPROT up-regulates phosphorylation Ser167 VLSRQITsPVSGING 9606 16351573 t lperfetto "Our results indicate that p38 kinase-mediated ser158 phosphorylation is essential for augmentation of the dna binding and transactivation potential of hnf4alpha" SIGNOR-143046 PLK1 protein P53350 UNIPROT CHEK2 protein O96017 UNIPROT unknown phosphorylation Thr26 SQPHGSVtQSQGSSS -1 12493754 t lperfetto "Plk1 overexpression enhances phosphorylation of Chk2 at Thr-68. Plk1 phosphorylates recombinant Chk2 in vitro." SIGNOR-249180 TWIST2 protein Q8WVJ9 UNIPROT PFDN4 protein Q9NQP4 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0004828 19051271 f miannu "we performed microarray analysis to compare the gene expression profiles in HGC-27 cells, with or without small interfering RNA (siRNA)-mediated depletion of TWIST. Our results showed that NF1, RAP1A, SRPX, RBL2, PFDN4, ILK, F2R, ERBB3, and MYB were up-regulated, whereas AKR1C2, FOS, GDF15, NR2F1, ATM, and CTPS were down-regulated after TWIST depletion" SIGNOR-255507 HMGB1 protein P09429 UNIPROT HOXD9 protein P28356 UNIPROT "up-regulates activity" binding 10090 BTO:0000944 8890171 t miannu "We show that HMG1 interacts with proteins encoded by the HOX gene family by establishing protein-protein contacts between the HMG box domains and the HOX homeodomain.ƒ‚‚ The functional role of these interactions was studied using the transcriptional activity of the human HOXD9 protein as a model. HMG1 enhances, in a dose-dependent fashion, the sequence-specific DNA binding activity in vitro, and the transcriptional activation in a co-transfection assay in vivo, of the HOXD9 protein." SIGNOR-236956 TTK protein P33981 UNIPROT TP53 protein P04637 UNIPROT up-regulates phosphorylation Thr18 EPPLSQEtFSDLWKL 9606 19332559 t llicata "Ttk/hmps1 mediates the p53-dependent postmitotic checkpoint by phosphorylating p53 at thr18. phosphorylation at thr18 enhances p53-dependent activation of not only p21 but also lats2, two mediators of the postmitotic checkpoint." SIGNOR-184931 INS protein P01308 UNIPROT INSR protein P06213 UNIPROT "up-regulates activity" binding 9606 2550426 t lperfetto "Our previous studies indicated that amino acid residues 240-250 in the cysteine-rich region of the human insulin receptor alpha-subunit constitute a site in which insulin binds." SIGNOR-23001 LRP6 protein O75581 UNIPROT GSK3B/Axin/APC complex SIGNOR-C110 SIGNOR "down-regulates activity" binding 9606 19107203 t "PPPSPxS motif in LRP6/5 must be phosphorylated." lperfetto "These observations demonstrate that phosphorylated lrp6/5 both recruits and directly inhibits gsk3beta using two distinct portions of its cytoplasmic sequence binding of wnts to the coreceptors frizzled and lrp6/5 leads to phosphorylation of pppspxs motifs in the lrp6/5 intracellular region and the inhibition of gsk3beta bound to the scaffold protein axin.These Observations demonstrate that phosphorylated lrp6/5 both recruits and directly inhibits gsk3beta using two distinct portions of its cytoplasmic sequence." SIGNOR-227942 MITF protein O75030 UNIPROT TRPM1 protein Q7Z4N2 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 14744763 f miannu "Mice homozygously mutated in MITF showed a dramatic decrease in TRPM1 expression. Finally, the slope of TRPM1 induction by MITF was particularly steep compared with other MITF target genes, suggesting it is a sensitive indicator of MITF expression and correspondingly of melanocytic differentiation." SIGNOR-254588 Gbeta proteinfamily SIGNOR-PF4 SIGNOR NFATC4 protein Q14934 UNIPROT up-regulates phosphorylation 9606 15657420 t "inferred from 70% family members" lperfetto "The formation of rsk-nfatc4-dna transcription complex is also apparent upon adipogenesis. Bound rsk phosphorylates ser(676) and potentiates nfatc4 dna binding by escalating nfat-dna association. Ser(676) is also targeted by the erk map kinase, which interacts with nfat at a distinct region than rsk. Thus, integration of the erk/rsk signaling pathway provides a mechanism to modulate nfatc4 transcription activity." SIGNOR-270047 PRKCE protein Q02156 UNIPROT IQGAP1 protein P46940 UNIPROT up-regulates phosphorylation Ser1443 DKMKKSKsVKEDSNL 9606 15355962 t gcesareni "Using a mass spectrometry-based assay, we show that egf induces phosphorylation of iqgap1 ser(1443), a residue known to be phosphorylated by pkcthe nonphosphorylatable iqgap1 s1441a/s1443a had no effect. In contrast, the s1441e/s1443d mutation markedly enhanced the ability of iqgap1 to induce neurite outgrowth." SIGNOR-128718 TRIM25 protein Q14258 UNIPROT SFN protein P31947 UNIPROT "down-regulates quantity by destabilization" ubiquitination 9534 BTO:0000298 12075357 t miannu "Here we show that Efp is a RING-finger-dependent ubiquitin ligase (E3) that targets proteolysis of 14-3-3 sigma, a negative cell cycle regulator that causes G2 arrest." SIGNOR-271548 GGCX protein P38435 UNIPROT F9 protein P00740 UNIPROT "up-regulates activity" carboxylation Glu53 RYNSGKLeEFVQGNL 10090 BTO:0001103 11133752 t lperfetto "The direct gamma-carboxyglutamic acid analysis and the N-terminal sequence analysis of the myotube-synthesized F.IX demonstrate efficient carboxylation at 11 of 12 γ-carboxyglutamic acid residues. |In previous work54 we have demonstrated that the γ-glutamyl carboxylase is present in skeletal muscle, but at a level only 5% to 10% of that found in the liver. This level of enzyme appears to be sufficient to provide full carboxylation of F.IX synthesized in myotubes|Glu 7, 8, 15, 17, 20, 21, 26, 27, 30, 33, and 36 are each less than 10% of the yield at the previous and subsequent cycles. Only a single γ-carboxylated residue, Gla 40, was not assessed by N-terminal sequencing." SIGNOR-263686 CBS protein P35520 UNIPROT "L-serine zwitterion" smallmolecule CHEBI:33384 ChEBI "down-regulates quantity" "chemical modification" 9606 23981774 t lperfetto "Cystathionine β-synthase (CBS) is a pyridoxal 5'-phosphate (PLP)-dependent enzyme that catalyzes the condensation of homocysteine with serine to generate cystathionine." SIGNOR-275829 GARS1 protein P41250 UNIPROT glycine smallmolecule CHEBI:15428 ChEBI "down-regulates quantity" "chemical modification" 9606 24898252 t miannu "Aminoacyl-tRNA synthetases are an ancient enzyme family that specifically charges tRNA molecules with cognate amino acids for protein synthesis. Glycyl- tRNA synthetase (GlyRS) is one of the most intriguing aminoacyl-tRNA synthetases due to its divergent quaternary structure and abnormal charging properties. . In this study we report crystal structures of wild type and mutant hGlyRS in complex with tRNA and with small substrates and describe the molecular details of enzymatic recognition of the key tRNA identity elements in the acceptor stem and the anticodon loop." SIGNOR-270478 MEF2D protein Q14814 UNIPROT "Myog/SWI/SNF complex" complex SIGNOR-C94 SIGNOR "form complex" binding 9606 BTO:0001103 17194702 t miannu "Upon the expression of myogenin, myogenin, mef2d, and brg1 localize to the myogenin promoter to maintain myogenin expression./ Swi/snf chromatin-remodeling activity is required for myogenin expression in differentiated skeletal muscle" SIGNOR-151679 MAPK14 protein Q16539 UNIPROT ATF2 protein P15336 UNIPROT up-regulates phosphorylation Thr71 IVADQTPtPTRFLKN 9606 20068231 t gcesareni "Phosphorylation of thr-69 by mapk14 and mapk11, and at thr-71 by mapk1/erk2, mapk3/erk1, mapk11, mapk12 and mapk14 in response to external stimulus like insulin causes increased transcriptional activity." SIGNOR-163250 NUP50 protein Q9UKX7 UNIPROT NPC complex SIGNOR-C263 SIGNOR "form complex" binding 27016207 t lperfetto "The protein inventory of the NPC has been studied for a very diverse set of eukaryotes, including trypanosomes, fungi, plants, animals, and humans [4], [5], [6], [7], [8], [9]. In all cases, about 30 different Nups were found (Fig. 2)." SIGNOR-262068 GPHA2 protein Q96T91 UNIPROT TSHR protein P16473 UNIPROT up-regulates binding 9606 12045258 t gcesareni "Recombinant a2/b5 heterodimeric glycoproteins, purified using cation exchange and size fractionation chromatography, activated human tsh receptors, but not lh and fsh receptors, and showed high affinity to tsh receptors in a radioligand receptor assay" SIGNOR-88614 MEF2A protein Q02078 UNIPROT SLC2A4 protein P14672 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 14630949 f lperfetto "Neither GEF nor MEF2A alone significantly activated GLUT4 promoter activity, but increased promoter activity 4- to 5-fold when expressed together." SIGNOR-271692 MMP14 protein P50281 UNIPROT ADAM9 protein Q13443 UNIPROT "down-regulates quantity by destabilization" cleavage 9606 BTO:0000007 22632802 t Giulio "Here we show that MT1-MMP forms a complex with FGFR2 and ADAM9 in osteoblasts and proteolytically inactivates ADAM9|Western blotting using antibodies against ectodomain of ADAM9 detected a fragment (around 26 kDa) of ADAM9 in the conditioned culture medium from cells cotransfected with wild-type MT1-MMP, but not in that with catalytic activity-dead MT1-MMP (Figure 6A, top)." SIGNOR-260301 DYRK1B protein Q9Y463 UNIPROT CDKN1A protein P38936 UNIPROT "up-regulates activity" phosphorylation Ser153 SMTDFYHsKRRLIFS 10090 15851482 t lperfetto "Mirk exerts its anti-apoptotic effects during muscle differentiation at least in part through effects on the cell cycle inhibitor and pro-survival molecule p21cip1. Overexpression and rna interference experiments demonstrated that mirk phosphorylates p21 within its nuclear localization domain at ser-153 causing a portion of the typically nuclear p21 to localize in the cytoplasm.Translocation to the cytoplasm enables p21 to block apoptosis through inhibitory interaction with pro-apoptotic molecules." SIGNOR-235635 MAPT protein P10636 UNIPROT "Neurofibrillary tangle formation" phenotype SIGNOR-PH58 SIGNOR down-regulates 9606 11578751 f lperfetto "Tau is a multifunctional microtubule-associated protein that plays major roles in the assembly of microtubules, the stabilization of microtubules against dynamic instability, and in bridging these polymers with other cytoskeletal filaments 43, 44, 45, 46 and 47. In normal brain, the equilibrium between phosphorylations and dephosphorylations of tau modulates the stability of the cytoskeleton and consequently axonal morphology. The earliest modification found in Alzheimer brains consists of hyperphosphorylations on tau by the action of different protein kinase and phosphatase systems that appear to lead to structural and conformational changes in this protein, thus affecting its binding with tubulin and the capacity to promote microtubule assembly" SIGNOR-251639 ATM protein Q13315 UNIPROT TP53 protein P04637 UNIPROT "up-regulates quantity by stabilization" phosphorylation Ser46 AMDDLMLsPDDIEQW 9606 11875057 t gcesareni "In response to ionizing radiation (ir), atm, the gene product mutated in ataxia telangiectasia, stabilizes and activates p53 through phosphorylation of ser15 and (indirectly) ser20. Here we show that phosphorylation of p53 on ser46, a residue important for p53 apoptotic activity, as well as on ser9, in response to ir also is dependent on the atm protein kinase. one pathway involves the phosphorylation of p53 and its negative regulator mdm2 by ataxia telangiectasia mutated (atm) and chk2 causing p53 activation and stabilization." SIGNOR-115344 CKB protein P12277 UNIPROT N-phosphocreatine smallmolecule CHEBI:17287 ChEBI "up-regulates quantity" "chemical modification" 9606 18502307 t miannu "Creatine kinase catalyses the reversible transphosphorylation of creatine by ATP. In the cell, creatine kinase isoenzymes are specifically localized at strategic sites of ATP consumption to efficiently regenerate ATP in situ via phosphocreatine or at sites of ATP generation to build-up a phosphocreatine pool." SIGNOR-265787 SIX1 protein Q15475 UNIPROT MYOG protein P15173 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000887 9826681 f gcesareni "We have demonstrated by studies of transgenic mice the importance of the mef3 motif present in the myogeninpromoter for its activation and have characterized the mef3 binding activity as consisting of two skeletal-muscle specific members of the six family, six1 and six4." SIGNOR-62104 MMP25 protein Q9NPA2 UNIPROT MMP2 protein P08253 UNIPROT "up-regulates activity" cleavage Asn109 CGNPDVAnYNFFPRK -1 14583471 t miannu "Direct activation of pro-matrix metalloproteinase-2 by leukolysin/membrane-type 6 matrix metalloproteinase/matrix metalloproteinase 25 at the asn(109)-Tyr bond. Leukolysin Cleaves ProMMP-2 at Asn66-Leu and Asn109-Tyr." SIGNOR-256345 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR MAPK6 protein Q16659 UNIPROT up-regulates phosphorylation Thr698 KSIQATLtPSAMKSS 9606 20236090 t lperfetto "Using ms analysis, we identified four novel phosphorylation sites, ser684, ser688, thr698 and ser705, located at the extreme c-terminus of erk3. All four sites are followed by a proline residue. We have shown that purified cyclin b-cdk1 (cyclindependent kinase 1) phosphorylates these sitesalanine substitution of the four c-terminal phosphorylation sites markedly decreased the half-life of erk3 in mitosis, thereby linking phosphorylation to the stabilization of the kinase." SIGNOR-216809 APH1B protein Q8WW43 UNIPROT NCSTN protein Q92542 UNIPROT up-regulates binding 9606 BTO:0000142 12297508 t gcesareni "By using co-immunoprecipitation and nickel affinity pull-down approaches, we now show that mammalian aph-1 (maph-1), a conserved multipass membrane protein, physically associates with nicastrin and the heterodimers of the presenilin amino- and carboxyl-terminal fragments in human cell lines and in rat brain.These data indicate that maph-1 is probably a functional component of the gamma-secretase complex" SIGNOR-93307 NfKb-p65/p50 complex SIGNOR-C13 SIGNOR CCR3 protein P51677 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 16604092 f miannu "Rosmarinic acid also inhibited TNF-alpha-induced phosphorylation and degradation of IkappaB-alpha, as well as nuclear translocation of NF-kappaB heterodimer induced by TNF-alpha. This suggests that rosmarinic acid downregulates the expression of CCL11 and CCR3 via the inhibition of NF-kappaB activation signaling." SIGNOR-254660 Ub:E2 complex SIGNOR-C497 SIGNOR VPS11 protein Q9H270 UNIPROT "up-regulates activity" ubiquitination 9606 34199813 t miannu "The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t" SIGNOR-271125 HPX protein P02790 UNIPROT HBB protein P68871 UNIPROT "down-regulates activity" 9606 20617898 f Regulation miannu "The endogenous molecule hemoglobin and its derivative heme are often released into tissue compartments where there is infection in the presence of degrading blood. We found that hemoglobin synergizes with multiple TLR agonists to induce high levels of tumor necrosis factor and interleukin-6 from macrophages and that this synergy is independent of TLR4 and MyD88. In contrast, heme synergized with some but not all TLR agonists studied. Furthermore, the synergy of both hemoglobin and heme with lipopolysaccharide was suppressed by hemopexin, a plasma heme-binding protein." SIGNOR-251811 NFKB1 protein P19838 UNIPROT CD80 protein P33681 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 BTO:0000776 12860928 f "Upon CD40 signaling, transcription of the CD80 gene is induced by the nuclear factor (NF)-kappaB transcription factor. Our results show that BCL6 prevents CD40-induced expression of CD80 by binding its promoter region in vivo and suppressing its transcriptional activation by NF-kappaB. Consistent with a physiologic role for BCL6 in suppressing CD80, the expression of these two genes is mutually exclusive in B cells, and BCL6-defective mice show increased expression of CD80 in B cells." SIGNOR-253934 CDK2 protein P24941 UNIPROT HIRA protein P54198 UNIPROT "up-regulates activity" phosphorylation Thr555 LSPSVLTtPSKIEPM 9606 BTO:0001938 SIGNOR-C16 11238922 t lperfetto "Hira bound to and was phosphorylated by cyclin a- and e-cdk2 in vitrohira became phosphorylated on threonine 555 in s phase when cyclin-cdk2 kinases are active.ectopic expression of hira in cells caused arrest in s phase and this is consistent with the notion that it is a cyclin-cdk2 substrate that has a role in control of the cell cycle." SIGNOR-105548 WNT1 protein P04628 UNIPROT LRP6 protein O75581 UNIPROT "up-regulates activity" binding 9606 BTO:0000007 21078818 t gcesareni "Ligands such as wnt1, wnt3a, and wnt8 couple the seventransmembrane domain receptor frizzled (fzd) and the single-membrane-spanning low-density receptor-related protein 5/6 (lrp5/6) to activate wnt?Beta-catenin signaling." SIGNOR-169648 "Ub:E1 (UBA1 substrate)" complex SIGNOR-C495 SIGNOR UBE2Q1 protein Q7Z7E8 UNIPROT "up-regulates activity" ubiquitination 9606 34199813 t miannu "The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t" SIGNOR-271338 TBXA2R protein P21731 UNIPROT GNA13 protein Q14344 UNIPROT "up-regulates activity" binding 9606 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257139 3-isobutyl-1-methylxanthine chemical CHEBI:48518 ChEBI CEBPB protein P17676 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 8754811 f fspada "The differentiation of 3t3 preadipocytes into adipocytes is accompanied by a transient induction of c/ebpbeta and c/ebpdelta expression in response to treatment of the cells with methylisobutylxanthine (mix) and dexamethasone (dex), respectively" SIGNOR-43310 AMP smallmolecule CHEBI:456215 ChEBI adenosine smallmolecule CHEBI:16335 ChEBI "up-regulates quantity" "precursor of" -1 18940592 t Luana "Specifically, PAP dephosphorylates extracellular adenosine monophosphate (AMP) to adenosine and activates A1-adenosine receptors in dorsal spinal cord." SIGNOR-269738 STK38L protein Q9Y2H1 UNIPROT STK38L protein Q9Y2H1 UNIPROT up-regulates phosphorylation Ser282 NRRQLAYsTVGTPDY 9606 BTO:0000007 16314523 t lperfetto "Ndr1/ndr2 protein kinase is activated by phosphorylation on the activation loop phosphorylation site ser281/ser282 and the hydrophobic motif phosphorylation site thr444/thr442. Autophosphorylation of ndr is responsible for phosphorylation on ser281/ser282, whereas thr444/thr442 is targeted by an upstream kinase. Here we show that mst3, a mammalian ste20-like protein kinase, is able to phosphorylate ndr protein kinase at thr444/thr442. In vitro, mst3 selectively phosphorylated thr442 of ndr2, resulting in a 10-fold stimulation of ndr activity." SIGNOR-142518 TWIST2 protein Q8WVJ9 UNIPROT RAP1A protein P62834 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0004828 19051271 f miannu "we performed microarray analysis to compare the gene expression profiles in HGC-27 cells, with or without small interfering RNA (siRNA)-mediated depletion of TWIST. Our results showed that NF1, RAP1A, SRPX, RBL2, PFDN4, ILK, F2R, ERBB3, and MYB were up-regulated, whereas AKR1C2, FOS, GDF15, NR2F1, ATM, and CTPS were down-regulated after TWIST depletion" SIGNOR-255508 "Naloxone benzoylhydrazone" chemical CID:9601084 PUBCHEM OPRK1 protein P41145 UNIPROT "up-regulates activity" "chemical activation" 10029 BTO:0000246 9686407 t miannu "Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors." SIGNOR-258423 CDH11 protein P55287 UNIPROT CTNNB1 protein P35222 UNIPROT "up-regulates activity" binding 9606 21255999 t miannu "At its C-terminus, cadherin interacts with β-catenin, which dynamically associates with α-catenin, a direct binding partner of filamentous actin" SIGNOR-265851 PRKD2 protein Q9BZL6 UNIPROT SSH1 protein Q8WYL5 UNIPROT down-regulates phosphorylation Ser937 SNLTRSSsSDSIHSV 9606 21525957 t gcesareni "Phosphorylation of ser 402 impedes phosphatase activity of slingshot 1." SIGNOR-173441 IKBKB protein O14920 UNIPROT TSC1 protein Q92574 UNIPROT down-regulates phosphorylation Ser487 AAISRELsEITTAEA 9606 BTO:0000150 17693255 t gcesareni "Here we show that ikkbeta, a major downstream kinase in the tnfalpha signaling pathway, physically interacts with and phosphorylates tsc1 at ser487 and ser511, resulting in suppression of tsc1phosphorylation of tsc2 (by akt and erk;refs. 28, 29) and tsc1(by ikkbeta;ref. 30) results in the disruption of the tsc1/2 complex, and thereby activates the oncogenic mtor signaling contributing to tumor progression." SIGNOR-157296 TGFB1 protein P01137 UNIPROT CDK2 protein P24941 UNIPROT down-regulates 9606 SIGNOR-C16 10611320 f gcesareni "Tgf-beta treatment resulted in the specific inactivation of cyclin cdk2 complexes caused by absence of the activating thr(160) phosphorylation on cdk2." SIGNOR-73537 CBS protein P35520 UNIPROT "L-cystathionine dizwitterion" smallmolecule CHEBI:58161 ChEBI "up-regulates quantity" "chemical modification" 9606 23981774 t lperfetto "Cystathionine β-synthase (CBS) is a pyridoxal 5'-phosphate (PLP)-dependent enzyme that catalyzes the condensation of homocysteine with serine to generate cystathionine." SIGNOR-275830 "oxotremorine M" chemical CHEBI:38322 ChEBI CHRM3 protein P20309 UNIPROT "up-regulates activity" "chemical activation" 10029 BTO:0000246 9224827 t miannu "We investigated whether the allosteric modulators can also increase the affinity of receptors for their agonists. Twelve agonists and five allosteric modulators were tested in experiments on membranes of CHO cells that had been stably transfected with genes for the M1-M4 receptor subtypes. Affinities of agonists for the M1–M4 receptor subtypes were determined according to the ability of the agonist to inhibit [3H]NMS binding in the presence of 0.5 mM GTP; in this way, the low affinity binding of agonists was measured.The computed pKi and nH values are summarized in Table 2." SIGNOR-258655 CyclinA2/CDK2 complex SIGNOR-C83 SIGNOR AKT proteinfamily SIGNOR-PF24 SIGNOR "up-regulates activity" phosphorylation Thr479 FSYSASGtA 9606 BTO:0000093 24670654 t gcesareni "Phosphorylation of S477 and T479 at the Akt extreme carboxy terminus by cyclin-dependent kinase 2 (Cdk2)/cyclin A or mTORC2, under distinct physiological conditions, promotes Akt activation through facilitating, or functionally compensating for, S473 phosphorylation" SIGNOR-252453 Ub:E2 complex SIGNOR-C497 SIGNOR TRIM45 protein Q9H8W5 UNIPROT "up-regulates activity" ubiquitination 9606 34199813 t miannu "The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t" SIGNOR-271225 AKT proteinfamily SIGNOR-PF24 SIGNOR EDC3 protein Q96F86 UNIPROT "down-regulates activity" phosphorylation Ser161 SFRRRHNsWSSSSRH 10029 BTO:0000246 20051463 t miannu "Together these data show that recombinant EDC3 co-immunoprecipitates with endogenous 14-3-3 isoforms in response to insulin in vivo and is phosphorylated at the putative 14-3-3 binding and AKT phosphorylation site Ser-161. Collectively, these data suggest that Ser-161 in EDC3 is phosphorylated in response to insulin principally by AKT and that this subsequently triggers 14-3-3 binding. Constitutive 14-3-3 binding to EDC3 alters p-body morphology and function" SIGNOR-262631 MAP3K14 protein Q99558 UNIPROT NFKB2 protein Q00653 UNIPROT "up-regulates activity" phosphorylation Ser866 TAEVKEDsAYGSQSV 9606 BTO:0000007 11239468 t lperfetto "NIK-induced p100 processing requires phosphorylation of p100 at serines 866 and 870" SIGNOR-105553 BECN1 protein Q14457 UNIPROT USP13 protein Q92995 UNIPROT "up-regulates quantity by stabilization" deubiquitination 9606 BTO:0003704 21962518 t Giulio "We found that endogenous Beclin1 can interact with USP13 and the interaction was reduced in the presence of spautin-1 (Figure 5C). Interestingly, the DUB activities were significantly increased when USP13 and USP10 coincubated together or with Beclin1 or all 3 proteins together, suggesting the DUB activity can be significantly enhanced when USP13 interacts with its substrate Beclin1 or USP10." SIGNOR-260296 WNT2B protein Q93097 UNIPROT LRP5 protein O75197 UNIPROT up-regulates binding 9606 15578921 t gcesareni "Wnt proteins bind to the frizzled receptors and lrp5/6 co-receptors andinitiate a complex signaling cascade that plays an important role in regulating cell proliferation and differentiation." SIGNOR-131780 GDF5 protein P43026 UNIPROT ID3 protein Q02535 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0004291 16716349 f Regulation miannu "GDF5 induces ID1 and ID3 in HUVSMC by a smad-dependent, MAPK-independent pathway. GDF5 binds to specific receptors, thereby inducing phosphorylation and translocation of smad1 to the nucleus where it is involved in the regulation of transcription." SIGNOR-251872 RPS6KA1 protein Q15418 UNIPROT RPS6 protein P62753 UNIPROT up-regulates phosphorylation Ser244 LRASTSKsESSQK 9606 21233202 t lperfetto "In response to mitogenic stimuli, rps6 undergoes ordered c-terminal phosphorylation by p70 s6 kinases and p90 ribosomal s6 kinases on four conserved ser residues (ser-235, ser-236, ser-240, and ser-244) whose modification potentiates rps6 cap binding activity" SIGNOR-171247 STON2 protein Q8WXE9 UNIPROT SYT1 protein P21579 UNIPROT "up-regulates quantity" binding 9606 BTO:0000938 26903854 t miannu " the monomeric adaptor proteins AP180/CALM and stonin-2 are required for the efficient retrieval of synaptobrevin II (sybII) and synaptotagmin-1 respectively .Stonin-2 and AP-2 are also Required for Efficient Synaptotagmin-1 Retrieval.  the monomeric adaptor proteins AP180/CALM and stonin-2 are required for the efficient retrieval of synaptobrevin II (sybII) and synaptotagmin-1 respectively." SIGNOR-264115 SEPTIN6 protein Q14141 UNIPROT SEPT6/SEPT2 complex SIGNOR-C71 SIGNOR "form complex" binding 9606 16914550 t miannu "We have characterized the conformation of a complex of filamentous human septins, sept2, sept6, and sept7. / we now show that sept6 and sept7 interact through a parallel coiled-coil, and that sept2 interacts with sept6 through their c-terminal domains." SIGNOR-148892 MAPK1 protein P28482 UNIPROT THR proteinfamily SIGNOR-PF84 SIGNOR "down-regulates activity" phosphorylation 9606 12809513 t "inferred from family member" llicata "We concluded that serine 142 of the tr dbd is the likely site of phosphorylation by t(4)-activated mapk and that the docking site on tr for activated mapk includes residues 128-133 (kgffrr), a basic amino acid-enriched motif novel for mapk substrates. Tr mutations in the proposed mapk docking domain and at residue 142 modulated t(4)-conditioned shedding of co-repressor and recruitment of co-activator proteins by the receptor, and they altered transcriptional activity of tr in a thyroid hormone response element-luciferase reporter assay." SIGNOR-270303 MYC protein P01106 UNIPROT CCNA2 protein P20248 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0001271 12835716 f gcesareni "These results suggest that e2f1 and cyclin a2 may be induced by c-myc to mediate the onset of mammary cancer, whereas overexpression of cyclins d1 and e may occur later to facilitate tumor progression." SIGNOR-102728 EDNRB protein P24530 UNIPROT GNAO1 protein P09471 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257254 "Multiaminoacyl-tRNA synthetase" complex SIGNOR-C472 SIGNOR ATP(4-) smallmolecule CHEBI:30616 ChEBI "down-regulates quantity" "chemical modification" 9606 28271488 t miannu "Aminoacyl-tRNA synthetases (AARSs) are essential enzymes that specifically aminoacylate one tRNA molecule by the cognate amino acid. In mammals, nine synthetases, those specific for amino acids Arg, Asp, Gln, Glu, Ile, Leu, Lys, Met and Pro, associate into a multi-aminoacyl-tRNA synthetase complex, an association which is believed to play a key role in the cellular organization of translation, but also in the regulation of the translational and nontranslational functions of these enzymes." SIGNOR-270404 TAGAP protein Q8N103 UNIPROT RHOA protein P61586 UNIPROT "down-regulates activity" "gtpase-activating protein" 9606 BTO:0000007 32203420 t Luana "We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2)." SIGNOR-260523 PTAFR protein P25105 UNIPROT GNAS protein Q5JWF2 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-256789 BRAF protein P15056 UNIPROT SLC5A5 protein Q92911 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 19861538 t miannu "The BRAFV600E oncogene induces transforming growth factor beta secretion leading to sodium iodide symporter repression and increased malignancy in thyroid cancer. BRAF induces TGFβ secretion leading to NIS repression in a MEK-ERK–independent manner but cooperating with the MEK-ERK pathway to induce strong tumor invasion, two major traits acquired during PTC progression." SIGNOR-251989 HTR7 protein P34969 UNIPROT GNAZ protein P19086 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257323 PRKCA protein P17252 UNIPROT ADRA1B protein P35368 UNIPROT "down-regulates activity" phosphorylation Ser402 GSLERSQsRKDSLDD 9534 BTO:0000298 9353340 t lperfetto " Phorbol ester-induced phosphorylation of the Ser394 and Ser400 as well as GRK2-mediated phosphorylation of the Ser404, Ser408, and Ser410, resulted in the desensitization of alpha1BAR-mediated inositol phosphate response. " SIGNOR-248986 PINK1 protein Q9BXM7 UNIPROT CYCS protein P99999 UNIPROT "down-regulates quantity" 9606 BTO:0000938 20012177 t lperfetto "There is a strong cyto-protective role of PINK1 in maintaining mitochondrial homeostasis via different mechanisms. Overexpression of wild-type PINK1 in SH-SY5Y neuroblastoma cells stabilizes respiring mitochondrial networks through various mechanisms that include maintaining mitochondrial membrane potential, reducing basal and neurotoxin-induced ROS, suppression of cytochrome c release, reversal of toxin-induced fission, and suppression of autophagy" SIGNOR-249704 PIM proteinfamily SIGNOR-PF34 SIGNOR MARK3 protein P27448 UNIPROT down-regulates phosphorylation Ser96 KTQLNPTsLQKLFRE 9606 15319445 t gcesareni "Here we show that the protein kinase cdc25 c-associated kinase 1 (c-tak1) is a binding partner and a substrate of pim-1." SIGNOR-259432 FUBP1 protein Q96AE4 UNIPROT BIK protein Q13323 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 19637194 f irozzo "FBP1 down-regulates cell cycle inhibitors and proapoptotic genes. Interestingly, we also observed the up-regulation of proapoptotic genes following FBP1 knockdown in Hep3B cells. In particular, elevated expression of the Bcl-2 family members Bik and Noxa was detected." SIGNOR-259127 MAP3K5 protein Q99683 UNIPROT MAP2K7 protein O14733 UNIPROT "up-regulates activity" phosphorylation 9606 BTO:0000007 17110930 t Barakat "Upon TNFα stimulation, MEKK1, ASK1, and TAK1 phosphorylate and activate MKK7, which in turn activates JNK" SIGNOR-274148 PLK1 protein P53350 UNIPROT ATXN10 protein Q9UBB4 UNIPROT down-regulates phosphorylation Thr82 ASSLQLItECFRCLR 9606 21857149 t lperfetto "Phosphorylation of ataxin-10 by polo-like kinase 1 is required for cytokinesis. Plk1 phosphorylates ataxin-10 at s77 and t82 in vitro. we found that ataxin-10 is ubiquitinated, and is subject to proteasome-dependent degradation, which is delayed in the 2a mutant. We propose a model in which plk1 phosphorylation of ataxin-10 influences its degradation and cytokinesis" SIGNOR-176126 JNK proteinfamily SIGNOR-PF15 SIGNOR ATN1 protein P54259 UNIPROT "down-regulates activity" phosphorylation 9606 BTO:0000142 12812981 t "inferred from 70% family members" lperfetto "Dentatorubral-pallidoluysian atrophy protein is phosphorylated by c-jun nh2-terminal kinase. serine 734 of the drpla protein is a phospho-acceptor site by jnk. The phosphorylation may be coupled to the activation of a protease. The molecular size of drpla protein detected in the rat brain with the specific phosphopeptide antibody was 150_kda, which was slightly smaller than that expected from the sequence and the results with the human protein. The phosphorylated forms of ha-tagged human drpla gradually disappeared after osmotic treatment," SIGNOR-269978 ILK protein Q13418 UNIPROT PPP1R12A protein O14974 UNIPROT "down-regulates activity" phosphorylation Thr696 ARQSRRStQGVTLTD -1 12030846 t miannu "MYPT1 was phosphorylated by ILK and phosphorylation sites in the N- and C-terminal fragments of MYPT1 were detected. From sequence analyses, three sites were identified: a primary site at Thr(709), and two other sites at Thr(695) and Thr(495). ILK produced an intermediate level of inhibition" SIGNOR-262886 GPC6 protein Q9Y625 UNIPROT WNT5A protein P41221 UNIPROT "down-regulates activity" binding 9606 BTO:0000007 31756413 t miannu "GPC6 binds to Wnt5a and inhibits its release from producing cells. Based on theseresults, and in our finding that GPC6 inhibits non-canonical Wnt signaling in the developing intestine,we tested the hypothesis that GPC6 binds to Wnt5aat the surface of the Wnt5a-producing mesenchymalcells and restrains its release from them." SIGNOR-264030 CDC42BPA protein Q5VT25 UNIPROT MYL9 protein P24844 UNIPROT up-regulates phosphorylation Ser20 KRPQRATsNVFAMFD 9606 19851336 t lperfetto "More than a dozen kinases have been reported to phosphorylate the rlcs of nm ii (fig. 2), including myosin light chain kinase (mlck;also known as mylk), rho-associated, coiled coil-containing kinase (rock), citron kinase, leucine zipper interacting kinase (zipk;also known as dapk3) and myotonic dystrophy kinase-related cdc42-binding kinase (mrck;also known as cdc42bp)6,34,45,46. These kinases phosphorylate rlcs on ser19, thr18 or both, to relieve the inhibition imposed on the myosin molecule by unphosphorylated rlcs and the head_head interaction outlined above." SIGNOR-188781 RPS6KA3 protein P51812 UNIPROT MAD2L1 protein Q13257 UNIPROT "up-regulates activity" 9606 BTO:0000567 20383198 f lperfetto "We also show that this kinase might also participate in the maintenance of the SAC in mammalian cells as Rsk2 knockdown in these cells prevents the kinetochore localization of Mad1, Mad2 and CENP-E under checkpoint conditions." SIGNOR-252039 reserpine chemical CHEBI:28487 ChEBI SLC18A2 protein Q05940 UNIPROT "down-regulates activity" "chemical inhibition" 9606 BTO:0000318 8643547 t miannu "Reserpine and ketanserin are slightly more potent inhibitors of VMAT2-mediated transport than of VMAT1-mediated transport, whereas tetrabenazine binds to and inhibits only VMAT2." SIGNOR-258490 CHEK1 protein O14757 UNIPROT TP53 protein P04637 UNIPROT "up-regulates activity" phosphorylation Ser378 SKKGQSTsRHKKLMF 9606 15659650 t lperfetto "Phosphorylation by chk1 of at least three of these sites, Ser366, Ser378, and Thr387, was induced by DNA damage." SIGNOR-217857 SMAD6 protein O43541 UNIPROT SMAD1 protein Q15797 UNIPROT down-regulates binding 9606 SIGNOR-C85 12857866 t gcesareni "Smad6 also inhibits bmp signaling by forming a complex with smad1 and by interfering with complex formation between smad1 and smad4" SIGNOR-103621 DNMT1 protein P26358 UNIPROT BAG4 protein O95429 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0001109 18413740 f lperfetto "In contrast, an increase in BAG-1, BAG-3, and BAG-4 gene expression was observed in HCT116 cells overexpressing either DNMT1 (DNMT1+) or DNMT3B (DNMT3B+)" SIGNOR-254112 KCTD10 protein Q9H3F6 UNIPROT "Cullin 3-RBX1-Skp1" complex SIGNOR-C526 SIGNOR "up-regulates activity" binding 9606 BTO:0004790 30404837 t miannu "Cullin-3-KCTD10-mediated CEP97 degradation promotes primary cilium formation. we identified the cullin-3-RBX1-KCTD10 complex as the E3 ligase that mediates CEP97 degradation and removal from the mother centriole." SIGNOR-272924 RNF168 protein Q8IYW5 UNIPROT H1-2 protein P16403 UNIPROT down-regulates polyubiquitination 9606 BTO:0000815 30517763 t miannu "ITCH biochemically antagonized RNF168 and RNF8 in polyubiquitination of histone H1.2 ITCH interacts with and ubiquitinates linker histone H1.2 at K46. ITCH biochemically competes with RNF168 and RNF8 to polyubiquitinate histone H1.2. Both RNF168 and RNF8 elicited higher Ubn levels of K46R-H1.2 compared to WT-H1.2, suggesting that Ubn of H1.2 by both E3 ligases occurs at a site apart from K46." SIGNOR-272927 CyclinE/CDK2 complex SIGNOR-C16 SIGNOR USP37 protein Q86T82 UNIPROT "up-regulates activity" phosphorylation Ser628 MVNSCITsPSTPSKK 9606 BTO:0000007;BTO:0000567 21596315 t lperfetto "There is positive reinforcement of this signaling mechanism because phosphorylation of Ser628 by CDK2/cyclin E and CDK2/cyclin A complexes produces maximal USP37 activity" SIGNOR-265053 FZD2 protein Q14332 UNIPROT DVL2 protein O14641 UNIPROT "up-regulates activity" binding 9606 23151663 t areggio "Upon ligand binding, DVL proteins are recruited to Frizzled receptors at the plasma membrane and co-recruit cytoplasmic transducers, such as Axin, CK1 and GSK3 binding protein (GBP), presumably along with their partners, to promote ?-catenin-dependent signalling. " SIGNOR-258959 LPAR1 protein Q92633 UNIPROT GNA12 protein Q03113 UNIPROT up-regulates binding 10090 15856019 t milica "Lysophosphatidic acid (lpa), a major g protein coupled receptor (gpcr)-activating ligand present in serum, elicits growth factor like responses by stimulating specific gpcrs coupled to heterotrimeric g proteins such as g(i), g(q), and g12/13." SIGNOR-236988 CSNK2A1 protein P68400 UNIPROT PIN4 protein Q9Y237 UNIPROT "down-regulates activity" phosphorylation Ser19 AGKGGAAsGSDSADK 9606 BTO:0000567 12860119 t lperfetto "As proved by MALDI-TOF mass spectrometry and MS/MS fragmentation, hPar14 is phosphorylated at Ser19 in vitro and in vivo. In human HeLa cells the protein is most likely modified by casein kinase 2 (CK2). |In contrast to wild-type hPar14, the in vitro DNA-binding affinity of the Glu19 mutant is strongly reduced, suggesting that only the dephosphorylated protein is the active DNA-binding form of hPar14 in the nucleus." SIGNOR-265753 PRKCZ protein Q05513 UNIPROT PSEN1 protein P49768 UNIPROT "up-regulates activity" phosphorylation Ser346 EWEAQRDsHLGPHRS 9606 14576165 t lperfetto "A phosphorylation site at serine residue 346 was identified that is selectively phosphorylated by PKC but not by PKA. This site is localized within a recognition motif for caspases, and phosphorylation strongly inhibits proteolytic processing of PS1 by caspase activity during apoptosis." SIGNOR-249239 SOX2/POU5F1 complex SIGNOR-C73 SIGNOR POU5F1 protein Q01860 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 31583686 t SimoneGraziosi "Both SOX2 and SOX17 are able to partner with OCT4 and, as a consequence, recognize and bind specific binding motifs.6, 7 In human and mouse ESCs, SOX2/OCT4 bind to canonical motifs (CTTTGTCATGCAAAT-like), which are composite SOX (CATTGTC-like) and OCT (ATGCAAAT-like) motifs|This way SOX17 and SOX2 regulate a common set of pluripotency and GC-related genes (PRDM14, DPPA4, TDGF1, NANOG, LIN28A, TRIM71, OTX2, PIM2) (Fig. 6). Additionally, in TCam-2 cells SOX17 binds to compressed motifs or SOX motifs (not bound by SOX2 in ECs), thereby regulating the PGC specifiers PRDM1 and TFAP2C, the GC-related genes NANOS3 and BMP7 and the cancer-related genes MYC and IGF1 (Fig. 6). In 2102EP cells, SOX2 further binds canonical elements or SOX motifs (not bound by SOX17 in TCam-2), regulating additional pluripotency genes (GDF3, LEFTY2, SALL4, SOX2 and POU5F1) (Fig. 6)." SIGNOR-269254 CSNK2A2 protein P19784 UNIPROT GTF2A1L protein Q9UNN4 UNIPROT "up-regulates activity" phosphorylation Ser423 LNSGDDVsEQDVPDL -1 12107178 t llicata "ALF was able to stabilize the binding of TBP to DNA, but it could not stabilize TBP mutants A184E, N189E, E191R, and R205E nor could it facilitate binding of the TBP-like factor TRF2/TLF to a consensus TATA element. However, phosphorylation of ALF with casein kinase II resulted in the partial restoration of complex formation using mutant TBPs. | Because the residues involved (Ser-280, Ser-281, Ser-316, and Ser-321) are conserved in ALF (Ser-356, Ser-357, Ser-418, and Ser-423), we tested whether its activity might also be affected by this modification. We first showed that ALF and TFIIAα/β polypeptides incubated with casein kinase II and [γ-32P]ATP could be labeled." SIGNOR-250994 NOS1 protein P29475 UNIPROT DGC complex SIGNOR-C217 SIGNOR "form complex" binding 9606 15117830 t apalma "The DGC is composed of dystrophin (blue), an elongated cytoskeletal protein that links to cytoplasmic γ-actin and the transmembrane components of the DGC. Dystrophin binds to the tail of β-dystroglycan (orange). Dystroglycan is composed of 2 subunits, α and β, each produced from the same gene. Dystroglycan binds to the extracellular matrix protein laminin-α2. The sarcoglycan complex (blue-green) is composed of multiple subunits. Mutations in the genes encoding α-, β-, γ-, and δ-sarcoglycan lead to a similar phenotype as dystrophin mutations and include cardiomyopathy and muscular dystrophy in humans and mice. Additional subcomplexes in the DGC in skeletal muscle include α and β dystrobrevin, the syntrophins, nNOS, and caveolin 3 (pink)." SIGNOR-255996 CRB3 protein Q9BUF7 UNIPROT AMOT/MPP5/INADL/LIN7C complex SIGNOR-C27 SIGNOR up-regulates binding 10090 BTO:0000150 21145499 t milica "Interestingly, knockdown of crb3, which facilitates crumbs complex assembly and localization to the apical junctions disrupted taz/yap interaction with multiple components of the complex, whereas the other knockdowns only disrupted their respective interaction." SIGNOR-170399 CUL1 protein Q13616 UNIPROT SCF-FBW2 complex SIGNOR-C525 SIGNOR "form complex" binding 9606 BTO:0000007 15640526 t miannu "FBW2 targets GCMa to the ubiquitin-proteasome degradation system. Here, we report the identification of an SCF complex as the GCM ubiquitin-protein isopeptide ligase (E3) that regulates human GCMa (hGCMa) degradation. We found that SKP1 and CUL1, two key components of the SCF complex, associate with hGCMa in vivo. We further identify the human F-box protein FBW2 (hFBW2) as the substrate recognition subunit in the SCF E3 complex for hGCMa. We show that hFBW2 interacts with hGCMa in a phosphorylation-dependent manner and promotes hGCMa ubiquitination. Supporting a critical role for hFBW2 in hGCMa degradation, knockdown of hFBW2 expression by RNA interference leads to a reduction in hGCMa ubiquitination and a concomitant increase in hGCMa protein stability. Our study identifies the SCF(hFBW2) E3 complex as the key machinery that targets hGCMa to the ubiquitin-proteasome degradation system" SIGNOR-271527 CyclinK/CDK13 complex SIGNOR-C38 SIGNOR POLR2A protein P24928 UNIPROT "up-regulates activity" phosphorylation Ser1941 SPKGSTYsPTSPGYS 9606 BTO:0006413 32917631 t "Ser2 in CTD of PolII" lperfetto "Together, these studies demonstrate the important, yet largely redundant, role for CDK12 and CDK13 for the regulation of POLII CTD phosphorylation at multiple residues, as well as the global role for both of these kinases in regulating POLII occupancy across the genome.|CDK12 and CDK13 are thus evolutionarily related and structurally similar kinases, and biochemical assays have demonstrated that both have POLII C-terminal domain (CTD) kinase activity and the ability to phosphorylate the Ser2 residue of the repetitive CTD heptad sequence" SIGNOR-273059 CALM3 protein P0DP25 UNIPROT KIF1A protein Q12756 UNIPROT "up-regulates activity" binding 10116 BTO:0003102 30021165 t miannu "To better understand how KIF1A-driven dense core vesicle (DCV) transport is regulated, we identified the KIF1A interactome and focused on three binding partners, the calcium binding protein calmodulin (CaM) and two synaptic scaffolding proteins: liprin-α and TANC2. We showed that calcium, acting via CaM, enhances KIF1A binding to DCVs and increases vesicle motility. In contrast, liprin-α and TANC2 are not part of the KIF1A-cargo complex but capture DCVs at dendritic spines. we can conclude that TANC2 and liprin-α are enriched in dendritic spines and interact with various synaptic proteins. TANC2 and Liprin-α2 Act as Immobile Postsynaptic Posts Able to Recruit KIF1A in a Subset of Dendritic Spines" SIGNOR-266890 IL1B protein P01584 UNIPROT ITGA3 protein P26006 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0001596 1744142 f lperfetto "TGF-beta 1 decreases the biosynthesis of alpha 3 subunit but increases the production of alpha 2 subunit. IL-1 beta potentiates the effects of TGF-beta 1. Furthermore, in the presence of TGF-beta 1 the increase in the expression of alpha 1 subunit by IL-1 beta is even larger. Thus, IL-1 beta and TGF-beta 1, which usually have antagonistic functions in connective tissue, can regulate integrin expression in a synergistic way." SIGNOR-253355 IRX1 protein P78414 UNIPROT PHYHIPL protein Q96FC7 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 20440264 f Luana "We identified a number of target genes by global microarray analysis after IRX1 transfection combined with real-time PCR and chromatin immunoprecipitation assay.| Downregulation of BDKRB2, PHYHIPL, HIST2H2BE, FGF7, PTGER1, NPTX1, EGR1, COL9A3, CUGBP2, DKK3 and BPI was confirmed." SIGNOR-261659 GRK2 protein P25098 UNIPROT SMO protein Q99835 UNIPROT up-regulates phosphorylation 9606 15618519 t gcesareni "We find that two molecules interact with mammalian smo in an activation-dependent manner: g protein-coupled receptor kinase 2 (grk2) leads to phosphorylation of smo, and beta-arrestin 2 fused to green fluorescent protein interacts with smo. Ck1a, grk2, and another still-unidentified protein kinase phosphorylate the c-tail of mammalian smo in the presence of hh proteins" SIGNOR-132669 PRKCD protein Q05655 UNIPROT NCF1 protein P14598 UNIPROT up-regulates phosphorylation Ser359 EERQTQRsKPQPAVP 9606 BTO:0000130 12056906 t esanto "Pkc alpha, beta ii, delta, and zeta expressed in human neutrophils can individually phosphorylate p47(phox) and induce both its translocation and nadph oxidase activation. The use of p47phox mutants identified serines 303, 304, 315, 320, 328, 359, 370, and 379 as targets of pkc?, ???, And ?." SIGNOR-89237 PPP3CC protein P48454 UNIPROT NFATC2 protein Q13469 UNIPROT "up-regulates activity" dephosphorylation Ser180 GSSASFIsDTFSPYT 9606 BTO:0000567 11030334 t "NFAT1 is phosphorylated on fourteen conserved phosphoserine residues in its regulatory domain, thirteen of which are dephosphorylated upon stimulation. Dephosphorylation of all thirteen residues is required to mask a nuclear export signal (NES), cause full exposure of a nuclear localization signal (NLS), and promote transcriptional activity" SIGNOR-248515 AKT2 protein P31751 UNIPROT FOXO3 protein O43524 UNIPROT "down-regulates activity" phosphorylation Thr32 QSRPRSCtWPLQRPE 9606 19188143 t lperfetto "Akt-dependent phosphorylation of foxo3a (thr32, ser253, and ser315 for human foxo3) enhances foxo3a/14-3-3 Interaction and promotes foxo3a nuclear export to the cytoplasm, resulting in the repression of foxo3a transcriptional function akt phosphorylates members of the foxo factors (forkhead family of transcription factors), leading to binding of 14-3-3 proteins and cytoplasmic localisation. In particular, akt phosphorylates foxo1 on thr24, ser256 and ser319. Foxo 3alfa and foxo4 are phosphorylated on equivalent sites." SIGNOR-236675 "SKA complex" complex SIGNOR-C364 SIGNOR "Ndc80 complex" complex SIGNOR-C361 SIGNOR "up-regulates activity" relocalization -1 22483620 t lperfetto "The Ska complex is an essential mitotic component required for accurate cell division in human cells. It is composed of three subunits that function together to establish stable kinetochore-microtubule interactions in concert with the Ndc80 network. |We discuss how this symmetric architecture might complement and stabilize the Ndc80-microtubule attachments" SIGNOR-265225 PRKACA protein P17612 UNIPROT MYBPC3 protein Q14896 UNIPROT up-regulates phosphorylation Ser311 SFRTPRDsKLEAPAE 9606 BTO:0000887 20151718 t miannu "Phosphorylation of cmybp-c by pka speeds actomyosin interactions and contributes to increased cardiac contractility following _-adrenergic stimulation.7, 8 phosphorylation by pka is essential for proper cardiac function /for the human isoform, three pka sites were previously identified (ser275, ser284, and ser304) /our results indicate that pka phosphorylates up to four sites in both the murine and human m-domains including a novel site not previously described for either protein (ser307 for mouse and ser311 for human)." SIGNOR-163764 NLGN2 protein Q8NFZ4 UNIPROT MAGI2 protein Q86UL8 UNIPROT "up-regulates activity" binding 9606 BTO:0000142 22626542 t miannu "S-SCAM is a member of the membrane-associated guanylate kinase (MAGUK) family of PDZ-domain-containing proteins that include the synaptic organising molecule PSD-95. The PDZ domain of S-SCAM binds to the C-terminal tail of NL2, forming a ternary complex at the cell membrane (Figure 2b). The DGC is potentially recruited to the postsynaptic membrane though a direct neurexin–dystroglycan interaction and an indirect interaction with NL2 via the synaptic scaffolding protein S-SCAM." SIGNOR-265444 Calcineurin complex SIGNOR-C155 SIGNOR NFATC2 protein Q13469 UNIPROT "up-regulates activity" dephosphorylation Ser217 AHYSPRTsPIMSPRT 9606 BTO:0000567 11030334 t "NFAT1 is phosphorylated on fourteen conserved phosphoserine residues in its regulatory domain, thirteen of which are dephosphorylated upon stimulation. Dephosphorylation of all thirteen residues is required to mask a nuclear export signal (NES), cause full exposure of a nuclear localization signal (NLS), and promote transcriptional activity" SIGNOR-252330 PGM1 protein P36871 UNIPROT "alpha-D-glucose 1-phosphate(2-)" smallmolecule CHEBI:58601 ChEBI "down-regulates quantity" "chemical modification" 9606 32898648 t miannu "Human PGM1 deficiency is an inborn error of metabolism (OMIM: 614921), affecting cellular glucose homeostasis, the storage of glucose as glycogen, and the N-glycosylation of proteins. Like other PGM enzymes, the human protein catalyzes the Mg2+-dependent interconversion of glucose 1-phosphate (G1P) and glucose 6-phosphate (G6P)." SIGNOR-267931 Ub:E2 complex SIGNOR-C497 SIGNOR TRIM25 protein Q14258 UNIPROT "up-regulates activity" ubiquitination 9606 34199813 t miannu "The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t" SIGNOR-271155 NCOA1 protein Q15788 UNIPROT CYP7A1 protein P22680 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000599 16891307 f miannu "Overexpression of SRC1 and PGC1alpha by recombinant adenoviruses led to a significant up-regulation of well characterized HNF4alpha-dependent genes (ApoCIII, ApoAV, PEPCK, AldoB, OTC, and CYP7A1) and forced HepG2 cells toward a more differentiated phenotype as demonstrated by increased ureogenic rate." SIGNOR-255063 CEBPB protein P17676 UNIPROT SLC19A1 protein P41440 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 15652157 t "Collectively, these results identify transcriptionally important regions in the hRFC-C minimal promoter that include a GC-box and CCAAT-box, and suggest that cooperative interactions between Sp1 and C/EBP beta are essential for hRFC-C transactivation." SIGNOR-254053 4-[[5-amino-1-[(2,6-difluorophenyl)-oxomethyl]-1,2,4-triazol-3-yl]amino]benzenesulfonamide chemical CHEBI:94506 ChEBI AURKB protein Q96GD4 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-193534 pimozide chemical CHEBI:8212 ChEBI DRD2 protein P14416 UNIPROT "down-regulates activity" "chemical inhibition" 10029 BTO:0000246 8301582 t miannu "The most selective compound from this group were (+)butaclamol and domperidone which showed 5-fold D3 selectivity. A number of high affinity dopamine receptor agonists, including apomorphine and bromocriptine, also failed to demonstrate selectivity. In contrast, the natural ligand dopamine and the efficacious synthetic agonists quinpirole, (+)4-propyl-9-hydroxynapthoxazine (PHNO), 2-amino-6,7-dihydroxy-1,2,3,4-tetrahydronaphthalene (6,7-ADTN), 7-OH DPAT and N-0434 showed marked apparent human dopamine D3 (hD3) receptor selectivity. In the aminotetralin series, this selectivity was observed preferentially with analogs of the 6,7-rotamer compared with compounds from the 5,6-rotamer series. Functional coupling of the hD3 receptor was investigated in a number of cell lines in which the hD3 receptor was stably expressed, including CHO cells, the neuroblastoma-glioma hybrid cell line NG108-15 and a rat 1 fibroblast cell line." SIGNOR-258719 COMT protein P21964 UNIPROT 3-methoxytyramine smallmolecule CHEBI:1582 ChEBI "up-regulates quantity" "chemical modification" 9606 NBK536726 t brain lperfetto "Dopamine is metabolized after reuptake into dopaminergic neurons or glial cells¬†|dopamine is metabolized to 3-methoxytyramine by COMT, which is in turn converted to 3-methoxy-4-hydroxyacetaldehyde by MAO." SIGNOR-263998 "Non-erythrocytic spectrin" complex SIGNOR-C385 SIGNOR Membrane_disruption phenotype SIGNOR-PH151 SIGNOR down-regulates 9606 24302288 f lperfetto "Spectrin is a large, cytoskeletal, and heterodimeric protein composed of modular structure of alpha and beta subunits, it typically contains 106 contiguous amino acid sequence motifs called “spectrin repeats”. Spectrin is crucial for maintaining the stability and structure of the cell membrane and the shape of a cell" SIGNOR-266029 P2RY11 protein Q96G91 UNIPROT GNAZ protein P19086 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257328 MTOR protein P42345 UNIPROT RPS6KB2 protein Q9UBS0 UNIPROT up-regulates phosphorylation 9606 23486913 t "mTORC1 phosphorylation of EIF4EBP1 causes dissociation of the complex allowing EIF4G1/EIF4G3 to bind and consequent initiation of translation." gcesareni "These results indicate that arg, leu, and gln act coordinately to stimulate proliferation of ptr cells through activation of the mtor-rps6k-rps6-eif4ebp1 signal transduction pathway." SIGNOR-201541 AURKB protein Q96GD4 UNIPROT KIF2C protein Q99661 UNIPROT up-regulates phosphorylation Ser95 IQKQKRRsVNSKIPA 9606 17567953 t lperfetto "Here, we show that the binding of mcak to chromosome arms is also regulated by aurora b and that aurora b-dependent chromosome arm and centromere localization is regulated by distinct two-site phosphoregulatory mechanisms. Mcak association with chromosome arms is promoted by phosphorylation of t95 on mcak, whereas phosphorylation of s196 on mcak promotes dissociation from the arms. Although targeting of mcak to centromeres requires phosphorylation of s110 on mcak, dephosphorylation of t95 on mcak increases the binding of mcak to centromeres." SIGNOR-155890 RAB6C protein Q9H0N0 UNIPROT Synaptic_vesicle_exocytosis phenotype SIGNOR-PH160 SIGNOR up-regulates 9534 20360680 f miannu "We show that BICDR-1 interacts with the dynein/dynactin motor complex, binds to kinesin-3 motor protein Kif1C and controls the pericentrosomal localization of Rab6-positive secretory vesicles." SIGNOR-266882 SREBF1 protein P36956 UNIPROT PKM protein P14618 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 16308421 t gcesareni "Well-described targets of srebp-1 and the carbohydrate response element binding protein (chrebp), which include the following: fatty acid synthase (fas), acetyl coa carboxylase (acc1), and liver pyruvate kinase (l-pk)" SIGNOR-142297 MRE11/RAD50/NBS1 complex SIGNOR-C147 SIGNOR UFL1 protein O94874 UNIPROT "up-regulates activity" relocalization 9606 BTO:0001938 30886146 t lperfetto "UFM1 specific ligase 1 (UFL1), an ufmylation E3 ligase, is important for ATM activation. UFL1 is recruited to double strand breaks by the MRE11/RAD50/NBS1 complex, and monoufmylates histone H4 following DNA damage." SIGNOR-265074 FFAR4 protein Q5NUL3 UNIPROT GNAO1 protein P09471 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257246 IKBKB protein O14920 UNIPROT IKBKB protein O14920 UNIPROT "down-regulates activity" phosphorylation Ser740 SFTALDWsWLQTEEE 9606 SIGNOR-C14 SIGNOR-C14 10195894 t lperfetto "Once activated, ikkbeta autophosphorylated at a carboxyl-terminal serine cluster. Such phosphorylation decreased ikk activity and may prevent prolonged activation of the inflammatory response" SIGNOR-236048 PI4K2A protein Q9BTU6 UNIPROT CLSPN protein Q9HAW4 UNIPROT down-regulates phosphorylation Ser984 ALALCSGsFPTDKEE 9606 18082599 t gcesareni "These results indicate that plx1 phosphorylates claspin on s934, which is relatively close to the plx1-docking site at t906. Human claspin also contains a serine at position 984 in a homologous sequence" SIGNOR-159937 RNF2 protein Q99496 UNIPROT "Polycomb repressive complex 1" complex SIGNOR-C408 SIGNOR "form complex" binding 9606 31608994 t miannu "PRC1 has been categorised into canonical and noncanonical/variant PRC1; canonical PRC1 (Morey, Aloia, Cozzuto, Benitah, & Di Croce, 2013) includes chromobox (Cbx) proteins, Ring1, human polyhomeotic homologue protein (Hph) and polycomb ring finger (Pcgf) (Pcgf2/Mel18 and Pcgf4/Bmi1) proteins whereas noncanonical/variant PRC1 involves RING1 and YY1 binding protein (Rybp), Ring1 and Pcgf (Pcgf 1–6) proteins (Wu, Johansen, & Helin, 2013). Figure 3 illustrates the various proteins that form the canonical and noncanonical PRC1. The Ring1 along with Pcgf2/4 forms a core heterodimer which interacts with other accessory components of PRC1 complex through C‐terminal ring finger and WD40 ubiquitin‐like (RAWUL) domains see Figure 4b" SIGNOR-266811 MARCHF5 protein Q9NX47 UNIPROT FIS1 protein Q9Y3D6 UNIPROT "down-regulates quantity by destabilization" ubiquitination 9606 16874301 t Barakat "MITOL associates with and ubiquitinates mitochondrial fission protein hFis1. (A) Ubiquitination of hFis1 by MITOL. Thus, MITOL may control the protein expression level of hFis1 through the ubiquitin‚Äìproteasome pathway." SIGNOR-274141 ITGB3 protein P05106 UNIPROT "Av/b3 integrin" complex SIGNOR-C177 SIGNOR "form complex" binding 16988024 t lperfetto "Integrins are one of the major families of cell adhesion receptors (Humphries, 2000; Hynes, 2002). All integrins are non-covalently-linked, heterodimeric molecules containing an α and a β subunit. Both subunits are type I transmembrane proteins, containing large extracellular domains and mostly short cytoplasmic domains (Springer and Wang, 2004; Arnaout et al., 2005). Mammalian genomes contain 18 α subunit and 8 β subunit genes, and to date 24 different α,β combinations have been identified at the protein level. Although some subunits only appear in a single heterodimer, twelve integrins contain the β1 subunit, and five contain αV." SIGNOR-253206 MBD2 protein Q9UBB5 UNIPROT "MBD2/NuRD complex" complex SIGNOR-C337 SIGNOR "form complex" binding 9606 27098840 t miannu "The NuRD complex is a multi-protein transcriptional corepressor that couples histone deacetylase and ATP-dependent chromatin remodelling activities.In humans, an assembly of proteins called the NuRD complex makes chromatin more compact by removing acetyl groups from nucleosomes. This complex is important for early development and for the stability and repair of our genes. Three proteins make up its core: HDAC1, which removes the acetyl group from the nucleosome; MTA1, which acts as a scaffold to hold the complex together; and RBBP4, which enables the complex to interact with nucleosomes. MBD2 and MBD3 are members of the methyl cytosine-guanosine (CpG)-binding domain (MBD) family of proteins42; 43. Of the five MBD members, only MBD2 and MBD3 associate with NuRD and are required for the complex formation and gene repression." SIGNOR-263835 CTDSPL protein O15194 UNIPROT SMAD3 protein P84022 UNIPROT "up-regulates activity" dephosphorylation Ser204 NHSMDAGsPNLSPNP 9606 BTO:0000007 17035229 t "Dephosphorylation of Smad2/3 Linkers by SCP2 and SCP3|MAPK-mediated linker phosphorylation appears to have a dual role in Smad2/3 regulation. Mitogens and hyperactive Ras result in extracellular signal-regulated kinase (ERK)-mediated phosphorylation of Smad3 at Ser-204, Ser-208, and Thr-179 and of Smad2 at Ser-245/250/255 and Thr-220. Mutation of these sites increases the ability of Smad3 to activate target genes, suggesting that MAPK phosphorylation of Smad3 is inhibitory (11, 12). However, in contrast, ERK-dependent phosphorylation of Smad2 at Thr-8 enhances its transcriptional activity" SIGNOR-248306 CDK18 protein Q07002 UNIPROT CyclinA2/CDK18 complex SIGNOR-C547 SIGNOR "form complex" binding 33781185 t lperfetto "PCTAIRE kinases (PCTKs) are a CDK subfamily, characterized by serine to cysteine mutation in the consensus PSTAIRE motif, involved in binding to the cyclin. One member of this class is PCTK3, which has two isoforms (a and b) and is also known as CDK18. After being activated by cyclin A2 or phosphorylation at Ser12 by PKA, PCTK3 can perform several functions." SIGNOR-273436 ACTL6A protein O96019 UNIPROT "SWI/SNF complex" complex SIGNOR-C92 SIGNOR "form complex" binding 9606 15627498 t miannu "We discuss recent insights in the functional differences between two evolutionary conserved subclasses of swi/snf-related chromatin remodeling factors. Onesubfamily comprises yeast swi/snf, fly bap and mammalian baf, whereas the other subfamily includes yeast rsc, fly pbap andmammalian pbaf. We review the subunit composition, conserved protein modules and biological functions of each of these subclasses ofswi/snf remodelers." SIGNOR-132916 FOXP2 protein O15409 UNIPROT RELN protein P78509 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000142 25232744 t miannu "By interacting with CASK, TBR1 regulates several ASD candidate genes, such as GRIN2B, AUTS2 and RELN—all of which are recurrently mutated in ASD. In areas of the brain with overlapping expression patterns, such as in glutamatergic layer 6 neurons, the TBR1–FOXP2 interaction may result in co-ordinated regulation of common downstream targets." SIGNOR-266833 CDK6 protein Q00534 UNIPROT CDKN1B protein P46527 UNIPROT up-regulates phosphorylation Ser10 NVRVSNGsPSLERMD 9606 16160006 t gcesareni "Phosphorylation on ser-10 is the major site of phosphorylation in resting cells, takes place at the g(0)-g1 phase and leads to protein stability.p27(kip1) was phosphorylated by v-cyclin-cdk6 predominantly on ser10, which enhances its cytoplasmic localization." SIGNOR-140401 CBX5 protein P45973 UNIPROT H3C1 protein P68431 UNIPROT "up-regulates activity" binding 9606 methylation:Lys10 RTKQTARkSTGGKAP 19111658 t miannu "A core characteristic of heterochromatin is its association with heterochromatin protein 1 (HP1) proteins, a highly conserved family of chromosomal proteins that bind to di- and trimethylated H3K9 via a conserved N-terminal domain called the chromodomain (CD) HP1 proteins are a highly conserved family of eukaryotic proteins that bind to methylated histone H3 lysine 9 (H3K9) and are required for heterochromatic gene silencing." SIGNOR-264490 WT1 protein P19544 UNIPROT RBM4 protein Q9BWF3 UNIPROT down-regulates binding 9606 16934801 t miannu "Wilm's tumor protein 1 (wt1), a protein implicated in various cancers and developmental disorders, consists of two major isoforms: wt1(-kts), a transcription factor, and wt1(+kts), a post-transcriptional regulator that binds to rna and can interact with splicing components. Here we show that wt1 interacts with the novel splicing regulator rbm4. / we conclude that the (+kts) form of wt1 is able to inhibit the effect of rbm4 on alternative splicing." SIGNOR-149166 RUNX3 protein Q13761 UNIPROT CASP2 protein P42575 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0002384 17956589 f miannu "Comprehensive analysis using a cDNA microarray showed that RUNX3 upregulated 17 apoptosis-related genes (including FADD, TRAF6, caspase-2, ING1, ING4, Calpain 10, and DNase1) and downregulated 135 apoptosis-related genes (including FLIP, PEA15, TXN2, HSPD1, IKK, and TIAL1) in MKN-1 cells." SIGNOR-255094 MAPK14 protein Q16539 UNIPROT TP53 protein P04637 UNIPROT up-regulates phosphorylation Ser33 LPENNVLsPLPSQAM 9606 BTO:0000093 11258706 t lperfetto "P38 regulates p53, but also in p53-defective tumor cells rewire their checkpoint response and become dependent in the p38/mk2 pathway in mcf-7 cells, p38 kinase activated p53 more effectively than other members of the ras pathway. p53 and p38 kinase exist in the same physical complex, and co-expression of p38 stabilized p53 protein. In vitro, p38 kinase phosphorylated p53 at ser33 and ser46, a newly identified site." SIGNOR-105741 CAPRIN2 protein Q6IMN6 UNIPROT OXT protein P01178 UNIPROT "up-regulates quantity by stabilization" "post transcriptional regulation" 9606 BTO:0000007 35051932 t lperfetto "Transcriptional and post-transcriptional regulation of oxytocin and vasopressin gene expression by CREB3L1 and CAPRIN2|Altogether, the data indicate that CAPRIN2 binds Oxt mRNA |Therefore, we propose that CAPRIN2 facilitates post-transcriptional modifications that increase Oxt transcript stability." SIGNOR-268556 PDPK1 protein O15530 UNIPROT RPS6KB1 protein P23443 UNIPROT up-regulates phosphorylation Thr412 NQVFLGFtYVAPSVL 9606 9445476 t miannu "A regulatory link between p70s6k and pkb was demonstrated, as pdk1 was found to selectively phosphorylate p70s6k at thr229. More importantly, pdk1 activated p70s6k in vitro and in vivo, whereas the catalytically inactive pdk1 blocked insulin-induced activation of p70s6k." SIGNOR-188911 IFNG protein P01579 UNIPROT Immune_response phenotype SIGNOR-PH17 SIGNOR up-regulates 9606 32283152 f miannu "High levels of expression of IL-1B, IFN-γ, IP-10, and monocyte chemoattractant protein 1 (MCP-1) have been detected in patients with COVID-19. These inflammatory cytokines may activate the T-helper type 1 (Th1) cell response. Th1 activation is a key event in the activation of specific immunity." SIGNOR-261024 Oxytocin protein P01178-PRO_0000020495 UNIPROT OXTR protein P30559 UNIPROT "up-regulates activity" binding 9606 11274341 t lperfetto "The neurohypophysial peptide oxytocin (OT) and OT-like hormones facilitate reproduction in all vertebrates at several levels. The major site of OT gene expression is the magnocellular neurons of the hypothalamic paraventricular and supraoptic nuclei. In response to a variety of stimuli such as suckling, parturition, or certain kinds of stress, the processed OT peptide is released from the posterior pituitary into the systemic circulation.| The OT receptor is a typical class I G protein-coupled receptor that is primarily coupled via G(q) proteins to phospholipase C-beta." SIGNOR-268545 PHLPP2 protein Q6ZVD8 UNIPROT AKT1 protein P31749 UNIPROT "down-regulates activity" dephosphorylation Ser473 RPHFPQFsYSASGTA 9606 BTO:0001544 19261608 t "The Abl kinase inhibitors and depletion of Bcr-Abl induced the expression of PHLPP1 and PHLPP2, which dephosphorylated Ser-473 on Akt1, -2, and -3, resulting in inhibited proliferation of CML cells.|Thus, Bcr-Abl represses the expression of PHLPP1 and PHLPP2 and continuously activates Akt1, -2, and -3 via phosphorylation on Ser-473, resulting in the proliferation of CML cells." SIGNOR-248728 COPS5 protein Q92905 UNIPROT SMAD4 protein Q13485 UNIPROT down-regulates ubiquitination 9606 11818334 t gcesareni "We report a novel mechanism of smad4 degradation. Jab1 interacts directly with smad4 and induces its ubiquitylation for degradation" SIGNOR-114697 MLL-AF9 "fusion protein" SIGNOR-FP5 SIGNOR RUNX1 protein Q01196 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 24449215 f miannu "However, the functional consequence of MLL fusions on RUNX1/CBFβ activity has not been fully understood. In this report, we show that MLL fusion proteins and the N-terminal MLL portion of MLL fusions downregulate RUNX1 and CBFβ protein expression via the MLL CXXC domain and flanking regions." SIGNOR-260128 SCN9A protein Q15858 UNIPROT Action_potential phenotype SIGNOR-PH82 SIGNOR up-regulates 9606 26043074 f miannu "The expression of voltage-gated sodium channels (NaVs) is a key feature for initiation and conduction of action potentials in excitable tissues and cells such as cardiac and skeletal muscle and neurons." SIGNOR-253449 NMBR protein P28336 UNIPROT GNA13 protein Q14344 UNIPROT up-regulates binding 9606 BTO:0001130;BTO:0000551 11313903 t gcesareni "These neuropeptides, including gastrin-releasing peptide, neuromedin b, neurotensin, gastrin, cholecystokinin and arginine vasopressin bind seven transmembrane-spanning receptors that couple to heterotrimeric g proteins. Studies with human small cell lung cancer (sclc) cells support a requirement for balanced signaling through g(q) and g(12/13) proteins leading to intracellular ca2+ mobilization, pkc activation and regulation of the erk and jnk map kinase pathways." SIGNOR-107028 FYN protein P06241 UNIPROT SCN5A protein Q14524 UNIPROT down-regulates phosphorylation Tyr1495 TEEQKKYyNAMKKLG 9606 15831816 t llicata "This study addresses the effects of the src family tyrosine kinase fyn on na(v)1.5 cardiac sodium channels. Sodium currents were acquired by whole cell recording on hek-293 cells transiently expressing na(v)1.5. Acute treatment of cells with insulin caused a depolarizing shift in steady-state inactivation, an effect eliminated by the src-specific tyrosine kinase inhibitor pp2 we provide evidence that this linker is a substrate for fyn in vitro, and that y1495 is a preferred phosphorylation site." SIGNOR-135600 clonidine chemical CHEBI:46631 ChEBI ADRA2A protein P08913 UNIPROT "up-regulates activity" "chemical activation" 9606 BTO:0000007 9605427 t miannu "AR agonists stimulated binding of [35S]GTPgS to HEK 293 cell membranes containing the human a2a, a2b, or a2c ARs (Fig. 6). EPI and NE were full agonists; clonidine and oxymetazoline were partial agonists, while antagonists (e.g. rauwolscine, 5 mM) did not stimulate [35S]GTPgS incorporation (Table 3). Although a few agonists showed a great deal of selectivity for a single receptor subtype, the rank order of agonist potency for selected compounds at the human receptors (Table 3) was: a2a: Dexmedetomidine . guanabenz . UK-14304 .clonidine . ST-91 . NE a2b: Dexmedetomidine . clonidine . guanabenz . NE .ST-91 . UK-14304 a2c: Dexmedetomidine . NE . UK-14304 . ST-91 $ clonidine .. guanabenz" SIGNOR-258905 FRAT1 protein Q92837 UNIPROT GSK3B protein P49841 UNIPROT up-regulates binding 9606 SIGNOR-C110 9635432 t gcesareni "The frat family consists of three members: frat-1, -2, and -3. It has been shown that different sites of frat-1 interact with gsk-3 and dvl-1 and that wnt-1 disintegrates the complex formation of frat-1, dvl-1, and axin, resulting in the activation of the wnt signaling pathway" SIGNOR-58219 GSK3B protein P49841 UNIPROT MACF1 protein Q9UPN3 UNIPROT "down-regulates activity" phosphorylation Ser7222 FRSRGRRsKPSSRAA 9606 BTO:0004905 21295697 t lperfetto "We discovered that GSK3β, a kinase inhibited by Wnt signaling, directly phosphorylates ACF7, a > 500 kDa microtubule-actin crosslinking protein abundant in hair follicle stem cells (HF-SCs). We map ACF7's GSK3β sites to the microtubule-binding domain and show that phosphorylation uncouples ACF7 from microtubules." SIGNOR-264426 RXRB protein P28702 UNIPROT THR proteinfamily SIGNOR-PF84 SIGNOR up-regulates binding 9606 10976919 t "inferred from family member" gcesareni "Like many receptors belonging to the superfamily of steroid/thyroid nuclear receptors, thyroid hormone receptors (trs) bind to specific th-dna responsive elements (tre) upstream of target gene in heterodimeric complex with the 9-cis retinoid acid receptor (rxr" SIGNOR-270297 RPS6KA3 protein P51812 UNIPROT TH protein P07101 UNIPROT up-regulates phosphorylation Ser40 GQGAPGPsLTGSPWP 9606 7901013 t "The effect has been demonstrated using P07101-3" gcesareni "Mitogen-activated protein-kinase (map) kinase-activated protein kinases 1 and 2 (mapkap kinase-1, mapkap kinase-2), were found to phosphorylate bacterially expressed human tyrosine hydroxylaserecombinant human tyrosine hydroxylase (hth1) was found to be phosphorylated by mitogen and stress-activated protein kinase 1 (msk1) at ser40 and by p38 regulated/activated kinase (prak) on ser19. Phosphorylation by msk1 induced an increase in vmax" SIGNOR-34682 CDK2 protein P24941 UNIPROT CROCC protein Q5TZA2 UNIPROT down-regulates phosphorylation Ser1460 APRPVPGsPARDAPA 9606 22610972 t llicata "Finally, phosphorylation of tax1bp2 at serine-763 by cyclin-dependent kinase (cdk)2 abolished the tax1bp2-mediated p38 activation and tumor-suppressive activity, indicating that tax1bp2 can adapt cdk2 signaling to the p38/p53/p21 pathway." SIGNOR-197593 FBXL18 protein Q96ME1 UNIPROT "Cullin 1-RBX1-Skp1" complex SIGNOR-C529 SIGNOR "up-regulates activity" binding 10090 BTO:0002268 25654763 t miannu "F-box protein Fbxl18 mediates polyubiquitylation and proteasomal degradation of the pro-apoptotic SCF subunit Fbxl7.. Here, we identified that an orphan F-box protein, Fbxl18, targets Fbxl7 for its polyubiquitylation and proteasomal degradation. Lys 109 within Fbxl7 is an essential acceptor site for ubiquitin conjugation by Fbxl18." SIGNOR-272449 NCOA1 protein Q15788 UNIPROT APOC3 protein P02656 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000599 16891307 f miannu "Overexpression of SRC1 and PGC1alpha by recombinant adenoviruses led to a significant up-regulation of well characterized HNF4alpha-dependent genes (ApoCIII, ApoAV, PEPCK, AldoB, OTC, and CYP7A1) and forced HepG2 cells toward a more differentiated phenotype as demonstrated by increased ureogenic rate." SIGNOR-255065 NDUFS8 protein O00217 UNIPROT "Mitochondrial respiratory chain complex I" complex SIGNOR-C277 SIGNOR "form complex" binding 30030361 t lperfetto "Thus, we now know the complete mammalian cI structure [22,23] and how the subunits are organized in six modules (N, Q, ND1, ND2, ND4 and ND5)|The Q-module is built through the association of NDUFA5, NDUFS2 and NDUFS3 plus NDUFS7 and NDUFS8. The chaperones NDUFAF3/C3ORF60 and NDUFAF4/C6ORF66 [36,37] remain bound to this module until the final assembly steps [34]. NDUFAF6/C8ORF38 [38] also seems to participate in the assembly of the Q-module [24,39]. NDUFAF3, 4 and 6, are necessary to maintain normal MT-ND1 synthesis [40,41]. NDUFAF5 adds a hydroxyl group to Arg73 of NDUFS7 [42] and NDUFAF7 dimethylates NDUFS2 in Arg85 [43], an essential modification for cI assembly [44]. NUBPL/IND1 delivers [4Fe–4S] clusters specifically to the N- and Q-module subunits [45,46]." SIGNOR-262182 C1R protein P00736 UNIPROT "Complement C1 complex" complex SIGNOR-C309 SIGNOR "form complex" binding -1 29449492 t lperfetto "The complement system is part of our innate immune system. The classical complement pathway is triggered by activation of the C1 initiation complex upon binding to cell surfaces. C1, or C1qr2s2, consists of four proteases, C1r and C1s, that associate with C1q, which contains antibody-binding sites.|The reconstruction reveals densities for all C1q collagen-like triple helices and gC1q modules, C1r and C1s proteases" SIGNOR-263395 PRKACA protein P17612 UNIPROT GFAP protein P14136 UNIPROT "down-regulates activity" phosphorylation Thr7 tSAARRSY -1 2155236 t miannu "GFAP can serve as a substrate for phosphorylation by CAMP-dependent protein kinase. CAMP-dependent protein kinase or protein kinase C phosphorylated Ser-8, Ser-13, and Ser-34.each phosphorylation was shown to induce disassembly of the glial filaments." SIGNOR-249712 Interferon-type-I proteinfamily SIGNOR-PF50 SIGNOR IFITMs proteinfamily SIGNOR-PF49 SIGNOR "up-regulates quantity by expression" "transcriptional regulation" 9606 25599080 f miannu "The IFITM (interferon-induced transmembrane) proteins comprise a family of interferon-induced antiviral cell-intrinsic restriction factors with high constitutive expression in many cells, including barrier epithelial cells. As their names imply, the expression of human IFITM1, IFITM2, and IFITM3 is also strongly upregulated by both type I and type II interferons" SIGNOR-260220 CyclinK/CDK13 complex SIGNOR-C38 SIGNOR POLR2A protein P24928 UNIPROT "up-regulates activity" phosphorylation Ser1878 SPKYSPTsPTYSPTT 9606 BTO:0006413 32917631 t "Ser2 in CTD of PolII" lperfetto "Together, these studies demonstrate the important, yet largely redundant, role for CDK12 and CDK13 for the regulation of POLII CTD phosphorylation at multiple residues, as well as the global role for both of these kinases in regulating POLII occupancy across the genome.|CDK12 and CDK13 are thus evolutionarily related and structurally similar kinases, and biochemical assays have demonstrated that both have POLII C-terminal domain (CTD) kinase activity and the ability to phosphorylate the Ser2 residue of the repetitive CTD heptad sequence" SIGNOR-273060 IRF2 protein P14316 UNIPROT DST protein Q03001 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 15560761 f miannu "Transient transfection studies with BPAG1 promoter-luciferase reporter gene plasmids and IRF1 and IRF2 expression plasmids revealed that IRF1 and IRF2 directly down-regulated BPAG1 gene transcription in cultured normal human epidermal keratinocytes." SIGNOR-254493 TAGLN2 protein P37802 UNIPROT ACTB protein P60709 UNIPROT "down-regulates activity" binding 21577206 t lperfetto "Taken together, our data propose a novel, oncogene-tumor suppressor interplay, where oncogenic PFTK1 confers HCC cell motility through inactivating the actin-binding motile suppressing function of TAGLN2 via phosphorylation." SIGNOR-265104 PRKCA protein P17252 UNIPROT DGKZ protein Q13574 UNIPROT unknown phosphorylation Ser265 SKKKKRAsFKRKSSK 9716136 t lperfetto "Two isoforms of protein kinase C, but not others, regulate the localization of DGK-zeta. |The PSD in MARCKS is phosphorylated by PKC, which suggested that DGK-zeta may also be a substrate for PKC, and that this couldregulate its intracellular location." SIGNOR-249010 BICRA protein Q9NZM4 UNIPROT GBAF complex SIGNOR-C467 SIGNOR "form complex" binding 9606 30397315 t miannu "Mammalian SWI/SNF (mSWI/SNF) complexes are ATP-dependent chromatin remodelers that modulate genomic architecture and DNA accessibility, enabling timely and appropriate control of gene expression. They are combinatorially assembled from the products of 29 total genes into three final-form complexes: canonical BAF, PBAF (polybromo-associated BAF complexes), and a newly-defined non-canonical BAF (ncBAF), with specific subunits specifying distinct complexes, such as PBRM1, ARID2, and BRD7 in PBAF complexes, ARID1A/ARID1B and DPF2 in canonical BAF (cBAF) complexes, and GLTSCR1/GLTSCR1L and BRD9 in ncBAF complexes" SIGNOR-269781 RUNX3 protein Q13761 UNIPROT ING1 protein Q9UK53 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0002384 17956589 f miannu "Comprehensive analysis using a cDNA microarray showed that RUNX3 upregulated 17 apoptosis-related genes (including FADD, TRAF6, caspase-2, ING1, ING4, Calpain 10, and DNase1) and downregulated 135 apoptosis-related genes (including FLIP, PEA15, TXN2, HSPD1, IKK, and TIAL1) in MKN-1 cells." SIGNOR-255099 FERMT3 protein Q86UX7 UNIPROT FBLIM1 protein Q8WUP2 UNIPROT "up-regulates activity" binding 10090 BTO:0000944 24165133 t miannu "Kindlin binds migfilin tandem LIM domains and regulates migfilin focal adhesion localization and recruitment dynamics. Two integrin-binding proteins present in FAs, kindlin-1 and kindlin-2, are important for integrin activation, FA formation, and signaling. By binding filamin, migfilin provides a link between kindlin and the actin cytoskeleton." SIGNOR-266104 PTPN6 protein P29350 UNIPROT ACTG1 protein P63261 UNIPROT down-regulates dephosphorylation Tyr218 DIKEKLCyVALDFEQ 9606 BTO:0000776 12646642 t gcesareni "Our data suggest that shp-1 plays a pivotal role in reorganization of cytoskeletal architecture inducing actin dephosphorylation. These results clearly demonstrate the direct interaction of shp-1 with actin" SIGNOR-99565 Ub:E2 complex SIGNOR-C497 SIGNOR RNF222 protein A6NCQ9 UNIPROT "up-regulates activity" ubiquitination 9606 34199813 t miannu "The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t" SIGNOR-271258 GSK3B protein P49841 UNIPROT MYOCD protein Q8IZQ8 UNIPROT "down-regulates activity" phosphorylation Ser626 DQTNVLSsTFLSPQC 9606 BTO:0000007 16141410 t "In vitro and in vivo (HEK 293 cells) kinase assays with synthetic peptides and full-length myocardin demonstrated that myocardin was a primed GSK3beta substrate, with serines 455 to 467 and 624 to 636 being the major GSK3beta phosphorylation sites.  GSK3β phosphorylation at the sites identified inhibits myocardin intrinsic transcriptional activity" SIGNOR-251247 SMURF1 protein Q9HCE7 UNIPROT MINDY3 protein Q9H8M7 UNIPROT unknown ubiquitination -1 20804422 t miannu "Recombinant proteins were used to profile substrate ubiquitination by the Smurf1 ubiquitin ligase on a global scale using protein microarrays. T Proteins ubiquitinated on the protein microarray were confirmed as potential substrates of the Smurf1 activity using an off chip in vitro ubiquitination assay." SIGNOR-272675 S1PR3 protein Q99500 UNIPROT GNAZ protein P19086 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257330 FBN1 protein P35555 UNIPROT EFEMP2 protein O95967 UNIPROT "down-regulates activity" binding 9606 19570982 t "Regulation of binding" miannu "Fibulin-4 and -5 are extracellular glycoproteins with essential non-compensatory roles in elastic fiber assembly. Both fibulins differentially bound N-terminal fibrillin-1, which strongly inhibited their binding to lysyl oxidase and tropoelastin." SIGNOR-251860 CTSL protein P07711 UNIPROT BGLAP protein P02818 UNIPROT "down-regulates quantity by destabilization" cleavage Arg94 IGFQEAYrRFYGPV -1 9076588 t miannu "This study has been undertaken to compare the degradation of BGP by the cysteine proteinases cathepsins L, B, H, S, and the aspartic proteinase cathepsin D. Cathepsins B, L, H, and S readily cleave BGP at the G7-A8 bond; cathepsin L also cleaves at R43-R44; cathepsin B also cleaves at R44-F45; and cathepsin D cleaves only at A41-Y42." SIGNOR-256322 "Av/b1 integrin" complex SIGNOR-C175 SIGNOR NANOG protein Q9H9S0 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 BTO:0001086 18757303 f lperfetto "Recombinant human LN-511 alone was suffi- cient to enable self-renewal of mouse ES cells for up to 169 days (31 passages). Cells cultured on LN-511 maintained expression of pluripotency markers, such as Oct4, Sox2, Tert, UTF1, and Nanog|ES cells interacted with LN-511 via 􏰇1-integrins, mostly a6b1 and aVb1." SIGNOR-253276 GPR35 protein Q9HC97 UNIPROT GNAZ protein P19086 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257112 KLHL13 protein Q9P2N7 UNIPROT AURKB protein Q96GD4 UNIPROT "up-regulates activity" binding 9606 BTO:0000567 17543862 t miannu "Aurora B Interacts with the Cul3 Complex during Mitosis and Is Ubiquitylated in a Cul3-Dependent Manner In Vivo and In Vitro. our results suggest that Cul3/KLHL9/KLHL13 activity is required to remove the chromosomal passenger protein Aurora B from mitotic chromosomes, and that Aurora B is ubiquitylated in vivo and in vitro in a KLHL9/13-dependent manner. We conclude that the Cul3/KLHL9/KLHL13 E3 ligase is an important cell-cycle regulator which, in addition to the anaphase-promoting complex (APC), coordinates mitotic progression and completion of cytokinesis." SIGNOR-271657 PSMB3 protein P49720 UNIPROT "26S Proteasome" complex SIGNOR-C307 SIGNOR "form complex" binding 9606 BTO:0000007 29636472 t lperfetto "Here, we report near-atomic resolution cryo-EM structures of the activated human proteasome|The proteasome is composed of a 28-subunit barrel-shaped core particle (CP) and two 19- subunit regulatory particles (RP)5–8 capped at both sides of the CP|Human proteasomes were purified through affinity chromatography on a large scale from a stable HEK293 cell line" SIGNOR-263359 Wnt proteinfamily SIGNOR-PF40 SIGNOR LRP5 protein O75197 UNIPROT up-regulates binding 9606 15578921 t "inferred from 70% family members" gcesareni "Wnt proteins bind to the frizzled receptors and lrp5/6 co-receptors, and through stabilizing the critical mediator betBeta-catenin, initiate a complex signaling cascade that plays an important role in regulating cell proliferation and differentiation." SIGNOR-269961 YWHAQ protein P27348 UNIPROT NEFL protein P07196 UNIPROT "down-regulates activity" binding 9606 23230147 t miannu "These results suggest the important role of 14-3-3 in the dynamic regulation of NF-L assembly, and in the capacity to prevent the formation of NF-L aggregates. all seven isoforms specifically interacted with NF-L, but not NF-M or NF-H. specific interaction of 14-3-3 proteins with phosphorylated NF-L subunits also indicated the role of 14-3-3 and NF-L phosphorylation in the disassembly of neurofilaments. What is more, binding of 14-3-3 to phosphorylated NF-L subunits may prevent the dephosphorylation of these subunits by phosphatases, maintaining the hyperphosphorylation state of the subunits, which facilitates the disassembly of neurofilaments." SIGNOR-252399 entinostat chemical CHEBI:132082 ChEBI HDAC9 protein Q9UKV0 UNIPROT "down-regulates activity" "chemical inhibition" -1 17868033 t Luana "Our findings suggest that hydroxamic acid-derived compounds such as TSA, NVP-LAQ824, panobinostat, ITF2357, vorinostat and belinostat act as potent pan-HDAC isoform inhibitors. A notable observation was the similarity between belinostat and vorinostat in the biochemical isoform assays; both compounds exhibit similar EC50 values in all but the HDAC8 assay." SIGNOR-257905 RPAP2 protein Q8IXW5 UNIPROT POLR2A protein P24928 UNIPROT "up-regulates activity" dephosphorylation Ser1696 SPSYSPTsPSYSPTS 9606 BTO:0000567 22137580 t "In addition, we show that RPAP2 is a CTD Ser5 phosphatase. Taken together, our results indicate that during transcription of snRNA genes, Ser7 phosphorylation facilitates recruitment of RPAP2, which in turn both recruits Integrator and dephosphorylates Ser5.|The Pol II CTD is first phosphorylated on Ser5 and then on Ser7 by CDK7. RPAP2 associates with the Pol II CTD after Ser7 phosphorylation and tethers a subcomplex of Integrator to snRNA genes. RPAP2 dephosphorylates Ser5P of the CTD, facilitating transcription and the subsequent recruitment of the Int11 catalytic subunit of Integrator" SIGNOR-248741 NLK protein Q9UBE8 UNIPROT LEF1 protein Q9UJU2 UNIPROT "down-regulates quantity" phosphorylation 9606 BTO:0000007 16714285 t miannu "NLK Augments the Ubiquitylation Activity of NARF against TCF/LEF. ctivation of NLK induced by unknown ligands leads to the phosphorylation of TCF/LEF. NARF then acts on TCF/LEF as an E3 ubiquitin-ligase and, together with E1 and E2 ubiquitylation enzymes, catalyze the ubiquitylation of TCF/LEF. Finally, ubiquitylated TCF/LEF is degraded by the 26 S proteasome." SIGNOR-271596 COX6C protein P09669 UNIPROT "Mitochondrial respiratory chain complex IV" complex SIGNOR-C280 SIGNOR "form complex" binding 30030361 t lperfetto "Complex IV (EC 1.9.31) or cytochrome c oxidase (COX) catalyses the oxidation of cytochrome c and the reduction of oxygen to water, coupled to proton translocation [108]. Mammalian cIV contains 13 or 14 subunits" SIGNOR-267750 SNAI2 protein O43623 UNIPROT MMP9 protein P14780 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0001033 22074556 f miannu "We demonstrated that forced expression of SLUG elevated CXCR4 and CXCL12 expression in human prostate cancer cell lines PC3, DU145, 22RV1, and LNCaP; conversely, reduced expression of SLUG by shRNA downregulated CXCR4 and CXCL12 expression at RNA and protein levels in prostate cancer cells. Furthermore, ectopic expression of SLUG increased MMP9 expression and activity in PC3, 22RV1, and DU-145 cells, and SLUG knockdown by shRNA downregulated MMP9 expression." SIGNOR-255170 DHODH protein Q02127 UNIPROT (S)-dihydroorotate smallmolecule CHEBI:30864 ChEBI "down-regulates quantity" "chemical modification" 9606 30449682 t miannu "OXPHOS directly drives the respiration-coupled mitochondrial enzyme dihydroorotate dehydrogenase (DHODH) that converts dihydroorotate (DHO) to orotate in the de novo pyrimidine synthesis pathway" SIGNOR-267430 TP53 protein P04637 UNIPROT RLIM protein Q9NVW2 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 23650532 f lperfetto "In the present study, we identified RLIM as a novel target of p53 and demonstrated that p53 repressed both mRNA and protein levels of RLIM." SIGNOR-268981 PDPK1 protein O15530 UNIPROT SGK3 protein Q96BR1 UNIPROT "up-regulates activity" phosphorylation Thr320 AISDTTTtFCGTPEY 10548550 t miannu "SGK2 and SGK3 are activated in vitro by PDK1, albeit more slowly than SGK1, and their activation is accompanied by the phosphorylation of Thr(193) and Thr(253) respectively. The PDK1-catalysed phosphorylation and activation of SGK2 and SGK3, like SGK1, is greatly potentiated by mutating Ser(356) and Ser(419) respectively to Asp, these residues being equivalent to the C-terminal phosphorylation site of PKB." SIGNOR-250279 IKBKB protein O14920 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR down-regulates phosphorylation Ser644 GLDFNFDsLISTQNV 9606 BTO:0000150 15084260 t gcesareni "Ikkbeta phosphorylates foxo3a at ser644. Ikappab kinase (ikk) physically interacts with, phosphorylates, and inhibits foxo3a independent of akt and causes proteolysis of foxo3a via the ub-dependent proteasome pathway" SIGNOR-252948 NFIX protein Q14938 UNIPROT ETV5 protein P41161 UNIPROT "down-regulates quantity" "transcriptional regulation" 10090 31838646 t Gianni "By integrating transcriptomic profiling (RNA-seq) of Nfia- and Nfix-deficient GNPs with epigenomic profiling (ChIP-seq against NFIA, NFIB and NFIX, and DNase I hypersensitivity assays), we reveal that these transcription factors share a large set of potential transcriptional targets, suggestive of complementary roles for these NFI family members in promoting neural development" SIGNOR-268886 CSNK2A1 protein P68400 UNIPROT ACE protein P12821 UNIPROT "up-regulates activity" phosphorylation Ser1299 SHGPQFGsEVELRHS 9823 BTO:0001176 12386153 t lperfetto "CK2 coprecipitated with ACE from endothelial cells, and CK2 phosphorylated both ACE and a peptide corresponding to the cytoplasmic tail. Mutation of serine(1270) within the CK2 consensus sequence almost abolished ACE phosphorylation.|These results indicate that the CK2-mediated phosphorylation of ACE regulates its retention in the plasma membrane and may determine plasma ACE levels." SIGNOR-264425 SCRIB protein Q14160 UNIPROT Scribble_complex_DLG4-LLGL1_variant complex SIGNOR-C509 SIGNOR "form complex" binding 9606 23397623 t miannu "The Scribble polarity complex or module is one of the three polarity modules that regulate cell polarity in multiple epithelia including blood-tissue barriers. This protein complex is composed of Scribble, Lethal giant larvae (Lgl) and Discs large (Dlg), which are well conserved across species from fruitflies and worms to mammals." SIGNOR-270904 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR KAT5 protein Q92993 UNIPROT "up-regulates activity" phosphorylation Ser86 TKNGLPGsRPGSPER 9606 BTO:0000567 12468530 t llicata "Baculovirus-based expression and purification of Tip60 combined with mass spectrometry allowed the identification of serines 86 and 90 as two major sites of phosphorylation in vivo. The phosphorylation of Tip60 was found to modulate its histone acetyltransferase activity. One of the identified phosphorylated serines, Ser-90, was within a consensus cyclin B/Cdc2 site. Ser-90 was specifically phosphorylatedin vitro by the cyclin B/Cdc2 complex." SIGNOR-250641 SSTR3 protein P32745 UNIPROT GNAI1 protein P63096 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-256677 NRG1 protein Q02297 UNIPROT ERBB4 protein Q15303 UNIPROT up-regulates binding 9606 14967450 t gcesareni "The neuregulins (also called heregulins and neu differentiation factors) nrg-1 and nrg-2 bind erbb-3 and erbb-4;and nrg-3 and nrg-4 bind erbb-4." SIGNOR-122053 PRKCB protein P05771 UNIPROT LASP1 protein Q14847 UNIPROT "down-regulates activity" phosphorylation Ser146 MEPERRDsQDGSSYR 9606 12571245 t lperfetto "Actin binding of human lim and sh3 protein is regulated by cgmp- and camp-dependent protein kinase phosphorylation on serine 146. Phosphorylation of lasp at ser-146 leads to a redistribution of the actin-bound protein from the tips of the cell membrane to the cytosol, accompanied with a reduced cell migration" SIGNOR-97942 CyclinK/CDK13 complex SIGNOR-C38 SIGNOR POLR2A protein P24928 UNIPROT "up-regulates activity" phosphorylation Ser1948 SPTSPGYsPTSPTYS 9606 BTO:0006413 32917631 t "Ser2 in CTD of PolII" lperfetto "Together, these studies demonstrate the important, yet largely redundant, role for CDK12 and CDK13 for the regulation of POLII CTD phosphorylation at multiple residues, as well as the global role for both of these kinases in regulating POLII occupancy across the genome.|CDK12 and CDK13 are thus evolutionarily related and structurally similar kinases, and biochemical assays have demonstrated that both have POLII C-terminal domain (CTD) kinase activity and the ability to phosphorylate the Ser2 residue of the repetitive CTD heptad sequence" SIGNOR-273061 BBC3 protein Q9BXH1 UNIPROT BAK1 protein Q16611 UNIPROT up-regulates binding 9606 17289999 t gcesareni "Bh3-only proteins induce apoptosis at least primarily by engaging the multiple pro-survival relatives guarding bax and bak enabler bh3-only proteins such as puma promote momp more indirectly. They activate bax and bak by forming inhibitory complexes with the anti-apoptotic bh1-4 proteins such as bcl2, bclxl and mcl1 that normally stabilize the outer membrane." SIGNOR-152974 EPAS1 protein Q99814 UNIPROT AP1 complex SIGNOR-C154 SIGNOR "down-regulates activity" binding 9606 BTO:0000093 24383088 t miannu "Co-transfection experiments revealed that HIF-2α had greater potency on the GLIS1 promoter activation than HIF-1α. Subsequent studies using wild-type and mutant HIF-2α demonstrated that DNA binding activity was not necessary but TADs were critical for GLIS1 induction. Finally, co-transfection experiments indicated that HIF-2α cooperated with AP-1 family members in upregulating GLIS1 transcription. These results suggest that the hypoxic signaling pathway may play a pivotal role in regulating the reprogramming factor GLIS1, via non-canonical mechanisms involving partner transcription factor rather than by direct HIF transactivation." SIGNOR-269042 PAPOLA protein P51003 UNIPROT mRNA_polyadenylation phenotype SIGNOR-PH200 SIGNOR up-regulates 9606 19224921 f lperfetto "Inositol 1,4,5-triphosphate receptor-binding protein released with inositol 1,4,5-triphosphate (IRBIT) associates with components of the mRNA 3' processing machinery in a phosphorylation-dependent manner and inhibits polyadenylation|In addition to CPSF, IRBIT interacted in vitro with poly(A) polymerase (PAP), which is the enzyme recruited by CPSF to elongate the poly(A) tail, and inhibited PAP activity in a phosphorylation-dependent manner." SIGNOR-268325 SUFU protein Q9UMX1 UNIPROT GLI1 protein P08151 UNIPROT "down-regulates activity" binding 15367681 t lperfetto "Here we characterize structural and functional determinants of Su(fu) required for Gli regulation and show that Su(fu) contains at least two distinct domains: a highly conserved carboxy-terminal region required for binding to the amino-terminal ends of the Gli proteins and a unique amino-terminal domain that binds the carboxy-terminal tail of Gli1. While each domain is capable of binding to different Gli1 regions independently, interactions between Su(fu) and Gli1 at both sites are required for cytoplasmic tethering and repression of Gli1" SIGNOR-249591 JQ1 chemical CHEBI:137113 ChEBI BRDT protein Q58F21 UNIPROT "down-regulates activity" "chemical inhibition" -1 20871596 t lperfetto "Enantiomerically pure (+)-JQ1 bound with a Kd of about 50 nM and 90 nM to the first and second bromodomains of BRD4, respectively (Fig. 1c, Supplementary Table 3). Comparable binding to both domains of BRD3 was observed, whereas the first bromodomains of BRDT and BRD2 revealed about 3-fold weaker binding.|Here, we present a first, thoroughly characterized inhibitor of the BET-family of bromodomains." SIGNOR-261990 Hexokinase proteinfamily SIGNOR-PF76 SIGNOR α-D-glucose smallmolecule CHEBI:17925 ChEBI "down-regulates quantity" "chemical modification" 9606 16051738 t miannu "Hexokinase catalyzes the phosphorylation of glucose to G6P, using ATP as a phosphoryl donor." SIGNOR-266459 KATNA1 protein O75449 UNIPROT Microtubule_polimerization phenotype SIGNOR-PH106 SIGNOR down-regulates 9606 19287380 f miannu "Katanin, one of the best-characterized microtubule (MT) severing proteins, is composed of two subunits: catalytic p60-katanin, and regulatory p80-katanin. p60-katanin triggers MT reorganization by severing them. MT reorganization is essential for both mitotic cells and post-mitotic neurons in numerous vital processes such as intracellular transport, mitosis, cellular differentiation and apoptosis. " SIGNOR-271794 MTCP1 protein P56278 UNIPROT AKT3 protein Q9Y243 UNIPROT up-regulates binding 9606 BTO:0000782;BTO:0001271 10983986 t miannu "Full-length tcl1 and its isoforms bind to akt / in in vitro kinase assays using gsk-3_ as a substrate, we found that the presence of any of the tcl1 family proteins (tcl1, mtcp1, or tcl1b) as gst fusion proteins significantly enhanced akt-induced gsk-3_ phosphorylation" SIGNOR-81677 CB-5083 chemical CID:73051434 PUBCHEM VCP protein P55072 UNIPROT "down-regulates activity" "chemical inhibition" -1 26565666 t miannu "Herein we describe our lead optimization efforts focused on in vitro potency, ADME, and pharmaceutical properties that led to the discovery of a potent, ATP-competitive, D2-selective, and orally bioavailable p97 inhibitor 71, CB-5083." SIGNOR-260189 PLCG1 protein P19174 UNIPROT 1,2-diacyl-sn-glycerol smallmolecule CHEBI:17815 ChEBI up-regulates "chemical modification" 9606 21918248 t gcesareni "Phospholypase c is an enzyme which catalyzes the hydrolysis of phosphatidylinositol-4,5-biphosphate (p(4,5)p(2)) into second messangers inositol-1,4,5-triphosphate (ins(1,4,5)p3) and dag." SIGNOR-176606 TYMS protein P04818 UNIPROT dihydrofolate(2-) smallmolecule CHEBI:57451 ChEBI "up-regulates quantity" "chemical modification" 9606 21876188 t lperfetto "In this pathway, 5,10-methyleneTHF, a one-carbon donor, is generated from serine by SHMT and used for the conversion of dUMP to dTMP in a reaction catalyzed by TYMS. The TYMS-catalyzed reaction generates dihydrofolate, which is converted to THF in an NADPH-dependent manner by DHFR." SIGNOR-268232 HDAC1 protein Q13547 UNIPROT ESR1 protein P03372 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0001570 23242655 f "Our previous studies demonstrated that mutant p53 along with repression complex proteins including DNMT1, HDAC1 and MeCP2 is associated with ER-negative promoter in MDA-MB-468 cells." SIGNOR-254029 LRP1B protein Q9NZR2 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR down-regulates 9606 BTO:0002940 27626682 f irozzo "Conversely, in Calu-1 cells, which express higher endogenous levels of the receptor, siRNA-mediated LRP1B knockdown significantly enhanced cellular proliferation. Taken together, these findings demonstrate that, consistent with the postulated tumor suppressor function, overexpression of full-length Lrp1b leads to impaired cellular proliferation, while LRP1B knockdown has the opposite effect." SIGNOR-259089 COX5B protein P10606 UNIPROT Cell_cycle_exit phenotype SIGNOR-PH41 SIGNOR down-regulates 10090 BTO:0000165 18701479 f lperfetto "Together, these data suggest that R-cadherin expression inhibits myogenesis and induces myoblast transformation through Rac1 activation. Therefore, the properties of R-cadherin make it an attractive target for therapeutic intervention in RMS.|R-cadherin expression inhibits myoblast cell cycle exit" SIGNOR-253105 CyclinK/CDK13 complex SIGNOR-C38 SIGNOR POLR2A protein P24928 UNIPROT "up-regulates activity" phosphorylation Ser1868 SPTSPKYsPTSPKYS 9606 BTO:0006413 32917631 t "Ser2 in CTD of PolII" lperfetto "Together, these studies demonstrate the important, yet largely redundant, role for CDK12 and CDK13 for the regulation of POLII CTD phosphorylation at multiple residues, as well as the global role for both of these kinases in regulating POLII occupancy across the genome.|CDK12 and CDK13 are thus evolutionarily related and structurally similar kinases, and biochemical assays have demonstrated that both have POLII C-terminal domain (CTD) kinase activity and the ability to phosphorylate the Ser2 residue of the repetitive CTD heptad sequence" SIGNOR-273062 CyclinK/CDK13 complex SIGNOR-C38 SIGNOR POLR2A protein P24928 UNIPROT "up-regulates activity" phosphorylation Ser1924 SPTSPKYsPTSPTYS 9606 BTO:0006413 32917631 t "Ser2 in CTD of PolII" lperfetto "Together, these studies demonstrate the important, yet largely redundant, role for CDK12 and CDK13 for the regulation of POLII CTD phosphorylation at multiple residues, as well as the global role for both of these kinases in regulating POLII occupancy across the genome.|CDK12 and CDK13 are thus evolutionarily related and structurally similar kinases, and biochemical assays have demonstrated that both have POLII C-terminal domain (CTD) kinase activity and the ability to phosphorylate the Ser2 residue of the repetitive CTD heptad sequence" SIGNOR-273063 LATS2 protein Q9NRM7 UNIPROT WWTR1 protein Q9GZV5 UNIPROT down-regulates phosphorylation Ser89 AQHVRSHsSPASLQL 9606 21808241 t "Together the YAP/TAZ-TEAD complex promotes proliferative and survival programs." gcesareni "Activated lats1/2 in turn phosphorylate and inhibit yap/taz transcription co-activators" SIGNOR-175787 FAD(3-) chemical CHEBI:57692 ChEBI ETF complex SIGNOR-C463 SIGNOR "form complex" binding 9606 33450351 t miannu "Human ETF is nuclear encoded by two separate genes, ETFA and ETFB, respectively. After translation, the two subunits are imported to the mitochondrial matrix space and assemble into a heterodimer containing one FAD and one AMP as cofactors." SIGNOR-269469 PPP2R5C protein Q13362 UNIPROT ATF1 protein P18846 UNIPROT up-regulates dephosphorylation Ser41 SLSESEEsQDSSDSI 9606 20730097 t lperfetto "We propose that constitutive hyperphosphorylation by ck1/ck2 maintains atf1 in an inactive state that promotes transcriptional repression. Pp2a/b56c antagonizes phosphorylation of atm sites in both creb and atf2" SIGNOR-167568 GSK3B protein P49841 UNIPROT MAPT protein P10636 UNIPROT "down-regulates activity" phosphorylation Thr522 SSPGSPGtPGSRSRT 9606 BTO:0000590 12387894 t lperfetto "We found that cdk5 phosphorylated tau(441) at Thr-181, Ser-199, Ser-202, Thr-205, Thr-212, Ser-214, Thr-217, Thr-231, Ser-235, Ser-396, and Ser-404, but not at Ser-262, Ser-400, Thr-403, Ser-409, Ser-413, or Ser-422. GSK-3beta phosphorylated all the cdk5-catalyzed sites above except Ser-235." SIGNOR-249347 CSNK2A1 protein P68400 UNIPROT IGFBP3 protein P17936 UNIPROT "up-regulates quantity by stabilization" phosphorylation Ser138 PPAPGNAsESEEDRS 9606 BTO:0000093 10650937 t llicata "The importance of Ser111 and Ser113 as targets for CK2 has also been shown in our laboratory, as mutation of either residue to alanine caused a major decrease in IGFBP-3 phosphorylation by this enzyme in vitro | These results indicate that IGFBP-3 interaction with acid-labile subunit and with the cell surface, both of which involve basic carboxyl-terminal residues, may be modulated by phosphorylation. Relative resistance to proteolysis and poor binding to cells suggest that CK2-phospho-IGFBP-3 may be a significant inhibitor of IGF activity in the extracellular environment." SIGNOR-250903 GARS1 protein P41250 UNIPROT Gly-tRNA(Gly) smallmolecule CHEBI:29156 ChEBI "up-regulates quantity" "chemical modification" 9606 24898252 t miannu "Aminoacyl-tRNA synthetases are an ancient enzyme family that specifically charges tRNA molecules with cognate amino acids for protein synthesis. Glycyl- tRNA synthetase (GlyRS) is one of the most intriguing aminoacyl-tRNA synthetases due to its divergent quaternary structure and abnormal charging properties. . In this study we report crystal structures of wild type and mutant hGlyRS in complex with tRNA and with small substrates and describe the molecular details of enzymatic recognition of the key tRNA identity elements in the acceptor stem and the anticodon loop." SIGNOR-270482 ELF1 protein P32519 UNIPROT FCER1A protein P12319 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0000732 11971001 f "Transcriptional regulation of the gene-encoding human Fc epsilon RI alpha-chain was analyzed in detail. EMSA revealed that either YY1 or PU.1 bound to the region close to that recognized by Elf-1|These up-regulating effects of PU.1 and YY1 with GATA-1 were inhibited by overexpression of Elf-1, indicating that Elf-1 serves as a repressor for the alpha-chain gene expression" SIGNOR-254287 GSK3B protein P49841 UNIPROT CCND1 protein P24385 UNIPROT down-regulates phosphorylation Thr286 EEVDLACtPTDVRDV 9606 9832503 t gcesareni "Phosphorylation of cyclin d1 on a single threonine residue near the carboxyl terminus (thr-286) positively regulates proteasomal degradation of d1. Now, we demonstrate that glycogen synthase kinase-3beta (gsk-3beta) phosphorylates cyclin d1 specifically on thr-286, thereby triggering rapid cyclin d1 turnover now, we demonstrate that glycogen synthase kinase-3beta (gsk-3beta) phosphorylates cyclin d1 specifically on thr-286, thereby triggering rapid cyclin d1 turnover." SIGNOR-62265 TRIP11 protein Q15643 UNIPROT THR proteinfamily SIGNOR-PF84 SIGNOR up-regulates binding 9606 9256431 t "inferred from 70% of family members" miannu "Trip230 binds to rb independently of thyroid hormone while it forms a complex with tr in a thyroid hormone-dependent manner. Ectopic expression of the protein trip230 in cells, but not a mutant form that does not bind to tr, enhances specifically tr-dependent transcriptional activity." SIGNOR-269879 Ub:E2 complex SIGNOR-C497 SIGNOR RNF126 protein Q9BV68 UNIPROT "up-regulates activity" ubiquitination 9606 34199813 t miannu "The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t" SIGNOR-270963 CNTF protein P26441 UNIPROT CRLF1 protein O75462 UNIPROT up-regulates binding 9606 11294841 t lperfetto "We recently demonstrated that cardiotrophin-like cytokine (clc) associates with the soluble orphan receptor cytokine-like factor-1 (clf) to form a heterodimeric cytokine that displayed activities only on cells expressing the tripartite cntf receptor on their surface" SIGNOR-106635 STAT5A protein P42229 UNIPROT CISH protein Q9NSE2 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 15769897 t "The STAT5 target gene CIS, a member of the suppressor of cytokine signaling (SOCS) protein family, was highly induced by Flt3-ITD" SIGNOR-261544 "Reduced Vitamin K" smallmolecule CHEBI:8784 ChEBI "vitamin K epoxide" smallmolecule CHEBI:28371 ChEBI "up-regulates quantity" "precursor of" 9606 31226734 t lperfetto "GGCX carboxylates the glutamic acid residues of vitamin K-dependent proteins (VKDP) to Gla using reduced vitamin K, while simultaneously oxidizing the reduced form of vitamin K to an epoxide form." SIGNOR-265909 PPP2CB protein P62714 UNIPROT SNCA protein P37840 UNIPROT "down-regulates activity" dephosphorylation Ser129 NEAYEMPsEEGYQDY 9606 21562258 t "α-Synuclein (α-Syn) is a key protein that accumulates as hyperphosphorylated aggregates in pathologic hallmark features of Parkinson's disease (PD) and other neurodegenerative disorders. Phosphorylation of this protein at serine 129 is believed to promote its aggregation and neurotoxicity, suggesting that this post-translational modification could be a therapeutic target. Here, we demonstrate that phosphoprotein phosphatase 2A (PP2A) dephosphorylates α-Syn at serine 129" SIGNOR-248592 KIT protein P10721 UNIPROT PTPN11 protein Q06124 UNIPROT "up-regulates activity" phosphorylation 10090 BTO:0002882 22806893 t irozzo "SHP2 can be phosphorylated at 2 C-terminal tyrosyl residues by receptor tyrosine kinases, including KIT as well as cytosolic tyrosine kinases, including Src and Abl. The level of tyrosyl phosphorylation of SHP2 has been associated with its recruitment to the receptor.Thus, pharmacologic inhibition of SHP2 phosphatase function might permit SHP2 to return to its inactive conformation resulting in reduced tyrosine phosphorylation." SIGNOR-256140 SF1 protein Q15637 UNIPROT EWSR1 protein Q01844 UNIPROT down-regulates binding 9606 9660765 t miannu "Here we report that zfm1 also interacts withews / overexpression of zfm1 in hepg2 cells represses the transactivation of reporter gene expression driven by gal4-ews-ntd fusion protein and this repression correlates with zfm1 binding to ews." SIGNOR-58928 SEM1 protein P60896 UNIPROT "26S Proteasome" complex SIGNOR-C307 SIGNOR "form complex" binding 9606 BTO:0000007 29636472 t lperfetto "Here, we report near-atomic resolution cryo-EM structures of the activated human proteasome|The proteasome is composed of a 28-subunit barrel-shaped core particle (CP) and two 19- subunit regulatory particles (RP)5–8 capped at both sides of the CP|Human proteasomes were purified through affinity chromatography on a large scale from a stable HEK293 cell line" SIGNOR-263343 RSPO3 protein Q9BXY4 UNIPROT LGR5 protein O75473 UNIPROT up-regulates binding 9606 21693646 t gcesareni "Here we demonstrate that lgr4 and lgr5 bind the r-spondins with high affinity and mediate the potentiation of wnt/betBeta-catenin signaling by enhancing wnt-induced lrp6 phosphorylation" SIGNOR-174535 rRNA_transcription phenotype SIGNOR-PH145 SIGNOR "39S mitochondrial large ribosomal subunit" complex SIGNOR-C285 SIGNOR up-regulates 25838379 f lperfetto "We have determined the structure of the intact mitoribosome to 3.5 angstrom resolution by means of single-particle electron cryogenic microscopy. It reveals 80 extensively interconnected proteins, 36 of which are specific to mitochondria, and three ribosomal RNA molecules." SIGNOR-262600 COPS6 protein Q7L5N1 UNIPROT "COP9 signalosome variant 1" complex SIGNOR-C489 SIGNOR "form complex" binding 9606 18850735 t miannu "The COP9 signalosome (CSN) is a multiprotein complex that plays a critical role in diverse cellular and developmental processes in various eukaryotic organisms. we have performed a comprehensive proteomic analysis of the human CSN complex using a new purification method and quantitative mass spectrometry. Purification of the human CSN complex from a stable 293 cell line expressing N-terminal HBTH-tagged CSN5 subunit was achieved by high-affinity streptavidin binding with TEV cleavage elution." SIGNOR-270768 "Chaperone-mediated autophagy" phenotype SIGNOR-PH118 SIGNOR HK2 protein P52789 UNIPROT "down-regulates quantity by destabilization" 9606 BTO:0004424 26323688 t "Our proteome analysis revealed that HK2 is a CMA substrate and that its degradation by CMA is regulated by glucose availability." SIGNOR-261247 CDK1 protein P06493 UNIPROT MAP4 protein P27816 UNIPROT down-regulates phosphorylation Ser787 KAPEKRAsPSKPASA 9606 10791892 t gcesareni "Ser787 in the proline-rich region of human map4 is a critical phosphorylation site that reduces its activity to promote tubulin polymerization. Phosphorylation on ser-787 negatively regulates map4 activity to promote microtubule assembly." SIGNOR-77087 PFKFB4 protein Q16877 UNIPROT "β-D-fructose 6-phosphate" smallmolecule CHEBI:57634 ChEBI "up-regulates quantity" "chemical modification" -1 30553771 t miannu "PFKFB3 has the highest kinase activity to shunt glucose toward glycolysis, whereas PFKFB4 has more FBPase-2 activity, redirecting glucose toward the pentose phosphate pathway, providing reducing power for lipid biosynthesis and scavenging reactive oxygen species" SIGNOR-268118 HOXA9 protein P31269 UNIPROT MEIS1 protein O00470 UNIPROT "up-regulates activity" binding -1 9343407 t 2 miannu "We now show that the Hoxa-9 protein physically interacts with Meis1 proteins. Hox proteins from the other AbdB-like paralogs, Hoxa-10, Hoxa-11, Hoxd-12, and Hoxb-13, also form DNA binding complexes with Meis1b. DNA binding complexes formed by Meis1 with Hox proteins dissociate much more slowly than DNA complexes with Meis1 alone, suggesting that Hox proteins stabilize the interactions of Meis1 proteins with their DNA targets." SIGNOR-241162 MLNR protein O43193 UNIPROT GNAI3 protein P08754 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-256880 EIF2AK2 protein P19525 UNIPROT EIF2AK2 protein P19525 UNIPROT "up-regulates activity" phosphorylation Thr446 LKNDGKRtRSKGTLR 4932 11337501 t "Trans-autophosphorylation of Thr-446 and Thr-451 by the two kinase moieties in a PKR dimer. autophosphorylation in the activation loop would promote proper alignment of key catalytic residues, or the correct orientation of the two lobes of the PKR kinase domain, required for substrate binding or phosphoryl transfer" SIGNOR-251110 UBE2E1 protein P51965 UNIPROT RNF167 protein Q9H6Y7 UNIPROT "up-regulates activity" binding 9606 BTO:0000007 16314844 t miannu " Here, we present evidences indicating that RING105, a novel conserved RING-finger protein with a PA (protease-associated) domain and a PEST sequence, is a ubiquitin ligase for TSSC5 that can function in concert with the ubiquitin-conjugating enzyme UbcH6. The polyubiquitin target site on TSSC5 was mapped to a region in the 6th hydrophilic loop." SIGNOR-271552 FGFR4 protein P22455 UNIPROT FGFR4 protein P22455 UNIPROT up-regulates phosphorylation Tyr642 RGVHHIDyYKKTSNG 9606 BTO:0001130 18670643 t lperfetto "Binding of fgf to fgf receptors leads to receptor dimerization and subsequent tyrosine autophosphorylation and phosphorylation of target substrates. Autophosphorylation on tyrosine is considered to have at least two functions. One such function is the stimulation of the intrinsic protein tyrosine kinase activity by an allosteric mechanismthis antibody specifically recognizes tyr642/643 in fgfr-4." SIGNOR-179776 MEF2C protein Q06413 UNIPROT α-Catenin proteinfamily SIGNOR-PF72 SIGNOR "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0002320 21598020 t miannu "GATA-4 and MEF2C are known to bind to the GATA box 2 in the major promoter of CTNNA3 and this element is essential in directly regulating expression of CTNNA3 in cardiac muscle cells. The co-transfection of GATA-4 with MEF2C leads to a synergistic activation of the CTNNA3 promoter" SIGNOR-265816 CDC20 protein Q12834 UNIPROT SP100 protein P23497 UNIPROT "down-regulates quantity by destabilization" binding 9606 BTO:0000007 22086178 t miannu "Cdc20 is a co-activator of the anaphase-promoting complex/cyclosome (APC/C complex), which recruits substrates at particular phases of the cell cycle and mediates their degradation. Overexpression of Cdc20 resulted in decreased levels of both endogenous Sp100 protein and overexpressed Sp100 mRNA in HEK 293 cells. Our results suggested that sp100 is a novel substrate of Cdc20 and it is degraded by the ubiquitination pathway. The intact D-box of Sp100 was necessary for this process." SIGNOR-272724 KLHL18 protein O94889 UNIPROT "Cullin 3-RBX1-Skp1" complex SIGNOR-C526 SIGNOR "up-regulates activity" binding 9606 BTO:0001938 23213400 t miannu "We identify Aurora-A as a KLHL18-interacting partner. Overexpression of KLHL18 and CUL3 promotes Aurora-A ubiquitylation in vivo, and the CUL3-KLHL18-ROC1 ligase ubiquitylates Aurora-A in vitro. Our study reveals that the CUL3-KLHL18 ligase is required for timely entry into mitosis, as well as for the activation of Aurora-A at centrosomes." SIGNOR-272022 MAPK1 protein P28482 UNIPROT PCBP2 protein Q15366 UNIPROT "up-regulates quantity by stabilization" phosphorylation Ser272 FSGIESSsPEVKGYW 9606 BTO:0000664 17475908 t miannu "We also identified 4 hnRNP-E2 MAPKERK1/2 phosphorylation sites and demonstrated that hnRNP-E2 is a bona fide MAPKERK1/2 substrate and that MAPKERK1/2-dependent phosphorylation of hnRNP-E2 at these amino acid residues is essential for increased hnRNP-E2 expression in BCR/ABL-expressing cells. Serine/threonine to alanine substitution abolishes hnRNP-E2 phosphorylation and markedly decreases its stability in BCR/ABL-expressing myeloid precursors. Consistent with the existence of a BCR/ABL-MAPK pathway that posttranslationally regulates hnRNP-E2 expression, sequence analysis of hnRNP-E2 revealed the presence of 4 consensus ERK phosphorylation sites (S/T-P)35,36 at amino acid residues 173, 189, 213, and 272 (Figure 2B)." SIGNOR-262912 AV412 chemical CID:11700696 PUBCHEM ERBB2 protein P04626 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-190053 MTOR protein P42345 UNIPROT ULK2 protein Q8IYT8 UNIPROT down-regulates phosphorylation 9606 19211836 t gcesareni "Mtor phosphorylates a mammalian homologue of atg13 and the mammalian atg1 homologues ulk1 and ulk2" SIGNOR-183961 10-formyltetrahydrofolate(2-) smallmolecule CHEBI:57454 ChEBI formate smallmolecule CHEBI:15740 ChEBI "up-regulates quantity" "precursor of" 9606 18767138 t lperfetto "Methylenetetrahydrofolate dehydrogenase)methenyltetrahydrofolate cyclohydrolase)formyltetrahydrofolate synthetase (MTHFD1) is a trifunctional enzyme that interconverts tetrahydrofolate (THF) derivatives for nucleotide synthesis.|The Arg653Gln substitution is located in the synthetase domain, which catalyzes the magnesium adenosine triphosphate (MgATP)-dependent production of formylTHF from THF and formate" SIGNOR-268248 PRKCA protein P17252 UNIPROT CTPS1 protein P17812 UNIPROT down-regulates phosphorylation Thr455 MRLGKRRtLFQTKNS 9606 17463002 t llicata "These data indicated that protein kinase c phosphorylation at ser(462) stimulates human ctp synthetase 1 activity, whereas phosphorylation at thr(455) inhibits activity." SIGNOR-154621 PRKACA protein P17612 UNIPROT KCNJ13 protein O60928 UNIPROT up-regulates phosphorylation Ser287 EICQRRTsYLPSEIM 9606 18976636 t gcesareni "Pka activation induced an increase of kir7.1 currents. This effect was absent in mutant kir7.1 channels lacking pka consensus site (287)s" SIGNOR-181859 EEF1A1P5 protein Q5VTE0 UNIPROT Cys-tRNA(Cys) smallmolecule CHEBI:29152 ChEBI up-regulates relocalization 9606 23699257 t lperfetto "During protein synthesis, eEF1A binds to and delivers aminoacylated tRNAs (aa-tRNAs) to the elongating ribosome (Fig. 1). GTP bound to eEF1A is hydrolyzed upon codon-anticodon match between an aa-tRNA in the A site of the ribosome and mRNA bound to the ribosome." SIGNOR-269548 "acetylsalicylic acid" chemical CHEBI:15365 ChEBI PTGS1 protein P23219 UNIPROT down-regulates "chemical inhibition" 9606 11809688 t gcesareni "Nsaids inhibit cyclooxygenase (cox) isozymes, which are responsible for the committed step in prostaglandin biosynthesis, and this has been considered the primary mechanism by which nsaids exert their antitumorigenic effects." SIGNOR-114377 GSK3B protein P49841 UNIPROT DPYSL3 protein Q14195 UNIPROT "down-regulates activity" phosphorylation Ser522 PAGSARGsPTRPNPP 10116 BTO:0000938 16611631 t lperfetto "Primary rat cortical neurons were treated with purvalanol, a more potent inhibitor of cdk5 and dyrk2 than roscovitine (25). Phosphorylation was monitored using antibodies that specifically recognize crmp2 when phosphorylated at thr514/thr509, or crmp4 when phosphorylated at thr509. Loss of phosphorylation of ser522 will prevent subsequent phosphorylation of ser518/thr514/thr509 by gsk3. Together, these results suggest that crmp4 is able to increase neurite formation and elongation in neurons, although not as potently as crmp2, and that this process is regulated by ser522/ser518/thr514/thr509 phosphorylation in both cases. We demonstrate that cdk5 primes crmp2 and crmp4 for subsequent phosphorylation by gsk3, whereas dyrk2, phosphorylates and primes only crmp4 in vitro" SIGNOR-146007 POU5F1 protein Q01860 UNIPROT THY1 protein P04216 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0001086 17068183 f miannu "To enhance our understanding of the molecular basis of this differentiation event in humans, we used a functional genomics approach involving RNA interference-mediated suppression of OCT4 function in a human ESC line and analysis of the resulting transcriptional profiles to identify OCT4-dependent genes in human cells. We detected altered expression of >1,000 genes, including targets regulated directly by OCT4 either positively (NANOG, SOX2, REX1, LEFTB, LEFTA/EBAF DPPA4, THY1, and TDGF1) or negatively (CDX2, EOMES, BMP4, TBX18, Brachyury [T], DKK1, HLX1, GATA6, ID2, and DLX5), as well as targets for the OCT4-associated stem cell regulators SOX2 and NANOG." SIGNOR-254931 CyclinK/CDK13 complex SIGNOR-C38 SIGNOR POLR2A protein P24928 UNIPROT "up-regulates activity" phosphorylation Ser1875 SPTSPKYsPTSPTYS 9606 BTO:0006413 32917631 t "Ser2 in CTD of PolII" lperfetto "Together, these studies demonstrate the important, yet largely redundant, role for CDK12 and CDK13 for the regulation of POLII CTD phosphorylation at multiple residues, as well as the global role for both of these kinases in regulating POLII occupancy across the genome.|CDK12 and CDK13 are thus evolutionarily related and structurally similar kinases, and biochemical assays have demonstrated that both have POLII C-terminal domain (CTD) kinase activity and the ability to phosphorylate the Ser2 residue of the repetitive CTD heptad sequence" SIGNOR-273064 80S_cytosolic_ribosome complex SIGNOR-C455 SIGNOR Protein_synthesis phenotype SIGNOR-PH29 SIGNOR up-regulates 9606 35489072 t lperfetto "In eukaryotes, mRNA is recruited to the 43S pre-initiation complex (43S PIC), which consists of the 40S ribosomal subunit, translation initiation factors eIF1, eIF1A, eIF3, eIF5, and a ternary complex (TC) composed of eIF2, GTP and Met-tRNAiMet. 43S PIC binds to the 5′ end of the mRNA and scans along the 5′ untranslated region (5′UTR) in the 3′ direction to find the start codon (AUG) within the context of an optimal Kozak sequence. Start codon recognition stabilizes the 48S initiation complex (48S IC), initiates dissociation of eIF1, eIF1A, eIF2 and eIF5, and promotes recruitment of the 60S ribosomal subunit to form 80S IC ready to enter the elongation cycle of protein synthesis." SIGNOR-269173 PRKCD protein Q05655 UNIPROT ADRB2 protein P07550 UNIPROT "down-regulates activity" phosphorylation Ser262 GHGLRRSsKFCLKEH -1 1848190 t lperfetto "We investigate the role of the beta 2-adrenergic receptor phosphorylation by protein kinase C in this regulatory process. Mutation of the serine-261, -262, -344 and -345 of the beta 2-adrenergic receptor prevented the phorbol-ester-induced phosphorylation of the receptor. This mutation also abolished the phorbol-ester-induced decrease in high-affinity agonist binding and potency of the beta 2-adrenergic receptor. We suggest that protein kinase C mediated phosphorylation of the receptor promotes its functional uncoupling." SIGNOR-248855 ASH2L protein Q9UBL3 UNIPROT GATA3 protein P23771 UNIPROT up-regulates binding 9606 BTO:0000150 25258321 t miannu "We identifiedgata3as the binding protein of ash2l. Ash2l was shown to potentiate the transcriptional activity ofgata3." SIGNOR-205312 PRKCA protein P17252 UNIPROT GABRR1 protein P24046 UNIPROT unknown phosphorylation Ser447 SQRSSYVsMRIDTHA -1 12175859 t miannu "Here, we have identified phosphorylation sites on the human ρ1 GABA receptor for six protein kinases widely expressed in the brain: protein kinase C (PKC); cAMP‐dependent protein kinase (PKA); calmodulin‐dependent kinase (CaMKII); casein kinase (CKII); mitogen‐activated protein kinase (MAPK); and cGMP‐dependent protein kinase (PKG). The PKC family contains 12 identified mammalian isoenzymes that are universally expressed in all cells and tissues and generally have a cytosolic distributionExamination of two groups of serine and threonine mutations (Fig. 3A, lanes 2 and 3) enabled us to localize the phosphorylation to four specific residues at positions 419, 422, 423, and 426. Fig. 3B shows the levels of phosphorylation with different combinations of the four mutations. Elimination of all four serines completely eliminated phosphorylation (Fig. 3B, lane 1).An extensive functional analysis comparing wild type 1 receptors and receptors with select or multiple phosphorylation sites removed as well as pharmacological manipulation of five kinase pathways failed to reveal any functional effects of phosphorylation" SIGNOR-262754 SMARCD1 protein Q96GM5 UNIPROT "SWI/SNF ACTL6B varian" complex SIGNOR-C476 SIGNOR "form complex" binding 9606 30397315 t miannu "Mammalian SWI/SNF (mSWI/SNF) complexes are ATP-dependent chromatin remodelers that modulate genomic architecture and DNA accessibility, enabling timely and appropriate control of gene expression. They are combinatorially assembled from the products of 29 total genes into three final-form complexes: canonical BAF, PBAF (polybromo-associated BAF complexes), and a newly-defined non-canonical BAF (ncBAF), with specific subunits specifying distinct complexes, such as PBRM1, ARID2, and BRD7 in PBAF complexes, ARID1A/ARID1B and DPF2 in canonical BAF (cBAF) complexes, and GLTSCR1/GLTSCR1L and BRD9 in ncBAF complexes" SIGNOR-270604 PPM1B protein O75688 UNIPROT IKBKB protein O14920 UNIPROT down-regulates dephosphorylation Ser181 DQGSLCTsFVGTLQY 9606 18930133 t lperfetto "Using a functional genomic approach, we have identified two protein serine/threonine phosphatases, ppm1a and ppm1b, as ikkbeta phosphatases. Overexpression of ppm1a or ppm1b results in dephosphorylation of ikkbeta at ser177 and ser181 and termination of ikkbeta-induced nf-kappab activation" SIGNOR-181667 PRKDC protein P78527 UNIPROT PRKDC protein P78527 UNIPROT "up-regulates activity" phosphorylation Ser3205 TPLPEDNsMNVDQDG 9606 BTO:0000773 12186630 t lperfetto "We have identified seven in vitro autophosphorylation sites in DNA-PKcs. Six of these sites (Thr2609, Ser2612, Thr2620, Ser2624, Thr2638 and Thr2647) are clustered in a region of 38 amino acids in the central region of the protein. Five of these sites (Thr2609, Ser2612, Thr2638, Thr2647 and Ser3205) are conserved between six vertebrate species. Moreover, we show that DNA-PKcs is phosphorylated in vivo at Thr2609, Ser2612, Thr2638 and Thr2647 in okadaic acid-treated human cells. | Thus phosphorylation of DNA-PKcs at one or more of the autophosphorylation sites identified in this study is likely to be required for DNA-PKcs function." SIGNOR-249157 ZAP70 protein P43403 UNIPROT LAT protein O43561 UNIPROT "up-regulates activity" phosphorylation Tyr200 SMESIDDyVNVPESG 9606 11368773 t lperfetto "In the present study we reconstituted the LAT signalling pathway by demonstrating that a direct tyrosine phosphorylation of LAT with activated protein-tyrosine kinase Zap70 is necessary and sufficient for the association and activation of signalling proteins. Zap-70 efficiently phosphorylates LAT on tyrosine residues at positions 226, 191, 171, 132 and 127." SIGNOR-247026 haloperidol chemical CHEBI:5613 ChEBI HTR2A protein P28223 UNIPROT "down-regulates activity" "chemical inhibition" 10090 BTO:0000331 8935801 t miannu "Risperidone and its active metabolite 9-OH-risperidone were compared to reference antipsychotic drugs (haloperidol, pipamperone, fluspirilene, clozapine, zotepine) and compounds under development (olanzapine, seroquel, sertindole, ORG-5222, ziprasidone) for in vitro binding to neurotransmitter receptors in brain tissue and on membranes of recombinant cells expressing cloned human receptors and for in vivo occupancy of neurotransmitter receptors in rat and guinea-pig brain following acute treatment (2 h., s.c.). The binding affinities of the compounds for various neurotransmitter receptors were measured using membrane preparations of animal brain regions and of recombinant cells expressing cloned, mostly human receptors. Receptors, tissues and cells are indicated in Table I; results are shown in Table 4A-B." SIGNOR-258520 HRAS protein P01112 UNIPROT RAF1 protein P04049 UNIPROT up-regulates binding 9606 9020159 t lperfetto "We have examined whether the other two members of the Raf family, A-Raf and B-Raf, are regulated in a similar way to Raf-1. A-Raf behaves like Raf-1, being weakly activated by oncogenic Ras more strongly activated by oncogenic Src, and these signals synergize to give maximal activation. B-Raf by contrast is strongly activated by oncogenic Ras alone and is not activated by oncogenic Src." SIGNOR-235786 Phenelzine chemical CHEBI:8060 ChEBI MAOB protein P27338 UNIPROT "down-regulates activity" "chemical inhibition" -1 18426226 t Luana "Phenylethylhydrazine stoichiometrically reduces the covalent FAD moieties of MAO A and of MAO B. Molecular oxygen is required for the inhibition reactions, and the level of O2 consumption for phenylethylhydrazine is 6-7-fold higher with either MAO A or MAO B than for the corresponding reactions with benzylhydrazine or phenylhydrazine." SIGNOR-257778 "SB 203580" chemical CHEBI:90705 ChEBI MAPK14 protein Q16539 UNIPROT down-regulates "chemical inhibition" 9606 BTO:0000567 15208625 t gcesareni "Pretreatment of hela cells with sb 203580, a pyridinyl imidazole compound that specifically inhibits p38 mitogen-activated protein kinase (mapk). It has previously been established that sb 203580 acts primarily to block the catalytic activity of p38 mapk. However, it has been suggested that in cells, the compounds could also inhibit p38 mapk activation by virtue of their ability to bind to the inactive enzyme." SIGNOR-126055 MAP3K5 protein Q99683 UNIPROT DAXX protein Q9UER7 UNIPROT "up-regulates quantity by stabilization" phosphorylation Ser176 TNAENTAsQSPRTRG 9606 BTO:0000567 19789335 t lperfetto "we show that TNFalpha treatment induces the accumulation of Daxx protein through ASK1 activation by preventing its proteasome-dependent degradation. ASK1 directly phosphorylates Daxx at Ser(176) and Ser(184) and Daxx is required for the sustained activation of JNK. Our results indicate that Daxx not only activates ASK1 but also is a downstream target of ASK1 and that accumulated Daxx further activates ASK1." SIGNOR-109680 PRKDC protein P78527 UNIPROT PRKDC protein P78527 UNIPROT "up-regulates activity" phosphorylation Ser2624 QTRTQEGsLSARWPV -1 12186630 t lperfetto "We have identified seven in vitro autophosphorylation sites in DNA-PKcs. Six of these sites (Thr2609, Ser2612, Thr2620, Ser2624, Thr2638 and Thr2647) are clustered in a region of 38 amino acids in the central region of the protein. Five of these sites (Thr2609, Ser2612, Thr2638, Thr2647 and Ser3205) are conserved between six vertebrate species. Moreover, we show that DNA-PKcs is phosphorylated in vivo at Thr2609, Ser2612, Thr2638 and Thr2647 in okadaic acid-treated human cells. | Thus phosphorylation of DNA-PKcs at one or more of the autophosphorylation sites identified in this study is likely to be required for DNA-PKcs function." SIGNOR-249156 PRKCA protein P17252 UNIPROT Cell_death phenotype SIGNOR-PH109 SIGNOR down-regulates 9606 BTO:0000599 15730925 f irozzo "PKC-alpha asODN (antisense oligonucleotides) could inhibit the growth and proliferation of HepG2 and induce its apoptosis by blocking the cell signal transduction related to PKC-alpha in vitro, and may be potentially used in the prevention and management of recurrent and metastatic HCC." SIGNOR-256660 PRKCZ protein Q05513 UNIPROT SP1 protein P08047 UNIPROT up-regulates phosphorylation Thr668 SYCGKRFtRSDELQR 9606 BTO:0000887;BTO:0001260 18258854 t llicata "Here we have used a variety of approaches to identify 3 amino acids (thr668, ser670, and thr681) in the zinc finger domain of sp1 that are modified by pkc-zeta angiotensin ii, which activates pkc-? Phosphorylation (at thr410) via the angiotensin ii type 1 receptor, stimulates sp1 phosphorylation and increases sp1 binding to the platelet-derived growth factor-d promoter." SIGNOR-160770 EGFR protein P00533 UNIPROT EZR protein P15311 UNIPROT up-regulates phosphorylation Tyr354 LMLRLQDyEEKTKKA 9606 BTO:0000017 15647376 t lperfetto "Ezrin was initially identified as a substrate for tyrosine phosphorylation by egfr (bretscher, 1989) and phosphorylation of residues y145 and y353 were detected to high stoichiometry after egf treatment . Phosphorylation of ezrin at y353 has been delineated to signal survival during epithelial cell differentiation via the phosphatidylinositol 3-kinase (pi3k)/akt pathway." SIGNOR-133215 IGF1R protein P08069 UNIPROT IGF1R protein P08069 UNIPROT up-regulates phosphorylation Tyr973 RLGNGVLyASVNPEY -1 7493944 t lperfetto "The insulin-like growth factor type I (IGF-I) receptor can become tyrosine phosphorylated and enzymatically activated either in response to ligand or because of the activity of the Src tyrosine kinase. We mapped the sites of IGF-I receptor autophosphorylation to peptides representing three different receptor domains: tyrosines 943 and 950 in the juxtamembrane region; tyrosines 1131, 1135, and 1136 within the kinase domain; and tyrosine 1316 in the carboxyl-terminal domain." SIGNOR-246252 DVL2 protein O14641 UNIPROT LRP6 protein O75581 UNIPROT "up-regulates activity" binding 9606 BTO:0000331 10196136 t amattioni "Dvl is required for lrp6 phosphorylation, which is essential for subsequent steps of signal transduction." SIGNOR-66362 P2RY1 protein P47900 UNIPROT GNA15 protein P30679 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257339 PRKD1 protein Q15139 UNIPROT ATP7B protein P35670 UNIPROT "up-regulates activity" phosphorylation Ser478 APDILAKsPQSTRAV 9606 BTO:0000599 21189263 t lperfetto "ATP7B trafficking was markedly reduced by the Ser-478/481/1121/1453 to Ala mutation. We conclude that PKD plays a key role in copper-dependent serine phosphorylation, permitting high levels of ATP7B protein expression and trafficking." SIGNOR-272296 CHFR protein Q96EP1 UNIPROT SMARCA4 protein P51532 UNIPROT "down-regulates quantity by destabilization" polyubiquitination 9534 BTO:0000298 22285184 t miannu "Here we report that CHFR interacts with BRG1, SNF5, and BAF60a of the SWI/SNF-like BAF complex and ubiquitinates them to target for degradation through a proteasome-mediated pathway, and that SRG3/mBAF155 stabilizes these components by blocking their interaction with CHFR. These results suggest that CHFR enhances the degradation of the components of the SWI/SNF-like BAF complex by inducing their poly-ubiquitination." SIGNOR-271457 SPI1 protein P17947 UNIPROT TAL1 protein P17542 UNIPROT "down-regulates activity" binding 9606 BTO:0000567 16298389 t irozzo "PU.1/Spi-1 binds to the human TAL-1 silencer to mediate its activity.By expressing a mutant protein containing only the ETS domain of PU.1 in human erythroleukemic HEL cells, we demonstrated that PU.1 mediates the transcriptional repression activity of the silencer. Our data clearly demonstrate that PU.1 mediates TAL-1 silencer activity" SIGNOR-256048 ADAMTS4 protein O75173 UNIPROT ACAN protein P16112 UNIPROT "down-regulates quantity by destabilization" cleavage Glu392 PRNITEGeARGSVIL 9606 9202061 t lperfetto "Aggrecan Degradation in Human Cartilage Evidence for both Matrix Metalloproteinase and Aggrecanase Activity in Normal, Osteoarthritic, and Rheumatoid Joints|Stromelysin-1 (MMP-3), as well as other MMPs, cleave aggrecan in the interglobular domain between Asn341 and Phe342 to generate a G1 fragment with the COOH terminus VDIPEN341 (11–13). This fragment has been isolated and identified by NH2-terminal sequence analysis from human OA cartilage (11). A second proteolytic activity identified as “aggrecanase” also cleaves aggrecan in the interglobular domain, but between Glu373 and Ala374 (19–24), generating a G1 fragment with a COOH terminus of NITEGE373" SIGNOR-266984 PINK1 protein Q9BXM7 UNIPROT HTRA2 protein O43464 UNIPROT up-regulates phosphorylation Ser142 VPSPPPAsPRSQYNF 9606 17906618 t gcesareni "Htra2 is phosphorylated on activation of the p38 pathway, occurring in a pink1-dependent mannerwe suggest that pink1-dependent phosphorylation of htra2 might modulate its proteolytic activity, thereby contributing to an increased resistance of cells to mitochondrial stress." SIGNOR-158052 JAK2 protein O60674 UNIPROT PRMT5 protein O14744 UNIPROT down-regulates phosphorylation Tyr297 NRPPPNAyELFAKGY 9606 21316606 t llicata "Oncogenic jak2 kinases phosphorylate prmt5 in_vivo phosphorylation of prmt5 by jak2v617f greatly impairs its methyltransferase activity" SIGNOR-171994 CDK1 protein P06493 UNIPROT EEF1D protein P29692 UNIPROT unknown phosphorylation Ser133 APQTQHVsPMRQVEP 9606 12551973 t gcesareni "The sequence flanking ser-133 of ef-1delta completely matches the consensus phosphorylation site for a cellular protein kinase, cdc2, and in vitro kinase assays revealed that purified cdc2 phosphorylates ser-133 of ef-1delta." SIGNOR-97733 NR0B2 protein Q15466 UNIPROT NR1I3 protein Q14994 UNIPROT down-regulates binding 9606 15000748 t gcesareni "The short heterodimer partner (shp), an orphan nuclear receptor that lacks a conventional dna binding domain, was initially identified by its interaction with car. We have examined the role of shp in car-mediated transactivation of the cyp2b gene. Coexpression of shp inhibited the transactivation of the cyp2b gene by car in cultured hepatoma cells and the p160 coactivator grip1 reversed the inhibition." SIGNOR-123154 MAPK8 protein P45983 UNIPROT HNRNPK protein P61978 UNIPROT "up-regulates activity" phosphorylation Ser353 DSAIDTWsPSEWQMA 9606 11259409 t lperfetto "The current studies demonstrate the identification of hnrnp-k as a jnk and erk substrate. The phosphoacceptor sites for jnk and erk on the k protein are different, and indeed, erk phosphorylation results in biological consequences different from those of phosphorylation by jnk (49). Whereas erk phosphorylation on aa 284 and 353 contributes to k protein nuclear export and concomitant inhibition of rna translation (49), phosphorylation by k protein on aa 216 and 353 increases the transcriptional effects of the k protein." SIGNOR-105251 PRKACG protein P22612 UNIPROT MYBPC3 protein Q14896 UNIPROT up-regulates phosphorylation Ser284 AGGGRRIsDSHEDTG 9606 BTO:0000887 20151718 t miannu "Phosphorylation of cmybp-c by pka speeds actomyosin interactions and contributes to increased cardiac contractility following _-adrenergic stimulation.7, 8 phosphorylation by pka is essential for proper cardiac function /for the human isoform, three pka sites were previously identified (ser275, ser284, and ser304) /our results indicate that pka phosphorylates up to four sites in both the murine and human m-domains including a novel site not previously described for either protein (ser307 for mouse and ser311 for human)." SIGNOR-163788 LATS1 protein O95835 UNIPROT VEPH1 protein Q14D04 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0000938 22055343 f "In the neuronal differentiation" lperfetto "Melted represses warts transcription to disrupt hippo pathway activity and specify rh5 fate wts and melt repress each other s transcription in a double negative, bistable feedback loop that directs robust expression of either rh5 or rh6 in r8" SIGNOR-177068 MASP2 protein O00187 UNIPROT C4B protein P0C0L5 UNIPROT "up-regulates activity" cleavage Arg756 KGQAGLQrALEILQE -1 17204478 t lperfetto "MASP-2 cleaves C4 releasing C4a and generating C4b, which attaches covalently to the pathogen surface upon exposure of its reactive thioester. C2 binds to C4b and is also cleaved by MASP-2 to form the C3 convertase (C4b2a)." SIGNOR-263425 8-OH-DPAT chemical CHEBI:73364 ChEBI HTR1A protein P08908 UNIPROT "up-regulates activity" "chemical activation" 10029 9550290 t miannu "Together, these data show that (i) [3H]-S 15535 is a highly selective 5-HT1A receptor ligand which labels both G-protein-coupled and uncoupled 5-HT1A receptors, (ii) antagonists, such as WAY 100,635, which yield monophasic isotherms in competition with both [3H]-agonists and [3H]-antagonists, are not sensitive to the G-protein coupling state of the receptor, but (iii) spiperone and methiothepin behaved as inverse agonists, their competition isotherms with [3H]-S 15535 being modulated in an opposite manner to those of agonists." SIGNOR-258890 48S_initiation_complex complex SIGNOR-C454 SIGNOR "60S cytosolic large ribosomal subunit" complex SIGNOR-C287 SIGNOR "up-regulates activity" binding 9606 35489072 t lperfetto "In eukaryotes, mRNA is recruited to the 43S pre-initiation complex (43S PIC), which consists of the 40S ribosomal subunit, translation initiation factors eIF1, eIF1A, eIF3, eIF5, and a ternary complex (TC) composed of eIF2, GTP and Met-tRNAiMet. 43S PIC binds to the 5′ end of the mRNA and scans along the 5′ untranslated region (5′UTR) in the 3′ direction to find the start codon (AUG) within the context of an optimal Kozak sequence. Start codon recognition stabilizes the 48S initiation complex (48S IC), initiates dissociation of eIF1, eIF1A, eIF2 and eIF5, and promotes recruitment of the 60S ribosomal subunit to form 80S IC ready to enter the elongation cycle of protein synthesis." SIGNOR-269169 AKT1 protein P31749 UNIPROT MDM2 protein Q00987 UNIPROT "up-regulates activity" phosphorylation Ser186 RQRKRHKsDSISLSF 9606 11504915 t lperfetto "Mitogen-induced activation of phosphatidylinositol 3-kinase (pi3-kinase) and its downstream target, the akt/pkb serine-threonine kinase, results in phosphorylation of mdm2 on serine 166 and serine 186. Phosphorylation on these sites is necessary for translocation of mdm2 from the cytoplasm into the nucleus.Both akt expression and serum treatment induced phosphorylation of mdm2 at ser186." SIGNOR-116274 CyclinE/CDK2 complex SIGNOR-C16 SIGNOR TICRR protein Q7Z2Z1 UNIPROT "up-regulates activity" phosphorylation Ser1001 DIGVVEEsPEKGDEI -1 21646402 t miannu " We found that Treslin also associated with TopBP1 in a Cdk-regulated manner in human cells and that Treslin was phosphorylated within a conserved Cdk consensus target sequence (on S976 in X. laevis and S1000 in humans). Recombinant human Cdk2-cyclin E also phosphorylated this residue of Treslin in vitro very effectively." SIGNOR-273600 amitriptyline chemical CHEBI:2666 ChEBI CHRM2 protein P08172 UNIPROT "down-regulates activity" "chemical inhibition" 10029 BTO:0000246 8100134 t miannu "Antagonism of the five cloned human muscarinic cholinergic receptors expressed in CHO-K1 cells by antidepressants and antihistaminics. Competition between [‘H]QNB and the antidepressant compounds (Table 1) showed that at the ml subtype the most potent drugs were amitriptyline > dothiepin > doxepin = nortriptyline; at the m2 receptor, amitriptyline > imipramine > nortriptyline = dothiepin; at the m3 recep- tor, amitriptyline > dothiepin > nortriptyline; at the m4 receptor, amitriptyline > dothiepin > doxepin = nortrip- tyline; and at the m5 receptor, amitriptyline > doxepin > imipramine." SIGNOR-258700 MAPK3 protein P27361 UNIPROT POLR2A protein P24928 UNIPROT down-regulates phosphorylation Ser1647 SPSYSPTsPSYSPTS 9606 14662762 t lperfetto "Erk1/2 are major ser-5 kinases after h2o2 treatment. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination." SIGNOR-120180 SLITRK5 protein O94991 UNIPROT SHH protein Q15465 UNIPROT "down-regulates activity" binding 10090 BTO:0001593 34326333 t miannu "SLITRK5 interacts with SHH and PTCH1. Mechanistically, SLITRK5 binds to hedgehog ligands via its extracellular domain and interacts with PTCH1 via its intracellular domain. SLITRK5 is present in the primary cilium, and loss of SLITRK5 enhances SMO ciliary enrichment upon SHH stimulation. Thus, SLITRK5 is a negative regulator of hedgehog signaling in osteoblasts that may be attractive as a therapeutic target to enhance bone formation." SIGNOR-268437 KLF10 protein Q13118 UNIPROT TGFBI protein Q15582 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000007 18359287 t lperfetto "Analyzing the mechanism of TGFBI up-regulation in clear cell carcinoma, we identified a novel VHL target, a Kruppel-like transcriptional factor 10 (KLF10). The TGFBI promoter, which we isolated and studied in Luc-reporter assay, was induced by KLF10 but not hypoxia." SIGNOR-253212 NDUFV2 protein P19404 UNIPROT "Mitochondrial respiratory chain complex I" complex SIGNOR-C277 SIGNOR "form complex" binding 30030361 t lperfetto "Thus, we now know the complete mammalian cI structure [22,23] and how the subunits are organized in six modules (N, Q, ND1, ND2, ND4 and ND5)The N-module, which is the tip of the hydrophilic arm and the last one to be incorporated [30,35], results from the assembly of NDUFV1, NDUFV2, NDUFS1 and NDUFA2 [34], to which NDUFA6, NDUFA7, NDUFA12, NDUFS4, NDUFS6 and NDUFV3 must be further associated with to complete the module [24]." SIGNOR-262184 "Vps34 Complex II" complex SIGNOR-C241 SIGNOR Autophagy phenotype SIGNOR-PH31 SIGNOR up-regulates 30397185 f lperfetto "PtdIns3P recruits specific recognition modules that are common in protein-sorting pathways, such as autophagy and endocytic sorting. It is best characterized in two heterotetramers, complexes I and II. Complex I is composed of VPS34, VPS15, Beclin 1, and autophagy-related gene (ATG)14L, whereas complex II replaces ATG14L with UVRAG. |Complexes I and II are critical for early events in autophagy and endocytic sorting, respectively." SIGNOR-260326 ZRSR2/U2AF2 complex SIGNOR-C81 SIGNOR Spliceosomal_snRNP_assembly phenotype SIGNOR-PH79 SIGNOR up-regulates 9606 11739736 f miannu "The essential splicing factor U2AF (U2 auxiliary factor) is a heterodimer composed of 65-kDa (U2AF(65)) and 35-kDa (U2AF(35)) subunits. U2AF(35) has multiple functions in pre-mRNA splicing. First, U2AF(35) has been shown to function by directly interacting with the AG at the 3' splice site. Second, U2AF(35) is thought to play a role in the recruitment of U2AF(65) by serine-arginine-rich (SR) proteins in enhancer-dependent splicing." SIGNOR-263946 EIF3M protein Q7L2H7 UNIPROT EIF3_complex complex SIGNOR-C401 SIGNOR "form complex" binding -1 16920360 t miannu "Consistent with its diverse functions, eIF3 is the largest and most complex initiation factor: the mammalian version, for example, contains 13 nonidentical subunits that are designated eIF3a to eIF3m 8, 9, 10, 11, 12, 13 (Table 1)." SIGNOR-266388 LPAR1 protein Q92633 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates binding 9606 12393875 t gcesareni "We conclude that lpa(1) receptors couple to a g(i)-phosphoinositide 3-kinase-tiam1 pathway to activate rac." SIGNOR-94635 CTDSP1 protein Q9GZU7 UNIPROT POLR2A protein P24928 UNIPROT "up-regulates activity" dephosphorylation Ser1721 SPTSPSYsPTSPSYS -1 22137580 t "Phosphorylation and dephosphorylation of the C-terminal domain (CTD) of RNA polymerase II (Pol II) represent a critical regulatory checkpoint for transcription. Transcription initiation requires Fcp1/Scp1-mediated dephosphorylation of phospho-CTD. | This combined structure-function analysis discloses the residues in Scp1 involved in CTD binding and its preferential dephosphorylation of P.Ser5 of the CTD heptad repeat." SIGNOR-248787 SMURF1 protein Q9HCE7 UNIPROT OTUD6B protein Q8N6M0 UNIPROT unknown ubiquitination -1 20804422 t miannu "Recombinant proteins were used to profile substrate ubiquitination by the Smurf1 ubiquitin ligase on a global scale using protein microarrays. T Proteins ubiquitinated on the protein microarray were confirmed as potential substrates of the Smurf1 activity using an off chip in vitro ubiquitination assay." SIGNOR-272687 CDK5 protein Q00535 UNIPROT PPP1R1A protein Q13522 UNIPROT unknown phosphorylation Ser67 LKSTLAMsPRQRKKM 10116 11278334 t lperfetto "In vitro and in vivo studies indicated that phospho-Ser-67 inhibitor-1 was dephosphorylated by protein phosphatases-2A and -2B. | However, inhibitor-1 phosphorylated at Ser-67 was a less efficient substrate for cAMP-dependent protein kinase. These results demonstrate regulation of a Cdk5-dependent phosphorylation site in inhibitor-1 and suggest a role for this site in modulating the amplitude of signal transduction events that involve cAMP-dependent protein kinase activation." SIGNOR-249194 SIRT1 protein Q96EB6 UNIPROT NOTCH1 protein P46531 UNIPROT down-regulates deacetylation 9606 22223095 t gcesareni "The acetylation marks on notch1-icd are removed by the deacetylase sirt1, suggesting that both deacetylation of notch1-icd and of histones inhibit notch signaling." SIGNOR-195333 ABL1 protein P00519 UNIPROT RBM39 protein Q14498 UNIPROT "up-regulates activity" phosphorylation Tyr95 DRRFRGRyRSPYSGP 9606 BTO:0000007 27018250 t miannu "In this paper, we report that RBM39 interacts with the nonreceptor tyrosine kinase c-Abl. Both the Src homology (SH) 2 and SH3 domains of c-Abl interact with RBM39. The major tyrosine phosphorylation sites on RBM39 that are phosphorylated by c-Abl are Y95 and Y99, as demonstrated by liquid chromatography coupled with tandem mass spectrometry (LC/MS/MS) and mutational analysis. c-Abl was shown boost the transcriptional coactivation activity of RBM39 for ERα and PRβ in a tyrosine kinase-dependent manner." SIGNOR-262609 OXGR1 protein Q96P68 UNIPROT GNAL protein P38405 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-256913 TWIST1 protein Q15672 UNIPROT SRPX protein P78539 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0004828 19051271 f miannu "we performed microarray analysis to compare the gene expression profiles in HGC-27 cells, with or without small interfering RNA (siRNA)-mediated depletion of TWIST. Our results showed that NF1, RAP1A, SRPX, RBL2, PFDN4, ILK, F2R, ERBB3, and MYB were up-regulated, whereas AKR1C2, FOS, GDF15, NR2F1, ATM, and CTPS were down-regulated after TWIST depletion" SIGNOR-255534 "sorafenib tosylate" chemical CHEBI:50928 ChEBI KIT protein P10721 UNIPROT "down-regulates activity" "chemical inhibition" -1 16757355 t miannu "Further characterization of sorafenib revealed that this molecule was a multikinase inhibitor that targeted the vascular endothelial growth factor receptor family (VEGFR-2 and VEGFR-3) and platelet-derived growth factor receptor family (PDGFR-beta and Kit), which play key roles in tumor progression and angiogenesis. The in vitro and cellular profile of sorafenib is summarized in Table I." SIGNOR-259226 MC5R protein P33032 UNIPROT GNA12 protein Q03113 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257441 AKT1 protein P31749 UNIPROT FOXO3 protein O43524 UNIPROT "down-regulates activity" phosphorylation Ser253 APRRRAVsMDNSNKY 9606 19188143 t lperfetto "Akt-dependent phosphorylation of foxo3a (thr32, ser253, and ser315 for human foxo3) enhances foxo3a/14?3?3 Interaction and promotes foxo3a nuclear export to the cytoplasm, resulting in the repression of foxo3a transcriptional function" SIGNOR-252522 PLK3 protein Q9H4B4 UNIPROT PTEN protein P60484 UNIPROT "down-regulates activity" phosphorylation Thr366 ASSSTSVtPDVSDNE 9606 20940307 t gcesareni "Plk3 phosphorylates pten on thr-366 and ser-370. Plk3-mediated phosphorylation facilitates pten stabilization, thereby negatively regulating the pi3k/pdk1/akt1 signaling axis" SIGNOR-168473 RPS6KA5 protein O75582 UNIPROT EIF4EBP1 protein Q13541 UNIPROT "down-regulates activity" phosphorylation Thr37 PPGDYSTtPGGTLFS 12213813 t lperfetto "In response to UV-B irradiation, the translation factor 4E-BP1 (eukaryotic initiation factor 4E [eIF4E]-binding protein 1) was phosphorylated at Thr36, Thr45, Ser64 and Thr69. Using either p38 MAPK inhibitors or the MSK inhibitor H89, UV-B-irradiation-induced phosphorylation was blocked [43]. 4E-BP1 binds to eIF4E in resting cells to prevent formation of a functional eIF4F complex, which is essential for cap-dependent initiation of translation. Phosphorylation of 4E-BP1 leads to dissociation from eIF4E" SIGNOR-262991 AURKB protein Q96GD4 UNIPROT ZWINT protein O95229 UNIPROT "up-regulates activity" phosphorylation Thr251 TRPQEQStGDTMGRD -1 21775627 t lperfetto "Zwint-1 is a novel Aurora B substrate required for the assembly of a dynein-binding platform on kinetochores|During prometaphase, AurB phosphorylation of zwint-1 is required for recruitment of ZW10-, pT89 dynein-, and RZZ-dependent proteins to kinetochores. This is defective after AurB inhibition or after expression of the triple-A zwint-1 mutant. Triple-E mutant zwint-1 mimics phospho–zwint-1 in RZZ recruitment, even after AurB inhibition" SIGNOR-265010 AKT1 protein P31749 UNIPROT FANCA protein O15360 UNIPROT unknown phosphorylation Ser1149 CLRSRDPsLMVDFIL -1 11855836 t "FANCA is phosphorylated at Ser1149 by Akt. The biological significance of FANCA phosphorylation and its regulation by Akt remains unclear at this time." SIGNOR-252567 PIP4K2A protein P48426 UNIPROT "1-phosphatidyl-1D-myo-inositol 4,5-bisphosphate(5-)" smallmolecule CHEBI:58456 ChEBI "up-regulates quantity" "chemical modification" 9606 9367159 t Gianni "The enzymes that produce PtdIns-4,5-P2 in vitro fall into two related subfamilies (type I and type II PtdInsP-5-OH kinases, or PIP(5)Ks) based on their enzymatic properties and sequence similarities'. Here we have reinvestigated the substrate specificities of these enzymes. As expected, the type I enzyme phosphorylates PtdIns-4-P at the D-5 position of the inositol ring. Surprisingly, the type II enzyme, which is abundant in some tissues, phosphorylates PtdIns-5-P at the D-4 position, and thus should be considered as a 4-OH kinase, or PIP(4)K" SIGNOR-268864 CCNB1 protein P14635 UNIPROT CyclinB/CDK1 complex SIGNOR-C17 SIGNOR "form complex" binding 9606 25603287 t lperfetto "The central mitotic kinase, cyclin-dependent kinase-1 (human cdk1 is present through all stages of the cell cycle, but its activity is cell-cycle regulated by phosphorylation/dephosphorylation and cyclin binding.Cdk1-cyclin b phosphorylates ser/thr residues directly preceding pro; thus, it is classified as a proline-directed kinase." SIGNOR-205590 UBE2I protein P63279 UNIPROT FOS protein P01100 UNIPROT "down-regulates activity" sumoylation Lys265 SISSMELkTEPFDDF 9606 SIGNOR-C154 16055711 t lperfetto "We report here that lysine 265 of c-Fos is conjugated by the peptidic posttranslational modifiers SUMO-1, SUMO-2, and SUMO-3 and that c-Jun can be sumoylated on lysine 257 as well as on the previously described lysine 229. Sumoylation of c-Fos preferentially occurs in the context of c-Jun/c-Fos heterodimers.|Inhibition of c-Fos and c-Jun sumoylation stimulates AP-1-dependent transcription activity." SIGNOR-263013 trimipramine chemical CHEBI:9738 ChEBI SLC6A2 protein P23975 UNIPROT "down-regulates activity" "chemical inhibition" 9606 9537821 t miannu "At the human norepinephrine transporter, among the antidepressants desipramine was the most potent with a KD=0.83±0.05 nM. All the tetracyclic antidepressants, except mirtazapine, which is a structural analog of mianserin, were more potent at the norepinephrine transporter than at the serotonin transporter. Tomoxetine, considered from animal data to be very selective for the norepinephrine transporter, had high affinity for the human norepinephrine transporter (KD=2.03±0.06 nM). However, at the human serotonin transporter, tomoxetine was nearly as potent and close to that for dothiepin and venlafaxine. Venlafaxine, considered a serotonin and norepinephrine re-uptake inhibitor based on animal data, was very weak at the human norepinephrine transporter. Its KD value was 5× less that than for norepinephrine. All of the serotonin selective re-uptake inhibitors, with the exception of paroxetine, were also weak at the human norepinephrine transporter. " SIGNOR-258742 IKBKE protein Q14164 UNIPROT TRAF3IP2 protein O43734 UNIPROT "up-regulates activity" phosphorylation Ser328 KVILNYPsPWDHEER 9606 21822257 t miannu "IKKi was required for IL-17-induced phosphorylation of Act1 on Ser311, adjacent to a putative TRAF-binding motif. Substitution of the serine at position 311 with alanine impaired the IL-17-mediated Act1-TRAF2-TRAF5 interaction and gene expression. Thus, IKKi is a kinase newly identified as modulating IL-17 signaling through its effect on Act1 phosphorylation and consequent function." SIGNOR-262883 CSNK2A1 protein P68400 UNIPROT ESR1 protein P03372 UNIPROT down-regulates phosphorylation Ser282 EGRGEVGsAGDMRAA 9606 BTO:0000150;BTO:0000567 20043841 t lperfetto "Additionally protein kinase ck2 was identified as a kinase that phosphorylated eralpha at s282 and s559 s282 and s559 represent the second and third sites of er_ regulation by ck2. Remarkably, mutation of s282 or s559 to alanine resulted in near opposite functional effects on er_ as compared to mutation of s167 to alanine. Er_ ligand independent transcriptional activity was markedly enhanced upon mutation of s282 and s559 to alanine" SIGNOR-162653 ZIC1 protein Q15915 UNIPROT GLI1 protein P08151 UNIPROT up-regulates relocalization 9606 11238441 t lperfetto "Co-expression of zic1 resulted in gli1 and gli3 proteins being translocated to the nucleus in varying levels" SIGNOR-105491 MMP19 protein Q99542 UNIPROT ACAN protein P16112 UNIPROT "down-regulates quantity by destabilization" cleavage Asn360 DFVDIPEnFFGVGGE -1 10922468 t lperfetto "Matrix metalloproteinases 19 and 20 cleave aggrecan and cartilage oligomeric matrix protein (COMP)|In this study we investigated the ability of MMP-19 and MMP-20 to cleave two of the macromolecules characterising the cartilage ECM, namely aggrecan and the cartilage oligomeric matrix protein (COMP). Both MMPs hydrolysed aggrecan efficiently at the well-described MMP cleavage site between residues Asn(341) and Phe(342), as shown by Western blotting using neo-epitope antibodies. Furthermore, the two enzymes cleaved COMP in a distinctive manner, generating a major proteolytic product of 60 kDa. Our results suggest that MMP-19 may participate in the degradation of aggrecan and COMP in arthritic disease, whereas MMP-20, due to its unique expression pattern, may primarily be involved in the turnover of these molecules during tooth development." SIGNOR-266978 SATB1 protein Q01826 UNIPROT MYC protein P01106 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0000725 23563689 f miannu "Satb1 simultaneously repressed sets of genes encoding molecules involved in HSC activation and cellular polarity, including Numb and Myc" SIGNOR-224831 SOX4 protein Q06945 UNIPROT Differentiation phenotype SIGNOR-PH37 SIGNOR down-regulates 9606 BTO:0001271 24183681 f apalma "Collectively, our experiments identified the oncogene Sox4 as a factor mediating increased serial-replating ability and blocked differentiation of Cebpa-deficient progenitors." SIGNOR-255676 RUNX2 protein Q13950 UNIPROT SP7 protein Q8TDD2 UNIPROT up-regulates "transcriptional regulation" 10090 16574347 f "Giulio Giuliani" "Osx promoter activity was up-regulated by 2 fold after Runx2 over-expression in ATDC5 cells. Osx Is Phosphorylated by p38 at Ser-73 and Ser-77" SIGNOR-255410 INSR protein P06213 UNIPROT PIK3R1 protein P27986 UNIPROT "up-regulates activity" phosphorylation Tyr580 LRKTRDQyLMWLTQK 9534 BTO:0000298 8385099 t "The alpha-type 85-kDa subunit of phosphatidylinositol 3-kinase is phosphorylated at tyrosines 368, 580, and 607 by the insulin receptor." SIGNOR-251321 HSP90AB1 protein P08238 UNIPROT APAF1 protein O14727 UNIPROT down-regulates binding 9606 10944114 t gcesareni "The present studies demonstrate that heat shock protein 90 (hsp90) forms a cytosolic complex with apaf-1 and thereby inhibits the formation of the active complex." SIGNOR-81043 MAPK8 protein P45983 UNIPROT MAPK8IP1 protein Q9UQF2 UNIPROT unknown phosphorylation Thr205 PLKTGEQtPPHEHIC 9534 BTO:0000298 12756254 t miannu "After mapping JNK-dependent JIP1 phosphorylation sites and testing their functional significance, it was observed that phosphorylation by JNK of JIP1 on Thr-103 and not other phosphorylated JIP1 residues is necessary for the regulation of DLK association with JIP1, DLK activation, and subsequent module activation. The data presented corroborates our previous observations using endogenous proteins, demonstrates that JNK binding to JIP1 is necessary for module activation, and shows that activation of JIP1-JNK module dynamics requires phosphorylation of JIP1 on Thr-103 by JNK. and Thr-205 are phosphorylated directly by JNK after JNK binds to JIP1." SIGNOR-250127 prazosin chemical CHEBI:8364 ChEBI ADRA1A protein P35348 UNIPROT "down-regulates activity" "chemical inhibition" 10029 BTO:0000246 7651358 t miannu "Membrane preparations from CHO cells stably transfected with the cloned human a1-AR genes showed saturable binding of [‘251]HEAT; Bm,,ı values were 1.3 ± 0.2, 5.5 ± 0.1, and 1.1 ± 0.1 pmol/mg of protein, with Kd values of 110 ± 21, 60 ± 1, and 300 ± 26 ıM (three experiments each), for the ala-, alb-, and ald-ARS, respectively. The potencies of a1-AR agonists and antagonists at the cloned human a1-ARs are shown in Table 1." SIGNOR-258473 pictrelisib chemical CHEBI:65326 ChEBI PIK3CA protein P42336 UNIPROT "down-regulates activity" "chemical inhibition" -1 22037378 t Luana "Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here." SIGNOR-258113 GGCX protein P38435 UNIPROT F10 protein P00742 UNIPROT "up-regulates activity" carboxylation 9606 31226734 t lperfetto "Thus, vitamin K acts as a cofactor for GGCX via the vitamin K cycle and exerts physiological effects through its regulation of VKDPs [29]. More than 20 VKDPs have been found. Osteocalcin promotes bone formation, and blood coagulation factors II, VII, IX, and X activate blood coagulation. Matrix Gla protein suppresses cardiovascular calcification, and brain-expressed Gas 6 promotes neural differentiation [29]. GGCX is an enzyme that converts glutamic acid (Glu) residues to Gla residues, so that the Gla-containing proteins can exert various physiological actions such as blood coagulation and bone formation." SIGNOR-265921 NDUFS4 protein O43181 UNIPROT "Mitochondrial respiratory chain complex I" complex SIGNOR-C277 SIGNOR "form complex" binding 30030361 t lperfetto "Thus, we now know the complete mammalian cI structure [22,23] and how the subunits are organized in six modules (N, Q, ND1, ND2, ND4 and ND5)The N-module, which is the tip of the hydrophilic arm and the last one to be incorporated [30,35], results from the assembly of NDUFV1, NDUFV2, NDUFS1 and NDUFA2 [34], to which NDUFA6, NDUFA7, NDUFA12, NDUFS4, NDUFS6 and NDUFV3 must be further associated with to complete the module [24]." SIGNOR-262178 ponatinib chemical CHEBI:78543 ChEBI RET protein P07949 UNIPROT "down-regulates activity" "chemical inhibition" 9606 BTO:0001271;BTO:0000184 23526464 t miannu "The RET tyrosine kinase encoding gene acts as a dominantly transforming oncogene in thyroid carcinoma and other malignancies. Ponatinib (AP24534) is an oral ATP-competitive tyrosine kinase inhibitor that is in advanced clinical experimentation in leukemia.Ponatinib is a potent inhibitor of RET kinase and has promising preclinical activity in models of RET-driven medullary thyroid carcinoma." SIGNOR-259275 GATA6 protein Q92908 UNIPROT RARB protein P10826 UNIPROT "up-regulates quantity by expression" 9606 BTO:0000195 24317510 f lperfetto "Many GATA6-dependent genes lacked nearby binding sites but several strongly dependent, synexpressed and GATA6-bound genes encode TFs such as MYC, HES1, RARB and CDX2." SIGNOR-253154 RPS6KA1 protein Q15418 UNIPROT PPP1R3A protein Q16821 UNIPROT "up-regulates activity" phosphorylation Ser46 PQPSRRGsDSSEDIY -1 10648825 t lperfetto "The protein G(M), which targets protein phosphatase 1 (PP1) to the glycogen particles and sarcoplasmic reticulum (SR) of striated muscles, is known to be phosphorylated at Ser48 and Ser67 in vitro by adenosine 3',5' cyclic monophosphate-dependent protein kinase (PKA) and at Ser48 by MAP kinase-activated protein kinase-1 (MAPKAP-K1, also called p90 RSK). The phosphorylation of Ser48 increases the rate at which the glycogen-associated PP1.G(M) complex dephosphorylates (activates) glycogen synthase, but the phosphorylation of Ser67 has the opposite effect, suppressing the activity of PP1 toward glycogen-bound substrates. " SIGNOR-249036 venlafaxine chemical CHEBI:9943 ChEBI SLC6A4 protein P31645 UNIPROT "down-regulates activity" "chemical inhibition" 9606 20378347 t Luana "The cycloalkanol ethylamine scaffold was successfully utilized in the discovery and development of dual serotonin (5-HT)/norepinephrine (NE) reuptake inhibitors (SNRIs).1 Drugs such as venlafaxine (1) and duloxetine (2) possessing norepinephrine reuptake inhibition, either selectively or in combination with serotonin reuptake inhibition were approved for major depressive disorder (MDD)." SIGNOR-257836 L-aspartate(1-) smallmolecule CHEBI:29991 ChEBI N-carbamoyl-L-aspartate(2-) smallmolecule CHEBI:32814 ChEBI "up-regulates quantity" "precursor of" 9606 28552578 t miannu "CAD is a 243 kDa polypeptide formed by the fusion of four enzymatic domains that initiate the de novo biosynthesis of pyrimidine nucleotides . The first two domains, glutaminase (GLN) and carbamoyl phosphate synthetase (CPS-II), initiate the pathway, catalyzing the formation of carbamoyl phosphate (CP) from bicarbonate, glutamine, and two ATP molecules. Next, the labile CP is partially channeled to the C-terminal aspartate transcarbamoylase (ATC) domain where it reacts with aspartate to form carbamoyl aspartate. Then, carbamoyl aspartate is condensated to dihydroorotate, the cyclic precursor of the pyrimidine ring, by the dihydroorotase (DHO), a Zn metalloenzyme fused between CPS and ATC domains." SIGNOR-267423 T_cell_activation phenotype SIGNOR-PH73 SIGNOR IFNG protein P01579 UNIPROT "up-regulates quantity" 9606 10653850 f miannu "IL-12 Synergizes With IL-18 or IL-1beta for IFN-gamma Production From Human T Cells. IL-12 and IL-18 acted in a synergistic manner for the development of T cells into IFN-γ-producing cells without their TCR. Here we show that IL-12 and IL-1beta synergistically induce T cells to proliferate and produce IFN-gamma without their TCR engagement. IL-12 stimulation induced an increase in the proportion of T cells positive for IL-18R engagement." SIGNOR-260967 CUL3 protein Q13618 UNIPROT ARIH1 protein Q9Y4X5 UNIPROT "up-regulates activity" binding 9606 BTO:0000007 24076655 t miannu "Here, we provide evidence that Ariadne RBR E3 ubiquitin ligases such as TRIAD1 and HHARI can bind and be activated by CRL complexes. Whereas TRIAD1 specifically associates with CUL5–RBX2, HHARI is more promiscuous towards cullin types and associates with RBX1-associated cullins 1, 2, 3, and 4A. Interestingly, both TRIAD1 and HHARI show a strong preference for binding the neddylated form of the cullin. Our data suggest a novel function of NEDD8 in directing specific CRLs to Ariadne RBR ligases, which in turn exert influence on the levels of their cognate neddylated cullin." SIGNOR-268846 ZNF318 protein Q5VUA4 UNIPROT AR protein P10275 UNIPROT "down-regulates activity" binding 9606 16469430 t Monia "Using different promoters and cells, we confirmed that AR-mediated transactivation was repressed by TZF in a dose-dependent manner (Fig. 1A and B). Endogenous ARmediated transactivation was also inhibited by expression of TZF; These results indicate that amino acid residues 512–663 are essential for the repressive effect of TZF on AR-mediated transactivation." SIGNOR-261187 MYC protein P01106 UNIPROT MYCBP2 protein O75592 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0001321 32814769 t miannu "We identified several E3 ligases as strong candidates responsible for AR and MYC protein loss as HECTD4, MYCBP2, and TRIM49. HECTD4 and MYCBP2 target AR and MYC for degradation while TRIM49 appears to promote AR and MYC stability. We have shown that these E3 ligases in turn are directly regulated by MYC. MYC in turn represses the expression of ubiquitin ligases, HECTD4 and MYCBP2 that promote AR and MYC protein degradation, further suppressing MYC and AR in a feed forward loop." SIGNOR-267145 "Complement C1q" complex SIGNOR-C308 SIGNOR "Complement C1 complex" complex SIGNOR-C309 SIGNOR "form complex" binding -1 29449492 t lperfetto "The complement system is part of our innate immune system. The classical complement pathway is triggered by activation of the C1 initiation complex upon binding to cell surfaces. C1, or C1qr2s2, consists of four proteases, C1r and C1s, that associate with C1q, which contains antibody-binding sites.|The reconstruction reveals densities for all C1q collagen-like triple helices and gC1q modules, C1r and C1s proteases" SIGNOR-263396 TEK protein Q02763 UNIPROT MYH2 protein Q9UKX2 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 BTO:0000222 26042050 f lperfetto "the effects of the angiopoietins are not specific for vascular endothelial cells, as their receptors (Tie1, Tie2) are known to be expressed in hematopoietic cells and they have also recently been shown to be expressed in skeletal muscle cellsExogenous Ang-1 enhanced myogenic (MyoD and Myogenin) mRNA in differentiating myoblasts and increased myosin heavy chain protein." SIGNOR-241538 TNF protein P01375 UNIPROT TNFRSF1A protein P19438 UNIPROT "up-regulates activity" binding 9606 14732063 t miannu "Tumour necrosis factor (TNF) exerts two main effects: a beneficial one as an anti-infection, anti-tumour cytokine, and a detrimental one in the systemic inflammatory response syndrome (SIRS). Two receptors (TNF-R) mediate these effects. two distinct types of TNF-Rs have been identified and molecularly cloned: TNF-R55 (also referred to as TNFR1, p55 or CD120a) and TNF-R75 (also called TNFR2, p75 or CD120b)" SIGNOR-253593 FGFR1 protein P11362 UNIPROT FGFR1 protein P11362 UNIPROT up-regulates phosphorylation Tyr154 NRMPVAPyWTSPEKM 9606 8443592 t lperfetto "Tyrosine residues 154 and 307, which are in the extracellular domain of transmembrane receptor isoforms and are in an unusual sequence context for tyrosine phosphorylation, were also phosphorylated." SIGNOR-98622 MAP2K7 protein O14733 UNIPROT MAPK9 protein P45984 UNIPROT up-regulates phosphorylation Tyr185 TNFMMTPyVVTRYYR 9606 11062067 t lperfetto "In the present study, we found that mkk7 phosphorylates sapk2a/p38 exclusively at tyr-182, albeit at a low rate. Therefore one possibility is that the interaction of mkk7 and/or sapk1/jnk with another cellular protein alters the conformation of one of these enzymes in such a way as to facilitate phosphorylation of tyr-185 by mkk7 in vivo." SIGNOR-83748 LCK protein P06239 UNIPROT DEF6 protein Q9H4E7 UNIPROT "up-regulates activity" phosphorylation Tyr133 NFLSEDKyPLIMVPD 9606 18976935 t lperfetto "Here, we report that the T cell receptor (TCR)-induced translocation of SLAT to the immunological synapse required Lck-mediated phosphorylation of two tyrosine residues located in an immunoreceptor tyrosine-based activation motif-like sequence but was independent of the SLAT PH domain. This subcellular relocalization was coupled to, and necessary for, activation of the NFAT pathway|These results indicate that SLAT undergoes Lck-dependent phosphorylation on Tyr-144 and Tyr-133 upon TCR and CD28 stimulation." SIGNOR-253367 "1-phosphatidyl-1D-myo-inositol 4,5-bisphosphate" smallmolecule CHEBI:18348 ChEBI "1D-myo-inositol 1,4,5-trisphosphate" smallmolecule CHEBI:16595 ChEBI "up-regulates quantity" "precursor of" 9606 23000145 t scontino "Upon stimulation with various immune receptors, PLCγ2 cleaves the membrane-bound phospholipid phosphatidyl inositol-4, 5-biphosphate (PIP2) into the second messenger molecules inositol-1,4,5-trisphosphate (IP3) and diacylglycerol (DAG)." SIGNOR-268450 CyclinK/CDK13 complex SIGNOR-C38 SIGNOR POLR2A protein P24928 UNIPROT "up-regulates activity" phosphorylation Ser1651 SPTSPSYsPTSPSYS 9606 BTO:0006413 32917631 t "Ser2 in CTD of PolII" lperfetto "Together, these studies demonstrate the important, yet largely redundant, role for CDK12 and CDK13 for the regulation of POLII CTD phosphorylation at multiple residues, as well as the global role for both of these kinases in regulating POLII occupancy across the genome.|CDK12 and CDK13 are thus evolutionarily related and structurally similar kinases, and biochemical assays have demonstrated that both have POLII C-terminal domain (CTD) kinase activity and the ability to phosphorylate the Ser2 residue of the repetitive CTD heptad sequence" SIGNOR-273065 MAPK1 protein P28482 UNIPROT POLR2A protein P24928 UNIPROT down-regulates phosphorylation Ser1717 SPSYSPTsPSYSPTS 9606 14662762 t lperfetto "Erk1/2 are major ser-5 kinases after h2o2 treatment. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination." SIGNOR-120108 CyclinK/CDK13 complex SIGNOR-C38 SIGNOR POLR2A protein P24928 UNIPROT "up-regulates activity" phosphorylation Ser1665 SPTSPSYsPTSPSYS 9606 BTO:0006413 32917631 t "Ser2 in CTD of PolII" lperfetto "Together, these studies demonstrate the important, yet largely redundant, role for CDK12 and CDK13 for the regulation of POLII CTD phosphorylation at multiple residues, as well as the global role for both of these kinases in regulating POLII occupancy across the genome.|CDK12 and CDK13 are thus evolutionarily related and structurally similar kinases, and biochemical assays have demonstrated that both have POLII C-terminal domain (CTD) kinase activity and the ability to phosphorylate the Ser2 residue of the repetitive CTD heptad sequence" SIGNOR-273066 SEC13 protein P55735 UNIPROT GATOR2 complex SIGNOR-C193 SIGNOR "form complex" binding 9606 23723239 t miannu "Here, we identify GATOR as a complex that interacts with the Rags and is composed of two subcomplexes we call GATOR1 and 2. Inhibition of GATOR1 subunits (DEPDC5, Nprl2, and Nprl3) makes mTORC1 signaling resistant to amino acid deprivation. In contrast, inhibition of GATOR2 subunits (Mios, WDR24, WDR59, Seh1L, Sec13) suppresses mTORC1 signaling and epistasis analysis shows that GATOR2 negatively regulates DEPDC5" SIGNOR-255305 RPN1 protein P04843 UNIPROT OPRM1 protein P35372 UNIPROT up-regulates binding 9606 19289571 t miannu "Ribophorin i (rpni), a component of the oligosaccharide transferase complex, could directly interact with mor. Rpni can be shown to participate in mor export by the intracellular retention of the receptor after small interfering rna knockdown of endogenous rpni." SIGNOR-184651 GLI2 protein P10070 UNIPROT HHIP protein Q96QV1 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 BTO:0002572 16571352 f lperfetto "Primary mouse embryonic fibroblasts responded to Shh stimulation with the induction of Hh target genes Gli1, Ptc1, and Hip1.These observations support the previously advanced notion of a functional redundancy or cooperativity between Gli2 and Gli1 in activation of target genes [18] and [43] and indicate a functional cooperation between Gli3 and Gli1." SIGNOR-209635 FOXO proteinfamily SIGNOR-PF27 SIGNOR FBXO32 protein Q969P5 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 BTO:0000165 15109499 t "The activity of the PI3K/AKT pathway decreases, leading to activation of Foxo transcription factors and atrogin-1 induction. IGF-1 treatment or AKT overexpression inhibits Foxo and atrogin-1 expression." SIGNOR-252926 PCDHA10 protein Q9Y5I2 UNIPROT PCDHGB3 protein Q9Y5G1 UNIPROT "up-regulates activity" binding 9606 BTO:0000227 16697637 t miannu "The clustered protocadherins comprise the largest subfamily of the cadherin superfamily and are predominantly expressed in the nervous system. Pcdh-alpha proteins interact with beta1-integrin to promote cell adhesion. They also form oligomers with Pcdh-gamma proteins at the same membrane sites." SIGNOR-265707 TFIIH complex SIGNOR-C457 SIGNOR E2F1 protein Q01094 UNIPROT down-regulates phosphorylation Ser403 PEEFISLsPPHEALD 9606 10428966 t lperfetto "These results suggest that tfiih-mediated phosphorylation of e2f-1 plays a role in triggering e2f-1 degradation during s phase.  here we show that the e2f-1 activation domain interacts with a kinase activity which phosphorylates two sites, ser403 and thr433, within the activation domain." SIGNOR-269353 "eribulin mesylate" chemical CHEBI:70710 ChEBI Tubulin proteinfamily SIGNOR-PF46 SIGNOR "down-regulates activity" "chemical inhibition" 9606 16940412 t miannu "The complex marine natural product halichondrin B was compared with NSC 707389 (E7389), a structurally simplified, synthetic macrocyclic ketone analog, which has been selected for clinical trials in human patients. NSC 707389 was invariably more potent than halichondrin B in its interactions with tubulin. Both compounds inhibited tubulin assembly, inhibited nucleotide exchange on beta-tubulin, and were noncompetitive inhibitors of the binding of radiolabeled vinblastine and dolastatin 10 to tubulin." SIGNOR-259444 oxymetazoline chemical CHEBI:7862 ChEBI ADRA2A protein P08913 UNIPROT "up-regulates activity" "chemical activation" 9606 BTO:0000007 9605427 t miannu "AR agonists stimulated binding of [35S]GTPgS to HEK 293 cell membranes containing the human a2a, a2b, or a2c ARs (Fig. 6). EPI and NE were full agonists; clonidine and oxymetazoline were partial agonists, while antagonists (e.g. rauwolscine, 5 mM) did not stimulate [35S]GTPgS incorporation (Table 3). Although a few agonists showed a great deal of selectivity for a single receptor subtype, the rank order of agonist potency for selected compounds at the human receptors (Table 3) was: a2a: Dexmedetomidine . guanabenz . UK-14304 .clonidine . ST-91 . NE a2b: Dexmedetomidine . clonidine . guanabenz . NE .ST-91 . UK-14304 a2c: Dexmedetomidine . NE . UK-14304 . ST-91 $ clonidine .. guanabenz" SIGNOR-258917 PRKCB protein P05771 UNIPROT OCLN protein Q16625 UNIPROT "up-regulates activity" phosphorylation Ser340 DKRFYPEsSYKSTPV 9615 BTO:0000837 11502742 t lperfetto "Protein kinase C regulates the phosphorylation and cellular localization of occludin. Ser(338) of occludin was identified as an in vitro protein kinase C phosphorylation site using peptide mass fingerprint analysis and electrospray ionization tandem mass spectroscopy. Both the phosphorylation of occludin and its incorporation into tight junctions induced by calcium switch were markedly inhibited by the PKC inhibitor GF-109203X." SIGNOR-249106 RPS6KB1 protein P23443 UNIPROT CAD protein P27708 UNIPROT "up-regulates activity" phosphorylation Ser1859 PPRIHRAsDPGLPAE 9606 BTO:0002181 23429703 t miannu "CAD as a direct substrate of S6K1. mTORC1 signaling posttranslationally regulated this metabolic pathway via its downstream target ribosomal protein S6 kinase 1 (S6K1), which directly phosphorylates S1859 on CAD (carbamoyl-phosphate synthetase 2, aspartate transcarbamoylase, dihydroorotase), the enzyme that catalyzes the first three steps of de novo pyrimidine synthesis. The direct regulation of CAD by S6K1 serves as a mechanism to increase the pool of nucleotides available for the RNA and DNA synthesis that accompanies cell growth." SIGNOR-267443 "Cullin 3-RBX1-Skp1" complex SIGNOR-C526 SIGNOR BECN1 protein Q14457 UNIPROT "down-regulates quantity by destabilization" polyubiquitination 9606 BTO:0000007 26687681 t miannu "Cul3-KLHL20 Ubiquitin Ligase Governs the Turnover of ULK1 and VPS34 Complexes to Control Autophagy Termination. KLHL20 promotes ubiquitination of phagophore-residing VPS34 and Beclin-1" SIGNOR-272419 mir-10b mirna URS00004CAC40_9606 RNAcentral CADM2 protein Q8N3J6 UNIPROT "down-regulates quantity" destabilization 9606 25477897 t miannu "The down-regulation of miR-29b is thought to promote DNA hypermethylation in AML since miR-29b can directly target DNMT3A, DNMT3B, and Sp1 (a transcriptional regulator of DNMT2" SIGNOR-255794 SMAD1/5/8 proteinfamily SIGNOR-PF35 SIGNOR SMAD4 protein Q13485 UNIPROT up-regulates binding 9606 SIGNOR-C85 21454478 t "inferred from 70% family members" lperfetto "Upon ligand binding, the specific heteromeric transmembrane serine/threonine kinase receptor complexes undergo phosphorylation/activation and subsequently phosphorylate the two ser residues in the c-terminal sxs motif of specific r-smads, smad1/5/8 for bmp pathway and smad2/3 for tgf-_/activin signaling. The activated r-smads then associate with co-smad, smad4. The heteromeric complexes translocate into the nucleus, where they bind to dna directly or indirectly to regulate the transcription of specific genes." SIGNOR-269952 Ub:E2 complex SIGNOR-C497 SIGNOR RNF144A protein P50876 UNIPROT "up-regulates activity" ubiquitination 9606 34199813 t miannu "The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t" SIGNOR-271154 ATR protein Q13535 UNIPROT DBF4 protein Q9UBU7 UNIPROT down-regulates phosphorylation Ser539 GLITINSsQEHLTVQ 9606 22123827 t lperfetto "Dbf4/cdc7 (dbf4-dependent kinase (ddk)) is activated at the onset of s-phase, and its kinase activity is required for dna replication initiation from each origin. We identified novel atm/atr phosphorylation sites on dbf4 and showed that atm/atr-mediated phosphorylation of dbf4 is critical for the intra-s-phase checkpoint to inhibit dna replication." SIGNOR-177809 ATM protein Q13315 UNIPROT MDM4 protein O15151 UNIPROT down-regulates phosphorylation 9606 16082221 t gcesareni "Atm directly and indirectly induces mdm2 and mdmx phosphorylation, resulting in decreased activity and stability of these proteins. We recently provided a mechanism for the reduced stability of mdm2 and mdmx by showing that atm-dependent phosphorylation lowers their affinity for the deubiquitinating enzyme hausp." SIGNOR-139403 RINT1 protein Q6NUQ1 UNIPROT "NRZ complex" complex SIGNOR-C358 SIGNOR "form complex" binding 25364732 t lperfetto "NRZ complex, which comprises NAG, RINT1, and ZW10, is also involved in Golgi-to-ER retrograde transport, but each component of the complex has diverse cellular functions including endosome-to-Golgi transport, cytokinesis, cell cycle checkpoint, autophagy, and mRNA decay." SIGNOR-265025 CDH8 protein P55286 UNIPROT CTNNB1 protein P35222 UNIPROT "up-regulates activity" binding 9606 21255999 t miannu "At its C-terminus, cadherin interacts with β-catenin, which dynamically associates with α-catenin, a direct binding partner of filamentous actin" SIGNOR-265870 gamma-secretase complex SIGNOR-C98 SIGNOR NOTCH2 protein Q04721 UNIPROT "up-regulates activity" cleavage 9606 25610395 t lperfetto "The membrane-bound Notch segment that results from this cleavage, known as Notch Intracellular Truncation domain (NEXT), is a -secretase substrate (Kopan and Ilagan, 2009). -Secretase performs the subsequent cleavage at S3 (De Strooper et al., 1999), releasing Notch intracellular domain (NICD) from the membrane and allowing for signal transduction through binding with the CBL-1, Su(H), Lag-1 (CSL; Schroeter et al., 1998; Struhl and Adachi, 1998) family of DNA binding proteins." SIGNOR-209723 Mob1 proteinfamily SIGNOR-PF42 SIGNOR LATS1 protein O95835 UNIPROT up-regulates binding 9606 21084559 t "Lats1 and Lats2 are nuclear Dbf2-related (NDR) family protein kinases." gcesareni "Lats1/2 are activated by association with the highly homologous scaffold proteins mps one binder kinase activator-like 1a (mobkl1a) and 1b (mobkl1b), which are collectively referred to as mob1." SIGNOR-269958 SEC23A protein Q15436 UNIPROT "COPII vesicle" complex SIGNOR-C370 SIGNOR "form complex" binding 9606 BTO:0000567 30605680 t lperfetto "The Core Components of COPII Vesicles from HeLa Cells|Membrane-bound Sar1 then recruits the inner COPII coat subcomplex, the Sec23/24 heterodimer. Subsequently, together with cargo proteins recruited by the Sec24 subunit, Sar1 and Sec23/24 assemble into so-called pre-budding complexes. Finally, outer coat subcomplexes, comprising heterotetrameric Sec13/31 complexes, are recruited onto pre-budding complexes to complete the two-layered COPII coat" SIGNOR-265289 LAMB1 protein P07942 UNIPROT Laminin-8 complex SIGNOR-C181 SIGNOR "form complex" binding 10809728 t lperfetto "Laminins are a large family of heterotrimeric extracellular matrix glycoproteins that, in addition to having structural roles, take part in the regulation of processes such as cell migration, differentiation, and proliferation. The laminin alpha(4) chain is widely distributed both in adults and during development in tissues such as cardiac, skeletal and smooth muscle fibers, vascular endothelia, lungs, and in peripheral nerves. It can associate with laminin beta(1)/gamma(1) chains to form laminin-8 and with the beta(2)/gamma(1) chains to form laminin-9." SIGNOR-253227 PFAS protein O15067 UNIPROT "L-glutamine zwitterion" smallmolecule CHEBI:58359 ChEBI "down-regulates quantity" "chemical modification" 9606 33179964 t miannu "The first two reactions catalyzed by TGART are sequential and produce FGAR, which is then acted upon by the third enzyme in the pathway, formylglycinamidine synthase (PFAS/FGAMS).The transferred ammonia is then used to convert FGAR to FGAM. The FGAMS protein exhibits interesting biophys ical properties and will be covered later in this review. The FGAM produced by FGAMS is then converted into AIR by the AIRS domain of TGART, resulting in a five membered ring closure." SIGNOR-267310 iodide smallmolecule CHEBI:16382 ChEBI diiodine smallmolecule CHEBI:17606 ChEBI "up-regulates quantity" "precursor of" 9606 23349248 t miannu "After transport through the apical membrane, I‚àí is covalently bound to the tyrosyl residues of Tg by thyroid peroxidase (TPO)." SIGNOR-268119 EIF2AK2 protein P19525 UNIPROT EIF2AK2 protein P19525 UNIPROT up-regulates phosphorylation Thr89 VSPLLLTtTNSSEGL 9606 11152499 t tpavlidou "Taken together, these results show that pkr is autophosphorylated on serine 83 and threonines 88, 89, and 90, that this autophosphorylation may enhance kinase activation, and that the inhibition of pkr by hcv e2 is not solely due to duplication of and competition with these autophosphorylation sites." SIGNOR-85785 14-3-3 proteinfamily SIGNOR-PF7 SIGNOR GPSM3 protein Q9Y4H4 UNIPROT "up-regulates quantity by stabilization" binding 9606 BTO:0000876 phosphorylation:Ser35 STTRPWRsAPPSPPP 22843681 t lperfetto "Mutation of serine 35 completely abrogates the 14-3-3 interaction (e.g. Fig. 2, B–F), suggesting that phosphorylation of serine 35 is obligatory for 14-3-3 binding|The GPSM3/14-3-3 interaction is seen to stabilize GPSM3 from degradation and also support the nuclear exclusion of both proteins." SIGNOR-264866 ASIP protein P42127 UNIPROT MC3R protein P41968 UNIPROT "down-regulates activity" binding 9606 BTO:0000142 20371771 t lperfetto "The melanocortin (MC) receptor family consists of five Gs-coupled receptors that control various physiological functions in response to four distinct agonists, adrenocorticotropic hormone (ACTH, also known as corticotrophin) and alpha, beta, and gamma melanocyte-stimulating hormone (MSH), which are derived from the proopiomelanocortin precursor protein, and two inverse agonists, agouti and agouti-related proteins" SIGNOR-268703 JAK1 protein P23458 UNIPROT STAT1 protein P42224 UNIPROT "up-regulates activity" phosphorylation Tyr701 DGPKGTGyIKTELIS 9606 BTO:0000567 11823427 t lperfetto "The central event in cytokine_dependent transcriptional regulation is phosphorylation of STATs on a single tyrosine residue at their C_terminus (Darnell, 1997b). The reaction is catalyzed by cytokine receptor_associated tyrosine kinases of the Janus type (Jak) at the cell membrane and triggers the homo_ and heterodimerization of STAT molecules via reciprocal phosphotyrosine“SH2 domain interactions" SIGNOR-236373 PPP2CA protein P67775 UNIPROT AKT3 protein Q9Y243 UNIPROT "down-regulates activity" dephosphorylation Thr305 TDAATMKtFCGTPEY 9606 18160256 t "Overexpression of BTBD10 increased phosphorylation levels of Akts at both Thr(308) and Ser(473) while the reduction of the endogenous BTBD10 level resulted in a decrease in the phosphorylation levels of Akts. In vitro analysis indicated that BTBD10 bound to protein phosphatase 2A (PP2A) and inhibited dephosphorylation of Akts by PP2A." SIGNOR-248651 PYCARD protein Q9ULZ3 UNIPROT "Pyrin inflammasome" complex SIGNOR-C226 SIGNOR "form complex" binding 30288079 t lperfetto "Canonical inflammasomes form activation platforms for caspase-1. Their assembly depends on some dedicated cytosolic PRRs from the nucleotide-binding domain leucin-rich repeat (NLR) family including NLR and pyrin domain containing receptor 1 (NLRP1), NLRP3, and NLR and caspase recruitment domain containing receptor 4 (NLRC4); the AIM2-like receptors (ALR) family including absent in melanoma 2 (AIM2); or the tripartite motif (TRIM) family including pyrin." SIGNOR-256414 PDPK1 protein O15530 UNIPROT MAP2K2 protein P36507 UNIPROT up-regulates phosphorylation Ser226 LIDSMANsFVGTRSY 9606 15175348 t gcesareni "The identified pdk1 phosphorylation sites in mek1 and mek2 are ser222 and ser226, respectively, and are known to be essential for full activation." SIGNOR-125176 CDK1 protein P06493 UNIPROT OSBP2 protein Q969R2 UNIPROT "up-regulates activity" phosphorylation 30925160 t lperfetto "CK1a1, JNK1 and CDK1 had the highest site-specific activity for ORP4L, while CDK1, GSK3a, CK1a1 and GSK3b showed the highest specificity for the site when corrected for background activity with ORP4L-S4A. Because of the complexity of the serine/proline-rich site, we did not determine which serine(s) in ORP4L were phosphorylated by candidate kinases.|We conclude that phosphorylation of a unique serine/proline motif in the ORD induces a conformation change in ORP4L that enhances interaction with vimentin and cholesterol extraction from membranes." SIGNOR-264878 MMP7 protein P09237 UNIPROT SPP1 protein P10451 UNIPROT "up-regulates activity" cleavage 25545242 t lperfetto "In this study, we found a novel motif, LRSKSRSFQVSDEQY, in the C-terminal fragment of MMP-3/7-cleaved mouse OPN binds to α9β1 integrin. Importantly, this novel motif is involved in the development of anti-type II collagen antibody-induced arthritis (CAIA). This study provides the first in vitro and in vivo evidence that OPN cleavage by MMP-3/7 is an important regulatory mechanism for CAIA." SIGNOR-253321 MAPK1 protein P28482 UNIPROT SP1 protein P08047 UNIPROT up-regulates phosphorylation Thr453 SGPIIIRtPTVGPNG 9606 11904305 t gcesareni "Here we show that p42/p44 mapk directly phosphorylates sp1 on threonines 453 and 739 both in vitro and in vivo. Mutation of these sites to alanines decreases by half the mapk-dependent transcriptional activity of sp1. Phosphorylated extracellular signal-regulated protein kinases 1 and 2 phosphorylate sp1 on serine 59 and regulate cellular senescence via transcription of p21sdi1/cip1/waf1." SIGNOR-116162 Ub:E2 complex SIGNOR-C497 SIGNOR RAPSN protein Q13702 UNIPROT "up-regulates activity" ubiquitination 9606 34199813 t miannu "The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t" SIGNOR-270996 MTOR protein P42345 UNIPROT NRBF2 protein Q96F24 UNIPROT "up-regulates activity" phosphorylation Ser113 AEDAEGQsPLSQKYS 9606 BTO:0001938 28059666 t miannu "Human NRBF2 is phosphorylated by MTORC1 at S113 and S120. Upon nutrient starvation or MTORC1 inhibition, NRBF2 phosphorylation is diminished. Phosphorylated NRBF2 preferentially interacts with PIK3C3/PIK3R4. Suppression of NRBF2 phosphorylation by MTORC1 inhibition alters its binding preference from PIK3C3/PIK3R4 to ATG14/BECN1, leading to increased autophagic PtdIns3K complex assembly, as well as enhancement of ULK1 protein complex association." SIGNOR-265874 CyclinK/CDK13 complex SIGNOR-C38 SIGNOR POLR2A protein P24928 UNIPROT "up-regulates activity" phosphorylation Ser1644 SPTSPSYsPTSPSYS 9606 BTO:0006413 32917631 t "Ser2 in CTD of PolII" lperfetto "Together, these studies demonstrate the important, yet largely redundant, role for CDK12 and CDK13 for the regulation of POLII CTD phosphorylation at multiple residues, as well as the global role for both of these kinases in regulating POLII occupancy across the genome.|CDK12 and CDK13 are thus evolutionarily related and structurally similar kinases, and biochemical assays have demonstrated that both have POLII C-terminal domain (CTD) kinase activity and the ability to phosphorylate the Ser2 residue of the repetitive CTD heptad sequence" SIGNOR-273067 CyclinK/CDK13 complex SIGNOR-C38 SIGNOR POLR2A protein P24928 UNIPROT "up-regulates activity" phosphorylation Ser1735 SPTSPSYsPTSPSYS 9606 BTO:0006413 32917631 t "Ser2 in CTD of PolII" lperfetto "Together, these studies demonstrate the important, yet largely redundant, role for CDK12 and CDK13 for the regulation of POLII CTD phosphorylation at multiple residues, as well as the global role for both of these kinases in regulating POLII occupancy across the genome.|CDK12 and CDK13 are thus evolutionarily related and structurally similar kinases, and biochemical assays have demonstrated that both have POLII C-terminal domain (CTD) kinase activity and the ability to phosphorylate the Ser2 residue of the repetitive CTD heptad sequence" SIGNOR-273068 DOK3 protein Q7L591 UNIPROT GRB2 protein P62993 UNIPROT "up-regulates activity" binding 9606 BTO:0000776 32323266 t scontino "An adaptor protein Dok-3 mediates the suppressive function of LYN. The Dok-3 phosphorylated by LYN upon BCR stimulation forms a complex with GRB2, which allows it to enter into the signalosome and associate with activation of SHIP protein. This translocation facilitates the efficient inhibition of PLCc2 and SYK from activation, subsequently resulting in the suppression of downstream Ca2+ signaling." SIGNOR-268448 ATM protein Q13315 UNIPROT SMC1A protein Q14683 UNIPROT up-regulates phosphorylation Ser957 ISQEEGSsQGEDSVS 9606 11877377 t lperfetto "Here we report that smc1 is a component of the dna damage response network that functions as an effector in the atm/nbs1-dependent s-phase checkpoint pathway. Smc1 associates with brca1 and is phosphorylated in response to ir in an atm- and nbs1-dependent manner. Using mass spectrometry, we established that atm phosphorylates s957 and s966 of smc1 in vivo." SIGNOR-115492 MAPKAPK3 protein Q16644 UNIPROT RCSD1 protein Q6JBY9 UNIPROT "down-regulates activity" phosphorylation Ser244 PPLRRSPsRTEKQEE -1 15850461 t miannu "Human CapZIP was phosphorylated at Ser-179 and Ser-244 by MAPKAP-K2 (mitogen-activated protein kinase-activated protein kinase 2) or MAPKAP-K3 in vitro. In the present paper we have identified CapZIP as a protein that is phosphorylated exceptionally rapidly by several SAPKs in vitro (Figure 4), and which is expressed in muscles and immune cells. Both MAPKAP-K2 and MAPKAP-K3 phosphorylated CapZIP at Ser-179 in vitro. An important clue to the function of CapZIP and its phosphorylation came from the finding that it binds to the actin-capping protein CapZ (Figure 7A), and that cellular stresses trigger the dissociation of these two proteins (Figure 7B).Such an effect is presumably lost when CapZIP is phosphorylated and dissociates from CapZ." SIGNOR-263082 NCK1 protein P16333 UNIPROT PAK1 protein Q13153 UNIPROT up-regulates binding 9534 8824201 t lperfetto "We describe here a specific interaction of the Nck adapter molecule with PAK1 both in vitro and in vivo. Association of Nck with PAK1 may serve to link this important regulatory kinase to cell activation by growth factor receptors." SIGNOR-236324 ARAP2 protein Q8WZ64 UNIPROT RHOA protein P61586 UNIPROT "down-regulates activity" "gtpase-activating protein" 9606 32203420 t Luana "We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2)." SIGNOR-260453 TLE5 protein Q08117 UNIPROT ZNF503 protein Q96F45 UNIPROT "down-regulates activity" binding 9534 19056829 t miannu "these results show that Grg5 can specifically interact with the C-terminus of Nolz1. these data suggest that Nolz1 functions as a repressor molecule, and that Grg5 interactions with Nolz1 serve to modulate Nolz1 repressor function. Mechanistically, Grg5 is known to modulate Grg co-repressor activity, raising the possibility that classical Grg proteins mediate Nolz1-dependent transcriptional repression. GalNolz1ΔC22 showed increased repressor activity compared with GalNolz1, consistent with the ability of Grg5 to modulate Nolz1 repressor function." SIGNOR-261192 SCN1A protein P35498 UNIPROT Action_potential phenotype SIGNOR-PH82 SIGNOR up-regulates 9606 26043074 f miannu "The expression of voltage-gated sodium channels (NaVs) is a key feature for initiation and conduction of action potentials in excitable tissues and cells such as cardiac and skeletal muscle and neurons." SIGNOR-253448 "MLL2 complex" complex SIGNOR-C88 SIGNOR ESR1 protein P03372 UNIPROT up-regulates binding 9606 16603732 t miannu "Eralpha directly binds to the mll2 complex through two lxxll motifs in a region of mll2 near the c terminus in a ligand-dependent manner. Disrupting the interaction between eralpha and the mll2 complex with small interfering rnas specific against mll2 or an mll2 fragment representing the interacting region with eralpha significantly inhibited the eralpha transcription activity." SIGNOR-145868 GGCX protein P38435 UNIPROT F10 protein P00742 UNIPROT "up-regulates activity" carboxylation Glu60 LERECMEeTCSYEEA -1 9538022 t lperfetto "This report describes the expression, purification, and characterization of a series of recombinant factor Xa variants bearing aspartate substitutions for each of the glutamate residues which normally undergo gamma-carboxylation. |We have produced fully active recombinant human factor Xa and demonstrated that gla residues 16, 26, and 29 are critical for normal activity of factor Xa.|This observation suggests that, for wild-type r-fX expressed in HEK cells, carboxylation by the gamma-glutamyl carboxylase proceeds to completion once initiated; | 11 amino terminal glutamic acid residues of fX which normally undergo gamma-carboxylation (glas 6, 7, 14, 16, 19, 20, 25, 26, 29, 32, 39)." SIGNOR-263669 MAPK1 protein P28482 UNIPROT PLCB1 protein Q9NQ66 UNIPROT "up-regulates activity" phosphorylation Ser982 KKKSEPSsPDHGSST -1 11287604 t lperfetto "coimmunoprecipitation detected a specific association between the activated erk and plc beta1 within the nucleus. In vitro studies revealed that recombinant plc beta1 could be efficiently phosphorylated by activated mitogen-activated protein kinase but not by pka. The erk phosphorylation site was mapped to serine 982 this result suggests that erk-evoked phosphorylation of plc beta1 at serine 982 plays a critical role in the activation of the nuclear pi cycle and is also crucial to the mitogenic action of igf-i." SIGNOR-106561 MYC protein P01106 UNIPROT GLS protein O94925 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0001518 19219026 f Luana "Here we report that the c-Myc (hereafter referred to as Myc) oncogenic transcription factor, which is known to regulate microRNAs and stimulate cell proliferation, transcriptionally represses miR-23a and miR-23b, resulting in greater expression of their target protein, mitochondrial glutaminase, in human P-493 B lymphoma cells and PC3 prostate cancer cells. " SIGNOR-268038 CDK4 protein P11802 UNIPROT PRDX1 protein Q06830 UNIPROT down-regulates phosphorylation Thr90 CHLAWVNtPKKQGGL 9606 BTO:0000567 11986303 t lperfetto "Peroxiredoxin (prx) i is a member of the peroxiredoxin family of peroxidases and contains a consensus site (thr(90)-pro-lys-lys) for phosphorylation by cyclin-dependent kinases (cdks). This protein has now been shown to be phosphorylated specifically on thr(90) by several cdks, including cdc2, in vitro. Phosphorylation of prx i on thr(90) reduced the peroxidase activity of this protein by 80%.Prx i was also phosphorylated, with an efficiency similar to that observed with cdc2, when incubated in vitro with cdk2, cdk4, or cdk6 that had been immunoprecipitated from hela cell lysates with specific antibodies (data not shown)." SIGNOR-87105 SRC protein P12931 UNIPROT DAB1 protein O75553 UNIPROT "up-regulates activity" phosphorylation Tyr198 EDVEDPVyQYIVFEA 10090 BTO:0000938 11279201 t lperfetto "Dab1 is rapidly phosphorylated when neurons isolated from embryonic brains are stimulated with Reelin, and several tyrosines have been implicated in this response. Mice with phenylalanine substitutions of all five tyrosines (Tyr(185), Tyr(198), Tyr(200), Tyr(220), and Tyr(232)) exhibit a reeler phenotype, implying that tyrosine phosphorylation is critical for Dab1 function. Here we report that, although Src can phosphorylate all five tyrosines in vitro, Tyr(198) and Tyr(220) represent the major sites of Reelin-induced Dab1 phosphorylation in embryonic neurons." SIGNOR-247076 ESR1 protein P03372 UNIPROT CRH protein P06850 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000614 8408641 t lperfetto "Evidence of direct estrogenic regulation of human corticotropin-releasing hormone gene expression. Potential implications for the sexual dimophism of the stress response and immune/inflammatory reaction.|Gel retardation and immunoprecipitation demonstrated specific association between the perfect half-palindromic EREs of hCRH gene and the DNA binding domain of hER in vitro." SIGNOR-268721 GART protein P22102 UNIPROT 10-formyltetrahydrofolate(2-) smallmolecule CHEBI:57454 ChEBI "down-regulates quantity" "chemical modification" 9606 11381136 t miannu "The third step is catalyzed by the enzyme glycinamide ribonucleotide transformylase (GAR Tfase). The two folate-requiring reactions, glycinamide ribonucleotide transformylase (GAR Tfase) and aminoimidazole ribonucleotide transformylase (AICAR Tfase), have attracted particular attention because some of the most successful anticancer drugs to date have been folate antimetabolites such as methotrexate (3). These two enzymes carry out similar chemistry in catalyzing the transfer of a formyl group from 10-formyltetrahydrofolate to the amino group of the substrates GAR and AICAR to form fGAR and fAICAR." SIGNOR-267303 CBLC protein Q9ULV8 UNIPROT LRIG1 protein Q96JA1 UNIPROT down-regulates ubiquitination 9606 BTO:0001253 15282549 t gcesareni "Upregulation of lrig1 is followed by enhanced ubiquitylation and degradation of egfr. The underlying mechanism involves recruitment of c-cbl, an e3 ubiquitin ligase that simultaneously ubiquitylates egfr and lrig1 and sorts them for degradation" SIGNOR-127292 STAT1 protein P42224 UNIPROT "ISGF3 complex" complex SIGNOR-C124 SIGNOR "form complex" binding -1 8943351 t 2 miannu "The first STAT-containing transcription factor to be studied, the alpha-interferon-induced ISGF3, is composed of a Stat1:2 heterodimer and a weak DNA-binding protein, p48. The p48 and Stat1:2 heterodimer do not associate stably in the absence of DNA, but we show that amino acids approximately 150 to 250 of Stat1 and a COOH-terminal portion of p48 exhibit physical interaction, implying contact that stabilizes ISGF3" SIGNOR-240606 ATM protein Q13315 UNIPROT DCLRE1C protein Q96SD1 UNIPROT up-regulates phosphorylation Ser516 SSTVAGGsQSPKLFS 9606 16874298 t lperfetto "The artemis nuclease is defective in radiosensitive severe combined immunodeficiency patients and is required for the repair of a subset of ionising radiation induced dna double-strand breaks (dsbs) in an atm and dna-pk dependent process. Here, we show that artemis phosphorylation by atm and dna-pk in vitro is primarily attributable to s503, s516 and s645 and demonstrate atm dependent phosphorylation at serine 645 in vivo" SIGNOR-148319 TNF protein P01375 UNIPROT SCN8A protein Q9UQD0 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 BTO:0004102 26112872 f miannu "TNF-α increases Na(+) currents by accelerating the channel activation as well as increasing the expression of VGSCs in a mechanism dependent upon NF-κB and p38 MAPK signal pathways in CNS neurons. TNF-α increased Na(+) currents by accelerating the activation of VGSCs. The threshold for action potential (AP) was decreased and firing rate were increased. VGSCs were up-regulated at both the mRNA and protein levels." SIGNOR-253482 CDK1 protein P06493 UNIPROT NPM1 protein P06748 UNIPROT "down-regulates activity" phosphorylation Thr234 SFKKQEKtPKTPKGP 10090 SIGNOR-C17 11278991 t lperfetto "CDK1-cyclin B phosphorylates NPM/B23 on Thr234." SIGNOR-235530 DKK1 protein O94907 UNIPROT WNT3A protein P56704 UNIPROT down-regulates 9606 22298955 f "Antagonizes canonical Wnt signaling by inhibiting LRP5/6 interaction with Wnt and by forming a ternary complex with the transmembrane protein KREMEN that promotes internalization of LRP5/6." gcesareni "It has been shown that both sclerostin and dkk1 act physiologically as downstream molecules of bmp signaling to inhibit canonical wnt signaling and therefore negatively regulate bone mass." SIGNOR-195573 TRIM62 protein Q9BVG3 UNIPROT CARD9 protein Q9H257 UNIPROT "up-regulates activity" polyubiquitination Lys125 LLMTEVMkLQKKVQD 9606 BTO:0000007 26488816 t miannu "We identified TRIM62 as a CARD9 binding partner and showed that TRIM62 facilitated K27-linked poly-ubiquitination of CARD9. We identified K125 as the ubiquitinated residue on CARD9 and demonstrated that this ubiquitination was essential for CARD9 activity. " SIGNOR-272420 "NUP98 Fusion" "fusion protein" SIGNOR-FP16 SIGNOR CDK6 protein Q00534 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 32344427 f miannu "NUP98-fusion proteins directly regulate leukemia-associated gene expression programs in AML. CDK6 expression is under direct transcriptional control of NUP98-fusions and NUP98-fusion AML is particularly sensitive to CDK6 inhibition." SIGNOR-261505 melatonin smallmolecule CHEBI:16796 ChEBI MTNR1B protein P49286 UNIPROT "up-regulates activity" "chemical activation" 9606 BTO:0002524 31160049 t "Ligand-GPCR dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257546 EDNRA protein P25101 UNIPROT GNAL protein P38405 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-256923 GNB1 protein P62873 UNIPROT SRC protein P12931 UNIPROT "up-regulates activity" 15345719 f "In this study, we investigated the possible role of the Gβγ heterodimer in signaling Gi-induced Src activation" SIGNOR-251107 FANCL protein Q9NW38 UNIPROT "Fanconi anemia core complex" complex SIGNOR-C300 SIGNOR "form complex" binding 9606 BTO:0000567 17396147 t lperfetto "This complex includes not only the five known FA proteins (FANC‐A, C, E, F, and G), but also four new polypeptides, which are named FAAPs for FANCA‐associated polypeptides. |Thus, eight of the nine components of the FA core complex are FA proteins (FANC‐A, B, C, E, F, G, L, and M). Furthermore, two of the newly discovered FA proteins have enzymatic activities: FANCL is a ubiquitin ligase essential for FANCD2 monoubiquitination in vivo " SIGNOR-263245 MAP2K2 protein P36507 UNIPROT MAPK1 protein P28482 UNIPROT up-regulates phosphorylation Thr185 HDHTGFLtEYVATRW 9606 11971971 t gcesareni "Mapk1 is phosphorylated by map2k1/mek1 and map2k2/mek2 on thr-185 and tyr-187 in response to external stimuli like insulin or ngf. Both phosphorylations are required for activity." SIGNOR-86709 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR TSC1 protein Q92574 UNIPROT down-regulates phosphorylation Thr417 SLPQATVtPPRKEER 9606 BTO:0000680;BTO:0001573;BTO:0001286 14551205 t lperfetto "Cell cycle-regulated phosphorylation of hamartin, the product of the tuberous sclerosis complex 1 gene, by cyclin-dependent kinase 1/cyclin b.Cyclin-dependent kinase 1 phosphorylates hamartin at three sites, one of which (thr417) is in the hamartin-tuberin interaction domain. Tuberin interacts with phosphohamartin, and tuberin expression attenuates the phosphorylation of exogenous hamartin. Hamartin with alanine mutations in the three cyclin-dependent kinase 1 phosphorylation sites increased the inhibition of p70s6 kinase by the hamartin-tuberin complex" SIGNOR-216953 IKBKE protein Q14164 UNIPROT IRF7 protein Q92985 UNIPROT up-regulates phosphorylation Ser471 GTQREGVsSLDSSSL 9606 10893229 t gcesareni "In response to a viral infection, phosphorylated on ser-477 and ser-479 by tbk1 and ikbke1. Phosphorylation, and subsequent activation is inhibited by vaccinia virus protein e3." SIGNOR-79139 MAP2K1 protein Q02750 UNIPROT Gbeta proteinfamily SIGNOR-PF4 SIGNOR up-regulates phosphorylation 9606 12270934 t "inferred from 70% of family members" lbriganti "Mek1 as indicated by extensive phosphorylation of erk1 and erk2 during the initial 2 h of adipogenesis." SIGNOR-269909 INS protein P01308 UNIPROT LPL protein P06858 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0001487 21966368 f Regulation miannu "Insulin has a major effect on LPL regulation in adipose tissue since in mature adipocytes insulin not only increases the level of LPL mRNA but also regulates LPL activity through both posttranscriptional and posttranslational mechanisms" SIGNOR-251857 DLK2 protein Q6UY11 UNIPROT NOTCH1 protein P46531 UNIPROT "down-regulates activity" binding 10090 BTO:0002572 21419176 t lperfetto "Moreover, the interaction of DLK1 with NOTCH1 caused an inhibition of basal NOTCH signaling in preadipocytes and mesenchymal multipotent cells. In this work, we demonstrate, for the first time, that DLK2 interacts with itself, with DLK1, and with the same NOTCH1 receptor region as DLK1 does. We demonstrate also that the interaction of DLK2 with NOTCH1 similarly results in an inhibition of NOTCH signaling in preadipocytes and Mouse Embryo fibloblasts." SIGNOR-219377 PPP2CA protein P67775 UNIPROT CARD11 protein Q9BXL7 UNIPROT "down-regulates activity" dephosphorylation Ser644 NLMFRKFsLERPFRP 9606 21157432 t "NF-kappaB activation is triggered by PKCtheta-dependent phosphorylation of Carma1 after TCR/CD28 co-stimulation. PKCtheta-phosphorylated Carma1 was suggested to function as a molecular scaffold that recruits preassembled Bcl10-Malt1 complexes to the membrane|we demonstrate that PP2A removes PKCtheta-dependent phosphorylation of Ser645 in Carma1, and show that maintenance of this phosphorylation is correlated with increased T-cell activation." SIGNOR-248650 EGFR protein P00533 UNIPROT EPB41 protein P11171 UNIPROT down-regulates phosphorylation Tyr660 RLDGENIyIRHSNLM 9606 1647028 t lperfetto "The phosphorylation site has been localized to the 8-kda domain, which has one tyrosine, tyrosine-418. The 8-kda region is required for the assembly of the spectrin/actin complex, and phosphorylation by egfr reduced the ability of protein 4.1 to promote the assembly of the spectrin/actin/protein 4.1 ternary complex" SIGNOR-20452 PPP5C protein P53041 UNIPROT CILK1 protein Q9UPZ9 UNIPROT "down-regulates activity" dephosphorylation Thr157 IRSKPPYtDYVSTRW 9606 16954377 t llicata "MAK and MRK require dual phosphorylation in a TDY motif catalyzed by an unidentified human threonine kinase and tyrosine autophosphorylation.| Protein phosphatase 5 (PP5) interacts with MRK in a complex and dephosphorylates MRK at T157 in vitro and in situ." SIGNOR-248541 CCP110 protein O43303 UNIPROT CALM3 protein P0DP25 UNIPROT "up-regulates activity" binding 9606 16760425 t miannu "We report that CP110 interacts with two different Ca2+-binding proteins, calmodulin (CaM) and centrin, in vivo. our data demonstrate a functional role for CaM binding to CP110 and suggest that CP110 cooperates with CaM and centrin to regulate progression through cytokinesis." SIGNOR-266348 CDK5/CDK5R1 complex SIGNOR-C144 SIGNOR DCX protein O43602 UNIPROT "up-regulates activity" phosphorylation Ser297 PQKTSAKsPGPMRRS 9606 14741103 t llicata "We identified that Ser297 is the major phosphorylation site by Cdk5. Phosphorylation of this site occurs in human. | Mutation of Ser297 blocks the effect of Dcx on migration in a fashion similar to pharmacological inhibition of Cdk5 activity." SIGNOR-250657 Ub:E2 complex SIGNOR-C497 SIGNOR VPS18 protein Q9P253 UNIPROT "up-regulates activity" ubiquitination 9606 34199813 t miannu "The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t" SIGNOR-271231 LATS1 protein O95835 UNIPROT YAP1 protein P46937 UNIPROT down-regulates phosphorylation Ser127 PQHVRAHsSPASLQL 9606 22658639 t milica "In response to high cell densities, activated LATS1/2 phosphorylates the WW-domain containing transcriptional co-activators YAP at Ser127 and TAZ at Ser89, promoting 14-3-3 binding and thereby inhibiting their translocation into the nucleus." SIGNOR-197647 MECP2 protein P51608 UNIPROT MEF2C protein Q06413 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 10090 BTO:0000614 18511691 t Luana "MeCP2 binds to the promoter region of six target genes. ChIP with anti-MeCP2 antibody shows that MeCP2 binds to the promoter regions of activated targets Sst, Oprk1, Gamt, and Gprin1, and repressed targets Mef2c and A2bp1." SIGNOR-264680 "MSL acetyltransferase" complex SIGNOR-C344 SIGNOR H2BW2 protein P0C1H6 UNIPROT "down-regulates activity" monoubiquitination Lys35 ANSTKAQkQKRRGCR 9606 21726816 t miannu "MSL1/2 ubiquitylates histone H2B on K 34. Importantly, only mono-ubiquitylation of H2B by MSL1/2 was detected in cells (data not shown), suggesting that MSL1/2, like RNF20/RNF40, was mainly a mono-ubiquitylase under physiological conditions.the MOF-MSL complex functions to promote both H4 K16ac and H2B K34ub. H2B K34ub, in turn, promotes H2B K120ub, H3 K4me3 and K79me2 to facilitate transcription elongation." SIGNOR-271981 TACR3 protein P29371 UNIPROT GNAL protein P38405 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-256937 CSNK2A1 protein P68400 UNIPROT SSB protein P05455 UNIPROT up-regulates phosphorylation Ser366 GKKTKFAsDDEHDEH 9606 18257391 t gcesareni "Prior studies indicate that hla is activated by phosphorylation of serine-366 by protein kinase ck2, neutralizing a negative effect of a short basic motif (sbm)" SIGNOR-160761 ABL1 protein P00519 UNIPROT CAT protein P04040 UNIPROT "up-regulates activity" phosphorylation Tyr231 NANGEAVyCKFHYKT 9606 BTO:0000093 12777400 t lperfetto "The SH3 domains of c-Abl and Arg bound directly to catalase at a P293FNP site. c-Abl and Arg phosphorylated catalase at Tyr231 and Tyr386 in vitro and in the response of cells to H2O2" SIGNOR-101298 SIRT1 protein Q96EB6 UNIPROT PPARGC1A protein Q9UBK2 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 21633182 t miannu "Interestingly, SIRT1 suppresses PPARγ but activates PGC-1α , and thus affects the clock network through multiple mechanisms." SIGNOR-268033 PPM1D protein O15297 UNIPROT CHEK1 protein O14757 UNIPROT "down-regulates activity" dephosphorylation Ser345 LVQGISFsQPTCPDH 9606 15870257 t "Here we show that the oncogenic p53-induced serine/threonine phosphatase, PPM1D (or Wip1), dephosphorylates two ATM/ATR targets, Chk1 and p53. PPM1D binds Chk1 and dephosphorylates the ATR-targeted phospho-Ser 345, leading to decreased Chk1 kinase activity." SIGNOR-248317 PRKACA protein P17612 UNIPROT PDE10A protein Q9Y233 UNIPROT unknown phosphorylation Thr15 SQHLTGLtDEKVKAY 9606 BTO:0000007 20610737 t llicata "When coexpressed with the catalytic subunit of pka in transfected hek293 cells, wild-type (wt) pde10a2 (pde10a2wt) was phosphorylated at thr-16 these data confirm the previously reported findings that pka phosphorylation of pde10a2 on thr-16 results in a cytosolic localization" SIGNOR-166559 USP36 protein Q9P275 UNIPROT SOD2 protein P04179 UNIPROT "up-regulates quantity by stabilization" deubiquitination 21268071 t lperfetto "Protein stability of mitochondrial superoxide dismutase SOD2 is regulated by USP36|Finally, USP36 was shown to be a specific deubiquitinating enzyme that reduces the ubiquitination level of SOD2 and was involved in SOD2 protein stability by extending its half-life." SIGNOR-272280 ITGA6 protein P23229 UNIPROT PMP22 protein Q01453 UNIPROT "up-regulates activity" binding 10090 16436605 t Regulation miannu "PMP22 is in a complex with α6β4 integrin and laminin. PMP22 and β4 integrin are in a complex in a variety of cell types. The interaction with the integrins provides PMP22 with the ability to modulate the cell–ECM communications, as well as intracellular events. Signaling between the ECM and the intracellular compartment is essential for SC myelination, as well as cellular differentiation and motility, in general. The identification of PMP22 as a binding partner for an integrin signaling complex provides a major step toward understanding the role of this disease-linked molecule in the nervous system and in non-neural cell types." SIGNOR-251895 PRKCB protein P05771 UNIPROT ILF3 protein Q12906 UNIPROT "up-regulates activity" phosphorylation Ser647 RGRGRGGsIRGRGRG 9606 20870937 t llicata "Upon T cell activation, NF90 translocates from the nucleus into the cytoplasm, where it binds to the AU-rich element-containing 3' untranslated regions of IL-2 mRNA and stabilizes it.|Our results support a model in which PMA stimulation activates PKCβI to phosphorylate NF90-Ser647, and this phosphorylation triggers NF90 relocation to the cytoplasm and stabilize IL-2 mRNA." SIGNOR-168173 RXRB protein P28702 UNIPROT PPARD protein Q03181 UNIPROT up-regulates binding 9606 11237216 t gcesareni "Although the three ppar subtypes are closely related and bind to similar dna response elements as heterodimers with the 9-cis retinoic acid receptor rxr, each subserves a distinct physiology" SIGNOR-105451 SRC protein P12931 UNIPROT CTNNB1 protein P35222 UNIPROT "up-regulates activity" phosphorylation Tyr654 RNEGVATyAAAVLFR 9606 11279024 t lperfetto "Beta-catenin is a good substrate of pp60c- src tyrosine kinase in vitro;this kinase modifies specifically tyr-86 and tyr-654,although consistently detected, this negative effect of tyr-86 phosphorylation on tbp binding was clearly less important than the positive effect observed after tyr-654 phosphorylation." SIGNOR-106454 PAX1 protein P15863 UNIPROT MEOX1 protein P50221 UNIPROT "up-regulates activity" binding -1 11423130 t miannu "We show that Mox1 and Mox2 proteins are capable of interacting with Pax1 and Pax3. We propose that the Mox family of homeodomain proteins participates in the molecular signaling network regulating the diverse events of somite development through the physical interaction with the Pax1 and Pax3 members of the Pax family." SIGNOR-222193 PSTPIP1 protein O43586 UNIPROT DNM2 protein P50570 UNIPROT down-regulates binding 9606 18480402 t miannu "We show that pstpip1 associates with the regulator of endocytosis, dynamin 2, and pstpip1 expression impairs transferrin uptake and endocytosis" SIGNOR-178628 CyclinK/CDK13 complex SIGNOR-C38 SIGNOR POLR2A protein P24928 UNIPROT "up-regulates activity" phosphorylation Ser1714 SPTSPSYsPTSPSYS 9606 BTO:0006413 32917631 t "Ser2 in CTD of PolII" lperfetto "Together, these studies demonstrate the important, yet largely redundant, role for CDK12 and CDK13 for the regulation of POLII CTD phosphorylation at multiple residues, as well as the global role for both of these kinases in regulating POLII occupancy across the genome.|CDK12 and CDK13 are thus evolutionarily related and structurally similar kinases, and biochemical assays have demonstrated that both have POLII C-terminal domain (CTD) kinase activity and the ability to phosphorylate the Ser2 residue of the repetitive CTD heptad sequence" SIGNOR-273069 COL14A1 protein Q05707 UNIPROT ECM_synthesis phenotype SIGNOR-PH8 SIGNOR up-regulates 9606 21949456 t "Types XII and XIV collagen are fibril-associated collagens with interrupted triple helices (FACITs) localized primarily to perimysium.23 While they appear to link fibrillar collagen to other ECM components, their precise function is not known" SIGNOR-254672 AURKB protein Q96GD4 UNIPROT TP53BP1 protein Q12888 UNIPROT "up-regulates activity" phosphorylation Ser1342 GPLRGKTsGTEPADF 9606 BTO:0001938 28415769 t lperfetto "Here we report for the first time that tumor suppressor p53-binding protein 1 (53BP1) is phosphorylated at serine 1342 (S1342) by Aurora kinase B both in vitro and in human cells, which is required for optimal recruitment of 53BP1 at kinetochores." SIGNOR-264411 KDM6A protein O15550 UNIPROT FLI1 protein Q01543 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 29736013 t miannu "Our findings reveal a dual role for UTX in suppressing acute myeloid leukaemia via repression of oncogenic ETS and upregulation of tumor suppressive GATA programs. several ETS transcription factors, including Elf4, Etv6, Erg, Fli1, Ets2, Spi1 and Elk3 were upregulated immediately after Utx loss in the preleukaemic phase" SIGNOR-260034 PAK5 protein Q9P286 UNIPROT SYNJ1 protein O43426 UNIPROT "up-regulates activity" phosphorylation -1 22371566 t miannu "We identified two novel Pak5 substrates, Pacsin1 and Synaptojanin1, proteins that directly interact with one another to regulate synaptic vesicle endocytosis and recycling. Pacsin1 and Synaptojanin1 were phosphorylated by Pak5 and the other group II Paks in vitro, and Pak5 phosphorylation promoted Pacsin1-Synaptojanin1 binding both in vitro and in vivo." SIGNOR-263026 mTORC2 complex SIGNOR-C2 SIGNOR AKT1 protein P31749 UNIPROT "up-regulates activity" phosphorylation Ser473 RPHFPQFsYSASGTA 9606 21157483 t lperfetto "Mammalian TOR complex 1 (mTORC1) and mTORC2 exert their actions by regulating other important kinases, such as S6 kinase (S6K) and Akt.Recent findings have revealed novel important roles for mTORC2 in the phosphorylation of AGC kinase family members. mTORC2 phosphorylates and activates Akt, SGK, and PKC, which regulate cell survival, cell cycle progression and anabolism" SIGNOR-217004 SEC23IP protein Q9Y6Y8 UNIPROT "long-chain fatty acid anion" smallmolecule CHEBI:57560 ChEBI "up-regulates quantity" "chemical modification" 9606 22922100 t miannu "Members of the intracellular phospholipase A1 family of proteins have been implicated in organelle biogenesis and membrane trafficking. The mammalian family comprises three members: phosphatidic acid-preferring phospholipase A1 (PA-PIA1)/DDHD1, p125/Sec23ip and KIAA0725p/DDHD2, all of which have a DDHD domain." SIGNOR-269654 SPDEF protein O95238 UNIPROT MMP13 protein P45452 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0003160 22761428 f miannu "Transcriptional analysis of several genes associated with tumor metastasis, invasion, and the epithelial-mesenchymal transition demonstrated that SPDEF expression selectively down-regulated MMP9 and MMP13 in prostate cancer cells." SIGNOR-255219 "Hair cells mechanotransduction channel" complex SIGNOR-C290 SIGNOR calcium(2+) smallmolecule CHEBI:29108 ChEBI "up-regulates quantity" relocalization 10090 23217710 t lperfetto "Despite this progress, it is not known which genes encode subunits of the mechanotransduction channel of hair cells. Ca2+ enters stereocilia upon mechanical stimulation near the lower tip-link insertion site, indicating that transduction channels are present in proximity to PCDH15" SIGNOR-262573 IL1B protein P01584 UNIPROT CTSK protein P43235 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 11920402 f lperfetto "This is supported by our finding that inflammatory cytokines such as IL-1b and TNFa increase the expres- sion of cathepsin K mRNA 􏰌6–8-fold and increase the secretion of the mature enzyme." SIGNOR-253316 MAPK1 protein P28482 UNIPROT PCYT1A protein P49585 UNIPROT down-regulates phosphorylation Ser315 GRMLQAIsPKQSPSS 9606 BTO:0000763 15788406 t gcesareni "Oxysterols inhibit phosphatidylcholine synthesis via erk docking and phosphorylation of ctp:phosphocholine cytidylyltransferase. Mutagenesis of ser315 within cctalpha was both required and sufficient to confer significant resistance to 22-hc/9-cis-ra inhibition of ptdcho synthesis." SIGNOR-134837 DLX2 protein Q07687 UNIPROT MSX1 protein P28360 UNIPROT "down-regulates activity" binding 10090 BTO:0000944 9111364 t 2 miannu "We demonstrate that dimerization by Msx and Dlx proteins is mediated through their homeodomains and that the residues required for this interaction correspond to those necessary for DNA binding. Unlike most other known examples of homeoprotein interactions, association of Msx and Dlx proteins does not promote cooperative DNA binding; instead, dimerization and DNA binding are mutually exclusive activities. Msx proteins act as transcriptional repressors and Dlx proteins act as activators, while in combination, Msx and Dlx proteins counteract each other's transcriptional activities." SIGNOR-240918 SPX protein Q9BT56 UNIPROT GALR3 protein O60755 UNIPROT "up-regulates activity" binding 9606 BTO:0000007 24517231 t lperfetto "Coevolution of the spexin/galanin/kisspeptin family: Spexin activates galanin receptor type II and III." SIGNOR-268575 MAPK14 protein Q16539 UNIPROT RBSN protein Q9H1K0 UNIPROT up-regulates phosphorylation 9606 16138080 t gcesareni "We found that p38alpha can phosphorylate the rab5 effectors eea1 and rabenosyn-5 on thr-1392 and ser-215, respectively, and these phosphorylation events regulate the recruitment of eea1 and rabenosyn-5 to membranes." SIGNOR-140146 UBXN2B protein Q14CS0 UNIPROT AURKA protein O14965 UNIPROT "down-regulates activity" binding 6239 23649807 t lperfetto "The UBXN-2/p37/p47 adaptors of CDC-48/p97 regulate mitosis by limiting the centrosomal recruitment of Aurora A.|We found that UBXN-2 and CDC-48 coimmunoprecipitated with AIR-1 from embryonic extracts" SIGNOR-265042 CEP135 protein Q66GS9 UNIPROT CENPJ protein Q9HC77 UNIPROT "up-regulates activity" binding 9606 23511974 t miannu "In this study, we demonstrate that the human microcephaly protein, CEP135, directly interacts with hSAS-6 via its carboxyl-terminus and with MTs via its amino-terminus. Unexpectedly, CEP135 also interacts with another microcephaly protein CPAP via its amino terminal domain. Depletion of CEP135 not only perturbed the centriolar localization of CPAP, but also blocked CPAP-induced centriole elongation. We propose that CEP135 may serve as a linker protein that directly connects the central hub protein, hSAS-6, to the outer MTs, and suggest that this interaction stabilizes the proper cartwheel structure for further CPAP-mediated centriole elongation." SIGNOR-269677 CHRM5 protein P08912 UNIPROT GNAI1 protein P63096 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-256730 PRKACA protein P17612 UNIPROT VTN protein P04004 UNIPROT unknown phosphorylation Ser397 NQNSRRPsRATWLSL -1 1706595 t miannu "Phosphorylation of vitronectin by protein kinase A is stoichiometric (approx. 1 mol/mol), that it is targeted to one site (Ser-378) at the C-terminal edge of the heparin-binding domain. gh the role of phosphorylation by PKA remains to be established, the identification of Ser-378 as the sole site for PKA action, and the proximity of the phosphorylation site to the point of cleavage that converts V75 into V65 10' focuses attention on a putative role for PKA in the modulation of this cleavage." SIGNOR-250072 CTDSP1 protein Q9GZU7 UNIPROT POLR2A protein P24928 UNIPROT "up-regulates activity" dephosphorylation Ser1714 SPTSPSYsPTSPSYS -1 22137580 t "Phosphorylation and dephosphorylation of the C-terminal domain (CTD) of RNA polymerase II (Pol II) represent a critical regulatory checkpoint for transcription. Transcription initiation requires Fcp1/Scp1-mediated dephosphorylation of phospho-CTD. | This combined structure-function analysis discloses the residues in Scp1 involved in CTD binding and its preferential dephosphorylation of P.Ser5 of the CTD heptad repeat." SIGNOR-248786 SRP72 protein O76094 UNIPROT SRP68 protein Q9UHB9 UNIPROT "up-regulates activity" binding -1 30649417 t miannu "Taken together our data show that binding of the SRP68/72 heterodimer follows an ultrasensitive response dependent on the SRP72 C-terminus. Although the large solenoids of SRP68/72 have not been structurally characterized due to intrinsic flexibility, they serve as important contact sites in ribosome interaction." SIGNOR-261164 CyclinK/CDK13 complex SIGNOR-C38 SIGNOR POLR2A protein P24928 UNIPROT "up-regulates activity" phosphorylation Ser1693 SPTSPSYsPTSPSYS 9606 BTO:0006413 32917631 t "Ser2 in CTD of PolII" lperfetto "Together, these studies demonstrate the important, yet largely redundant, role for CDK12 and CDK13 for the regulation of POLII CTD phosphorylation at multiple residues, as well as the global role for both of these kinases in regulating POLII occupancy across the genome.|CDK12 and CDK13 are thus evolutionarily related and structurally similar kinases, and biochemical assays have demonstrated that both have POLII C-terminal domain (CTD) kinase activity and the ability to phosphorylate the Ser2 residue of the repetitive CTD heptad sequence" SIGNOR-273070 FBXO3 protein Q9UK99 UNIPROT EP300 protein Q09472 UNIPROT "down-regulates quantity by destabilization" binding 9606 BTO:0004573 18809579 t miannu "O clarify the role of PML in transcription regulation, we purified the PML complex and identified Fbxo3 (Fbx3), Skp1, and Cullin1 as novel components of this complex. Fbx3 formed SCF(Fbx3) ubiquitin ligase and promoted the degradation of HIPK2 and p300 by the ubiquitin-proteasome pathway. " SIGNOR-271742 CyclinK/CDK13 complex SIGNOR-C38 SIGNOR POLR2A protein P24928 UNIPROT "up-regulates activity" phosphorylation Ser1672 SPTSPSYsPTSPSYS 9606 BTO:0006413 32917631 t "Ser2 in CTD of PolII" lperfetto "Together, these studies demonstrate the important, yet largely redundant, role for CDK12 and CDK13 for the regulation of POLII CTD phosphorylation at multiple residues, as well as the global role for both of these kinases in regulating POLII occupancy across the genome.|CDK12 and CDK13 are thus evolutionarily related and structurally similar kinases, and biochemical assays have demonstrated that both have POLII C-terminal domain (CTD) kinase activity and the ability to phosphorylate the Ser2 residue of the repetitive CTD heptad sequence" SIGNOR-273071 KLF11 protein O14901 UNIPROT HBE1 protein P02100 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 10207080 f Regulation miannu "Transfection of K562 cells with FKLF cDNA enhanced the expression of the endogenous epsilon- and gamma-globin genes, suggesting an in vivo role of FKLF in fetal and embryonic globin gene expression." SIGNOR-251829 PRKCG protein P05129 UNIPROT CHAT protein P28329 UNIPROT up-regulates phosphorylation Ser558 VPTYESAsIRRFQEG 9606 BTO:0000938 15381704 t "The effect has been demonstrated using P28329-3" gcesareni "We show that chat is differentially phosphorylated by protein kinase c (pkc) isoforms on four serines (ser-440, ser-346, ser-347, and ser-476) and one threonine (thr-255). This phosphorylation is hierarchical, with phosphorylation at ser-476 required for phosphorylation at other serines. Phosphorylation at some, but not all, sites regulates basal catalysis and activation." SIGNOR-129324 RPS6K proteinfamily SIGNOR-PF26 SIGNOR YBX1 protein P67809 UNIPROT up-regulates phosphorylation Ser102 NPRKYLRsVGDGETV 9606 BTO:0000150 19036157 t lperfetto "We therefore conclude that rsk1/rsk2 are novel activators of yb-1, able to phosphorylate the serine 102 residue." SIGNOR-252804 LRRC4 protein Q9HBW1 UNIPROT CCND1 protein P24385 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0000142 25526788 f miannu "LRRC4/NGL-2 can delay the cell cycle in late G1 by increasing the expression of cell cycle inhibitory molecules (p21, p27) and reducing the expression of cell cycle regulatory proteins (CyclinD1, CDK2, CyclinE, CDK4) via the inhibition of K-Ras/c-Raf/ERK/MAPK, PI-3K/AKT/NF- κB, p70S6/PKC and STAT3, and the upregulation of the JNK2/c-Jun/mp53 signaling pathway." SIGNOR-264056 ARHGEF7 protein Q14155 UNIPROT CBLC protein Q9ULV8 UNIPROT down-regulates binding 9606 14505571 t gcesareni "Here, we show that activation of cdc42 protects the egf receptor from the negative regulatory activity of the c-cbl ubiquitin ligase. Activated cdc42 binds to p85cool-1 (for cloned-out-of-library)/beta-pix (for pak-interactive exchange factor), a protein that directly associates with c-cbl. This inhibits the binding of cbl by the egf receptor and thus prevents cbl from catalyzing receptor ubiquitination" SIGNOR-118135 AKT proteinfamily SIGNOR-PF24 SIGNOR CDK2 protein P24941 UNIPROT up-regulates phosphorylation Thr39 LKKIRLDtETEGVPS 9606 18354084 t lperfetto "Akt phosphorylates cdk2 at threonine 39 residue both in vitro and in vivo. Although cdk2 threonine 39 phosphorylation mediated by akt enhances cyclin-a binding, it is dispensable for its basal binding and the kinase activity." SIGNOR-244176 WDR24 protein Q96S15 UNIPROT GATOR2 complex SIGNOR-C193 SIGNOR "form complex" binding 9606 23723239 t miannu "Here, we identify GATOR as a complex that interacts with the Rags and is composed of two subcomplexes we call GATOR1 and 2. Inhibition of GATOR1 subunits (DEPDC5, Nprl2, and Nprl3) makes mTORC1 signaling resistant to amino acid deprivation. In contrast, inhibition of GATOR2 subunits (Mios, WDR24, WDR59, Seh1L, Sec13) suppresses mTORC1 signaling and epistasis analysis shows that GATOR2 negatively regulates DEPDC5" SIGNOR-255302 H4C1 protein P62805 UNIPROT "Nucleosome_H3.3 variant" complex SIGNOR-C339 SIGNOR "form complex" binding 9606 15776021 t miannu "Variant histone H3.3 is incorporated into nucleosomes by a mechanism that does not require DNA replication and has also been implicated as a potential mediator of epigenetic memory of active transcriptional states. In this study, we have used chromatin immunoprecipitation analysis to show that H3.3 is found mainly at the promoters of transcriptionally active genes." SIGNOR-263877 STIP1 protein P31948 UNIPROT HSP90AB1 protein P08238 UNIPROT "down-regulates activity" binding 9606 BTO:0000007 27353360 t miannu "Hsp90 chaperone cycle is tightly regulated by another group of proteins referred to as ‘co-chaperones'. Their stability does not depend on Hsp90 function but they interact with distinct Hsp90 conformational states, providing directionality to the Hsp90 cycle4. Furthermore, certain co-chaperones, such as HOP and Cdc37p50 inhibit the Hsp90 chaperone cycle, assisting in delivery of distinct sets of client proteins (steroid hormone receptors and kinases, respectively) to the Hsp90 chaperone machine." SIGNOR-261412 CYP2R1 protein Q6VVX0 UNIPROT calcidiol smallmolecule CHEBI:17933 ChEBI "up-regulates quantity" "chemical modification" 9606 BTO:0000759 30080183 t lperfetto "Vitamin D-binding protein transports vitamin D to the liver, where it undergoes 25-hydroxylation by CYP2R1. CYP27B1 further hydroxylates 25-hydroxyvitamin D at the 1-alpha position, resulting in the formation of the active hormone 1,25-dihydroxyvitamin D." SIGNOR-270568 PPP2CA protein P67775 UNIPROT PAK1 protein Q13153 UNIPROT "down-regulates activity" dephosphorylation Thr423 PEQSKRStMVGTPYW 10116 18586681 t "Both sites were dephosphorylated with the same kinetics; the anti-Ser(P)198 antibody was subsequently used as it exhibited lower background staining. Direct comparison of PP2Cα with purified PP1 and PP2A lead us to conclude that at the same molar ratio PP2Cα was the most efficient in dephosphorylating PAK1 (Fig. 1D). In this case we monitored two autophosphorylation sites in the Pak1 N-terminal regulatory region (Ser57 and Ser198/203) using phosphospecific antibodies: both sites showed the same kinetics of inactivation." SIGNOR-248643 POMC protein P01189 UNIPROT MC2R protein Q01718 UNIPROT "up-regulates activity" binding 10029 BTO:0000047 20371771 t lperfetto "Here, we show that, whereas MRAP was essential for activation of MC2R signaling, MRAP2 was an endogenous inhibitor that competed with MRAP for binding to MC2R and decreased the potency of adrenocorticotropic hormone (ACTH), the endogenous agonist for MC2Rs, in stimulating the production of adenosine 3',5'-monophosphate (cAMP)." SIGNOR-268615 GPR34 protein Q9UPC5 UNIPROT GNAI3 protein P08754 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-256831 ASIP protein P42127 UNIPROT MC2R protein Q01718 UNIPROT "down-regulates activity" binding 9606 20371771 t lperfetto "The melanocortin (MC) receptor family consists of five Gs-coupled receptors that control various physiological functions in response to four distinct agonists, adrenocorticotropic hormone (ACTH, also known as corticotrophin) and α, β, and γ melanocyte–stimulating hormone (MSH), which are derived from the proopiomelanocortin precursor protein, and two inverse agonists, agouti and agouti-related proteins" SIGNOR-268695 MEF2A protein Q02078 UNIPROT MYH1 protein P12882 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 15728583 t lperfetto "Myocyte enhancer factor-2 and serum response factor binding elements regulate fast Myosin heavy chain transcription in vivo. We show that the upstream promoter region of the gene most abundantly expressed in mouse skeletal muscles, IIb MyHC, retains binding activity and transcriptional activation for three positive transcription factors, the serum response factor, Oct-1, and myocyte enhancer factor-2, whereas the other two genes (IIa and IId/x) have nucleotide substitutions in these sites that reduce binding and transcriptional activation" SIGNOR-238748 AURKB protein Q96GD4 UNIPROT RACGAP1 protein Q9H0H5 UNIPROT "up-regulates activity" phosphorylation Ser144 NAGNKRLsTIDESGS 9606 BTO:0000567 14744859 t llicata "It was found that the 5A fragment in which five Ser/Thr residues were substituted with Ala (S144A/T145A/S185A/T186A/S187A) fully prevented phosphorylation (Fig. 5B), confirming that Aurora B primarily phosphorylates five Ser/Thr residues in the basic region of MgcRacGAP. | the strong phosphorylation of the basic region of MgcRacGAP by Aurora B kinase was demonstrated, and this phosphorylation prevents the inhibition of MgcRacGAP GAP activity by PRC1" SIGNOR-250586 MRAP protein Q8TCY5 UNIPROT MC2R protein Q01718 UNIPROT "up-regulates activity" binding 10029 BTO:0000246 19329486 t miannu "We report that MRAP and MRAP2 can interact with all 5 MCRs. This interaction results in MC2R surface expression and signaling.We have previously identified MRAP as an accessory protein for MC2R, required for receptor trafficking to the cell surface and the formation of a functional MC2R. Here we have identified MRAP2 as a homologue of MRAP. Like MRAP, MRAP2 is able to support MC2R cell-surface expression, producing a functional ACTH-responsive receptor." SIGNOR-252360 GHSR protein Q92847 UNIPROT GNAI3 protein P08754 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257167 (-)-anisomycin chemical CHEBI:338412 ChEBI JUN protein P05412 UNIPROT up-regulates "chemical activation" 9606 Other t CellSignaling gcesareni SIGNOR-189632 5-[(Z)-(5-Fluoro-2-oxo-1H-indol-3-ylidene)methyl]-N-[(2S)-2-hydroxy-3-morpholin-4-ylpropyl]-2,4-dimethyl-3H-pyrrole-3-carboxamide chemical CID:73755145 PUBCHEM PDGFRB protein P09619 UNIPROT "down-regulates activity" "chemical inhibition" -1 22037378 t llicata "Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here." SIGNOR-258288 HTR1B protein P28222 UNIPROT GNAO1 protein P09471 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-256999 GART protein P22102 UNIPROT 5-phospho-beta-D-ribosylaminium(1-) smallmolecule CHEBI:58681 ChEBI "down-regulates quantity" "chemical modification" 9606 34283828 t miannu "In humans, GART [phosphoribosylglycinamide formyltransferase (EC 2.1.2.2) / phosphoribosylglycinamide synthetase (EC 6.3.4.13) / phosphoribosylaminoimidazole synthetase (EC 6.3.3.1)] is a trifunctional protein which catalyzes the second, third, and fifth reactions of the ten step de novo purine synthesis (DNPS) pathway. The second step of DNPS is conversion of phosphoribosylamine (5-PRA) to glycineamide ribonucleotide (GAR)." SIGNOR-267298 CAMK2A protein Q9UQM7 UNIPROT ITGB1BP1 protein O14713 UNIPROT "up-regulates activity" phosphorylation Thr38 GGLSRSStVASLDTD 9813144 t llicata "The point mutation T38D localized within the optimal CaMKII recognition motif of ICAP-1alpha results in a strong defect in cell spreading which cannot be overcome by the inhibition of the endogenous CaMKII. This fact strongly suggests that the phosphorylation of Threonine 38 by CaMKII modulates the alpha5beta1 integrin function. Conversely, the mutation T38A produces an analog of ICAP-1alpha that cannot be phosphorylated and that stimulates cell spreading on fibronectin to a similar extent when CaMKII is inhibited." SIGNOR-250632 EIF2AK2 protein P19525 UNIPROT EIF2AK2 protein P19525 UNIPROT up-regulates phosphorylation Ser242 NQRKAKRsLAPRFDL 9606 11152499 t tpavlidou "We previously identified four autophosphorylated amino acids and elucidated their participation in pkr activation.Replacement Of all four of these residues in pkr with alanines did not dramatically affect kinase activity in vitro or in yeast saccharomyces cerevisiae.However, when coupled with mutations of serine 242 and threonines 255 and 258 in the central region, these mutations increased pkr protein expression in mammalian cells, consistent with diminished kinase activity." SIGNOR-85765 CyclinK/CDK13 complex SIGNOR-C38 SIGNOR POLR2A protein P24928 UNIPROT "up-regulates activity" phosphorylation Ser1623 SPTSPSYsPTSPSYS 9606 BTO:0006413 32917631 t "Ser2 in CTD of PolII" lperfetto "Together, these studies demonstrate the important, yet largely redundant, role for CDK12 and CDK13 for the regulation of POLII CTD phosphorylation at multiple residues, as well as the global role for both of these kinases in regulating POLII occupancy across the genome.|CDK12 and CDK13 are thus evolutionarily related and structurally similar kinases, and biochemical assays have demonstrated that both have POLII C-terminal domain (CTD) kinase activity and the ability to phosphorylate the Ser2 residue of the repetitive CTD heptad sequence" SIGNOR-273072 CyclinK/CDK13 complex SIGNOR-C38 SIGNOR POLR2A protein P24928 UNIPROT "up-regulates activity" phosphorylation Ser1721 SPTSPSYsPTSPSYS 9606 BTO:0006413 32917631 t "Ser2 in CTD of PolII" lperfetto "Together, these studies demonstrate the important, yet largely redundant, role for CDK12 and CDK13 for the regulation of POLII CTD phosphorylation at multiple residues, as well as the global role for both of these kinases in regulating POLII occupancy across the genome.|CDK12 and CDK13 are thus evolutionarily related and structurally similar kinases, and biochemical assays have demonstrated that both have POLII C-terminal domain (CTD) kinase activity and the ability to phosphorylate the Ser2 residue of the repetitive CTD heptad sequence" SIGNOR-273073 PSMC3 protein P17980 UNIPROT "26S Proteasome" complex SIGNOR-C307 SIGNOR "form complex" binding 9606 BTO:0000007 29636472 t lperfetto "Here, we report near-atomic resolution cryo-EM structures of the activated human proteasome|The proteasome is composed of a 28-subunit barrel-shaped core particle (CP) and two 19- subunit regulatory particles (RP)5–8 capped at both sides of the CP|Human proteasomes were purified through affinity chromatography on a large scale from a stable HEK293 cell line" SIGNOR-263369 GGCX protein P38435 UNIPROT F7 protein P08709 UNIPROT "up-regulates activity" carboxylation 9606 31226734 t lperfetto "Thus, vitamin K acts as a cofactor for GGCX via the vitamin K cycle and exerts physiological effects through its regulation of VKDPs [29]. More than 20 VKDPs have been found. Osteocalcin promotes bone formation, and blood coagulation factors II, VII, IX, and X activate blood coagulation. Matrix Gla protein suppresses cardiovascular calcification, and brain-expressed Gas 6 promotes neural differentiation [29]. GGCX is an enzyme that converts glutamic acid (Glu) residues to Gla residues, so that the Gla-containing proteins can exert various physiological actions such as blood coagulation and bone formation." SIGNOR-265919 BMPR1A/1B/2 complex SIGNOR-C29 SIGNOR SMAD1 protein Q15797 UNIPROT "up-regulates activity" phosphorylation Ser463 SPHNPISsVS 9606 BTO:0000416 9136927 t lperfetto "Here, we report that BMP receptors phosphorylate and activate Smad1 directly. Phosphorylation of Smad1 in vivo involves serines in the carboxy-terminal motif SSXS. These residues are phosphorylated directly by a BMP type I receptor in vitro" SIGNOR-217985 GAS6 protein Q14393 UNIPROT AXL protein P30530 UNIPROT up-regulates binding 9606 7867073 t gcesareni "Receptor tyrosine kinases of the axl family are activated by the vitamin k-dependent protein gas6. We report the identification of ligands for tyro 3 (alternatively called sky, rse, brt, or tif) and axl (alternatively, ark or ufo), members of a previously orphan family of receptor-like tyrosine kinases. These ligands correspond to protein s, a protease regulator that is a potent anticoagulant, and gas6, a protein related to protein s but lacking any known function." SIGNOR-34339 MAPK8 protein P45983 UNIPROT MAPK8IP1 protein Q9UQF2 UNIPROT unknown phosphorylation Ser421 DNCASVSsPYESAIG 9534 BTO:0000298 12756254 t miannu "After mapping JNK-dependent JIP1 phosphorylation sites and testing their functional significance, it was observed that phosphorylation by JNK of JIP1 on Thr-103 and not other phosphorylated JIP1 residues is necessary for the regulation of DLK association with JIP1, DLK activation, and subsequent module activation. The data presented corroborates our previous observations using endogenous proteins, demonstrates that JNK binding to JIP1 is necessary for module activation, and shows that activation of JIP1-JNK module dynamics requires phosphorylation of JIP1 on Thr-103 by JNK. and Thr-205 are phosphorylated directly by JNK after JNK binds to JIP1." SIGNOR-250126 NAE complex SIGNOR-C131 SIGNOR CUL5 protein Q93034 UNIPROT "up-regulates activity" neddylation 9606 25504797 t lperfetto "The family of cullin proteins is the most established target for NEDD8. In humans, it is composed of seven cullins (Cul1, 2, 3, 4A, 4B, 5 and 7), whereas PARC (CUL9) and APC2 (component of the anaphase promoting complex APC) contain a cullin-homology domain. All cullins are modified with NEDD8The role of cullin NEDDylation is to enhance the activity of the CRLs and subsequent ubiquitination and degradation of the regulated substrates." SIGNOR-243166 SMAD5 protein Q99717 UNIPROT HAND1 protein O96004 UNIPROT "up-regulates quantity" "transcriptional regulation" 10090 22219353 t Gianni "Chromatin immunoprecipitation (ChIP) revealed a subset of the BIG (BMP4 induced genes) signature, including Satb2, Smad6, Hand1, Gadd45γ and Gata3, that was bound by Smad1/5 in the developing mandible, revealing direct Smad-mediated regulation" SIGNOR-268941 ATM protein Q13315 UNIPROT FANCI protein Q9NVI1 UNIPROT unknown phosphorylation Ser730 LDKSADFsQSTSIGI 9606 BTO:0000007 17412408 t "Three phosphorylation sites were detected in a human KIAA1794 protein: S730, T952, S1121, and two other sites in the mouse protein S555, T558. We renamed the KIAA1794 protein as FANCI, since, as shown below, the locus encoding this protein is mutated in an individual with Fanconi anemia complementation group I" SIGNOR-255590 NCR2 protein O95944 UNIPROT Immune_response phenotype SIGNOR-PH17 SIGNOR up-regulates 9606 BTO:0000914 22021614 f miannu "NK cells play an important role in the early immune response to cancer. The NKp44 activating receptor is the only natural cytotoxicity receptor that is expressed exclusively by primate NK cells, yet its cellular ligands remain largely unknown. Proliferating cell nuclear Ag (PCNA) is overexpressed in cancer cells. In this study, we show that the NKp44 receptor recognizes PCNA. Their interaction inhibits NK cell function through NKp44/ITIM." SIGNOR-260044 FER protein P16591 UNIPROT PECAM1 protein P16284 UNIPROT "up-regulates activity" phosphorylation Tyr690 PLNSDVQyTEVQVSS 9606 BTO:0000007 12972546 t miannu "PECAM-1 Is Phosphorylated by Fer and, To a Lesser Extent, by Fes. These results suggest that Fer not only functions as a tyrosine kinase for PECAM-1 but also that Fer modulates the downstream signaling of PECAM-1 by inducing phosphorylation of SHP-2 and Gab1." SIGNOR-262865 P2RY13 protein Q9BPV8 UNIPROT GNA14 protein O95837 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257027 FLT1 protein P17948 UNIPROT FLT1 protein P17948 UNIPROT up-regulates phosphorylation Tyr1242 ATSMFDDyQGDSSTL 9606 9722576 t lperfetto "Receptor tyrosine phosphorylation is crucial for signal transduction by creating high affinity binding sites for src homology 2 domain-containing molecules. By expressing the intracellular domain of flt-1/vascular endothelial growth factor receptor-1 in the baculosystem, we identified two major tyrosine phosphorylation sites at tyr-1213 and tyr-1242 and two minor tyrosine phosphorylation sites at tyr-1327 and tyr-1333 in this receptor." SIGNOR-59754 PTEN protein P60484 UNIPROT PTK2 protein Q05397 UNIPROT "down-regulates activity" dephosphorylation Tyr397 SVSETDDyAEIIDEE 9606 BTO:0000356 10400703 t "The tumor suppressor PTEN is a phosphatase with sequence homology to tensin. PTEN dephosphorylates phosphatidylinositol 3,4, 5-trisphosphate (PIP3) and focal adhesion kinase (FAK), and it can inhibit cell growth, invasion, migration, and focal adhesions. We investigated molecular interactions of PTEN and FAK in glioblastoma and breast cancer cells lacking PTEN. The PTEN trapping mutant D92A bound wild-type FAK, requiring FAK autophosphorylation site Tyr397" SIGNOR-248547 "trichostatin A" chemical CHEBI:46024 ChEBI HDAC5 protein Q9UQL6 UNIPROT "down-regulates activity" "chemical inhibition" -1 20139990 t Luana "Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1)." SIGNOR-258010 LAT protein O43561 UNIPROT PIK3R2 protein O00459 UNIPROT "up-regulates activity" binding 9606 phosphorylation:Tyr161;Tyr200 DDYHNPGyLVVLPDS;SMESIDDyVNVPESG 11368773 t lperfetto "By substituting these tyrosine residues in LAT with phenylalanine and by utilizing phosphorylated peptides derived from these sites, we mapped the tyrosine residues in LAT required for the direct interaction and activation of Vav, p85/p110alpha and phospholipase Cgamma1 (PLCgamma1). Our results indicate that Tyr(226) and Tyr(191) are required for Vav binding, whereas Tyr(171) and Tyr(132) are necessary for association and activation of phosphoinositide 3-kinase activity and PLCgamma1 respectively." SIGNOR-246055 BBS9 protein Q3SYG4 UNIPROT "BBsome complex" complex SIGNOR-C288 SIGNOR "form complex" binding 9606 BTO:0004910 19081074 t lperfetto "We recently showed that seven highly conserved BBS proteins form a stable complex, the BBSome, that functions in membrane trafficking to and inside the primary cilium.|As a first step in characterizing this protein, we investigated the biochemical properties of its binding to the core BBSome (previously defined as the BBS1, -2, -4, -5, -7, -8, and -9 complex). We subjected the native LAP-BBS4 eluate to velocity sedimentation analysis (Figure 1C). BBIP10 clearly cosedimented with BBS4 at 14S, suggesting that BBIP10 strongly associates with the core BBSome" SIGNOR-262555 MSX1 protein P28360 UNIPROT TBP protein P20226 UNIPROT "down-regulates activity" binding -1 8700832 t 2 miannu "Msx-1 is a potent transcriptional repressor and that this activity is independent of its DNA binding function. Here we show that Msx-1 interacts directly with the TATA binding protein (TBP) but not with several other general transcription factors. This interaction is mediated by the Msx-1 homeodomain, specifically through residues in the N-terminal arm. These same N-terminal arm residues are required for repression by Msx-1, suggesting a functional relationship between TBP association and transcriptional repression." SIGNOR-240401 FOXO1 protein Q12778 UNIPROT G6PC1 protein P35575 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 16308421 f gcesareni "In the gk gene regulation, foxo1 represses hnf-4-potentiated transcription of the gene, whereas it synergizes with hnf-4 in activating the g6pase gene transcription." SIGNOR-142147 "B-WICH complex" complex SIGNOR-C447 SIGNOR "RNA Polymerase III" complex SIGNOR-C389 SIGNOR "up-regulates activity" binding 9606 BTO:0000567 25883140 t miannu "The chromatin-remodelling complex B-WICH, comprised of William syndrome transcription factor, the ATPase SNF2h and nuclear myosin, specifically activates RNA polymerase III transcription of the 5S rRNA and 7SL genes." SIGNOR-268841 MAP3K21 protein Q5TCX8 UNIPROT MAP2K1 protein Q02750 UNIPROT "up-regulates activity" phosphorylation Ser218 VSGQLIDsMANSFVG 9606 23319808 t Manara "These experiments showed that MEK1 is phosphorylated by MLK4 on Ser217/221" SIGNOR-260767 2-O-acetyl-1-O-hexadecyl-sn-glycero-3-phosphocholine smallmolecule CHEBI:44811 ChEBI PTAFR protein P25105 UNIPROT "up-regulates activity" "chemical activation" 9606 BTO:0002524 31160049 t "Ligand-GPCR dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257567 MYOD1 protein P15172 UNIPROT ITGA7 protein Q13683 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 8798472 t lperfetto "Only myogenin and MyoD were able to efficiently trans-activate the alpha7 promoter-CAT construct (Fig. 7). Myogenin trans-activated the promoter by _2-fold whereas MyoD was able to trans-activate by nearly 4-fold, indicating that both of these factors may play a role in alpha7 gene expression during muscle development." SIGNOR-241518 ACAN protein P16112 UNIPROT "Av/b3 integrin" complex SIGNOR-C177 SIGNOR "up-regulates activity" binding 9606 BTO:0003858 16051604 t lperfetto "Cartilage Oligomeric Matrix Protein/Thrombospondin 5 Supports Chondrocyte Attachment through Interaction with Integrins|We show that COMP/TSP5 can support chondrocyte attachment and that the RGD sequence in COMP/TSP5 and the integrin receptors alpha5beta1 and alphaVbeta3 on the chondrocytes are involved in mediating this attachment. The interactions of COMP/TSP5 with the integrins are dependent on COMP/TSP5 conformation." SIGNOR-266987 PTCRA protein Q6ISU1 UNIPROT ZAP70 protein P43403 UNIPROT "up-regulates activity" binding 9606 BTO:0000782 1717999 t lperfetto "Stimulation of the T-cell antigen receptor (TCR) leads to tyrosine phosphorylation of a number of cellular proteins, including phospholipase C (PLC) gamma 1 and the TCR zeta chain. We describe here a 70-kDa tyrosine phosphoprotein (ZAP-70) that associates with zeta within 15 sec following TCR stimulation. The phosphorylation of ZAP-70 and its association with zeta is independent of the other TCR chains" SIGNOR-134325 MRGPRX1 protein Q96LB2 UNIPROT GNAI3 protein P08754 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257171 MAPK14 protein Q16539 UNIPROT ATF2 protein P15336 UNIPROT up-regulates phosphorylation Thr69 SVIVADQtPTPTRFL 9606 12110590 t gcesareni "Here, we show that in fibroblasts, insulin, epidermal growth factor (egf) and serum activate atf2 via a so far unknown two-step mechanism involving two distinct ras effector pathways: the raf-mek-erk pathway induces phosphorylation of atf2 thr71, whereas subsequent atf2 thr69 phosphorylation requires the ral-ralgds-src-p38 pathway." SIGNOR-90521 PHF10 protein Q8WUB8 UNIPROT "SWI/SNF ACTL6B varian" complex SIGNOR-C476 SIGNOR "form complex" binding 9606 30397315 t miannu "Mammalian SWI/SNF (mSWI/SNF) complexes are ATP-dependent chromatin remodelers that modulate genomic architecture and DNA accessibility, enabling timely and appropriate control of gene expression. They are combinatorially assembled from the products of 29 total genes into three final-form complexes: canonical BAF, PBAF (polybromo-associated BAF complexes), and a newly-defined non-canonical BAF (ncBAF), with specific subunits specifying distinct complexes, such as PBRM1, ARID2, and BRD7 in PBAF complexes, ARID1A/ARID1B and DPF2 in canonical BAF (cBAF) complexes, and GLTSCR1/GLTSCR1L and BRD9 in ncBAF complexes" SIGNOR-270598 NDUFS5 protein O43920 UNIPROT "Mitochondrial respiratory chain complex I" complex SIGNOR-C277 SIGNOR "form complex" binding 30030361 t lperfetto "Thus, we now know the complete mammalian cI structure [22,23] and how the subunits are organized in six modules (N, Q, ND1, ND2, ND4 and ND5)|The ND2-module is formed by an initial intermediate that contains MT-ND2, NDUFC1 and NDUFC2 bound to NDUFAF1/CIA30 [49,50], ECSIT [51] and ACAD9 [52,53]. Then, MT-ND3 is added together with TMEM126B [54], forming a larger intermediate to which subunits MT-ND6 and MT-ND4L bind. The latest assembly stages involve the incorporation of subunits NDUFA1, NDUFA10 and NDUFS5 [24,34]." SIGNOR-262179 TNF protein P01375 UNIPROT MC1R protein Q01726 UNIPROT "down-regulates activity" "transcriptional regulation" 9606 BTO:0000847 9767234 f miannu "MSH receptor (MSH-R) binding activity was upregulated by UVB, IL-1alpha, -1beta and ET-1, but was downregulated by TNF-alpha.Northern blotanalysis showed that MC1-R mRNA expression was induced 24 h after UVB irradiation in a dose-dependent manner, and that 24-h treatment with ET-1 also induced an expression of MC1-R mRNA,whereas TNF-a downregulated the expression. In addition, IL-1a and -1b have a small but real inductiveeffect on MC1-R mRNA expression." SIGNOR-252381 PRKACA protein P17612 UNIPROT NFKB1 protein P19838 UNIPROT up-regulates phosphorylation Ser337 FVQLRRKsDLETSEP 9606 SIGNOR-C13 17959673 t llicata "In this study, we demonstrate that the phosphorylation of p50 and p65 by the catalytic subunit of protein kinase a (pkac) is essential for nf-kappab dna binding and transactivation activity. treatment with h89 and knockdown of pkac in cells led to the inhibition of phosphorylation at p50 ser(337) and p65 ser(276) and loss of dna binding by nf-kappab." SIGNOR-158595 NR3C1 protein P04150 UNIPROT CEBPA protein P49715 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 BTO:0000746 27777311 t "We show that in addition, DEX-bound GR directly promotes the expression of adipogenic TFs, including C/EBPβ, Klf5, Klf9, and C/EBPα" SIGNOR-256116 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR BANP protein Q8N9N5 UNIPROT "down-regulates activity" phosphorylation Thr337 VKSFSRRtPNSSSYC 9606 BTO:0000567 26080397 t miannu "ERK-MAPK pathway that regulates alternative splicing facilitates ERK-1/2-mediated phosphorylation of SMAR1 at threonines 345 and 360 and localizes SMAR1 to the cytoplasm, preventing its interaction with Sam68." SIGNOR-266377 PRKD1 protein Q15139 UNIPROT PRKD1 protein Q15139 UNIPROT unknown phosphorylation Ser742 GEKSFRRsVVGTPAY -1 10867018 t lperfetto "The last two autophosphorylation sites (Ser(744) and Ser(748)) are located in the activation loop but are only phosphorylated in the isolated PKD-catalytic domain and not in the full-length PKD; they may affect enzyme catalysis but are not involved in the activation of wild-type PKD by phorbol ester. | These results indicate that neither of the activation loop serines is involved in PDBu-induced activation but that they may be involved in catalysis or in maintaining the conformation of the enzyme prot" SIGNOR-249047 PRKD1 protein Q15139 UNIPROT PPP1R14A protein Q96A00 UNIPROT "up-regulates activity" phosphorylation Thr38 QKRHARVtVKYDRRE 9606 32471307 t lperfetto "A major kinase for GPCR‐induced CPI‐17 phosphorylation is PKC which is activated by the PLCbeta‐produced signaling messenger diacylglycerol (DAG). It phosphorylates CPI‐17 at Thr38 residue that directly docks at the active site of MLCP, thereby inhibiting its activity and promoting an increase of phosphorylation of myosin and of other MLCP.| CPI-17 can be also directly phosphorylated at Thr38 residue by MYPT1-associated kinase [222], by PAK, which is downstream of Rac and/or Cdc42 cascade [223], by Rho-associated coiled-coil kinase (ROCK) [224] and by PKN [225]." SIGNOR-123226 MET protein P08581 UNIPROT GAB1 protein Q13480 UNIPROT "up-regulates activity" phosphorylation Tyr285 TEADGELyVFNTPSG 9606 BTO:0000018 10734310 t miannu "Gab-1 is phosphorylated on the same residues by HGF and EGF receptors. Among 16 peptides only nine were phosphorylated by the EGF and HGF receptors, namely peptides containing the tyrosine residues 285, 307, 373, 407, 448, 473, 590, 628 and 660. we show that in the response to HGF or EGF, Gab1 is phosphorylated in vivo on the same residues. However, a sustained activation of signaling pathways downstream to Gab1 (as a result of its sustained phosphorylation) is achieved only in response to HGF." SIGNOR-250552 PPP1CA protein P62136 UNIPROT AHCYL1 protein O43865 UNIPROT unknown dephosphorylation Ser68 RSLSRSIsQSSTDSY 10090 17635105 t "Moreover, IRBIT-associated PP1 specifically dephosphorylated Ser68 of IRBIT. Phosphorylation of Ser68 was required for subsequent phosphorylation of Ser71 and Ser74, but the latter two sites were not targeted by PP1. We found that phosphorylation of Ser71 and Ser74 were sufficient to enable inhibition of IP3 binding to the IP3R|Given the importance of phosphorylation for the function of IRBIT in suppressing IP3R activity [7,10], in the present study, we searched for a protein phosphatase involved in the dephosphorylation and, hence, inactivation of IRBIT. We found that IRBIT contains a specific well-conserved binding site for PP1." SIGNOR-248555 CSNK1A1L protein Q8N752 UNIPROT GLI2 protein P10070 UNIPROT up-regulates phosphorylation 9606 16481469 t gcesareni "Gli2 is phosphorylated by gsk3 and ck1 for the fbxw11 (betatrcp2)-mediated degradation ci is phosphorylated by pka at multiple sites priming phosphorylation by both gsk3 and cki, leading to partial proteolysis. The pka, gsk3, and cki sites are conserved in gli2 and gli3, vertebrate homologs of ci that are similarly processed" SIGNOR-144551 ATF4 protein P18848 UNIPROT CARS2 protein Q9HA77 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 33384352 t miannu "QRICH1 promotes the expression of translation-related genes. our combined ChIP-seq and RNA-seq analyses identified that QRICH1 and ATF4 were enriched at the promoters of these specific tRNA synthetases, and that ER stress positively regulated their transcription (Fig. 4I). Together, these findings suggest that QRICH1 and ATF4 modulate tRNA metabolic processes to promote secreted protein synthesis during ER stress." SIGNOR-269417 GRM1 protein Q13255 UNIPROT GNAS protein P63092 UNIPROT "up-regulates activity" binding 9606 BTO:0000227 20055706 t miannu "MGluRs are members of the G-protein-coupled receptor (GPCR) superfamily, the most abundant receptor gene family in the human genome. GPCRs are membrane-bound proteins that are activated by extracellular ligands such as light, peptides, and neurotransmitters, and transduce intracellular signals via interactions with G proteins. The resulting change in conformation of the GPCR induced by ligand binding activates the G protein, which is composed of a heterotrimeric complex of α, β, and γ subunits." SIGNOR-264077 AARS1 protein P49588 UNIPROT diphosphate(3-) smallmolecule CHEBI:33019 ChEBI "up-regulates quantity" "chemical modification" 9606 32314272 t miannu "Alanyl-tRNA synthetase 1 (AARS1) gene encodes a ubiquitously expressed class II enzyme that catalyzes the attachment of alanine to the cognate tRNA. AARS1 mutations are frequently responsible for autosomal dominant Charcot-Marie-Tooth disease type 2N (CMT2N)." SIGNOR-270449 PRKCA protein P17252 UNIPROT TNNI3 protein P19429 UNIPROT "up-regulates activity" phosphorylation Ser24 APIRRRSsNYRAYAT -1 11121119 t lperfetto "In addition to the established phosphorylation sites (S22 and S23) we found that S38 and S165 were the other two main sites of phosphorylation. | Phosphorylation of S22/23A also decreased its affinity for troponin C indicating that phosphorylation of S38 and/or S165 impedes binding of troponin I to troponin C. Formation of a troponin I/troponin C complex prior to cAMP-dependent protein kinase treatment did not prevent overphosphorylation." SIGNOR-249067 NEXMIF protein Q5QGS0 UNIPROT Neurite_outgrowth phenotype SIGNOR-PH134 SIGNOR up-regulates 10116 BTO:0000938 27822498 f miannu "The X-Linked Autism Protein KIAA2022/KIDLIA Regulates Neurite Outgrowth via N-Cadherin and δ-Catenin Signaling. We found that KIDLIA is distributed exclusively in the nucleus" SIGNOR-269659 GXYLT2 protein A0PJZ3 UNIPROT NOTCH1 protein P46531 UNIPROT up-regulates binding 9606 22117070 t "Xylosylation in ER membrane." gcesareni "Recently, we have shown (28) that two members of the human glycosyltransferase 8 family (gt8) (29), gxylt1 and gxylt2 (glucoside-xylosyltransferase 1/2), are able to transfer the first alfa1,3-linked xylose to o-glucosylated mammalian notch egf repeats." SIGNOR-177714 bromocriptine chemical CHEBI:3181 ChEBI DRD3 protein P35462 UNIPROT "up-regulates activity" "chemical activation" 10029 BTO:0000246 1975644 t miannu "Molecular cloning and characterization of a novel dopamine receptor (D3) as a target for neuroleptics. A dopamine receptor has been characterized which differs in its pharmacology and signalling system from the D1 or D2 receptor and represents both an autoreceptor and a postsynaptic receptor. Table1. pharmacology of D2 and D3 receptors expressed in CHO cells." SIGNOR-258367 ESR1 protein P03372 UNIPROT CCND1 protein P24385 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000150 15808510 t gcesareni "Ikkalpha in conjunction with eralpha and aib1/src-3, is important in activating the transcription of estrogen-responsive genes, including cyclin d1." SIGNOR-135053 NCSTN protein Q92542 UNIPROT PSEN1 protein P49768 UNIPROT up-regulates binding 9606 BTO:0000975 14572442 t "Gamma secretase subunit. Leads to PS1/PS2 eterodimer complex stabilisation" gcesareni "Nicastrin, a transmembrane glycoprotein, forms high molecular weight complexes with presenilin 1 and presenilin 2." SIGNOR-118852 MAP2K4 protein P45985 UNIPROT MAPK10 protein P53779 UNIPROT up-regulates phosphorylation 9606 11242034 t "Phosphorylation of a threonine and a tyrosine residue in a Thr-Pro-Tyr motif." gcesareni "A map kinase kinase kinase (mapkkk), termed ask1, was identified that activated two different subs of map kinase kinases (mapkk), sek1 (or mkk4) and mkk3/mapkk6 (or mkk6), which in turn activated stress-activated protein kinase (sapk, also known as jnk;c-jun amino-terminal kinase) and p38 subs of map kinases, respectively. Here we report that mkk4 shows a striking preference for the tyrosine residue (tyr-185), and mkk7 a striking preference for the threonine residue (thr-183) in three sapk1/jnk1 isoforms tested (jnk1 alpha 1, jnk2 alpha 2 and jnk3 alpha 1)." SIGNOR-105692 MAP3K5 protein Q99683 UNIPROT DAXX protein Q9UER7 UNIPROT up-regulates phosphorylation Ser176 TNAENTAsQSPRTRG 9606 19789335 t gcesareni "Our data demonstrated that ask1 controls the cytoplasmic localization of daxx (fig.1). our results indicate that daxx not only activates ask1 but also is a downstream target of ask1 and that accumulated daxx further activates ask1. Thus, the daxx-ask1 positive feedback loop amplifying jnk/p38 signaling plays an important role in the cell-killing effects of stressors, such as tnfalpha." SIGNOR-188321 CSF1 protein P09603 UNIPROT CSF3R protein Q99062 UNIPROT up-regulates binding 9606 16492764 t gcesareni "A crystal structure of the signaling complex between human granulocyte colony-stimulating factor (gcsf) and a ligand binding region of gcsf receptor (gcsf-r), has been determined to 2.8 a resolution" SIGNOR-144737 "prostaglandin H2(1-)" smallmolecule CHEBI:57405 ChEBI "prostaglandin G2(1-)" smallmolecule CHEBI:82629 ChEBI "up-regulates quantity" "precursor of" -1 7592599 t Luana "[14C]Arachidonate metabolism by oPGHS-1 and hPGHS-2 was examined in reactions with a series of GSP/Cox ratios (Fig. 3). The principal metabolite for both isoforms was the endoperoxide PGH2, with lesser amounts of PGF2a, PGE2, PGD2," SIGNOR-269769 "Food intake" phenotype SIGNOR-PH152 SIGNOR "folic acid" smallmolecule CHEBI:27470 ChEBI up-regulates 9606 19706381 f lperfetto "The U.S. Reference Daily Intake (Daily Value) for FA is 0.4 mg for adults to aid in the prevention of birth defects and anemia, or double this amount for pregnant or lactating women." SIGNOR-268262 MAPK1 protein P28482 UNIPROT GABRR1 protein P24046 UNIPROT unknown phosphorylation Ser435 TLASERSsPQRKSQR -1 12175859 t miannu "Here, we have identified phosphorylation sites on the human ρ1 GABA receptor for six protein kinases widely expressed in the brain: protein kinase C (PKC); cAMP‐dependent protein kinase (PKA); calmodulin‐dependent kinase (CaMKII); casein kinase (CKII); mitogen‐activated protein kinase (MAPK); and cGMP‐dependent protein kinase (PKG). From these data we conclude that T373 is the predominant site of phosphorylation, with a low level of phosphorylation at S413 and/or S414. An extensive functional analysis comparing wild type 1 receptors and receptors with select or multiple phosphorylation sites removed as well as pharmacological manipulation of five kinase pathways failed to reveal any functional effects of phosphorylation" SIGNOR-262747 PTPN13 protein Q12923 UNIPROT INSR protein P06213 UNIPROT down-regulates dephosphorylation Tyr999 YASSNPEyLSASDVF 9606 15611135 t gcesareni "We demonstrate that ptpl1, like ptp1b, interacts with and dephosphorylates a bis-phosphorylated insulin receptor peptide more efficiently than monophosphorylated peptides, indicating that ptpl1 may down-regulate the phosphatidylinositol 3-kinase pathway, by dephosphorylating insulin or growth factor receptors that contain tandem phosphotyrosines." SIGNOR-132563 ATM protein Q13315 UNIPROT BRCA1 protein P38398 UNIPROT up-regulates phosphorylation Ser1423 AVLEQHGsQPSNSYP 9606 BTO:0000150 10550055 t lperfetto "Phosphorylation of serine 1387 in brca1 is specifically required for the atm-mediated s-phase checkpoint after ionizing irradiation.We recently reported that brca1 function is required for appropriate cell cycle arrests after ionizing irradiation in both the s-phase and the g2 phase of the cell cycle. We also found that mutation of serine 1423 in brca1, a target of atm phosphorylation, abrogates the g2-m checkpoint but not the ionizing irradiation-induced s-phase checkpoint. Here we demonstrate that mutation of serine 1387 in brca1, another target of atm phosphorylation, conversely abrogates the radiation-induced s-phase arrest but does not affect the g2-m checkpoint." SIGNOR-72052 PRKCA protein P17252 UNIPROT TNNI3 protein P19429 UNIPROT down-regulates phosphorylation Ser42 AKKKSKIsASRKLQL 9606 BTO:0000887 15769444 t lperfetto "Phosphorylation at ser 23/24 (e.g., by pka or pkg) results in reduction in myofilament ca2+ sensitivity and an increase in crossbridge cycling rate, leading to acceleration of relaxation and an increase in power output but a reduced economy of contraction. Conversely, phosphorylation at ser 43/45 (by pkc) is associated with reduced maximum ca2+-activated force and decreased crossbridge cycling rates, which are likely to reduce power output and delay relaxation, with an increased economy of contraction." SIGNOR-134613 5-(1,1-Dimethylheptyl)-2-[5-hydroxy-2-(3-hydroxypropyl)cyclohexyl]phenol chemical CID:104895 PUBCHEM CNR1 protein P21554 UNIPROT "up-regulates activity" "chemical activation" 9606 BTO:0002524 31160049 t "Ligand-GPCR dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257473 RELA protein Q04206 UNIPROT IEX-1L protein O75353 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 9703517 f gcesareni "Transcription factors of the nuclear factor-kappab/rel (nf-kappab) family may be important in cell survival by regulating unidentified, anti-apoptotic genes. One such gene that protects cells from apoptosis induced by fas or tumor necrosis factor type alpha (tnf), iex-1l, is described here." SIGNOR-59542 SIRT2 protein Q8IXJ6 UNIPROT AFP protein P02771 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000599 14522900 f miannu " In this study, we found that a subset of ING family members strongly repressed human alpha-fetoprotein (AFP) promoter activity but stimulated the p21(WAF1) promoter in parallel experiments in the same cell type, similar to the effects of p53. Both ING1 and p53 were able to suppress AFP transcription and cause p21 induction; hSIR2, a negative regulator of the p53 protein, showed the opposite effects on the AFP promoter and, like HDAC1, repressed p21 promoter activity." SIGNOR-254487 PRKCD protein Q05655 UNIPROT TBL1XR1 protein Q9BZK7 UNIPROT "up-regulates activity" phosphorylation Ser123 AAASQQGsAKNGENT 9606 18374649 t Manara "In addition, we describe that the functions and the specificity of these two highly- related exchange factors is tightly regulated by signal-induced phosphorylation events at the level of target gene promoters, as exemplified by the role of TBLR1 phosphorylation at Ser 123 by PKCδ upon retinoic acid or estrogen stimulation." SIGNOR-260903 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR G2/M_transition phenotype SIGNOR-PH52 SIGNOR up-regulates 15549093 f lperfetto "The critical target of the G2 checkpoint is the mitosis-promoting activity of the cyclin B/CDK1 kinase, whose activation after various stresses is inhibited by ATM/ATR, CHK1/CHK2 and/or p38-kinase-mediated subcellular sequestration, degradation and/or inhibition of the CDC25 family of phosphatases that normally activate CDK1 at the G2/M boundary" SIGNOR-251497 CDK1 protein P06493 UNIPROT TP53BP1 protein Q12888 UNIPROT "down-regulates activity" phosphorylation Ser1678 ITSEEERsPAKRGRK -1 30685087 t lperfetto "Nuclear import of 53BP1 is required for proper localization of 53BP1 and maintenance of genome integrity. 53BP1 has a classical bipartite nuclear localization signal (NLS) of sequence 1666-GKRKLITSEEERSPAKRGRKS-1686. Ser1678 within the 53BP1 NLS can be phosphorylated by CDK1/cyclin B, and a phosphomimetic substitution of Ser1678 with aspartate has been shown to negatively regulate nuclear import of 53BP1." SIGNOR-264412 MAPK1 protein P28482 UNIPROT POLR2A protein P24928 UNIPROT down-regulates phosphorylation Ser1626 SPSYSPTsPSYSPTS 9606 14662762 t lperfetto "Erk1/2 are major ser-5 kinases after h2o2 treatment. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination." SIGNOR-120088 EGFR protein P00533 UNIPROT ERBB2 protein P04626 UNIPROT up-regulates binding 9606 11279155 t gcesareni "These results demonstrate that egfr-erbb2 oligomers are potent activators of mapk and akt, and this signaling does not require egfr kinase activity" SIGNOR-106500 Gbeta proteinfamily SIGNOR-PF4 SIGNOR CTTN protein Q14247 UNIPROT up-regulates phosphorylation 9606 BTO:0000938 20444238 t "inferred from 70% family members" gcesareni "Cortactin is regulated by multiple phosphorylation events, including phosphorylation of s405 and s418 by extracellular regulated kinases (erk)1/2. Erk1/2 phosphorylation of cortactin has emerged as an important positive regulatory modification, enabling cortactin to bind and activate the arp2/3 regulator neuronal wiskott-aldrich syndrome protein (n-wasp), promoting actin polymerization and enhancing tumor cell movement." SIGNOR-270051 PABPC1 protein P11940 UNIPROT NFX1 protein Q12986 UNIPROT "up-regulates activity" binding 9606 BTO:0000009 17267499 t Simone "We identifiednew protein partners of NFX1-123, including several cytoplasmic poly(A) binding proteins (PABPCs) thatinteracted with NFX1-123 through its N-terminal PAM2 motif. Central to our findings were our observations that PABPCs copurify with NFX1-123, that a PAM2 motif is present in NFX1, and this motif and the PABPCs are important in the enhancement of hTERT activity by NFX1-123." SIGNOR-261052 QRICH1 protein Q2TAL8 UNIPROT WARS2 protein Q9UGM6 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 33384352 t miannu "QRICH1 promotes the expression of translation-related genes. our combined ChIP-seq and RNA-seq analyses identified that QRICH1 and ATF4 were enriched at the promoters of these specific tRNA synthetases, and that ER stress positively regulated their transcription (Fig. 4I). Together, these findings suggest that QRICH1 and ATF4 modulate tRNA metabolic processes to promote secreted protein synthesis during ER stress." SIGNOR-269411 Selinexor chemical CID:71481097 PUBCHEM XPO1 protein O14980 UNIPROT "down-regulates activity" "chemical inhibition" 9606 30510142 t miannu "Selinexor (KPT-330) is a first-in-class selective inhibitor of nuclear export (C17H11F6N7O; see ref. 4; for its chemical structure). The drug binds and inhibits exportin XPO-1 that mediates nuclear export of proteins and mRNAs." SIGNOR-262537 SMO protein Q99835 UNIPROT STK36 protein Q9NRP7 UNIPROT up-regulates binding 9606 17089004 t gcesareni "Smo then activates stk36 serine/threonine kinase to stabilize gli family members and to phosphorylate sufu for nuclear accumulation of gli.| sufu binds to the kinesin cos2 to transduce the hh signal downstream of smo" SIGNOR-150540 ELE1-RET "fusion protein" SIGNOR-FP10 SIGNOR SHC1 protein P29353 UNIPROT "up-regulates activity" binding 9606 16946010 t miannu "RET/PTC is tumorigenic in thyroid follicular cells; it transforms thyroid cells in culture and gives rise to thyroid carcinomas in transgenic mice. effects of RET/PTC activation require signaling along the MAPK pathway and, more specifically, the presence of the functional BRAF kinase. all breakpoints in the RET gene occur within intron 11, leaving intact the TK domain of the receptor and enabling the RET/PTC oncoprotein to bind SHC via Y1062 and activate the RAS-RAF-MAPK cascade" SIGNOR-251985 CDH1 protein P12830 UNIPROT Epithelial-mesenchymal_transition phenotype SIGNOR-PH45 SIGNOR down-regulates 15601859 f lperfetto "A hallmark characteristic of epithelial tumor progression as well as some processes of normal development is the loss of the epithelial phenotype and acquisition of a motile or mesenchymal phenotype. Such epithelial to mesenchymal transitions are accompanied by the loss of E-cadherin function by either transcriptional or posttranscriptional mechanisms." SIGNOR-252261 SMAD5 protein Q99717 UNIPROT SMAD4 protein Q13485 UNIPROT up-regulates phosphorylation 9606 20957627 t gcesareni "Whereas alk5 signalling is mediated by phosphorylation of smad2 and smad3 proteins, alk1 signalling is mediated by smad1, smad5, and smad8. Activated smads form a complex with the common smad (co-smad; smad4 in mammals) and shuttle into the nucleus." SIGNOR-168737 NRF1 protein Q16656 UNIPROT RETREG3 protein Q86VR2 UNIPROT up-regulates 9606 BTO:0000934 23939472 f lperfetto "We found that NRF-1 positively regulates FAM134C and ENOX1, but negatively regulates C3orf10 in human neuroblastoma IMR-32 cells and primary rat cortical neurons. In IMR-32 cells, FAM134C positively regulates and C3orf10 negatively regulates neurite outgrowth, but ENOX1 plays no role in neurite outgrowth regulation. " SIGNOR-261489 MRPL43 protein Q8N983 UNIPROT "39S mitochondrial large ribosomal subunit" complex SIGNOR-C285 SIGNOR "form complex" binding -1 25838379 t lperfetto "We have determined the structure of the intact mitoribosome to 3.5 angstrom resolution by single-particle electron cryo-microscopy. It reveals 80 extensively interconnected proteins, 36 of which are specific to mitochondria, and three rRNA molecules" SIGNOR-262353 PRKAA1 protein Q13131 UNIPROT DNMT1 protein P26358 UNIPROT "down-regulates activity" phosphorylation Ser714 DNIPEMPsPKKMHQG -1 28143904 t lperfetto "Together, these results indicate that AMPK phosphorylated DNMT1-Ser730, RBBP7-Ser314, and HAT1-Ser190|AMPK decreased DNMT1 activity" SIGNOR-264783 LAMC1 protein P11047 UNIPROT Laminin-9 complex SIGNOR-C180 SIGNOR "form complex" binding 10809728 t lperfetto "Laminins are a large family of heterotrimeric extracellular matrix glycoproteins that, in addition to having structural roles, take part in the regulation of processes such as cell migration, differentiation, and proliferation. The laminin alpha(4) chain is widely distributed both in adults and during development in tissues such as cardiac, skeletal and smooth muscle fibers, vascular endothelia, lungs, and in peripheral nerves. It can associate with laminin beta(1)/gamma(1) chains to form laminin-8 and with the beta(2)/gamma(1) chains to form laminin-9." SIGNOR-253225 KDM3B protein Q7LBC6 UNIPROT UCP1 protein P25874 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 BTO:0005964 19194461 t miannu "We show that Jhdm2a expression is induced by beta-adrenergic stimulation, and that Jhdm2a directly regulates peroxisome proliferator-activated receptor alpha (Ppara) and Ucp1 expression." SIGNOR-266638 FOXA1 protein P55317 UNIPROT NFIB protein O00712 UNIPROT up-regulates binding 9606 24801505 t miannu "Androgen receptor (ar) action throughout prostate development and in maintenance of the prostatic epithelium is partly controlled by interactions between ar and forkhead box (fox) transcription factors, particularly foxa1./ Foxa1 is capable of bringing ar and nfix into proximity, indicating that foxa1 facilitates the ar and nfi interaction by bridging the complex." SIGNOR-205027 CRYAB protein P02511 UNIPROT CRYGD protein P07320 UNIPROT "up-regulates activity" binding -1 20621668 t miannu "Human gamma-crystallins are long-lived, unusually stable proteins of the eye lens exhibiting duplicated, double Greek key domains. The lens also contains high concentrations of the small heat shock chaperone alpha-crystallin, which suppresses aggregation of model substrates in vitro. Mature-onset cataract is believed to represent an aggregated state of partially unfolded and covalently damaged crystallins. The alphaB-crystallin oligomers formed long-lived stable complexes with their gammaD-crystallin substrates. These in vitro results provide support for protein unfolding/protein aggregation models for cataract, with alpha-crystallin suppressing aggregation of damaged or unfolded proteins through early adulthood but becoming saturated with advancing age." SIGNOR-253621 FNIP2 protein Q9P278 UNIPROT HSP90AA1 protein P07900 UNIPROT "down-regulates activity" binding 9606 BTO:0000007 27353360 t miannu "FNIP1 and FNIP2 facilitate FLCN binding to Hsp90 chaperone. Our results suggest that FNIP1 is a potent inhibitor of Hsp90 ATPase activity, as 200 nM of FNIP1 inhibits Hsp90 ATPase activity by 50-fold. FNIP2 also has shown inhibitory activity towards Hsp90; however, it required 1.6 μM of FNIP2 to inhibit the ATPase activity by eightfold. Although we use the term ‘inhibition' here, FNIPs seem only to be slowing the chaperone cycle." SIGNOR-261414 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR CASP8 protein Q14790 UNIPROT down-regulates phosphorylation Ser387 YLEMDLSsPQTRYIP 9606 BTO:0000149 24342355 t lperfetto "We demonstrate that perk 1/2 can phosphorylate pro-caspase-8 at s387 by knocking-down the endogenous pro-caspase-8 using rnai and replacing it with its non-phosphorylatable counterpart (s387a), a significant increase in caspase-8 activity" SIGNOR-244509 CSNK2A1 protein P68400 UNIPROT MDC1 protein Q14676 UNIPROT up-regulates phosphorylation Ser376 LQESQAGsDTDVEEG 9606 18678890 t gcesareni "The mdc1-nbs1 interaction occurs through a specific region (residues 200-420) of mdc1, which contains multiple consensus casein kinase 2 (ck2) phosphorylation sites." SIGNOR-179879 RARA protein P10276 UNIPROT THRA protein P10827 UNIPROT up-regulates binding 9606 15650024 t gcesareni "We report that the retinoic acid receptors (rars), a distinct class of nuclear receptors, are also efficient heterodimer partners for trs." SIGNOR-133231 CyclinK/CDK13 complex SIGNOR-C38 SIGNOR POLR2A protein P24928 UNIPROT "up-regulates activity" phosphorylation Ser1931 SPTSPTYsPTSPKGS 9606 BTO:0006413 32917631 t "Ser2 in CTD of PolII" lperfetto "Together, these studies demonstrate the important, yet largely redundant, role for CDK12 and CDK13 for the regulation of POLII CTD phosphorylation at multiple residues, as well as the global role for both of these kinases in regulating POLII occupancy across the genome.|CDK12 and CDK13 are thus evolutionarily related and structurally similar kinases, and biochemical assays have demonstrated that both have POLII C-terminal domain (CTD) kinase activity and the ability to phosphorylate the Ser2 residue of the repetitive CTD heptad sequence" SIGNOR-273074 PRKACA protein P17612 UNIPROT BAD protein Q92934 UNIPROT "down-regulates activity" phosphorylation Ser99 PFRGRSRsAPPNLWA -1 10949026 t gcesareni "Survival factors, acting through kinases such as Akt and PKA, induce endogenous BAD phosphorylation at two evolutionarily conserved sites, Ser-112 and Ser-136, which leads to the translocation of BAD from the mitochondria to the cytoplasm and the inhibition of BAD-dependent death" SIGNOR-180780 CyclinK/CDK13 complex SIGNOR-C38 SIGNOR POLR2A protein P24928 UNIPROT "up-regulates activity" phosphorylation Ser1896 SPTSPTYsPTSPVYT 9606 BTO:0006413 32917631 t "Ser2 in CTD of PolII" lperfetto "Together, these studies demonstrate the important, yet largely redundant, role for CDK12 and CDK13 for the regulation of POLII CTD phosphorylation at multiple residues, as well as the global role for both of these kinases in regulating POLII occupancy across the genome.|CDK12 and CDK13 are thus evolutionarily related and structurally similar kinases, and biochemical assays have demonstrated that both have POLII C-terminal domain (CTD) kinase activity and the ability to phosphorylate the Ser2 residue of the repetitive CTD heptad sequence" SIGNOR-273076 PRKCA protein P17252 UNIPROT PLA2G4A protein P47712 UNIPROT up-regulates phosphorylation 9606 16963226 t gcesareni "Pkcalfa, but not pkcbeta, is the predominant cpkc isoenzyme required for cpla2 protein phosphorylation and maximal induction of cpla2 enzymatic activity." SIGNOR-149406 PNMT protein P11086 UNIPROT noradrenaline smallmolecule CHEBI:33569 ChEBI "down-regulates quantity" "chemical modification" 9606 7961964 t brain lperfetto "In the adrenal medulla NA (noradrenaline) is N-methylated by the enzyme phenylethanolamine N-methyl transferase (PNMT, EC 2.1.1.28) to form A (adrenaline)." SIGNOR-264008 WNT4 protein P56705 UNIPROT LRP6 protein O75581 UNIPROT up-regulates binding 9606 15578921 t gcesareni "Wnt proteins bind to the frizzled receptors and lrp5/6 co-receptors, and through stabilizing the critical mediator betBeta-catenin, initiate a complex signaling cascade that plays an important role in regulating cell proliferation and differentiation." SIGNOR-131835 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR MKNK2 protein Q9HBH9 UNIPROT up-regulates phosphorylation 9606 9155017 t "inferred from 70% family members" gcesareni "Erk and p38 phosphorylate mnk1 and mnk2, which stimulates their in vitro kinase activity." SIGNOR-270204 "okadaic acid" chemical CHEBI:44658 ChEBI STK3/4 proteinfamily SIGNOR-PF41 SIGNOR up-regulates 9606 23493077 f "inferred from 70% of family members" gcesareni "Okadaic acid has been frequently used to enhance the phosphorylation of mst1 and mst2 and to trigger the activation of the hippo pathway." SIGNOR-269947 TRPC4AP protein Q8TEL6 UNIPROT Cullin4-RBX1-DDB1 complex SIGNOR-C119 SIGNOR "up-regulates activity" binding 9606 BTO:0000007 20551172 t miannu "We characterize a new Myc-interacting factor, TRPC4AP (transient receptor potential cation channel, subfamily C, member 4-associated protein)/TRUSS (tumor necrosis factor receptor-associated ubiquitous scaffolding and signaling protein), which is the receptor for a DDB1 (damage-specific DNA-binding protein 1)-CUL4 (Cullin 4) E3 ligase complex for selective Myc degradation through the proteasome. TRPC4AP/TRUSS binds specifically to the Myc C terminus and promotes its ubiquitination and destruction through the recognition of evolutionarily conserved domains in the Myc N terminus. " SIGNOR-271964 UBE2D2 protein P62837 UNIPROT TRIM9 protein Q9C026 UNIPROT "up-regulates activity" binding 9606 BTO:0000142 20085810 t miannu "Collectively, these results indicated that TRIM9 is an E3 ligase for its self-ubiquitination and that the ubiquitination of TRIM9 likely serves as a signal for proteasomal degradation. As shown in Fig. 1A, TRIM9 was ubiquitinated by itself when incubated with UbcH5b. In contrast, ubiquitination was observed when incubated with other E2 enzymes. These results suggest that TRIM9 cooperates with UbcH5b for its self-ubiquitination. N" SIGNOR-271420 RPS6KA3 protein P51812 UNIPROT PFKFB2 protein O60825 UNIPROT "up-regulates activity" phosphorylation Ser466 PVRMRRNsFTPLSSS 9606 BTO:0000562 9211863 t gcesareni "Heart 6-phosphofructo-2-kinase activation by insulin results from ser-466 and ser-483 phosphorylation and requires 3-phosphoinositide-dependent kinase-1, but not protein kinase b." SIGNOR-49367 CHEK1 protein O14757 UNIPROT TLK2 protein Q86UE8 UNIPROT "down-regulates activity" phosphorylation Ser750 PHIRKSVsTSSPAGA -1 12955071 t miannu "Chk1 phosphorylates GST-fusion fragments of TLK1 in vitro.When Chk1 protein was depleted in cells transfected with pSuper-Chk1, TLK activity was not suppressed after short aphidicolin treatment of S-phase cells (Figure 8a, b)." SIGNOR-262740 MMP2 protein P08253 UNIPROT HAPLN1 protein P10915 UNIPROT "down-regulates quantity by destabilization" cleavage His31 LDHDRAIhIQAENGP -1 7694569 t miannu "Matrix metalloproteinases cleave at two distinct sites on human cartilage link protein. Sequencing studies of modified link protein components revealed that stromelysins-1 and -2, gelatinases A and B and collagenase cleaved specifically between His16 and Ile17, and matrilysin, stromelysin-2 and gelatinase A cleaved between Leu25 and Leu26. Based on previously determined in situ cleavage sites it is evident that matrix metalloproteinases are not solely responsible for the accumulation of link protein degradation products in adult human cartilage, indicating that additional proteolytic agents are involved in the normal catabolism of human cartilage matrix." SIGNOR-256327 ABL1 protein P00519 UNIPROT YAP1 protein P46937 UNIPROT up-regulates phosphorylation Tyr407 SGLSMSSySVPRTPD 9606 18280240 t llicata "In this study, we show that c-abl directly phosphorylates yap1 at position y357 in response to dna damage. Tyrosine-phosphorylated yap1 is a more stable protein that displays higher affinity to p73 and selectively coactivates p73 proapoptotic target genes." SIGNOR-160860 PARP1 protein P09874 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR down-regulates 10090 11907276 f amattioni "Caspase-3 cleaves parp-1. During cd95-mediated apoptosis proteolytic inactivation of parp-1 by caspases prevents atp depletion and thereby ensures the execution of the apoptotic process" SIGNOR-111680 PIAS1 protein O75925 UNIPROT AKT1 protein P31749 UNIPROT "up-regulates activity" sumoylation Lys276 NVVYRDLkLENLMLD 10090 BTO:0002572 23884910 t gcesareni "Although multiple sites on Akt could be SUMOylated, K276 was identified as a major SUMO acceptor site. K276R or E278A mutation reduced SUMOylation of Akt but had little effect on its ubiquitination. Strikingly, these mutations also completely abolished Akt kinase activity. In support of these results, we found that expression of PIAS1 and SUMO1 increased Akt activity, whereas expression of SENP1 reduced Akt1 activity." SIGNOR-252735 PRKG1 protein Q13976 UNIPROT HRH1 protein P35367 UNIPROT down-regulates phosphorylation Ser398 WKRLRSHsRQYVSGL 9606 BTO:0000975 10101032 t "Translocation from Endosome to Lysosome" fspada "Ser396 and ser398 are also potential phosphorylation sites for capk, cgmp-dependent protein kinase, and camk ii. Elevation of intracellular camp content has been shown to attenuate histamine-induced accumulation of ip in c6 glioma cells (peakman and hill, 1994) and in ddt1 mf-2 smooth muscle cells (sipma et al., 1995" SIGNOR-66019 ABL1 protein P00519 UNIPROT CAT protein P04040 UNIPROT up-regulates phosphorylation Tyr386 YRARVANyQRDGPMC 9606 12950161 t lperfetto "C-abl and arg phosphorylated catalase at tyr231 and tyr386 in vitrocatalase is a major effector in the defense of aerobic cells against oxidative stress. Recent studies have shown that catalase activity is stimulated by the c-abl and arg tyrosine kinases" SIGNOR-86585 QOCYWLABLBUJOR-UHFFFAOYSA-N chemical CID:53299324 PUBCHEM SLC6A3 protein Q01959 UNIPROT "down-regulates activity" "chemical inhibition" 9606 BTO:0000007 18487050 t Luana "For [3H]paroxetine, [3H]citalopram, [3H]nisoxetine, and [3H]WIN35,428 the following KD values were obtained on the human monoamine transporters hSERT, hNET, and hDAT by homologous competition experiments: 0.69 nM [3H]paroxetine, 4.46 nM [3H]citalopram, 6.77 nM [3H]nisoxetine, and 24.1 [3H]WIN35,428. " SIGNOR-257796 E2F1 protein Q01094 UNIPROT G1/S_transition phenotype SIGNOR-PH50 SIGNOR up-regulates 9606 21524151 f lperfetto "In its hypophosphorylated state, pRb binds transcription factors of the E2F family which are required for cell cycle progression. As the level of CyclinD/Cdk4/6 complexes increases, pRb becomes phosphorylated and progression through G1 occurs. At a critical level of phosphorylation, E2F is released from pRb. This activates the transcription of CyclinE which complexes with Cdk2 to fully release pRb repression by further phosphorylation, establishing a positive feedback loop. E2F further promotes the transcription of S-phase genes. Thus, CyclinD/Cdk4/6 and CyclinE/Cdk2 together regulate S-phase entry via phosphorylating pRb, which controls pRb binding to E2F" SIGNOR-245477 IKBKB protein O14920 UNIPROT IRS1 protein P35568 UNIPROT "down-regulates activity" phosphorylation Ser527 RFRKRTHsAGTSPTI -1 12351658 t "IRS-1 is a novel direct substrate for IKK and that phosphorylation of IRS-1 at Ser(312) (and other sites) by IKK may contribute to the insulin resistance mediated by activation of inflammatory pathways." SIGNOR-251296 ADRA1A protein P35348 UNIPROT GNA13 protein Q14344 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257279 GSK3B protein P49841 UNIPROT SNAI1 protein O95863 UNIPROT down-regulates phosphorylation Ser115 PAPSSFSsTSVSSLE 9606 20305697 t lperfetto "Snail is a well-known zn-finger transcription factor that promotes emt by repressing e-cadherin expression. It is known that snail is phosphorylated by gsk3beta and degraded by beta-trcp-mediated ubiquitination. A variant of snail (snail-6sa), which abolishes these phosphorylations, is much more stable and resides exclusively in the nucleus to induce emt" SIGNOR-164629 GTF2F2 protein P13984 UNIPROT POLR2E protein P19388 UNIPROT "up-regulates activity" binding 9534 11278533 t miannu "Direct Interaction Between the Subunit RAP30 of Transcription Factor IIF (TFIIF) and RNA Polymerase Subunit 5, Which Contributes to the Association Between TFIIF and RNA Polymerase II. we showed that RPB5 binds RAP30 but not RAP74 and associates to TFIIF through the binding to RAP30." SIGNOR-261179 "CAK complex" complex SIGNOR-C456 SIGNOR TP53 protein P04637 UNIPROT unknown phosphorylation Ser33 LPENNVLsPLPSQAM 9606 9372954 t llicata "We have mapped a major site of phosphorylation by cak to ser-33 of p53 and have demonstrated as well that p53 is phosphorylated at this site in vivo." SIGNOR-269326 CRK protein P46108 UNIPROT MAP4K5 protein Q9Y4K4 UNIPROT "up-regulates activity" binding -1 9788432 t lperfetto "Two novel candidates for signalling partners of Crk family adapter proteins, the hematopoietic progenitor kinase 1 (HPK1) and the kinase homologous to SPS1/STE20 (KHS), were found to bind with great selectivity to the first SH3 domains of c-Crk and CRKL.|These results make it likely that HPK1 and KHS participate in the signal transduction of Crk family adapter proteins in certain cell types." SIGNOR-262830 SMDT1 protein Q9H4I9 UNIPROT MCU_MICU3_variant complex SIGNOR-C501 SIGNOR "form complex" binding 9606 32315830 t miannu "MCU is a Ca2+-selective channel that mediates mitochondrial Ca2+ influx. The human channel contains tetrameric pore-forming MCU, regulatory subunits MICU1/2, and EMRE that is required both for channel function and MICU1/2-mediated Ca2+ regulation." SIGNOR-270870 ATM protein Q13315 UNIPROT TP63 protein Q9H3D4 UNIPROT down-regulates phosphorylation Ser477 NSMNKLPsVSQLINP 9606 18769144 t lperfetto "Atm kinase is a master switch for the delta np63 alpha phosphorylation/degradation in human head and neck squamous cell carcinoma cells upon dna damage. We previously found that the pro-apoptotic dna damaging agent, cisplatin, mediated the proteasome-dependent degradation of delta np63 alpha associated with its increased phosphorylated status. We found that delta np63 alpha is phosphorylated in the time-dependent fashion at the following positions: s385, t397 and s466, which were surrounded by recognition motifs for atm, cdk2 and p70s6k kinases, respectively" SIGNOR-180747 H2AZ1 protein P0C0S5 UNIPROT "Nucleosome_H2A.Z.1 variant" complex SIGNOR-C322 SIGNOR "form complex" binding -1 24311584 t miannu "In the nucleosome, two of each of the histones H2A, H2B, H3 and H4 form the histone octamer and about 145–147 base pairs of DNA are wrapped around it . The histone H2A.Z variant is widely conserved among eukaryotes. Two isoforms, H2A.Z.1 and H2A.Z.2, have been identified in vertebrates and may have distinct functions in cell growth and gene expression. However, no structural differences between H2A.Z.1 and H2A.Z.2 have been reported. In the present study, the crystal structures of nucleosomes containing human H2A.Z.1 and H2A.Z.2 were determined." SIGNOR-263715 IL1A protein P01583 UNIPROT TNF protein P01375 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000667 19005488 f miannu "UVB and proinflammatory cytokines synergistically activate TNF-alpha production in keratinocytes through enhanced gene transcription. UVB and IL-1alpha treatment synergistically enhanced TNF-alpha secretion and mRNA levels in human keratinocytes, similar to the findings reported previously in human fibroblasts." SIGNOR-252209 TCF4 protein P15884 UNIPROT ABCB1 protein P08183 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 20459685 f miannu "Cd2+ reduced the interaction of beta-catenin with AJ components (E-cadherin, alpha-catenin) and increased binding to the transcription factor TCF4 of the Wnt pathway, which was upregulated and translocated to the nucleus. While Wnt target genes (c-Myc, cyclin D1 and ABCB1) were up-regulated by Cd2+, electromobility shift assays showed increased TCF4 binding to cyclin D1 and ABCB1 promoter sequences with Cd2+. Overexpression of wild-type and mutant TCF4 confirmed Cd2+-induced Wnt signaling." SIGNOR-255389 CDC25A protein P30304 UNIPROT CDK1 protein P06493 UNIPROT "up-regulates activity" dephosphorylation Tyr15 EKIGEGTyGVVYKGR 9606 10454565 t "Phosphatase activity of Cdc25A is critical for its activating capacity (data not shown). In this context, it should also be mentioned that Cdc25A is able to activate cyclin B-Cdk1 in vitro" SIGNOR-248480 CyclinK/CDK13 complex SIGNOR-C38 SIGNOR POLR2A protein P24928 UNIPROT "up-regulates activity" phosphorylation Ser1882 SPTSPTYsPTTPKYS 9606 BTO:0006413 32917631 t "Ser2 in CTD of PolII" lperfetto "Together, these studies demonstrate the important, yet largely redundant, role for CDK12 and CDK13 for the regulation of POLII CTD phosphorylation at multiple residues, as well as the global role for both of these kinases in regulating POLII occupancy across the genome.|CDK12 and CDK13 are thus evolutionarily related and structurally similar kinases, and biochemical assays have demonstrated that both have POLII C-terminal domain (CTD) kinase activity and the ability to phosphorylate the Ser2 residue of the repetitive CTD heptad sequence" SIGNOR-273077 PRKCA protein P17252 UNIPROT EDF1 protein O60869 UNIPROT "down-regulates activity" phosphorylation Thr91 GRQSKGLtQKDLATK 9606 BTO:0001949 10816571 t lperfetto "EDF-1 was phosphorylated in vitro by PKC in the presence of Ca2+ and phospholipids | This results shows that introduction of a single negative charge by phosphorylation at Thr-91 inhibited CaM-EDF-1 interactions." SIGNOR-249041 NANOG protein Q9H9S0 UNIPROT SOX17 protein Q9H6I2 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0003298 22795133 f lperfetto "Knockdown of Oct4 or Nanog induced an increase in the expression of Pax6, Gata4, Gata6, Sox17, and FoxA2 in E, H, and p21KD MSCs ( Figure 3F and Figure S2D)" SIGNOR-253168 SGK1 protein O00141 UNIPROT NR3C1 protein P04150 UNIPROT "up-regulates activity" phosphorylation Ser211 PGKETNEsPWRSDLL 9606 23650397 t gcesareni "SGK1 also potentiated and maintained GR activation in the presence of cortisol, and even after cortisol withdrawal, by increasing GR phosphorylation and GR nuclear translocation|Having demonstrated that SGK1 mediates the cortisol-induced increase in GR phosphorylation at the S203 and S211 phospho-sites, which enhance GR nuclear translocation, but not at the S226 site, which inhibits nuclear translocation" SIGNOR-251670 NOTCH1 protein P46531 UNIPROT NFKB2 protein Q00653 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 9528780 f gcesareni "In transient-transfection assays we show that truncated notch-1 strongly induces nf-kappab2 promoter activity." SIGNOR-56097 STK11 protein Q15831 UNIPROT MARK3 protein P27448 UNIPROT "up-regulates activity" phosphorylation Ser215 KLDTFCGsPPYAAPE 9606 BTO:0000568 12879020 t lperfetto "Regulation of the wnt signalling component par1a by the peutz-jeghers syndrome kinase lkb1. Lkb1 is a master kinase that activates 13 kinases of the ampk subfamily, including mark/par-1. Mark3 is activated by phosphorylation on thr-211." SIGNOR-104059 GALR2 protein O43603 UNIPROT GNA13 protein Q14344 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257356 PPARA protein Q07869 UNIPROT ARNTL protein O00327 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 16556735 t miannu "We demonstrate that PPARalpha plays a specific role in the peripheral circadian control because it is required to maintain the circadian rhythm of the master clock gene brain and muscle Arnt-like protein 1 (bmal1) in vivo. This regulation occurs via a direct binding of PPARalpha on a potential PPARalpha response element located in the bmal1 promoter. Reversely, BMAL1 is an upstream regulator of PPARalpha gene expression." SIGNOR-268024 CSNK2A1 protein P68400 UNIPROT CLIP1 protein P30622 UNIPROT up-regulates phosphorylation Ser1364 DDLNNYDsDDQEKQS 9606 20664522 t lperfetto "Herein, we have identified polo-like kinase 1 (plk1) and casein kinase 2 (ck2) as two kinases of clip-170 and mapped s195 and s1318 as their respective phosphorylation sites.Plk1- and ck2-associated phosphorylations of clip-170 are involved in the timely formation of kinetochore-microtubule attachments in mitosis" SIGNOR-167168 S100A9 protein P06702 UNIPROT Macrophage_differentiation phenotype SIGNOR-PH99 SIGNOR down-regulates 10090 18809714 f miannu "We report here that up-regulation of S100A9 in myeloid precursors in cancer inhibits DC and macrophage differentiation and induces accumulation of MDSCs. This may represent a universal molecular mechanism of tumor-induced abnormalities in myeloid cells in cancer, directly linking inflammation and immune suppression." SIGNOR-261933 ITGB1BP1 protein O14713 UNIPROT ITGB2 protein P05107 UNIPROT "down-regulates activity" binding 9606 19118207 t miannu "Integrins also bind to many PTBdomain-containing proteins (Calderwood et al., 2003) – including Dok1 and integrincytoplasmic-domain-associated protein 1 (ICAP1) – and these can compete with talin for binding to integrin and so can impair activation" SIGNOR-257649 NOG protein Q13253 UNIPROT BMPR1A protein P36894 UNIPROT "down-regulates activity" binding 9031 BTO:0000140 12478285 t lperfetto "Noggin binds the domain that is re-quired for bmp-7 to interact with bmp type i and type ii receptors (PMID 22298955).Noggin Inhibits bmp by blocking the molecular interfaces of the binding epitopes for both type i and type ii receptors." SIGNOR-219221 PP1 proteinfamily SIGNOR-PF54 SIGNOR MAPK3 protein P27361 UNIPROT down-regulates dephosphorylation 9606 12840032 t lperfetto "P-erk1/2 proteins were efficiently dephosphorylated in vitro by protein phosphatases 1 and 2a (pp1/2a) and mapk phosphatase 3 (mkp3). the dual specificity phosphatases that specifically dephosphorylate and inactivate the p-erk1/2 are called mapk phosphatases" SIGNOR-264665 CEBPA protein P49715 UNIPROT Monocyte_differentiation phenotype SIGNOR-PH101 SIGNOR "up-regulates activity" 10090 BTO:0000725 19706798 f "Conditional cebpa deficiency in adult mice blocks the transition from common myeloid progenitors (CMP) to granulocyte monocyte progenitors (GMP) resulting in the accumulation of myeloid blasts" SIGNOR-259965 JAK3 protein P52333 UNIPROT JAK3 protein P52333 UNIPROT up-regulates phosphorylation Tyr980 LLPLDKDyYVVREPG 9606 9391116 t gcesareni "We found that jak3 is autophosphorylated on multiple sites including y980 and y981. Compared with the activity of wild-type (wt) jak3, mutant y980f demonstrated markedly decreased kinase activity, and optimal phosphorylation of jak3 on other sites was dependent on y980 phosphorylation. The mutant y980f also exhibited reduced phosphorylation of its substrates, gammac and stat5a. In contrast, mutant y981f had greatly increased kinase activity, whereas the double mutant, yy980/981ff, had intermediate activity." SIGNOR-53590 IL22 protein Q9GZX6 UNIPROT IL10RB protein Q08334 UNIPROT up-regulates binding 9606 17208301 t gcesareni "See table 2" SIGNOR-151880 CIITA protein P33076 UNIPROT HLA-C protein P10321 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0002269 11053628 f miannu "Transfection of CIITA in JEG-3 cells also upregulated functional HLA-B and HLA-C expression." SIGNOR-253775 GPR174 protein Q9BXC1 UNIPROT GNA13 protein Q14344 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257029 DDX20 protein Q9UHI6 UNIPROT "SMN complex" complex SIGNOR-C158 SIGNOR "form complex" binding 12065586 t lperfetto "SMN is part of a large macromolecular complex that also contains Gemin2, Gemin3, Gemin4, Gemin5, and Gemin6. The SMN complex functions in the assembly of spliceosomal small nuclear ribonucleoproteins and probably other ribonucleoprotein particles. We have identified a novel protein component of the SMN complex termed Gemin7 using native purified SMN complexes and peptide sequencing by mass spectrometry." SIGNOR-253117 UDP(3-) smallmolecule CHEBI:58223 ChEBI P2RY6 protein Q15077 UNIPROT "up-regulates activity" "chemical activation" 9606 BTO:0002524 31160049 t "Ligand-GPCR dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257565 Gbeta proteinfamily SIGNOR-PF4 SIGNOR HIF1A protein Q16665 UNIPROT up-regulates phosphorylation 9606 BTO:0000567 18519666 t "inferred from 70% family members" lperfetto "We show that at least two different nuclear protein kinases, one of them identified as p42/p44 mapk, can modify hif-1_. Analysis of in vitro phosphorylated hif-1_ by mass spectroscopy revealed residues ser-641 and ser-643 as possible mapk phosphorylation sites these data suggest that phosphorylation of ser-641/643 by mapk promotes the nuclear accumulation and transcriptional activity of hif-1_" SIGNOR-270095 EFNA5 protein P52803 UNIPROT EPHA3 protein P29320 UNIPROT up-regulates binding 9606 9330863 t gcesareni "Highly promiscuous for ephrin-a ligands it binds preferentially efna5 and became active." SIGNOR-52470 MYC protein P01106 UNIPROT HNRNPA1 protein P09651 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 20010808 t "We also demonstrate that the oncogenic transcription factor c-Myc upregulates transcription of PTB, hnRNPA1 and hnRNPA2," SIGNOR-268690 CBFA2T3 protein O75081 UNIPROT ZNF652 protein Q9Y2D9 UNIPROT "down-regulates activity" binding 9606 BTO:0000007 20116376 t "Previously we reported that a classical C2H2 zinc finger DNA binding protein ZNF652 functionally interacts with CBFA2T3 to repress transcription of genes containing ZNF652 consensus DNA binding sequence within the promoters of these target genes." SIGNOR-253954 BMPR1A/1B/2 complex SIGNOR-C29 SIGNOR BMPR1A/1B/2 complex SIGNOR-C29 SIGNOR up-regulates phosphorylation 9606 18756288 t lperfetto "Bmp ligands bind to the bmp receptors bmpr1 and bmpr2, and bmpr2 then phosphorylates and activates bmpr1." SIGNOR-217029 AP3B2 protein Q13367 UNIPROT "Neuronal AP-3" complex SIGNOR-C445 SIGNOR "form complex" binding 9606 BTO:0000938 19497727 t miannu "Mammals contain more than one AP-3 complex owing to the existence of pairs of genes encoding β3, μ3, and σ3 subunits (A and B isoforms). While both σ3A and σ3B are expressed ubiquitously and seem to be functionally equivalent, the B isoforms of β3 and μ3 display rather restricted expression patterns, mostly in cells of neuronal origin. This has led to the notion of the existence of two types of mammalian AP-3 complexes: a ubiquitous AP-3 comprising δ, β3A, μ3A, and σ3(A or B) subunits, and a brain-specific AP-3 complex containing δ, β3B, μ3B, and σ3(A or B)" SIGNOR-268521 MAPK8 protein P45983 UNIPROT WDR62 protein O43379 UNIPROT "down-regulates quantity by destabilization" phosphorylation Thr1053 PSSSLPQtPEQEKFL 9606 BTO:0000007 30566428 t lperfetto "WDR62 is also negatively regulated by T1053 phosphorylation, leading to the recruitment of F-box and WD repeat domain-containing protein 7 (FBW7) and proteasomal degradation. |JNK1 can induce the phosphorylation of WDR62 T1053" SIGNOR-271710 HTR3D protein Q70Z44 UNIPROT Excitatory_synaptic_transmission phenotype SIGNOR-PH133 SIGNOR up-regulates 9606 BTO:0000142 18761359 f miannu "The 5-hydroxytryptamine type-3 (5-HT3) receptor is a cation-selective ion channel of the Cys-loop superfamily. 5-HT3 receptor activation in the central and peripheral nervous systems evokes neuronal excitation and neurotransmitter release. " SIGNOR-264319 oxaloacetate(2-) smallmolecule CHEBI:16452 ChEBI citrate(3-) smallmolecule CHEBI:16947 ChEBI "up-regulates quantity" "precursor of" 9606 3013232 t miannu "Citrate synthase catalyzes an important step within the cycle, the Claisen condensation of acetyl-Coenzyme A with oxaloacetate to form citrate; and it is the only enzyme in the cycle that can catalyze the formation of a carbon-carbon bond." SIGNOR-266237 IL5RA protein Q01344 UNIPROT SOX4 protein Q06945 UNIPROT "up-regulates activity" binding 10090 BTO:0003104 11498591 t miannu "Sox4 activation by IL-5R_ appears to be direct, with syntenin functioning as an adaptor molecule. Syntenin mediates IL-5–induced Sox4 activation." SIGNOR-223010 abarelix chemical CHEBI:337298 ChEBI GNRHR protein P30968 UNIPROT "down-regulates activity" "chemical inhibition" 9606 BTO:0001033 22416801 t miannu "Two GnRH antagonists are currently available: abarelix and degarelix." SIGNOR-259159 SSTR4 protein P31391 UNIPROT GNAI1 protein P63096 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-256680 TNF protein P01375 UNIPROT TNFRSF1B protein P20333 UNIPROT "up-regulates activity" binding 14732063 t "[...] two distinct types of TNF-Rs have been identified and molecularly cloned: TNF-R55 (also referred to as TNFR1, p55 or CD120a) and TNF-R75 (also called TNFR2, p75 or CD120b)" SIGNOR-253594 AMPK complex SIGNOR-C15 SIGNOR KLC2 protein Q9H0B6 UNIPROT up-regulates phosphorylation Ser582 PRMKRASsLNFLNKS 9606 21725060 t lperfetto "Consistent with phosphorylation of both ser545 and ser582 of klc2 contributing to its 14-3-3 binding, a ser545ala mutant of klc2 could be phosphorylated in vitro by ampk on ser582" SIGNOR-216468 CSNK2B protein P67870 UNIPROT CTDP1 protein Q9Y5B0 UNIPROT "down-regulates activity" phosphorylation Ser740 TKAQRENsPAAFPDR 9606 BTO:0000567 12591939 t llicata "We found that only phosphorylated FCP1 can physically interact with TFIIF. We set out to purify an FCP1 kinase from HeLa cells and identified casein kinase 2, which, surprisingly, displayed a negative effect on FCP1-associated activities.| Phosphorylation of FCP1 by CK2 Inhibits the Transcription Elongation Activity of FCP1. | Two in vivo phosphorylation sites within the C terminus of FCP1 at Ser-575 and Ser-740 were identified" SIGNOR-251064 SRC protein P12931 UNIPROT STAT3 protein P40763 UNIPROT "up-regulates activity" phosphorylation 10090 BTO:0000944 9566874 t lperfetto "Previous studies have demonstrated that one STAT family member, Stat3, possesses constitutively elevated tyrosine phosphorylation and DNA-binding activity in fibroblasts stably transformed by the Src oncoprotein.We conclude that Stat3 activation by the Src oncoprotein leads to specific gene regulation and that Stat3 is one of the critical signaling pathways involved in Src oncogenesis." SIGNOR-235445 DLGAP4 protein Q9Y2H0 UNIPROT DLG4 protein P78352 UNIPROT "up-regulates activity" binding 9606 BTO:0000938 9115257 t miannu "SAPAPs are specifically expressed in neuronal cells and enriched in the PSD fraction. SAPAPs induce the enrichment of PSD-95/SAP90 to the plasma membrane in transfected cells. Thus, SAPAPs may have a potential activity to maintain the structure of PSD by concentrating its components to the membrane area." SIGNOR-264212 PTPN18 protein Q99952 UNIPROT ERBB2 protein P04626 UNIPROT "down-regulates quantity by destabilization" dephosphorylation Tyr1112 DPSPLQRySEDPTVP 9606 BTO:0000007 25081058 t lperfetto "PTPN18 knockdown selectively enhances the EGF-induced tyrosine phosphorylation of the HER2 Y1112, Y1196 and Y1248 sites. |Whereas the catalytic domain of PTPN18 blocks lysosomal routing and delays the degradation of HER2 by dephosphorylation of HER2 on pY(1112), the PEST domain of PTPN18 promotes K48-linked HER2 ubiquitination and its rapid destruction via the proteasome pathway and an HER2 negative feedback loop." SIGNOR-262595 TSHB protein P01222 UNIPROT SLC5A5 protein Q92911 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 14623893 t miannu "I– uptake is stimulated by TSH, the master hormone for thyroid gland regulation. TSH stimulation results, at least in part, from the cAMP-mediated increase in NIS biosynthesis. TSH not only stimulates NIS transcription and biosynthesis but is also required for modulating the NIS phosphorylation pattern, maintaining its half-life, and retaining NIS at the thyrocyte plasma membrane" SIGNOR-251995 NR3C1 protein P04150 UNIPROT CEBPA protein P49715 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 BTO:0000011 11279134 f lperfetto "The differentiation of 3T3-L1 preadipocytes is regulated in part by a cascade of transcriptional events involving activation of the CCAAT/enhancer-binding proteins (C/EBPs) and peroxisome proliferator-activated receptor gamma (PPARgamma) by dexamethasone (DEX), 3-isobutyl-1-methylxanthine (MIX), and insulin" SIGNOR-235346 PCDHA2 protein Q9Y5H9 UNIPROT PCDHGA9 protein Q9Y5G4 UNIPROT "up-regulates activity" binding 9606 BTO:0000227 16697637 t miannu "The clustered protocadherins comprise the largest subfamily of the cadherin superfamily and are predominantly expressed in the nervous system. Pcdh-alpha proteins interact with beta1-integrin to promote cell adhesion. They also form oligomers with Pcdh-gamma proteins at the same membrane sites." SIGNOR-265678 TLN1 protein Q9Y490 UNIPROT "Av/b8 integrin" complex SIGNOR-C185 SIGNOR "up-regulates activity" binding 10090 BTO:0000132 19118207 t miannu "Over the past 10 years, the binding of talin to the cytoplasmic tail of integrin-β subunits has been established to have a key role in integrin activation. Binding of the phosphotyrosinebinding (PTB)-domain-like subdomain of the protein 4.1, ezrin, radixin, moesin (FERM) domain of talin to the conserved WxxxNP(I/L)Y motif of the β-integrin tail permits additional weaker interactions between talin and the membrane-proximal region of the tail that trigger integrin activation, probably through the disruption of inhibitory interactions between α- and β-subunit cytoplasmic tails." SIGNOR-257637 KMT2D protein O14686 UNIPROT HMT complex SIGNOR-C19 SIGNOR "form complex" binding 9606 17500065 t lperfetto "The evolutionarily conserved hdpy-30, ash2l, rbbp5, and wdr5 likely constitute a subcomplex that is shared by all human set1-like hmt complexes." SIGNOR-154763 PRKACA protein P17612 UNIPROT NOS3 protein P29474 UNIPROT up-regulates phosphorylation Ser1177 TSRIRTQsFSLQERQ 9606 11729179 t gcesareni "Recently many investigators have shown that protein phosphorylation of enos by several serine/threonine kinases is a critical control step for no production by endothelial cells. Phosphorylation by amp kinase, akt (or protein kinase b), or protein kinase aon serine 1179 (bovine) or serine 1177 (human) of enos leads to enhanced activity of the enzyme and, thus, augmented production of no." SIGNOR-112371 OAT protein P04181 UNIPROT L-ornithine smallmolecule CHEBI:15729 ChEBI "down-regulates quantity" "chemical modification" 9606 14617280 t miannu "Arginase generates ornithine, an aminoacid that can be further metabolized to proline via ornithine aminotransferase and to polyamines via ornithine decarboxylase (ODC)" SIGNOR-256032 RPS6K proteinfamily SIGNOR-PF26 SIGNOR L1CAM protein P32004 UNIPROT "up-regulates activity" phosphorylation Ser1152 RSKGGKYsVKDKEDT 10116 BTO:0001009 8663493 t lperfetto "Western blot analysis demonstrated that the L1 kinase activity from PC12 cells that phosphorylated this site was co-eluted with the S6 kinase, p90(rsk). Moreover, S6 kinase activity and p90(rsk) immunoreactivity co-immunoprecipitate with L1 from brain, and metabolic labeling studies have demonstrated that Ser1152 is phosphorylated in vivo in the developing rat brain. | These data demonstrate that the membrane-proximal 15 amino acids of the cytoplasmic domain of L1 are important for neurite outgrowth on L1, and the interactions it mediates may be regulated by phosphorylation of Ser1152." SIGNOR-252766 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR RPS6KA2 protein Q15349 UNIPROT up-regulates phosphorylation 9606 8939914 t "inferred from 70% family members" gcesareni "Several lines of investigation have suggested that rsk is phosphorylated and activated by erk1/2 mapk isoforms" SIGNOR-270144 MAP1LC3A protein Q9H492 UNIPROT SQSTM1 protein Q13501 UNIPROT up-regulates binding 9606 17580304 t gcesareni "Sqstm1/p62 (named a170 in the mouse;hereafter p62) is the first proposed example of such proteins (bj_?_?Rk_?_?Y et al.,2005). It binds polyubiquitinated protein aggregates via its uba domain and interacts with lc3 on the autophagosome/ this interaction is necessary for autophagic degradation of p62-positive cytoplasmic inclusion bodies containing ubiquitinated proteins. We also demonstrate that alis are indistinguishable from p62 inclusion bodies and that p62 is required for their formation." SIGNOR-156353 CHEK2 protein O96017 UNIPROT CHEK2 protein O96017 UNIPROT "up-regulates activity" phosphorylation Thr68 SSLETVStQELYSIP 9606 BTO:0000007 11901158 t lperfetto "Thus, activation of chk2 in irradiated cells may occur through oligomerization of chk2 via binding of the thr-68-phosphorylated region of one chk2 to the fha domain of another. Oligomerization of chk2 may therefore increase the efficiency of trans-autophosphorylation resulting in the release of active chk2 monomers that proceed to enforce checkpoint control in irradiated cells." SIGNOR-116135 MASP2 protein O00187 UNIPROT C4A protein P0C0L4 UNIPROT "up-regulates activity" cleavage Arg756 KGQAGLQrALEILQE -1 17204478 t lperfetto "MASP-2 cleaves C4 releasing C4a and generating C4b, which attaches covalently to the pathogen surface upon exposure of its reactive thioester. C2 binds to C4b and is also cleaved by MASP-2 to form the C3 convertase (C4b2a)." SIGNOR-263434 PRKACA protein P17612 UNIPROT NOS1 protein P29475 UNIPROT unknown phosphorylation -1 1375933 t miannu "NOS is stoichiometrically phosphorylated by PKA, PKC, and CaMK, with each enzyme predominantly phosphorylating a distinct serine. CPT-CAMP has no effect on NOS activity" SIGNOR-250021 "neuropeptide FF receptor agonist" smallmolecule CHEBI:141000 ChEBI NPFFR1 protein Q9GZQ6 UNIPROT "up-regulates activity" "chemical activation" 9606 BTO:0002524 31160049 t "Ligand-GPCR dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257549 Gbeta proteinfamily SIGNOR-PF4 SIGNOR PDE4D protein Q08499 UNIPROT down-regulates phosphorylation 9606 10828059 t "The effect has been demonstrated using Q08499-2" gcesareni "These straddle the target residue, ser(579), for erk2 phosphorylation of pde4d3. Mutation of either or both of these docking sites prevented erk2 from being co-immunoprecipitated with pde4d3, ablated the ability of epidermal growth factor to inhibit pde4d3 through erk2 action in transfected cos cells, and attenuated the ability of erk2 to phosphorylate pde4d3 in vitro." SIGNOR-270069 NARS2 protein Q96I59 UNIPROT AMP smallmolecule CHEBI:456215 ChEBI "up-regulates quantity" "chemical modification" 9606 32788587 t miannu "Asparaginyl-tRNA synthetase1 (NARS1) is a member of the ubiquitously expressed cytoplasmic Class IIa family of tRNA synthetases required for protein translation. Asparaginyl-tRNA synthetase1 (NARS1) belongs to the class IIa family, based upon a 7 beta-strand protein structure. There are two NARS genes: NARS1 functions in the cytoplasm while NARS2 functions in mitochondria, solely responsible for asparagine tRNA charging in these locations." SIGNOR-270466 GOLGA7 protein Q7Z5G4 UNIPROT HRAS protein P01112 UNIPROT "up-regulates activity" palmitoylation 9606 BTO:0000007 16000296 t miannu "Covalent lipid modifications mediate the membrane attachment and biological activity of Ras proteins. All Ras isoforms are farnesylated and carboxyl-methylated at the terminal cysteine; H-Ras and N-Ras are further modified by palmitoylation. Here we report that H- and N-Ras are palmitoylated by a human protein palmitoyltransferase encoded by the ZDHHC9 and GCP16 genes. DHHC9 is an integral membrane protein that contains a DHHC cysteine-rich domain. GCP16 encodes a Golgi-localized membrane protein." SIGNOR-261351 HTR1F protein P30939 UNIPROT GNAI3 protein P08754 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-256816 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR MAPK6 protein Q16659 UNIPROT up-regulates phosphorylation Ser684 IGIPQFHsPVGSPLK 9606 20236090 t lperfetto "Using ms analysis, we identified four novel phosphorylation sites, ser684, ser688, thr698 and ser705, located at the extreme c-terminus of erk3. All four sites are followed by a proline residue. We have shown that purified cyclin b-cdk1 (cyclindependent kinase 1) phosphorylates these sitesalanine substitution of the four c-terminal phosphorylation sites markedly decreased the half-life of erk3 in mitosis, thereby linking phosphorylation to the stabilization of the kinase." SIGNOR-216797 PRKCE protein Q02156 UNIPROT GJA1 protein P17302 UNIPROT up-regulates phosphorylation Ser373 RASSRASsRPRPDDL 9606 16474210 t lperfetto "We previously showed that follicle-stimulating hormone (fsh) promoted phosphorylation of cx43 in rat primary granulosa cells. We further identified ser365, ser368, ser369, and ser373 in the carboxy-terminal tail as the major sites of phosphorylation by fsh, and found that the phosphorylation of these residues was essential for channel activity." SIGNOR-144473 MLL-AF4 "fusion protein" SIGNOR-FP4 SIGNOR miR-495 mirna URS000075C517_9606 RNAcentral "down-regulates quantity by repression" "transcriptional regulation" 10090 21730352 f miannu "We provide evidence that PU.1 directly controls expression of at least 4 of these miRs (miR-146a, miR-342, miR-338, and miR-155) through temporally dynamic occupation of binding sites within regulatory chromatin regions adjacent to their genomic coding loci. We conclude that PU.1 bound to open chromatin near 4 of its induced miR loci with 2 types of kinetics: (1) permanent (miR-146a, miR-342, and miR-338) and (2) transient (miR-155) during myeloid differentiation." SIGNOR-256242 "Cullin 1-RBX1-Skp1" complex SIGNOR-C529 SIGNOR CCNE2 protein O96020 UNIPROT "down-regulates quantity by destabilization" polyubiquitination 9606 BTO:0002524 17298674 t miannu "Cdk2 (S384) and GSK3 (T380) prime cyclin E for destruction. The hyper-phosphorylated T380/S384 degron has high affinity for monomeric Fbw7α, which engages the remainder of the SCF to initiate cyclin E's ubiquitination by an E2 enzyme" SIGNOR-271638 "Cullin 3-RBX1-Skp1" complex SIGNOR-C526 SIGNOR WNK3 protein Q9BYP7 UNIPROT "down-regulates quantity by destabilization" polyubiquitination 9606 BTO:0000007 23838290 t miannu "We found that KLHL2, as well as KLHL3, was co-immunoprecipitated with all four WNK isoforms. The direct interaction of KLHL2 with WNKs was confirmed on fluorescence correlation spectroscopy. Co-expression of KLHL2 and Cullin3 decreased the abundance of WNK1, WNK3 and WNK4 within HEK293T cells, and a significant increase of WNK4 ubiquitination by KLHL2 and Cullin3 was observed both in HEK293T cells and in an in vitro ubiquitination assay. These results suggest that KLHL2-Cullin3 also functions as an E3-ligase for WNK isoforms within the body." SIGNOR-272126 MAPK3 protein P27361 UNIPROT TSC2 protein P49815 UNIPROT "down-regulates activity" phosphorylation Ser664 KKTSGPLsPPTGPPG 10090 BTO:0000944 15851026 t lperfetto "Here, we show that Erk may play a critical role in TSC progression through posttranslational inactivation of TSC2. Erk-dependent phosphorylation leads to TSC1-TSC2 dissociation and markedly impairs TSC2 ability to inhibit mTOR signaling, cell proliferation, and oncogenic transformation. |Serine to alanine substitution at S664 or double S664A/S540A mutagenesis resulted in a marked reduction in TSC2 phosphorylation to a similar extent. In contrast, S540A substitution only moderately impaired TSC2 phosphorylation (Figure 3D), corroborating the notion that in vivo S664 is the most relevant residue for Erk-mediated phosphorylation." SIGNOR-249457 "MSL acetyltransferase" complex SIGNOR-C344 SIGNOR H2BS1 protein P57053 UNIPROT "down-regulates activity" monoubiquitination Lys35 RKRKRSRkESYSVYV 9606 21726816 t miannu "MSL1/2 ubiquitylates histone H2B on K 34. Importantly, only mono-ubiquitylation of H2B by MSL1/2 was detected in cells (data not shown), suggesting that MSL1/2, like RNF20/RNF40, was mainly a mono-ubiquitylase under physiological conditions.the MOF-MSL complex functions to promote both H4 K16ac and H2B K34ub. H2B K34ub, in turn, promotes H2B K120ub, H3 K4me3 and K79me2 to facilitate transcription elongation." SIGNOR-271984 p38 proteinfamily SIGNOR-PF16 SIGNOR MAPT protein P10636 UNIPROT down-regulates phosphorylation Thr548 KKVAVVRtPPKSPSS 9606 21215781 t "The effect has been demonstrated using P10636-8" lperfetto "However, other kinases, such as cdk5, p38 and pka, also phosphorylate tau at t231tau phosphorylation at t231, s235 and s262 also contributes to the dissociation of tau from microtubules" SIGNOR-171062 CyclinK/CDK13 complex SIGNOR-C38 SIGNOR POLR2A protein P24928 UNIPROT "up-regulates activity" phosphorylation Ser1616 TPQSPSYsPTSPSYS 9606 BTO:0006413 32917631 t "Ser2 in CTD of PolII" lperfetto "Together, these studies demonstrate the important, yet largely redundant, role for CDK12 and CDK13 for the regulation of POLII CTD phosphorylation at multiple residues, as well as the global role for both of these kinases in regulating POLII occupancy across the genome.|CDK12 and CDK13 are thus evolutionarily related and structurally similar kinases, and biochemical assays have demonstrated that both have POLII C-terminal domain (CTD) kinase activity and the ability to phosphorylate the Ser2 residue of the repetitive CTD heptad sequence" SIGNOR-273079 "bisphenol F" chemical CHEBI:34575 ChEBI ESR1 protein P03372 UNIPROT "up-regulates activity" "chemical activation" -1 31995776 t miannu "This study investigated the endocrine-disrupting activity of BPA, BPF, and BPS alone or as a mixture and the agonistic and antagonistic activity of the BPs using an in vitro bioassay to detect ER-, AR-, and AhR-mediated activity. Here, we evaluated the endocrine-disrupting risks of the bisphenols by investigating their agonist and antagonist activities with the estrogen (ER), androgen (AR), and aryl hydrocarbon (AhR) receptors. Our results showed that BPA, BPS, and BPF (BPs) have estrogen agonist and androgen antagonist activities and decrease the ERα protein level. ." SIGNOR-268731 CDK6 protein Q00534 UNIPROT RUNX1 protein Q01196 UNIPROT "up-regulates activity" phosphorylation Ser276 VHPATPIsPGRASGM 9606 16046550 t "The effect has been demonstrated using Q01196-8." gcesareni "We have identified four phosphorylation sites on aml1c that are necessary for transcriptional activity of aml1c in k562 and 293t cells (27).4 mutation of these four sites (serine 276, serine 293, serine 303, and threonine 300) to alanine abolishes transcriptional activation, whereas mutation of these sites to aspartic acid (which mimics phosphorylation) results in a hyperactive protein." SIGNOR-138961 SPART protein Q8N0X7 UNIPROT ITCH protein Q96J02 UNIPROT "up-regulates activity" binding 9606 19580544 t miannu "Cytosolic endogenous spartin is mono-ubiquitinated and we demonstrate that it interacts via a PPXY motif with the ubiquitin E3 ligases AIP4 [atrophin-interacting protein 4; ITCH (itchy E3 ubiquitin protein ligase homologue] [corrected] and AIP5 (WWP1). Surprisingly, the PPXY motif, AIP4 and AIP5 are not required for spartin's ubiquitination, and so we propose that spartin acts as an adaptor for these proteins." SIGNOR-261306 FNTA protein P49354 UNIPROT HRAS protein P01112 UNIPROT "up-regulates activity" 9606 24294527 t lperfetto "Major investments have been made to target Ras through indirect routes. Inhibition of farnesyl transferase to block Ras maturation has failed in large clinical trials." SIGNOR-242568 ABL1 protein P00519 UNIPROT PLSCR1 protein O15162 UNIPROT unknown phosphorylation Tyr69 PVPNQPVyNQPVYNQ 9606 11390389 t Manara "Our data establish that the Abl SH3 domain binds to the N-terminal proline-rich segment of PLSCR1 and that ABL1 phosphorylates Tyr residues of the PLSCR1 polypeptide, most likely Tyr69 and Tyr74 within the tandem repeat sequence" SIGNOR-260807 ITGB1BP1 protein O14713 UNIPROT ITGB5 protein P18084 UNIPROT "down-regulates activity" binding 9606 19118207 t miannu "Integrins also bind to many PTBdomain-containing proteins (Calderwood et al., 2003) – including Dok1 and integrincytoplasmic-domain-associated protein 1 (ICAP1) – and these can compete with talin for binding to integrin and so can impair activation" SIGNOR-257660 GRPR protein P30550 UNIPROT GNAI1 protein P63096 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257046 MAP3K7 protein O43318 UNIPROT NfKb-p65/p50 complex SIGNOR-C13 SIGNOR "up-regulates activity" 9606 9480845 f lperfetto "Overexpression of tak1 together with its activator protein, tak1 binding protein 1 (tab1), induced the nuclear translocation of nf-kappa b p50/p65 heterodimer accompanied by the degradation of i kappa b alpha and i kappa b beta, and the expression of kappa b-dependent reporter gene...[]...These Results suggest that tak1 induces nf-kappa b activation through a novel nik-independent signaling pathway" SIGNOR-55710 P2RY10 protein O00398 UNIPROT GNAI3 protein P08754 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-256869 NLRX1 protein Q86UT6 UNIPROT NfKb-p65/p50 complex SIGNOR-C13 SIGNOR "up-regulates activity" relocalization 9606 BTO:0002181 18219313 f lperfetto "NLRX1 synergistically potentiated ROS production induced by tumour necrosis factor alpha, Shigella infection and double-stranded RNA, resulting in amplified NF-kappaB-dependent and JUN amino-terminal kinases-dependent signalling. We observed that NLRX1-positive cells showed increased p65 translocation as early as 15 min after infection, an effect that was maintained over time." SIGNOR-260399 ECM stimulus SIGNOR-ST20 SIGNOR "A10/b1 integrin" complex SIGNOR-C167 SIGNOR up-regulates 9606 30889378 t miannu "Upon binding to the extracellular matrix (ECM), the integrins organize the cytoskeleton and activate intracellular signaling, regulating complex cellular behaviors, including survival, proliferation, migration, and various cell fate transitions" SIGNOR-259049 PC protein P11498 UNIPROT oxaloacetate(2-) smallmolecule CHEBI:16452 ChEBI "up-regulates quantity" "chemical modification" 9606 24363178 t miannu "As an alternative to decarboxylation by PDH, the second major fate of mitochondrial pyruvate is the irreversible, ATP-dependent carboxylation of pyruvate to oxaloacetate by pyruvate carboxylase (PC). Oxaloacetate is a critical intermediate in metabolism, linking carbohydrate, lipid, amino acid, and nucleotide metabolism (Fig. 2)" SIGNOR-266552 Gbeta proteinfamily SIGNOR-PF4 SIGNOR RPS6K proteinfamily SIGNOR-PF26 SIGNOR "up-regulates activity" phosphorylation 9606 BTO:0000007 12832467 t "inferred from 70% family members" lperfetto "Phosphorylation of p90 ribosomal S6 kinase (RSK) regulates extracellular signal-regulated kinase docking and RSK activity.Erk-activates the rsk family of serine/threonine kinases,rsk1, rsk2, and rsk3." SIGNOR-270006 CyclinK/CDK13 complex SIGNOR-C38 SIGNOR POLR2A protein P24928 UNIPROT "up-regulates activity" phosphorylation Ser1861 TPTSPKYsPTSPKYS 9606 BTO:0006413 32917631 t "Ser2 in CTD of PolII" lperfetto "Together, these studies demonstrate the important, yet largely redundant, role for CDK12 and CDK13 for the regulation of POLII CTD phosphorylation at multiple residues, as well as the global role for both of these kinases in regulating POLII occupancy across the genome.|CDK12 and CDK13 are thus evolutionarily related and structurally similar kinases, and biochemical assays have demonstrated that both have POLII C-terminal domain (CTD) kinase activity and the ability to phosphorylate the Ser2 residue of the repetitive CTD heptad sequence" SIGNOR-273080 "RNA Polymerase III" complex SIGNOR-C389 SIGNOR tRNA(Ile) smallmolecule CHEBI:29174 ChEBI "up-regulates quantity" "chemical modification" 9606 27911719 t lperfetto "RNAPIII is specialized for transcription of short, abundant nonprotein-coding RNA transcripts. In addition to all tRNAs, RNAPIII transcribes the 5S rRNA and other essential RNAs, including the U6 small nuclear RNA (snRNA), the snR52 small nucleolar RNA and the RNA components of the signal recognition particle (SRP1) and RNase P (RPR1)" SIGNOR-269501 MRPS25 protein P82663 UNIPROT "28S mitochondrial small ribosomal subunit" complex SIGNOR-C266 SIGNOR "form complex" binding 9606 25838379 t miannu "The mammalian mitochondrial ribosome (mitoribosome) has a highly protein-rich composition with a small sedimentation coefficient of 55 S, consisting of 39 S large and 28 S small subunits. . We report here the identification of 28 S small subunit proteins." SIGNOR-261448 ATM protein Q13315 UNIPROT MDM4 protein O15151 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser367 PDCRRTIsAPVVRPK 9606 16943424 t lperfetto "Recently we showed that atm- and hdm2-dependent ubiquitination and subsequent degradation of hdmx following dsb induction are mediated by phosphorylation of hdmx on s403, s367, and s342, with s403 being targeted directly by atm." SIGNOR-149296 FCN2 protein Q15485 UNIPROT MASP2 protein O00187 UNIPROT "up-regulates activity" binding 17204478 t lperfetto "In the lectin pathway, mannose-binding lectin (MBL) and ficolins bind to pathogens and activate MBL-associated serine protease-2 (MASP-2)" SIGNOR-263413 2-[2-Amino-5-(3,4-dimethoxyphenyl)pyrimidin-4-yl]-5-[(4-bromobenzyl)oxy]phenol smallmolecule CID:135651766 PUBCHEM GIPR protein P48546 UNIPROT "up-regulates activity" "chemical activation" 9606 BTO:0002524 31160049 t "Ligand-GPCR dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257498 CDK9 protein P50750 UNIPROT POLR2A protein P24928 UNIPROT up-regulates phosphorylation Ser1665 SPTSPSYsPTSPSYS 9606 24385927 t lperfetto "Cyclin-dependent kinase 9 (cdk9) promotes elongation by rna polymerase ii (rnapii), mrna processing, and co-transcriptional histone modification. Cdk9 phosphorylates multiple targets, including the conserved rnapii elongation factor spt5 and rnapii itself" SIGNOR-203524 CTCF protein P49711 UNIPROT TERT protein O14746 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 16326864 t miannu "CTCF binds the proximal exonic region of hTERT and inhibits its transcription" SIGNOR-253832 MEF2D protein Q14814 UNIPROT MYH7 protein P12883 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 BTO:0000165 17111365 f Regulation miannu "Transient transfection assays demonstrated that the calcineurin/NFATc1 signaling pathway is essential for MyHCbeta promoter activation during transformation of C2C12 myotubes but is not sufficient for complete fast MyHCIId/x promoter inhibition. Along with NFATc1, myocyte enhancer factor-2D (MEF-2D) and the myogenic transcription factor MyoD transactivated the MyHCbeta promoter in calcium-ionophore-treated myotubes in a calcineurin-dependent manner." SIGNOR-251957 "all-trans-retinoic acid" smallmolecule CHEBI:15367 ChEBI PML-RARalpha "fusion protein" SIGNOR-FP2 SIGNOR "down-regulates quantity by destabilization" "chemical inhibition" 9606 19029980 t "Retinoic acid and arsenic synergize to clear LICs through cooperative PML-RARA degradation, this combination does not enhance differentiation." SIGNOR-259926 PRKD1 protein Q15139 UNIPROT OSBP protein P22059 UNIPROT down-regulates phosphorylation Ser240 TALQRSLsELESLKL 9606 21285358 t gcesareni "Pkd attenuates the function of both cert and osbp by phosphorylation at their respective ser(132) and ser(240) residues (phosphorylation inhibition)" SIGNOR-171756 TYK2 protein P29597 UNIPROT STAT3 protein P40763 UNIPROT up-regulates phosphorylation 9606 30029643 t "Since Jak-STAT pathway primarily activated in IL-15-me- diated cell proliferation, we tested whether it is also participates in IL-15-mediated proliferation of FAPs. Interestingly, we found the expression of phospho-Jak3 and phospho-Tyk2, as well as their downstream, phospho- STAT3 and phospho-STAT5, was significantly upregulated" SIGNOR-256255 GNG3 protein P63215 UNIPROT PIK3CA protein P42336 UNIPROT up-regulates binding 9606 16537363 t gcesareni "Gbetagamma subunits released from gi can activate pi3k (phosphoinositide 3-kinase), and can be therefore implicated in smo-dependent activation of akt" SIGNOR-145125 CDX2 protein Q99626 UNIPROT UGT1A8 protein Q9HAW9 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000195 15044625 t "Using gel shift and functional assays, HNF1alpha was demonstrated to bind to and activate the UGT1A8, -1A9, and -1A10 promoters. In contrast, Cdx2 bound to and activated the UGT1A8 and -1A10 promoters but could not activate the UGT1A9 promoter." SIGNOR-253969 1-[4-[[2-(2-amino-5-pyrimidinyl)-7-methyl-4-(4-morpholinyl)-6-thieno[3,2-d]pyrimidinyl]methyl]-1-piperazinyl]-2-hydroxy-1-propanone chemical CHEBI:93753 ChEBI MTOR protein P42345 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-192601 HTR2C protein P28335 UNIPROT GNAI1 protein P63096 UNIPROT "up-regulates activity" binding 9606 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-256734 ruxolitinib chemical CHEBI:66919 ChEBI JAK2 protein O60674 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-206670 MTOR protein P42345 UNIPROT EIF4EBP1 protein Q13541 UNIPROT "down-regulates activity" phosphorylation Ser65 FLMECRNsPVTKTPP 9606 BTO:0000007 SIGNOR-C3 12747827 t lperfetto "Here, we show that a functional TOS motif is required for 4E-BP1 to bind to raptor (a recently identified mTOR-interacting protein), for 4E-BP1 to be efficiently phosphorylated in vitro by themTOR/raptor complex, and for 4E-BP1 to be phosphorylated in vivo at all identified mTOR-regulated sites. mTOR/raptor regulated phosphorylation is necessary for 4E-BP’s efficient release from the translational initiation factor eIF4E. We find that the TOS motif is absolutely required for efficient phosphorylation of 4E-BP1 at all the identified mTOR-regulated sites, namely, Thr37/46, Ser65, and Thr70 in vivo." SIGNOR-101115 FOXA1 protein P55317 UNIPROT AR protein P10275 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 24875621 t miannu "FOXA1 directly inhibits AR expression and thus the transcription of its target genes. FOXA1 inhibits AR gene expression in prostate cancer. oss of FOXA1 may lead to androgen-independent AR signaling and thus castration-resistant prostate cancer progression. Indeed, we have recently reported that FOXA1 is downregulated in CRPC" SIGNOR-251541 STAT5A protein P42229 UNIPROT HBB protein P68871 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 BTO:0000574 9168989 f Regulation miannu "We describe the roles of Stat5 and of these tyrosine residues in the EPOR in the erythroid differentiation of murine hematopoietic cell line SKT6 which produces hemoglobin in response to EPO. Chimeric receptors carrying the extracellular domain of the EGF receptor and the intracellular domain of the EPOR were introduced into SKT6 cells. Like EPO, EGF equally activated Stat5 and induced hemoglobin." SIGNOR-251784 ATF2 protein P15336 UNIPROT YTHDC2 protein Q9H6S0 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0001911 24269672 t lperfetto "Collectively, these data show that YTHDC2 plays an important role in tumor cells growth and activation/recruitment of c-Jun and ATF-2 to the YTHDC2 promoter is necessary for the transcription of YTHDC2, and that HDAC activity is required for the efficient expression of YTHDC2 in both of hepatocyte and HCC cells." SIGNOR-269001 MYOD1 protein P15172 UNIPROT CDKN1A protein P38936 UNIPROT up-regulates 10090 7791789 f lperfetto "The upregulation of p21 occurred at the levels of mrna and protein," SIGNOR-235831 GSK3A protein P49840 UNIPROT PKD2 protein Q13563 UNIPROT unknown phosphorylation Ser76 AGAAASPsPPLSSCS 9606 BTO:0000007 BTO:0000671 16551655 t llicata "We report the identification of a new phosphorylation site for pc2 within its n-terminal domain (ser(76)) and demonstrate that this residue is phosphorylated by glycogen synthase kinase 3 (gsk3)." SIGNOR-145306 PRKCA protein P17252 UNIPROT NCF1 protein P14598 UNIPROT up-regulates phosphorylation Ser370 PAVPPRPsADLILNR 9606 BTO:0000130 12056906 t lperfetto "Phosphopeptide mapping of p47(phox) showed that, as opposed to pkc zeta, pkc alpha, beta ii, and delta are able to phosphorylate all the major pkc sites. The use of p47(phox) mutants identified serines 303, 304, 315, 320, 328, 359, 370, and 379 as targets of pkc alpha, beta ii, and delta.Taken together, these results suggest that pkc alpha, beta ii, delta, and zeta expressed in human neutrophils can individually phosphorylate p47(phox) and induce both its translocation and nadph oxidase activation." SIGNOR-89174 ELANE protein P08246 UNIPROT F2RL1 protein P55085 UNIPROT "down-regulates activity" cleavage Val48 KVDGTSHvTGKGVTV -1 10978167 t lperfetto "PAR1E and PAR2E (10 microM) were incubated in the presence of the different proteases | The enzymes were used at the following concentrations: 0.5 unit/mL thrombin, 2.5 nM trypsin, 20 nM plasmin, 20 nM cathepsin G, 20 nM elastase, 20 nM proteinase 3, and 2 units/mL calpain I and II|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus.|Mass spectrometry studies of PAR2E predicted activation of PAR2 by trypsin through cleavage at the Arg36-Ser37 site, no effect of thrombin, and inactivation of the receptor by plasmin, calpain and leukocyte elastase, cathepsin G, and proteinase 3" SIGNOR-263589 AMPK complex SIGNOR-C15 SIGNOR RPTOR protein Q8N122 UNIPROT down-regulates phosphorylation Ser792 LTQSAPAsPTNKGVH 10090 SIGNOR-C15 SIGNOR-C3 18439900 t lperfetto "These results suggest that AMPK activation can induce phosphorylation of both serine 722 and serine 792.|Raptor phosphorylation is required for inhibition of mTORC1 by AMPK" SIGNOR-263044 FCGR3A protein P08637 UNIPROT TNF protein P01375 UNIPROT "up-regulates quantity by expression" 9606 BTO:0000801 10728755 f lperfetto "This study suggests a dominant role for FcgammaRIIIA in the induction of both TNFalpha and IL-1alpha production by human macrophages in rheumatoid arthritis following receptor ligation by small immune complexes. The signaling of TNFalpha production may require the ligation of either 3 FcgammaRIIIA receptors or only 2 FcgammaRIIIA receptors, where one interaction must involve binding via an Fc domain." SIGNOR-249526 TRiC complex SIGNOR-C539 SIGNOR STAT3 protein P40763 UNIPROT "up-regulates quantity by stabilization" binding 9606 36185250 t miannu "Mammalian cells contain an evolutionarily conserved type II chaperonin called chaperonin containing tailless complex polypeptide 1 (CCT) or tailless complex polypeptide 1 ring complex (TRiC). The CCT complex is composed of eight subunits [CCT1-8 (yeast) or CCTα-θ (mammals)] and folds substrates needed for cell invasion and proliferation, such as actin, tubulin, and cell division cycle protein 20 homolog (cdc20), as well as oncoproteins like signal transducer and activator of transcription 3 (STAT3), Kirsten rat sarcoma viral oncogene homolog (KRAS), and Myelocytomatosis (MYC)." SIGNOR-272870 GALR2 protein O43603 UNIPROT GNA12 protein Q03113 UNIPROT "up-regulates activity" binding 9606 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257296 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR CDKN1A protein P38936 UNIPROT "down-regulates quantity by destabilization" phosphorylation Thr57 NFDFVTEtPLEGDFA 9606 19364816 t lperfetto "We have shown that erk2 interacts with and phosphorylates p21cip1, promoting p21cip1_ubiquitination. We identified two erk2 phosphorylation sites, thr57 and ser130, in p21cip1_and showed that phosphorylation of these residues increases p21cip1_cytoplasmic distribution and proteasome-dependent degradation." SIGNOR-244513 CyclinK/CDK12 complex SIGNOR-C37 SIGNOR POLR2A protein P24928 UNIPROT "up-regulates activity" phosphorylation Ser1665 SPTSPSYsPTSPSYS 9606 BTO:0006413 32917631 t "Ser2 in CTD of PolII" lperfetto "Together, these studies demonstrate the important, yet largely redundant, role for CDK12 and CDK13 for the regulation of POLII CTD phosphorylation at multiple residues, as well as the global role for both of these kinases in regulating POLII occupancy across the genome.|CDK12 and CDK13 are thus evolutionarily related and structurally similar kinases, and biochemical assays have demonstrated that both have POLII C-terminal domain (CTD) kinase activity and the ability to phosphorylate the Ser2 residue of the repetitive CTD heptad sequence" SIGNOR-273091 retinal smallmolecule CHEBI:15035 ChEBI "all-trans-retinoic acid" smallmolecule CHEBI:15367 ChEBI "up-regulates quantity" "precursor of" 9606 21621639 t lperfetto "All-trans-retinoic acid (atRA) provides essential support to diverse biological systems and physiological processes.| An accrual of biochemical, physiological and genetic data have identified specific functional outcomes for the retinol dehydrogenases, RDH1, RDH10, and DHRS9, as physiological catalysts of the first step in atRA biosynthesis, and for the retinal dehydrogenases RALDH1, RALDH2, and RALDH3, as catalysts of the second and irreversible step." SIGNOR-265124 WNK1 protein Q9H4A3 UNIPROT WNK1 protein Q9H4A3 UNIPROT "up-regulates activity" phosphorylation Ser382 LKRASFAkSVIGTPE 9606 12374799 t Manara "Activation of WNKs requires autophosphorylation of at least one serine residue, serine 382 in WNK1, within the WNK activation loop." SIGNOR-260826 SMAD3 protein P84022 UNIPROT NKX2-1 protein P43699 UNIPROT "down-regulates activity" binding 9606 BTO:0004299 18003659 t miannu "TGF-beta represses transcription of pulmonary surfactant protein-B gene in lung epithelial cells. Repression is mediated by SMAD3 through interactions with NKX2.1 and FOXA1, two key transcription factors that are positive regulators of SpB transcription. In this study, we found that SMAD3 interacts through its MAD domains, MH1 and MH2 with NKX2.1 and FOXA1 proteins. The sites of interaction on NKX2.1 are located within the NH2 and COOH domains, known to be involved in transactivation function." SIGNOR-254169 PRKACA protein P17612 UNIPROT CREB1 protein P16220 UNIPROT "up-regulates activity" phosphorylation Ser119 EILSRRPsYRKILND 10116 BTO:0001009 8336722 t gcesareni "The degree of CREB phosphorylation, assessed with antiserum specific for CREB phosphorylated at Ser-133, correlated with the amount of PKA liberated. The time course of phosphorylation closely paralleled the nuclear entry of the catalytic subun" SIGNOR-166342 CyclinK/CDK12 complex SIGNOR-C37 SIGNOR POLR2A protein P24928 UNIPROT "up-regulates activity" phosphorylation Ser1735 SPTSPSYsPTSPSYS 9606 BTO:0006413 32917631 t "Ser2 in CTD of PolII" lperfetto "Together, these studies demonstrate the important, yet largely redundant, role for CDK12 and CDK13 for the regulation of POLII CTD phosphorylation at multiple residues, as well as the global role for both of these kinases in regulating POLII occupancy across the genome.|CDK12 and CDK13 are thus evolutionarily related and structurally similar kinases, and biochemical assays have demonstrated that both have POLII C-terminal domain (CTD) kinase activity and the ability to phosphorylate the Ser2 residue of the repetitive CTD heptad sequence" SIGNOR-273093 CyclinK/CDK12 complex SIGNOR-C37 SIGNOR POLR2A protein P24928 UNIPROT "up-regulates activity" phosphorylation Ser1693 SPTSPSYsPTSPSYS 9606 BTO:0006413 32917631 t "Ser2 in CTD of PolII" lperfetto "Together, these studies demonstrate the important, yet largely redundant, role for CDK12 and CDK13 for the regulation of POLII CTD phosphorylation at multiple residues, as well as the global role for both of these kinases in regulating POLII occupancy across the genome.|CDK12 and CDK13 are thus evolutionarily related and structurally similar kinases, and biochemical assays have demonstrated that both have POLII C-terminal domain (CTD) kinase activity and the ability to phosphorylate the Ser2 residue of the repetitive CTD heptad sequence" SIGNOR-273095 CyclinK/CDK12 complex SIGNOR-C37 SIGNOR POLR2A protein P24928 UNIPROT "up-regulates activity" phosphorylation Ser1672 SPTSPSYsPTSPSYS 9606 BTO:0006413 32917631 t "Ser2 in CTD of PolII" lperfetto "Together, these studies demonstrate the important, yet largely redundant, role for CDK12 and CDK13 for the regulation of POLII CTD phosphorylation at multiple residues, as well as the global role for both of these kinases in regulating POLII occupancy across the genome.|CDK12 and CDK13 are thus evolutionarily related and structurally similar kinases, and biochemical assays have demonstrated that both have POLII C-terminal domain (CTD) kinase activity and the ability to phosphorylate the Ser2 residue of the repetitive CTD heptad sequence" SIGNOR-273096 CyclinK/CDK12 complex SIGNOR-C37 SIGNOR POLR2A protein P24928 UNIPROT "up-regulates activity" phosphorylation Ser1623 SPTSPSYsPTSPSYS 9606 BTO:0006413 32917631 t "Ser2 in CTD of PolII" lperfetto "Together, these studies demonstrate the important, yet largely redundant, role for CDK12 and CDK13 for the regulation of POLII CTD phosphorylation at multiple residues, as well as the global role for both of these kinases in regulating POLII occupancy across the genome.|CDK12 and CDK13 are thus evolutionarily related and structurally similar kinases, and biochemical assays have demonstrated that both have POLII C-terminal domain (CTD) kinase activity and the ability to phosphorylate the Ser2 residue of the repetitive CTD heptad sequence" SIGNOR-273097 PRKD1 protein Q15139 UNIPROT CTNNB1 protein P35222 UNIPROT up-regulates phosphorylation Thr120 QFDAAHPtNVQRLAE 9606 BTO:0001130 19141652 t lperfetto "This study provides evidence that pkd1 interacts with and phosphorylates beta-catenin at thr(112) and thr(120) we postulate that pkd1 phosphorylation is required to maintain _-catenin transcription activity." SIGNOR-183388 WNK1 protein Q9H4A3 UNIPROT STK39 protein Q9UEW8 UNIPROT up-regulates phosphorylation Ser371 VRRVPGSsGHLHKTE 9606 BTO:0000007 BTO:0000671 18270262 t gcesareni "Activation of wnk1 coincides with the phosphorylation and activation of two wnk1 substrates, namely, the protein kinases ste20/sps1-related proline alanine-rich kinase (spak) and oxidative stress response kinase-1 (osr1)." SIGNOR-160842 FLT3 protein P36888 UNIPROT PTPN11 protein Q06124 UNIPROT "up-regulates activity" binding 10090 BTO:0002882 phosphorylation:Tyr599 VDFREYEyDLKWEFP 16684964 t gcesareni "Y599 was additionally found to interact with the protein tyrosine phosphatase SHP2 in a phosphorylation-dependent manner. As Y599F-Flt3-32D was unable to associate with and to phosphorylate SHP2 and since silencing of SHP2 in WT-Flt3-expressing cells mimicked the Y599F-Flt3 phenotype, we hypothesize that recruitment of SHP2 to pY599 contributes to FL-mediated Erk activation and proliferation." SIGNOR-245057 DTX1 protein Q86Y01 UNIPROT NOTCH1 protein P46531 UNIPROT "up-regulates activity" ubiquitination 9606 11153911 t gcesareni "The human Deltex (DTX1) gene encodes a cytoplasmic protein that functions as a positive regulator of the Notch signaling pathway." SIGNOR-85942 TRIP11 protein Q15643 UNIPROT THRA protein P10827 UNIPROT up-regulates binding 9606 9256431 t miannu "Trip230 binds to rb independently of thyroid hormone while it forms a complex with tr in a thyroid hormone-dependent manner. Ectopic expression of the protein trip230 in cells, but not a mutant form that does not bind to tr, enhances specifically tr-dependent transcriptional activity." SIGNOR-50348 Ub:E2 complex SIGNOR-C497 SIGNOR MEX3D protein Q86XN8 UNIPROT "up-regulates activity" ubiquitination 9606 34199813 t miannu "The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t" SIGNOR-271189 CyclinK/CDK12 complex SIGNOR-C37 SIGNOR POLR2A protein P24928 UNIPROT "up-regulates activity" phosphorylation Ser1882 SPTSPTYsPTTPKYS 9606 BTO:0006413 32917631 t "Ser2 in CTD of PolII" lperfetto "Together, these studies demonstrate the important, yet largely redundant, role for CDK12 and CDK13 for the regulation of POLII CTD phosphorylation at multiple residues, as well as the global role for both of these kinases in regulating POLII occupancy across the genome.|CDK12 and CDK13 are thus evolutionarily related and structurally similar kinases, and biochemical assays have demonstrated that both have POLII C-terminal domain (CTD) kinase activity and the ability to phosphorylate the Ser2 residue of the repetitive CTD heptad sequence" SIGNOR-273102 MIOS protein Q9NXC5 UNIPROT GATOR2 complex SIGNOR-C193 SIGNOR "form complex" binding 9606 23723239 t miannu "Here, we identify GATOR as a complex that interacts with the Rags and is composed of two subcomplexes we call GATOR1 and 2. Inhibition of GATOR1 subunits (DEPDC5, Nprl2, and Nprl3) makes mTORC1 signaling resistant to amino acid deprivation. In contrast, inhibition of GATOR2 subunits (Mios, WDR24, WDR59, Seh1L, Sec13) suppresses mTORC1 signaling and epistasis analysis shows that GATOR2 negatively regulates DEPDC5" SIGNOR-255301 CSNK1D protein P48730 UNIPROT GJA1 protein P17302 UNIPROT "up-regulates activity" phosphorylation Ser325 NRMGQAGsTISNSHA 10116 BTO:0000067 12270943 t lperfetto "We have examined the role of casein kinase 1 (CK1) in connexin-43 (Cx43) gap junction assembly. Cellular co-immunoprecipitation experiments and in vitro CK1 phosphorylation reactions indicate that CK1 interacted with and phosphorylated Cx43, initially on serine(s) 325, 328, or 330.| To examine CK1 function, normal rat kidney cells were treated with CKI-7, and Cx43 content was analyzed by Triton X-100 extraction, cell-surface biotinylation, and immunofluorescence. Western blot analysis indicated a slight increase in total Cx43, whereas gap junctional (Triton-insoluble) Cx43 decreased, and non-junctional plasma membrane Cx43 increased (as detected by cell surface biotinylation)." SIGNOR-249329 FBXO22 protein Q8NEZ5 UNIPROT SNAI1 protein O95863 UNIPROT "down-regulates quantity by destabilization" ubiquitination 9606 BTO:0000356 29945959 t lperfetto "FBXO22 elicits its antimetastatic effects by targeting SNAIL, a master regulator of EMT and breast cancer metastasis, for ubiquitin-mediated proteasomal degradation in a glycogen synthase kinase 3β phosphorylation-dependent manner. " SIGNOR-273446 PPP3CC protein P48454 UNIPROT NFATC2 protein Q13469 UNIPROT "up-regulates activity" dephosphorylation Ser217 AHYSPRTsPIMSPRT 9606 BTO:0000567 11030334 t "NFAT1 is phosphorylated on fourteen conserved phosphoserine residues in its regulatory domain, thirteen of which are dephosphorylated upon stimulation. Dephosphorylation of all thirteen residues is required to mask a nuclear export signal (NES), cause full exposure of a nuclear localization signal (NLS), and promote transcriptional activity" SIGNOR-248517 DNAJC6 protein O75061 UNIPROT HSPA8 protein P11142 UNIPROT "up-regulates activity" relocalization 24789820 t lperfetto "Hsc70, recruited by the J-domain protein auxilin, mediates clathrin uncoating and release of a free vesicle, primed to fuse with a target membrane." SIGNOR-260719 PLK1 protein P53350 UNIPROT CEP68 protein Q76N32 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser332 ADPVLQDsGVDLDSF 25503564 t lperfetto "We show that the intercentrosomal linker protein Cep68 is degraded in prometaphase through the SCF(βTrCP) (Skp1-Cul1-F-box protein) ubiquitin ligase complex. Cep68 degradation is initiated by PLK1 phosphorylation of Cep68 on Ser 332, allowing recognition by βTrCP." SIGNOR-275621 SIK2 protein Q9H0K1 UNIPROT LRP6 protein O75581 UNIPROT "up-regulates activity" phosphorylation Ser1490 AILNPPPsPATERSH 9606 BTO:0006293 35277657 t miannu "Mechanistically, SIK2, phosphorylated by CK1α, directly phosphorylated LRP6 in a SIK2 kinase activity-dependent manner, leading to Wnt/β-catenin signaling pathway activation." SIGNOR-275404 PRKAA1 protein Q13131 UNIPROT FOXO3 protein O43524 UNIPROT "up-regulates activity" phosphorylation 22848740 t "When AMPK is stimulated, pre-existing FOXO3 becomes reverted toward an active form." SIGNOR-255755 DCAF1 protein Q9Y4B6 UNIPROT Cullin4-RBX1-DDB1 complex SIGNOR-C119 SIGNOR "up-regulates activity" binding 9606 BTO:0005907 25026211 t miannu "CRL4 DCAF1 ubiquitylates and inhibits Lats." SIGNOR-272228 Ub:E2 complex SIGNOR-C497 SIGNOR RNF212B protein A8MTL3 UNIPROT "up-regulates activity" ubiquitination 9606 34199813 t miannu "The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t" SIGNOR-271257 SNRPB2 protein P08579 UNIPROT "U2 snRNP complex" complex SIGNOR-C479 SIGNOR "form complex" binding 9606 30765414 t lperfetto "The major spliceosomal building blocks are the U1, U2, U4/U6, and U5 small nuclear ribonucleoproteins (snRNPs). Each consists of a small nuclear RNA (snRNA) (or two, in the case of U4/U6), seven Sm proteins that form a ring (or seven Lsm proteins in the case of U6), and a variable number of snRNP-specific proteins (Fig. 1F) (Will and Lührmann 2011). Under splicing conditions, the U4/U6 and U5 snRNPs form a 25S U4/U6.U5 tri-snRNP, in which the U4 and U6 snRNAs are base-paired, forming a three-way junction." SIGNOR-270654 ATM protein Q13315 UNIPROT CHEK2 protein O96017 UNIPROT "up-regulates activity" phosphorylation Thr26 SQPHGSVtQSQGSSS 9606 BTO:0000007 12024051 t gcesareni "We show here that autophosphorylation of chk2 produced in a cell-free system requires trans phosphorylation by a wortmannin-sensitive kinase, probably atm or atr" SIGNOR-87850 MAPK1 protein P28482 UNIPROT ARRB1 protein P49407 UNIPROT down-regulates phosphorylation Ser412 EEEDGTGsPQLNNR 9606 10347142 t gcesareni "Erk1 and erk2 phosphorylate beta-arrestin1 at ser-412 in vitro. . in the resting state, cytosolic arrestin1 proteins are constitutively phosphorylated by extracellular signal-regulated kinase (erk) at ser412, located within their distal c terminus. erk-phosphorylated arrestin1 is unable to associate with clathrin cages, whereas this constraint is removed upon its dephosphorylation" SIGNOR-67630 paliperidone chemical CHEBI:82978 ChEBI HTR1E protein P28566 UNIPROT "down-regulates activity" "chemical inhibition" 9534 BTO:0000298 8935801 t miannu "Risperidone and its active metabolite 9-OH-risperidone were compared to reference antipsychotic drugs (haloperidol, pipamperone, fluspirilene, clozapine, zotepine) and compounds under development (olanzapine, seroquel, sertindole, ORG-5222, ziprasidone) for in vitro binding to neurotransmitter receptors in brain tissue and on membranes of recombinant cells expressing cloned human receptors and for in vivo occupancy of neurotransmitter receptors in rat and guinea-pig brain following acute treatment (2 h., s.c.). The binding affinities of the compounds for various neurotransmitter receptors were measured using membrane preparations of animal brain regions and of recombinant cells expressing cloned, mostly human receptors. Receptors, tissues and cells are indicated in Table I; results are shown in Table 4A-B." SIGNOR-258561 MAPK1 protein P28482 UNIPROT EIF4EBP1 protein Q13541 UNIPROT "down-regulates activity" phosphorylation Thr70 RNSPVTKtPPRDLPT 9606 BTO:0000007 11691836 t lperfetto "The 4E-BPs inhibit translation in a reversible manner. Hypophosphorylated 4E-BPs interact avidly with eIF4E, whereas 4E-BP hyperphosphorylation, elicited by stimulation of cells with hormones, cytokines, or growth factors, results in an abrogation of eIF4E-binding activity.|These results are at variance with reports that have characterized the 4E-BP1/eIF4E interaction utilizing recombinant 4E-BP1 proteins phosphorylated in vitro with ERK, and harboring alanine substitutions at Thr 37, Thr 46, Thr 70, and Ser 83 |phosphorylation of either Thr 46 or Ser 65 was reported to result in a decrease in eIF4E binding" SIGNOR-249394 VRK1 protein Q99986 UNIPROT BANF1 protein O75531 UNIPROT down-regulates phosphorylation Ser4 sQKHRDFV 9606 BTO:0000567 16371512 t gcesareni "We demonstrate that phosphorylation of ser4 and/or thr2/thr3 abrogates the interaction of baf with dna and reduces its interaction with the lem domain. Coexpression of vrk1 and gfp-baf greatly diminishes the association of baf with the nuclear chromatin/matrix and leads to its dispersal throughout the cell" SIGNOR-143285 RET protein P07949 UNIPROT RET protein P07949 UNIPROT up-regulates phosphorylation Tyr900 FGLSRDVyEEDSYVK 9606 16928683 t gcesareni "Mass spectrometric analysis revealed that ret tyr(900) was autophosphorylation site. Tyr900 can partially replace the function of tyr905 as a local switch for kinase activation" SIGNOR-148992 AKT2 protein P31751 UNIPROT RALGAPA2 protein Q2PPJ7 UNIPROT "down-regulates activity" phosphorylation Thr715 PMRFRSAtTSGAPGV 10090 SIGNOR-C469 21148297 t miannu "RGC2 is an endogenous substrate for Akt2 downstream of PI 3-kinase" SIGNOR-269799 CyclinD3/CDK11A complex SIGNOR-C542 SIGNOR SPDEF protein O95238 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser238 SEESWTDsEVDSSCS 9606 BTO:0000007 26885618 t lperfetto "In this study we provide evidence that the cell cycle kinase CDK11p58, a protein involved in G2/M transition and degradation of several transcription factors, directly interacts with and phosphorylates SPDEF on serine residues|Western blot analysis demonstrated that only one of the mutant constructs, consisting of mutations of serine 238, 242 and 243, resulted in increased levels of SPDEF protein expression as compared to wild type SPDEF, leading to subsequent ubiquitination and degradation of SPDEF through the proteasome pathway.|" SIGNOR-273121 "Embryonic stem cell-specific SWI/SNF" complex SIGNOR-C484 SIGNOR Epigenetic_regulation phenotype SIGNOR-PH203 SIGNOR up-regulates 10090 BTO:0001086 19279220 f miannu "An embryonic stem cell chromatin remodeling complex, esBAF, is essential for embryonic stem cell self-renewal and pluripotency" SIGNOR-270727 PRKCB protein P05771 UNIPROT KCNC4 protein Q03721 UNIPROT down-regulates phosphorylation Ser15 SSYRGRKsGNKPPSK 9606 9649584 t gcesareni "This study investigated the molecular physiology of the nh2-terminal phosphorylation sites that regulate inactivation gating of an a-type k+ channel. The main results show that: (a) pkc acts on four phosphate acceptors (s8, s9, s15, and s21) within the inactivation domain because mutation of these residues to alanine is necessary and sufficient to remove the action of pkc on channel inactivation." SIGNOR-58498 MTMR3 protein Q13615 UNIPROT mTORC1 complex SIGNOR-C3 SIGNOR "down-regulates activity" 9606 BTO:0000007 26787466 t lperfetto "The PtdIns3-phosphatase MTMR3 interacts with mTORC1 and suppresses its activity." SIGNOR-245108 GATA3 protein P23771 UNIPROT GATA3 protein P23771 UNIPROT up-regulates 9606 16386358 t "Experimental data indeed supports the existence of a positive circuit involvingGATA-3 that excludes IL-4 and STAT-6, specifically in mouse cells" SIGNOR-254300 ALK protein Q9UM73 UNIPROT STAT3 protein P40763 UNIPROT up-regulates binding 9606 BTO:0000785 16084951 t gcesareni "Npm-alk has been shown to activate signal transducer and activator of transcription (stat) 3, a transcriptional regulator of cyclin d3.Proteins that interact with alk tyrosine kinase play important roles in mediating downstream cellular signals. Previously reported proteins in the alk signal pathway were identified including pi3-k, jak2, jak3, stat3, grb2, irs, and plcgamma1." SIGNOR-139460 SLC4A1 protein P02730 UNIPROT "4.1 complex" complex SIGNOR-C386 SIGNOR "form complex" binding 9606 BTO:0000424 33187473 t lperfetto "The cytoskeleton plays a key role in maintaining the morphology and function of erythrocyte membranes. Many proteins, such as ankyrin, spectrin alpha- and beta-chains, proteins 4.1, or 4.1R and actin, cover the inner surface of the erythrocyte membrane to form two protein complexes, the ankyrin and protein 4.1 complex| the latter consists of Band 3 dimers binding Adducins alpha and beta, Glycophorin C, GLUT1 and Stomatin [15, 16]" SIGNOR-266036 PDK2 protein Q15119 UNIPROT PDHA1 protein P08559 UNIPROT down-regulates phosphorylation Ser300 SMSDPGVsYRTREEI -1 7782287 t gcesareni "Mammalian pyruvate dehydrogenase (?2_2) (e1) is regulated by phosphorylation-dephosphorylation, catalyzed by the e1-kinase and the phospho-e1-phosphatase." SIGNOR-33141 tandutinib chemical CHEBI:90237 ChEBI FLT3 protein P36888 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-207209 PML-RARalpha "fusion protein" SIGNOR-FP2 SIGNOR MYB protein P10242 UNIPROT "up-regulates quantity" "transcriptional regulation" 9606 BTO:0005790 30335887 t "PML/RARa blocks the differentiation and promotes the proliferation of acute promyelocytic leukemia through activating MYB expression by transcriptional and epigenetic regulation mechanisms." SIGNOR-259939 CSNK1E protein P49674 UNIPROT DVL2 protein O14641 UNIPROT "up-regulates activity" phosphorylation 6239 10517632 t gcesareni "In addition, CKI bound to and increased the phosphorylation of dishevelled, a known component of the Wnt pathway" SIGNOR-244097 CSNK2A1 protein P68400 UNIPROT CDC34 protein P49427 UNIPROT "down-regulates activity" phosphorylation Ser231 FGDDEDDsGTEES 9606 BTO:0000567 11546811 t lperfetto "The ubiquitin-conjugating enzyme, cdc34, has been implicated in the ubiquitination of a number of vertebrate substrates, including p27(kip1), ikappabalpha, wee1, and myod. We show that mammalian cdc34 is a phosphoprotein that is phosphorylated in proliferating cells. Phosphorylation of cdc34 by the associated kinase maps predominantly to residues 203 and 222. Mutation of cdc34 at ck2-targeted residues, ser-203, ser-222, ser-231, thr-233, and ser-236, abolishes the phosphorylation of cdc34 observed in vivo and markedly shifts nuclearly localized cdc34 to the cytoplasm." SIGNOR-110399 CDK19 protein Q9BWU1 UNIPROT NOTCH1 protein P46531 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser2513 EHPFLTPsPESPDQW -1 25344755 t lperfetto "Mapping of cyclin C-dependent phosphosites on ICN1, using mass spectrometry revealed that several of them are located within the PEST-domain of Notch1, which controls ICN1 degradation38,39 (Fig. 5g and Supplementary Table 1). Three of them (T2512, S2514 and S2517) are localized within the consensus motif, “Cdc4 phosphodegron”, which is shared by most substrates of Fbw7 (Cdc4) ubiquitin ligase38. Two of these residues (S2514 and S2517) were previously shown by Fryer et al.20 to be phosphorylated by cyclin C-CDK8 in vitro, and all three were shown to play a role in controlling ICN1 stability via Fbw740. We verified that cyclin C-CDK8, C-CDK19 and C-CDK3 phosphorylate ICN1 on these three residues" SIGNOR-273136 AKT1 protein P31749 UNIPROT MEF2D protein Q14814 UNIPROT up-regulates 9606 BTO:0000222 BTO:0000887;BTO:0001103 10896679 f lperfetto "Two candidates that may function as mediators of pi3-k in the phosphorylation of mef2 proteins are pkb and big map kinase 1." SIGNOR-79338 ELP2 protein Q6IA86 UNIPROT "Elongator complex" complex SIGNOR-C466 SIGNOR "form complex" binding 9606 28601220 t miannu "Elongator is a highly conserved eukaryotic protein complex consisting of two sets of six Elp proteins, while homologues of its catalytic subunit Elp3 are found in all the kingdoms of life. Although it was originally described as a transcription elongation factor, cumulating evidence suggests that its primary function is catalyzing tRNA modifications. In humans, defects in Elongator subunits are associated with neurological disorders and cancer." SIGNOR-269709 "CKM complex" complex SIGNOR-C406 SIGNOR CCNH protein P51946 UNIPROT "down-regulates activity" phosphorylation Ser5 sSQKRHWT 9606 10993082 t gcesareni "Here we show that cdk8/cyclin c can regulate transcription by targeting the cdk7/cyclin h subunits of the general transcription initiation factor iih (tfiih). cdk8 phosphorylates mammalian cyclin h in the vicinity of its functionally unique amino-terminal and carboxy-terminal alpha-helical domains. This phosphorylation represses both the ability of tfiih to activate transcription and its ctd kinase activity. In addition, mimicking cdk8 phosphorylation of cyclin h in vivo has a dominant-negative effect on cell growth." SIGNOR-273139 "CKM complex" complex SIGNOR-C406 SIGNOR SMAD1 protein Q15797 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser195 PNSSYPNsPGSSSST 9606 19914161 t lpetrilli "Phosphorylation of the linker region of smad1, a receptor-activated smad (r-smad), at serine 206 (s206) and s214 induced by bmp and mediated by cdk8/9 is critical for binding of the e3 ubiquitin ligase smurf1. Binding of smurf1 leads to polyubiquitination of smad1 and its degradation by the proteasome;cdk8 and cyclint-cdk9 showed a preference for s206 and s214 but also phosphorylated s186 and s195 in the case of smad1;and t179, s208 and s213 in the case of smad3." SIGNOR-273140 CDC14B protein O60729 UNIPROT SKP2 protein Q13309 UNIPROT "down-regulates quantity by destabilization" dephosphorylation Ser64 SNLGHPEsPPRKRLK 9606 18239684 t "The activity of SCF(Skp2) is regulated by the Cyclin-dependent kinase (CDK)2-mediated phosphorylation of Skp2 on Ser64 allows its expression in mid-G1 phase, even in the presence of active APC(Cdh1). Reciprocally, dephosphorylation of Skp2 by the mitotic phosphatase Cdc14B at the M --> G1 transition promotes its degradation by APC(Cdh1)." SIGNOR-248333 AKT2 protein P31751 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR "down-regulates quantity by destabilization" phosphorylation Thr32 QSRPRSCtWPLQRPE 19951971 t lperfetto "AKT phosphorylates FOXO3a at three conserved sites (Thr32, Ser253 and Ser315), therefore creating binding sites for the 14-3-3 chaperone proteins and leading to the active export of FOXO3a to the cytoplasm where it is targeted for proteasomal degradation." SIGNOR-252865 SEC31B protein Q9NQW1 UNIPROT "COPII vesicle" complex SIGNOR-C370 SIGNOR "form complex" binding 9606 BTO:0000567 30605680 t lperfetto "The Core Components of COPII Vesicles from HeLa Cells|Membrane-bound Sar1 then recruits the inner COPII coat subcomplex, the Sec23/24 heterodimer. Subsequently, together with cargo proteins recruited by the Sec24 subunit, Sar1 and Sec23/24 assemble into so-called pre-budding complexes. Finally, outer coat subcomplexes, comprising heterotetrameric Sec13/31 complexes, are recruited onto pre-budding complexes to complete the two-layered COPII coat" SIGNOR-265287 DLL1 protein O00548 UNIPROT NOTCH proteinfamily SIGNOR-PF30 SIGNOR up-regulates binding 23729744 t apalma "The NECD undergoes O-linked glycosylation during Notch synthesis and secretion, which is crucial for proper folding of the Notch receptor and the interaction with its ligand DSL (Delta, Serrate, Lag-2)(Rana and Haltiwanger, 2011). The Notch receptor on the signal-receiving cell binds directly to ligands located on the apposing signal-sending cell" SIGNOR-255369 IKBKG protein Q9Y6K9 UNIPROT IKK-complex complex SIGNOR-C14 SIGNOR "form complex" binding 10090 SIGNOR-C14 SIGNOR-C14 19666475 t lperfetto "Proinflammatory NF-kappaB activation requires the IkappaB (inhibitor of NF-kappaB) kinase (IKK) complex that contains two catalytic subunits named IKKalpha and IKKbeta and a regulatory subunit named NF-kappaB essential modulator (NEMO)." SIGNOR-209762 EPN1 protein Q9Y6I3 UNIPROT EGFR protein P00533 UNIPROT down-regulates relocalization 9606 19054389 t gcesareni "Epsin 1 is involved in recruitment of ubiquitinated egf receptors into clathrin-coated pits this supports the contention that epsin 1 promotes endocytosis of the ubiquitinated egfr." SIGNOR-182562 AKT1 protein P31749 UNIPROT XIAP protein P98170 UNIPROT "up-regulates quantity by stabilization" phosphorylation Ser87 VGRHRKVsPNCRFIN 9606 BTO:0001023 14645242 t lperfetto "Akt, including akt1 and akt2, interacts with and phosphorylates x-linked inhibitor of apoptosis protein (xiap) at residue serine-87 in vitro and in vivo. Phosphorylation of xiap by akt protects xiap from ubiquitination and degradation in response to cisplatin." SIGNOR-119488 Ub:E2 complex SIGNOR-C497 SIGNOR MECOM protein Q03112 UNIPROT "up-regulates activity" ubiquitination 9606 34199813 t miannu "The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t" SIGNOR-271024 CHRNB3 protein Q05901 UNIPROT APC protein P25054 UNIPROT "up-regulates activity" binding 9606 BTO:0002916 14502292 t miannu "Treatment of muscle cells with neural agrin causes tyrosine phosphorylation of the AChR β subunit and induces AChR clustering by promoting anchoring of the receptor protein to postsynaptic cytoskeleton. Regulation of acetylcholine receptor clustering by the tumor suppressor APC. By showing a direct requirement for APC in AChR clustering, our present study suggests that the Wnt/β-catenin pathway may crosstalk with the agrin signaling cascade during the formation of mammalian neuromuscular junction." SIGNOR-264261 AIP protein O00170 UNIPROT TFF1 protein P04155 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 21984905 t miannu "We show that XAP2 is recruited to the promoter of ERα regulated genes like the breast cancer marker gene pS2 or GREB1 and negatively regulate the expression of these genes in MCF-7 cells." SIGNOR-259911 CD22 protein P20273 UNIPROT SH2B1 protein Q9NRF2 UNIPROT "up-regulates activity" binding 9606 BTO:0000776 32323266 t scontino "SHP-1 is recruited by the phosphorylated ITIM-bearing receptors such as CD22 and it dephosphorylates proximal BCR signaling molecules such as CD79, SYK, BLNK." SIGNOR-268444 PTPN6 protein P29350 UNIPROT KDR protein P35968 UNIPROT unknown dephosphorylation Tyr996 EEAPEDLyKDFLTLE 9606 BTO:0000007 18840653 t "Src homology 2 (SH2) domain containing protein tyrosine phosphatase-1 (SHP-1) dephosphorylates VEGF Receptor-2 and attenuates endothelial DNA synthesis, but not migration|Knockdown of SHP-1 by siRNA or inhibition of c-Src by an inhibitor, results in augmented DNA synthesis perhaps due to increased phosphorylation of at least three tyrosine residues of KDR 996, 1059 and 1175" SIGNOR-248476 MAPK14 protein Q16539 UNIPROT PIAS2 protein O75928 UNIPROT "up-regulates activity" phosphorylation Ser116 VTPHSPSsPVGSVLL 9606 BTO:0000007 16713578 t miannu "The switch between the coactivating and inhibitory actions of PIASxα is controlled, at least in part, through PIASxα phosphorylation. PIASxα is itself phosphorylated by p38 in vitro and in vivo in response to the activation of stress signaling pathways (Figure 2, Figure 3, Figure 4). We identify Ser113 and Ser 116 as two residues that are phosphorylated by p38 and have important functional roles" SIGNOR-262949 ZAP70 protein P43403 UNIPROT ZAP70 protein P43403 UNIPROT "up-regulates activity" phosphorylation Tyr126 RDAMVRDyVRQTWKL 9606 BTO:0000661 7961936 t lperfetto "We show that ZAP-70 has a primary autophosphorylation site at Tyr-292, with a secondary site at Tyr-126. We also show additional phosphorylation at Tyr-69, Tyr-178, Tyr-492, and Tyr-493 upon the addition of the protein tyrosine kinase, p56lck. By comparative two-dimensional phosphopeptide mapping, we show that ZAP-70 isolated from Jurkat T cells also autophosphorylates at Tyr-292 and Tyr-126" SIGNOR-247044 CBFB protein Q13951 UNIPROT "Core Binding Factor complex" complex SIGNOR-C214 SIGNOR "form complex" binding 9606 12495904 t irozzo "The core binding factor (CBF) transcription complex, consisting of the interacting proteins RUNX1 and CBFβ, is essential for normal hematopoiesis" SIGNOR-255711 DLG4 protein P78352 UNIPROT NOS1 protein P29475 UNIPROT "up-regulates activity" binding 9606 BTO:0000938 11052931 t miannu "Neuronal NOS, a Ca2+-activated form of NOS, can bind to PSD-95 through a class III PDZ domain interaction in which its own amino-terminal PDZ domain binds to a PDZ domain of PSD-95. PSD-95 may concentrate nNOS near the NMDA receptor at postsynaptic sites in these neurons." SIGNOR-264227 COPS5 protein Q92905 UNIPROT "COP9 signalosome variant 2" complex SIGNOR-C487 SIGNOR "form complex" binding 9606 18850735 t miannu "The COP9 signalosome (CSN) is a multiprotein complex that plays a critical role in diverse cellular and developmental processes in various eukaryotic organisms. we have performed a comprehensive proteomic analysis of the human CSN complex using a new purification method and quantitative mass spectrometry. Purification of the human CSN complex from a stable 293 cell line expressing N-terminal HBTH-tagged CSN5 subunit was achieved by high-affinity streptavidin binding with TEV cleavage elution." SIGNOR-270761 AKT proteinfamily SIGNOR-PF24 SIGNOR BAD protein Q92934 UNIPROT "down-regulates activity" phosphorylation Ser75 EIRSRHSsYPAGTED 9606 BTO:0000007 9381178 t "Active Akt induced a significant increase in BAD phosphorylation. mutant BAD with alanine substitutions at Ser112 and Ser136 was not phosphorylated by active Akt . phosphorylation of BAD by Akt will preclude its binding to membrane-anchored Bcl-xL, leading to increased cell survival." SIGNOR-251469 SMURF1 protein Q9HCE7 UNIPROT BMPR1A protein P36894 UNIPROT down-regulates ubiquitination 9606 22298955 t gcesareni "Smurf1 and smurf2 are e3 ubiquitin ligases known to suppress tgf-beta signaling through degradation of smads and receptors for tgf-beta and bmps." SIGNOR-195651 KDM1A protein O60341 UNIPROT "Histone H3" proteinfamily SIGNOR-PF69 SIGNOR "up-regulates activity" demethylation 9606 BTO:0000567 15620353 t miannu "Here, we provide evidence that LSD1 (KIAA0601), a nuclear homolog of amine oxidases, functions as a histone demethylase and transcriptional corepressor. LSD1 specifically demethylates histone H3 lysine 4, which is linked to active transcription." SIGNOR-265332 SUZ12 protein Q15022 UNIPROT TWIST1 protein Q15672 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0001939 23836662 f miannu "We further demonstrated that PER2 served as a transcriptional corepressor, which recruited polycomb proteins EZH2 and SUZ12 as well as HDAC2 to octamer transcription factor 1 (OCT1) (POU2F1) binding sites of the TWIST1 and SLUG promoters to repress expression of these EMT genes." SIGNOR-254155 "CKM complex" complex SIGNOR-C406 SIGNOR NOTCH1 protein P46531 UNIPROT "down-regulates quantity by destabilization" phosphorylation -1 25344755 t lperfetto "Mapping of cyclin C-dependent phosphosites on ICN1, using mass spectrometry revealed that several of them are located within the PEST-domain of Notch1, which controls ICN1 degradation38,39 (Fig. 5g and Supplementary Table 1). Three of them (T2512, S2514 and S2517) are localized within the consensus motif, “Cdc4 phosphodegron”, which is shared by most substrates of Fbw7 (Cdc4) ubiquitin ligase38. Two of these residues (S2514 and S2517) were previously shown by Fryer et al.20 to be phosphorylated by cyclin C-CDK8 in vitro, and all three were shown to play a role in controlling ICN1 stability via Fbw740. We verified that cyclin C-CDK8, C-CDK19 and C-CDK3 phosphorylate ICN1 on these three residues" SIGNOR-273158 "RFX complex" complex SIGNOR-C104 SIGNOR HLA-DQA2 protein P01906 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" -1 11258423 f "The RFX complex is comprised of three proteins – RFX5, RFXB, and RFXAP – all of which are required for expression of MHCII genes|In our current studies, we have utilized electrophoretic mobility shift assays to characterize the DNA binding of the RFX5(1–330)2•RFXAP•RFXB complex to the proximal regulatory region from the HLA-DRα gene to gain insight into the DNA binding properties of the RFX complex" SIGNOR-253996 RFX5 protein P48382 UNIPROT HLA-DRA protein P01903 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000460 10586057 t Luana "In this report, we correlate the loss of IFN-γ induction of MHC class II genes with the identification of a molecular defect in an essential regulator, namely RFX5. | We have further confirmed this finding by showing that new RFX5 leucine mutants created in vitro are incapable of transactivating a class II promoter, suggesting the identification of residues essential for RFX activity." SIGNOR-266228 F2R protein P25116 UNIPROT TNFRSF12A protein Q9NP84 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000007 21072196 f miannu "Both PAR2 and PAR1 activation resulted in up-regulated expression of several genes (CD44, FOSL1, TNFRSF12A, RAB3A, COPEB, CORO1C, THBS1, SDC4) known to be important in cancer." SIGNOR-254846 ARHGAP28 protein Q9P2N2 UNIPROT RHOA protein P61586 UNIPROT "down-regulates activity" "gtpase-activating protein" 9606 BTO:0000007 32203420 t Luana "We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2)." SIGNOR-260483 RPS6KA4 protein O75676 UNIPROT FOS protein P01100 UNIPROT "up-regulates activity" phosphorylation Ser362 AAAHRKGsSSNEPSS 9606 8248197 t gcesareni "Rsk1/2 phosphorylates the transcription factor c-fos on s362 and increases its activity." SIGNOR-37216 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR RPS6KA3 protein P51812 UNIPROT up-regulates phosphorylation Ser227 DHEKKAYsFCGTVEY 9606 10980595 t lperfetto "We have generated two monoclonal antibodies that recognize two phosphorylated sites, p-ser227 and p-thr577, in the n- and c-terminal kinase domains of rsk2, respectively. phosphorylation and activation of rsk2 by uv light involves the erk pathway" SIGNOR-244692 regorafenib chemical CHEBI:68647 ChEBI BRAF protein P15056 UNIPROT "down-regulates activity" "chemical inhibition" 9606 26254357 t miannu "A novel multi-kinase inhibitor, regorafenib (Figure 1), inhibits vascular endothelial growth factor receptor (VEGFR) 1, VEGFR2, and VEGFR3, that play key roles in angiogenesis, and fibroblast growth factor receptor (FGFR) 1, platelet-derived growth factor receptor-β (PDGFR-β), tyrosine kinase with immunoglobulin and epidermal growth factor homology domain 2 (TIE2) and the mutant oncogenic kinase KIT, RET, B-RAF" SIGNOR-259176 WWTR1 protein Q9GZV5 UNIPROT ASNS protein P08243 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0001615 22470139 f miannu "Efficient knockdown of WWTR1, demonstrated by quantitative real-time PCR, led to upregulation of ASNS and downregulation of SMAD3, LTBR, BAX and BAK1 in WWTR1 knockdown cells, suggesting that these genes may be involved in the repression of cell proliferation." SIGNOR-255608 Gbeta proteinfamily SIGNOR-PF4 SIGNOR PML protein P29590 UNIPROT up-regulates phosphorylation 9606 BTO:0001271 15093545 t "The effect has been demonstrated using P29590-4" gcesareni "Phosphorylation of pml by mitogen-activated protein kinases plays a key role in arsenic trioxide-mediated apoptosis." SIGNOR-270034 SNX9 protein Q9Y5X1 UNIPROT EGFR protein P00533 UNIPROT down-regulates 9606 16316319 f gcesareni "We have previously shown that sh3px1, phosphorylated by ack2 (activated cdc42-associated tyrosine kinase 2), regulates the degradation of egf (epidermal growth factor) receptor.The cdc42 target ack2 interacts with sorting nexin 9 (sh3px1) to regulate epidermal growth factor receptor degradation." SIGNOR-142566 KDM3B protein Q7LBC6 UNIPROT H3-3A protein P84243 UNIPROT "down-regulates activity" demethylation Lys10 RTKQTARkSTGGKAP 9534 16603237 t miannu "We have purified a JmjC domain-containing protein, JHDM2A, which specifically demethylates mono- and dimethyl-H3K9. JHDM2A exhibits hormone-dependent recruitment to androgen-receptor target genes, resulting in H3K9 demethylation and transcriptional activation. Thus, our work identifies a histone demethylase and links its function to hormone-dependent transcriptional activation." SIGNOR-266636 MARK2 protein Q7KZI7 UNIPROT MAPT protein P10636-2 UNIPROT "down-regulates activity" phosphorylation Ser324 RHLSNVSsTGSIDMV -1 10090741 t miannu "We have studied the relationship between the phosphorylation oftau by several kinases (MARK, PKA, MAPK, GSK3) and its assembly into PHFs. By contrast, MARK and PKA phosphorylate several sites within the repeats (notably theKXGS motifs including Ser262, Ser324, and Ser356, plus Ser320); in addition PKA phosphorylates somesites in the flanking domains, notably Ser214. This type of phosphorylation strongly reduces tau’s affinityfor microtubules, and at the same time inhibits tau’s assembly into PHFs." SIGNOR-275437 RPAP3 protein Q9H6T3 UNIPROT "R2TP core co-chaperone" complex SIGNOR-C515 SIGNOR "form complex" binding 9606 29662061 t miannu " Here we use cryo-EM and biochemical studies on the human R2TP core (RUVBL1-RUVBL2-RPAP3-PIH1D1) which reveal the distinctive role of RPAP3, distinguishing metazoan R2TP from the smaller yeast equivalent. RPAP3 spans both faces of a single RUVBL ring, providing an extended scaffold that recruits clients and provides a flexible tether for HSP90. " SIGNOR-270927 MAPK3 protein P27361 UNIPROT CASP8 protein Q14790 UNIPROT down-regulates phosphorylation Ser387 YLEMDLSsPQTRYIP 9606 BTO:0000149 24342355 t lperfetto "We demonstrate that perk 1/2 can phosphorylate pro-caspase-8 at s387 by knocking-down the endogenous pro-caspase-8 using rnai and replacing it with its non-phosphorylatable counterpart (s387a), a significant increase in caspase-8 activity" SIGNOR-203480 gemcitabine chemical CHEBI:175901 ChEBI RRM1 protein P23921 UNIPROT "down-regulates activity" "chemical inhibition" -1 2233693 t miannu "Direct assays of partially purified ribonucleoside diphosphate reductase (EC 1.17.4.1) demonstrated 50% inhibition by 4 microM dFdC 5'-diphosphate; dFdC 5'-triphosphate was much less inhibitory. We conclude that dFdC 5'-diphosphate acts as an inhibitor of ribonucleoside diphosphate reductase." SIGNOR-258386 PRKCA protein P17252 UNIPROT MAPT protein P10636-2 UNIPROT "down-regulates activity" phosphorylation Ser324 RHLSNVSsTGSIDMV -1 10090741 t miannu "We have studied the relationship between the phosphorylation oftau by several kinases (MARK, PKA, MAPK, GSK3) and its assembly into PHFs. By contrast, MARK and PKA phosphorylate several sites within the repeats (notably theKXGS motifs including Ser262, Ser324, and Ser356, plus Ser320); in addition PKA phosphorylates somesites in the flanking domains, notably Ser214. This type of phosphorylation strongly reduces tau’s affinityfor microtubules, and at the same time inhibits tau’s assembly into PHFs." SIGNOR-275441 PRKCB protein P05771 UNIPROT MAPT protein P10636-2 UNIPROT "down-regulates activity" phosphorylation Ser324 RHLSNVSsTGSIDMV -1 10090741 t miannu "We have studied the relationship between the phosphorylation oftau by several kinases (MARK, PKA, MAPK, GSK3) and its assembly into PHFs. By contrast, MARK and PKA phosphorylate several sites within the repeats (notably theKXGS motifs including Ser262, Ser324, and Ser356, plus Ser320); in addition PKA phosphorylates somesites in the flanking domains, notably Ser214. This type of phosphorylation strongly reduces tau’s affinityfor microtubules, and at the same time inhibits tau’s assembly into PHFs." SIGNOR-275442 MARK2 protein Q7KZI7 UNIPROT MAPT protein P10636-2 UNIPROT "down-regulates activity" phosphorylation Ser267 RVQSKIGsLDNITHV -1 10090741 t miannu "We have studied the relationship between the phosphorylation oftau by several kinases (MARK, PKA, MAPK, GSK3) and its assembly into PHFs. By contrast, MARK and PKA phosphorylate several sites within the repeats (notably theKXGS motifs including Ser262, Ser324, and Ser356, plus Ser320); in addition PKA phosphorylates somesites in the flanking domains, notably Ser214. This type of phosphorylation strongly reduces tau’s affinityfor microtubules, and at the same time inhibits tau’s assembly into PHFs." SIGNOR-275435 PRKAA1 protein Q13131 UNIPROT MAPT protein P10636-2 UNIPROT "down-regulates activity" phosphorylation Ser267 RVQSKIGsLDNITHV -1 10090741 t miannu "We have studied the relationship between the phosphorylation oftau by several kinases (MARK, PKA, MAPK, GSK3) and its assembly into PHFs. By contrast, MARK and PKA phosphorylate several sites within the repeats (notably theKXGS motifs including Ser262, Ser324, and Ser356, plus Ser320); in addition PKA phosphorylates somesites in the flanking domains, notably Ser214. This type of phosphorylation strongly reduces tau’s affinityfor microtubules, and at the same time inhibits tau’s assembly into PHFs." SIGNOR-275438 HSPA1B protein P0DMV9 UNIPROT NOD2 protein Q9HC29 UNIPROT "up-regulates quantity by stabilization" binding 9606 24790089 t miannu "The molecular chaperone HSP70 binds to and stabilizes NOD2, an important protein involved in Crohn disease." SIGNOR-252417 PRKCB protein P05771 UNIPROT MAPT protein P10636-2 UNIPROT "down-regulates activity" phosphorylation Ser324 RHLSNVSsTGSIDMV -1 10090741 t miannu "We have studied the relationship between the phosphorylation oftau by several kinases (MARK, PKA, MAPK, GSK3) and its assembly into PHFs. By contrast, MARK and PKA phosphorylate several sites within the repeats (notably theKXGS motifs including Ser262, Ser324, and Ser356, plus Ser320); in addition PKA phosphorylates somesites in the flanking domains, notably Ser214. This type of phosphorylation strongly reduces tau’s affinityfor microtubules, and at the same time inhibits tau’s assembly into PHFs." SIGNOR-275443 PRKCE protein Q02156 UNIPROT MAPT protein P10636-2 UNIPROT "down-regulates activity" phosphorylation Ser324 RHLSNVSsTGSIDMV -1 10090741 t miannu "We have studied the relationship between the phosphorylation oftau by several kinases (MARK, PKA, MAPK, GSK3) and its assembly into PHFs. By contrast, MARK and PKA phosphorylate several sites within the repeats (notably theKXGS motifs including Ser262, Ser324, and Ser356, plus Ser320); in addition PKA phosphorylates somesites in the flanking domains, notably Ser214. This type of phosphorylation strongly reduces tau’s affinityfor microtubules, and at the same time inhibits tau’s assembly into PHFs." SIGNOR-275444 PRKCG protein P05129 UNIPROT MAPT protein P10636-2 UNIPROT "down-regulates activity" phosphorylation Ser324 RHLSNVSsTGSIDMV -1 10090741 t miannu "We have studied the relationship between the phosphorylation oftau by several kinases (MARK, PKA, MAPK, GSK3) and its assembly into PHFs. By contrast, MARK and PKA phosphorylate several sites within the repeats (notably theKXGS motifs including Ser262, Ser324, and Ser356, plus Ser320); in addition PKA phosphorylates somesites in the flanking domains, notably Ser214. This type of phosphorylation strongly reduces tau’s affinityfor microtubules, and at the same time inhibits tau’s assembly into PHFs." SIGNOR-275445 PRKCI protein P41743 UNIPROT MAPT protein P10636-2 UNIPROT "down-regulates activity" phosphorylation Ser324 RHLSNVSsTGSIDMV -1 10090741 t miannu "We have studied the relationship between the phosphorylation oftau by several kinases (MARK, PKA, MAPK, GSK3) and its assembly into PHFs. By contrast, MARK and PKA phosphorylate several sites within the repeats (notably theKXGS motifs including Ser262, Ser324, and Ser356, plus Ser320); in addition PKA phosphorylates somesites in the flanking domains, notably Ser214. This type of phosphorylation strongly reduces tau’s affinityfor microtubules, and at the same time inhibits tau’s assembly into PHFs." SIGNOR-275446 PRKCZ protein Q05513 UNIPROT MAPT protein P10636-2 UNIPROT "down-regulates activity" phosphorylation Ser324 RHLSNVSsTGSIDMV -1 10090741 t miannu "We have studied the relationship between the phosphorylation oftau by several kinases (MARK, PKA, MAPK, GSK3) and its assembly into PHFs. By contrast, MARK and PKA phosphorylate several sites within the repeats (notably theKXGS motifs including Ser262, Ser324, and Ser356, plus Ser320); in addition PKA phosphorylates somesites in the flanking domains, notably Ser214. This type of phosphorylation strongly reduces tau’s affinityfor microtubules, and at the same time inhibits tau’s assembly into PHFs." SIGNOR-275447 BMP7 protein P18075 UNIPROT UCP1 protein P25874 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 18719589 f fspada "Bmp7 activates a full program of brown adipogenesis including induction of early regulators of brown fat fate prdm16 (pr-domain-containing 16;ref. 4) and pgc-1alpha (peroxisome proliferator-activated receptor-gamma (ppargamma) coactivator-1alpha;ref. 5), increased expression of the brown-fat-defining marker uncoupling protein 1 (ucp1) and adipogenic transcription factors ppargamma and ccaat/enhancer-binding proteins (c/ebps), and induction of mitochondrial biogenesis via p38 mitogen-activated protein (map) kinase-(also known as mapk14) and pgc-1-dependent pathways" SIGNOR-180354 CyclinC/CDK3 complex SIGNOR-C545 SIGNOR NOTCH1 protein P46531 UNIPROT "down-regulates quantity by destabilization" phosphorylation -1 25344755 t lperfetto "Mapping of cyclin C-dependent phosphosites on ICN1, using mass spectrometry revealed that several of them are located within the PEST-domain of Notch1, which controls ICN1 degradation38,39 (Fig. 5g and Supplementary Table 1). Three of them (T2512, S2514 and S2517) are localized within the consensus motif, “Cdc4 phosphodegron”, which is shared by most substrates of Fbw7 (Cdc4) ubiquitin ligase38. Two of these residues (S2514 and S2517) were previously shown by Fryer et al.20 to be phosphorylated by cyclin C-CDK8 in vitro, and all three were shown to play a role in controlling ICN1 stability via Fbw740. We verified that cyclin C-CDK8, C-CDK19 and C-CDK3 phosphorylate ICN1 on these three residues" SIGNOR-273166 AKT proteinfamily SIGNOR-PF24 SIGNOR FOXO proteinfamily SIGNOR-PF27 SIGNOR down-regulates phosphorylation 9606 21798082 t lperfetto "Akt inactivates protein degradation by phosphorylating and thus repressing the transcription factors of the foxo family, and stimulates protein synthesis via the mammalian target of rapamycin (mtor) and glycogen synthase kinase 3b (gsk3b)." SIGNOR-252820 Ast-487 chemical CID:11409972 PUBCHEM KIT protein P10721 UNIPROT "down-regulates activity" "chemical inhibition" -1 22037378 t llicata "Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here." SIGNOR-258070 "AP-2 complex" complex SIGNOR-C245 SIGNOR SYNJ1 protein O43426 UNIPROT "up-regulates activity" binding 10116 15496985 t Giorgia "Some of the more minor interactors are very strongly enriched (AAK, auxilin, Dab2, eps15, epsin1 and synaptojanin170). All these enriched proteins have multiple copies of short alpha‐appendage interaction motifs" SIGNOR-260396 EGFR protein P00533 UNIPROT GAB1 protein Q13480 UNIPROT up-regulates phosphorylation Tyr659 VADERVDyVVVDQQK 9606 BTO:0000527;BTO:0000017 9890893 t lperfetto "Gab-1 is a multisubstrate docking protein downstream in the signaling pathways of different receptor tyrosine kinases, including the epidermal growth factor receptor (egfr)the entire protein was phosphorylated by regfr at eight tyrosine residues (y285, y373, y406, y447, y472, y619, y657, and y689)." SIGNOR-236404 MAPK3 protein P27361 UNIPROT MAPT protein P10636-2 UNIPROT "down-regulates activity" phosphorylation Ser267 RVQSKIGsLDNITHV -1 10090741 t miannu "We have studied the relationship between the phosphorylation oftau by several kinases (MARK, PKA, MAPK, GSK3) and its assembly into PHFs. By contrast, MARK and PKA phosphorylate several sites within the repeats (notably theKXGS motifs including Ser262, Ser324, and Ser356, plus Ser320); in addition PKA phosphorylates somesites in the flanking domains, notably Ser214. This type of phosphorylation strongly reduces tau’s affinityfor microtubules, and at the same time inhibits tau’s assembly into PHFs." SIGNOR-275434 RAD51 protein Q06609 UNIPROT Synaptonemal_complex complex SIGNOR-C351 SIGNOR "up-regulates activity" binding 10090 BTO:0001275 10525529 t miannu "The eukaryotic RecA homologues RAD51 and DMC1 function in homology recognition and formation of joint-molecule recombination intermediates during yeast meiosis. We also show that mouse RAD51 and DMC1 establish protein-protein interactions with each other and with the chromosome core component COR1(SCP3) in a two-hybrid system and in vitro binding analyses. These results suggest that the formation of a multiprotein recombination complex associated with the meiotic chromosome cores is essential for the development and fulfillment of the meiotic recombination process." SIGNOR-264207 RPS6KB1 protein P23443 UNIPROT RICTOR protein Q6R327 UNIPROT down-regulates phosphorylation Thr1135 NRRIRTLtEPSVDFN 9606 19995915 t gcesareni "Phosphorylation of rictor on thr1135 did not affect mtorc2 assembly, kinase activity, or cellular localization. However, cells expressing a rictor t1135a mutant were found to have increased mtorc2-dependent phosphorylation of akt" SIGNOR-161995 PRKCQ protein Q04759 UNIPROT TBK1 protein Q9UHD2 UNIPROT "up-regulates activity" phosphorylation Ser716 HILERFGsLTMDGGL 9606 31792381 t "TBKBP1 recruits TBK1 to protein kinase C-theta (PKCθ) through a scaffold protein, CARD10. This enables PKCθ to phosphorylate TBK1 at Ser 716, a crucial step for TBK1 activation" SIGNOR-272472 MAPK14 protein Q16539 UNIPROT NCOA3 protein Q9Y6Q9 UNIPROT "up-regulates activity" phosphorylation Ser867 SPVSVGSsPPVKNIS 9606 BTO:0000093 15383283 t miannu "P38 MAPK and JNK can phosphorylate multiple sites on SRC-3, including S505, S543, S860, and S867. Our results suggest that several kinases are important for phosphorylating SRC-3 and enhancing its interaction with DNA-dependent transcription factors and other coactivators." SIGNOR-250106 RNF167 protein Q9H6Y7 UNIPROT VAMP3 protein Q15836 UNIPROT "down-regulates quantity by destabilization" ubiquitination Lys68 ETSAAKLkRKYWWKN 9606 BTO:0000007 23353890 t miannu "Here, we show that Godzilla/RNF167 regulates endosome recycling by the ubiquitylation of VAMP3 on Lys66, Lys68 and Lys77; namely, two adjacent Lys residues on the both sides of the critical interface of SNARE complex are ubiquitylated. In agreement with VAMP3 being a target for Goliath family ubiquitin ligases, we show that recycling endosome trafficking is abrogated in response to their activity. While we observed ubiquitylation of VAMP3 by Godzilla, we are unable to describe the nature of this ubiquitination, be it mono-ubiquitin or extended ubiquitin chains." SIGNOR-272094 CDK3 protein Q00526 UNIPROT NOTCH1 protein P46531 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser2516 FLTPSPEsPDQWSSS -1 25344755 t lperfetto "Mapping of cyclin C-dependent phosphosites on ICN1, using mass spectrometry revealed that several of them are located within the PEST-domain of Notch1, which controls ICN1 degradation38,39 (Fig. 5g and Supplementary Table 1). Three of them (T2512, S2514 and S2517) are localized within the consensus motif, “Cdc4 phosphodegron”, which is shared by most substrates of Fbw7 (Cdc4) ubiquitin ligase38. Two of these residues (S2514 and S2517) were previously shown by Fryer et al.20 to be phosphorylated by cyclin C-CDK8 in vitro, and all three were shown to play a role in controlling ICN1 stability via Fbw740. We verified that cyclin C-CDK8, C-CDK19 and C-CDK3 phosphorylate ICN1 on these three residues" SIGNOR-273168 CDK3 protein Q00526 UNIPROT NOTCH1 protein P46531 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser2513 EHPFLTPsPESPDQW -1 25344755 t lperfetto "Mapping of cyclin C-dependent phosphosites on ICN1, using mass spectrometry revealed that several of them are located within the PEST-domain of Notch1, which controls ICN1 degradation38,39 (Fig. 5g and Supplementary Table 1). Three of them (T2512, S2514 and S2517) are localized within the consensus motif, “Cdc4 phosphodegron”, which is shared by most substrates of Fbw7 (Cdc4) ubiquitin ligase38. Two of these residues (S2514 and S2517) were previously shown by Fryer et al.20 to be phosphorylated by cyclin C-CDK8 in vitro, and all three were shown to play a role in controlling ICN1 stability via Fbw740. We verified that cyclin C-CDK8, C-CDK19 and C-CDK3 phosphorylate ICN1 on these three residues" SIGNOR-273169 MAPK14 protein Q16539 UNIPROT EWSR1 protein Q01844 UNIPROT unknown phosphorylation Thr79 QPPTGYTtPTAPQAY 9606 19076070 t lperfetto "Here we report that ews and ews-fli1 become phosphorylated at thr79 . but the p38_/p38_ mapks were the major kinases phosphorylating ews-fli1. It will be important to investigate how the p38_/p38_-stimulated phosphorylation of ews-fusion proteins affects their ability to transactivate and their oncogenic potential." SIGNOR-182778 KIF3B protein O15066 UNIPROT "Plus-end directed sliding movement" phenotype SIGNOR-PH216 SIGNOR up-regulates 9606 28290984 f "In general, N-kinesins and C-kinesins drive microtubule plus end- and minus end-directed motilities, respectively, and M-kinesins depolymerize microtubules1,9 (Box 1).|Forty-five genes that encode kinesin superfamily proteins (also known as KIFs) have been discovered in the mouse and human genomes.|KIFs are molecular motors that directionally transport various cargos, including membranous organelles, protein complexes and mRNAs, along the microtubule system." SIGNOR-272516 SRC protein P12931 UNIPROT RAPGEF1 protein Q13905 UNIPROT up-regulates phosphorylation Tyr504 APIPSVPyAPFAAIL 9606 15320955 t llicata "C3g is activated upon phosphorylation at tyrosine 504 c3g is phosphorylated in vivo on y504 upon coexpression with src or hck, two members of the src family tyrosine kinases." SIGNOR-128273 CTDSPL protein O15194 UNIPROT SMAD2 protein Q15796 UNIPROT "down-regulates activity" dephosphorylation Ser255 ELSPTTLsPVNHSLD 9606 BTO:0000007 17035229 t "Dephosphorylation of Smad2/3 Linkers by SCP2 and SCP3|MAPK-mediated linker phosphorylation appears to have a dual role in Smad2/3 regulation. Mitogens and hyperactive Ras result in extracellular signal-regulated kinase (ERK)-mediated phosphorylation of Smad3 at Ser-204, Ser-208, and Thr-179 and of Smad2 at Ser-245/250/255 and Thr-220. Mutation of these sites increases the ability of Smad3 to activate target genes, suggesting that MAPK phosphorylation of Smad3 is inhibitory (11, 12). However, in contrast, ERK-dependent phosphorylation of Smad2 at Thr-8 enhances its transcriptional activity" SIGNOR-248312 USP9X protein Q93008 UNIPROT RPS27A protein P62979 UNIPROT "up-regulates quantity" cleavage 9606 BTO:0000567 26235645 t miannu "Here we provide data suggesting that two of the four mammalian ubiquitin precursors, UBA52 and UBA80, are processed mostly post-translationally whereas the other two, UBB and UBC, probably undergo a combination of co- and post-translational processing. Using an unbiased biochemical approach we found that UCHL3, USP9X, USP7, USP5 and Otulin/Gumby/FAM105b are by far the most active DUBs acting on these precursors." SIGNOR-270826 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR EWSR1 protein Q01844 UNIPROT unknown phosphorylation 9606 19076070 t "inferred from 70% family members" lperfetto "Here we report that ews and ews-fli1 become phosphorylated at thr79 in the n-terminal domain in response to mitogens or dna damage. Mitogen-induced phosphorylation of ews and ews-fli1 was weak and catalysed by erk1 (extracellular signal-regulated kinase 1) and erk2." SIGNOR-270172 RAF1 protein P04049 UNIPROT STK3/4 proteinfamily SIGNOR-PF41 SIGNOR down-regulates binding 9606 15618521 t "inferred from 70% of family members" gcesareni "Raf-1 prevents dimerization and phosphorylation of the activation loop of mst2 independently of its protein kinase activity.Raf-1 counteracts apoptosis by suppressing the activation of mammalian sterile 20-like kinase (mst2)" SIGNOR-269942 Ub:E2 complex SIGNOR-C497 SIGNOR FANCL protein Q9NW38 UNIPROT "up-regulates activity" ubiquitination 9606 34199813 t miannu "The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t" SIGNOR-271099 CENPS protein Q8N2Z9 UNIPROT "CCAN complex" complex SIGNOR-C365 SIGNOR "form complex" binding 9606 BTO:0000567 18007590 t lperfetto "CENP-A NAC/CAD components have been subdivided into either NAC proteins (nucleosome-associated complex; CENP-C, CENP-H, CENP-50CENP−U, CENP-M, CENP-T and Chl4RCENP−N) or CAD proteins (CENP-A Distal; CENP-I, Mcm21RCENP−O, Fta1RCENP−L, Sim4RCENP−K, CENP-P, CENP-Q, CENP-R and CENP-S)." SIGNOR-265205 thiocyanate smallmolecule CHEBI:18022 ChEBI Cell_killing phenotype SIGNOR-PH149 SIGNOR up-regulates 9606 BTO:0000133 9922160 f lperfetto "Myeloperoxidase plays a fundamental role in oxidant production by neutrophils. The enzyme uses hydrogen peroxide to oxidize chloride (Cl-), bromide (Br-), iodide (I-), and the pseudohalide thiocyanate (SCN-) to their respective hypohalous acids.| Our results show that thiocyanate is an important substrate of myeloperoxidase in most environments and that hypothiocyanate is likely to contribute to leukocyte antimicrobial activity." SIGNOR-270592 ABL1 protein P00519 UNIPROT STK3/4 proteinfamily SIGNOR-PF41 SIGNOR up-regulates phosphorylation 9606 BTO:0000938 22590567 t "inferred from 70% of family members" llicata "We demonstrate that c-abl kinase phosphorylates mst2 at an evolutionarily conserved site, y81, within the kinase domain. We further show that the phosphorylation of mst2 by c-abl leads to the disruption of the interaction with raf-1 proteins and the enhancement of homodimerization of mst2 proteins. It thereby enhances the mst2 activation and induces neuronal cell death." SIGNOR-269946 CDK8 protein P49336 UNIPROT H3-3A protein P84243 UNIPROT "down-regulates activity" phosphorylation Ser11 TKQTARKsTGGKAPR 18418385 t "Ser 11 phosphorylation of H3 is either activatory and inhibitory as promotes DNA condensation (activatory) and induce transcription (inhibitory)." lperfetto "However, within T/G-Mediator, cdk8 phosphorylates serine-10 on histone H3, which in turn stimulates H3K14 acetylation by GCN5L within the complex. Tandem phosphoacetylation of H3 correlates with transcriptional activation, and ChIP assays demonstrate co-occupancy of T/G-Mediator components at several activated genes in vivo." SIGNOR-273173 PRKACA protein P17612 UNIPROT RYR1 protein P21817 UNIPROT "up-regulates activity" phosphorylation Ser2843 KKKTRKIsQSAQTYD -1 14532276 t miannu "PKA-mediated hyperphosphorylation of a conserved serine, Ser-2843 in skeletal RyR and Ser-2809 in cardiac RyR, results in an aberrant SR function during heart failure. hyperphosphorylated RyRs are leaky and therefore lead to a reduced SR Ca2+ load and impaired contractile function in heart failure" SIGNOR-250078 HK2 protein P52789 UNIPROT Cell_death phenotype SIGNOR-PH109 SIGNOR "down-regulates activity" 10090 16892090 f "HK II via its mitochondrial location also suppresses the death of cancer cells, thus increasing their possibility for metastasis and the ultimate death of the human host" SIGNOR-259979 "CKM complex" complex SIGNOR-C406 SIGNOR STAT1 protein P42224 UNIPROT "up-regulates activity" phosphorylation Ser727 TDNLLPMsPEEFDEV 29239838 t lperfetto "We previously demonstrated that Mediator kinase inhibitor cortistatin A (CA) reduced proliferation of JAK2-mutant AML in vitro and in vivo and also suppressed CDK8-dependent phosphorylation of STAT1 at serine 727. Here we report that phosphorylation of STAT1 S727 promotes the proliferation of AML cells with JAK-STAT pathway activation." SIGNOR-273182 CYP24A1 protein Q07973 UNIPROT propan-2-ol smallmolecule CHEBI:17824 ChEBI "up-regulates quantity" "chemical modification" 30080183 t lperfetto "Homozygous mutations in the vitamin D 24-hydroxylase CYP24A1, the major enzyme responsible for inactivation of 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D, lead to idiopathic infantile hypercalcemia (IIH)." SIGNOR-270574 RARB protein P10826 UNIPROT OXT protein P01178 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 6153132 f lperfetto "The human and rat OT promoters could be stimulated by the ligand-activated estrogen receptors ERalpha and ERbeta, the thyroid hormone receptor THRapha, and the retinoic acid receptors RARalpha and RARbeta in a variety of cells (3, 477, 478). However, it is important to note that these results were obtained from cotransfection experiments in cell lines, i.e., under nonphysiological circumstances." SIGNOR-268549 CDK4 protein P11802 UNIPROT RUNX3 protein Q13761 UNIPROT down-regulates phosphorylation Ser356 SSSGGDRsPTRMLAS 9606 SIGNOR-C18 19351720 t llicata "Our findings demonstrate that the cell cycle proteins cyclin d1 and cdk4 induce runx2 and runx3 phosphorylation, ubiquitylation and proteasomal degradation." SIGNOR-185120 risperidone chemical CHEBI:8871 ChEBI HRH1 protein P35367 UNIPROT "down-regulates activity" "chemical inhibition" -1 8935801 t miannu "Risperidone and its active metabolite 9-OH-risperidone were compared to reference antipsychotic drugs (haloperidol, pipamperone, fluspirilene, clozapine, zotepine) and compounds under development (olanzapine, seroquel, sertindole, ORG-5222, ziprasidone) for in vitro binding to neurotransmitter receptors in brain tissue and on membranes of recombinant cells expressing cloned human receptors and for in vivo occupancy of neurotransmitter receptors in rat and guinea-pig brain following acute treatment (2 h., s.c.). The binding affinities of the compounds for various neurotransmitter receptors were measured using membrane preparations of animal brain regions and of recombinant cells expressing cloned, mostly human receptors. Receptors, tissues and cells are indicated in Table I; results are shown in Table 4A-B." SIGNOR-258530 LPAR1 protein Q92633 UNIPROT GNA12 protein Q03113 UNIPROT up-regulates binding 9606 22863277 t milica "Serum-borne lysophosphatidic acid (LPA) and sphingosine 1-phosphophate (S1P) act through G12/13-coupled receptors to inhibit the Hippo pathway kinases Lats1/2, thereby activating YAP and TAZ transcription." SIGNOR-198507 RPS6KA4 protein O75676 UNIPROT "Histone H3" proteinfamily SIGNOR-PF69 SIGNOR unknown phosphorylation 10090 12773393 t lperfetto "The results presented here show that MSK2 and, to a lesser extent, MSK1 are the major protein kinases required for the phosphorylation of histone H3 at both Ser10 and Ser28" SIGNOR-265355 PPP2CB protein P62714 UNIPROT CHEK1 protein O14757 UNIPROT "down-regulates activity" dephosphorylation Ser345 LVQGISFsQPTCPDH 9606 17015476 t "Phosphorylation of Chk1 by ATR is antagonized by a Chk1-regulated protein phosphatase 2A circuit|In response to genotoxic stress, Chk1 is phosphorylated on serines 317 (S317) and 345 (S345) by the ataxia-telangiectasia-related (ATR) protein kinase. Phosphorylation of Chk1 on these C-terminal serine residues is used as an indicator of Chk1 activation in vivo." SIGNOR-248578 ATM protein Q13315 UNIPROT MECOM protein Q03112 UNIPROT "up-regulates activity" phosphorylation Ser1039 NSNHGSQsPRNVEER 29939287 t "phosphorylation site remapping based on Fig 1" lperfetto "To investigate to what extent EVI1 function might be regulated by post-translational modifications we carried out mass spectrometry- and antibody-based analyses and uncovered an ATM-mediated double phosphorylation of EVI1 at the carboxy-terminal S858/S860 SQS motif." SIGNOR-273434 PDPK1 protein O15530 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR "up-regulates activity" phosphorylation Thr308 KDGATMKtFCGTPEY 10090 12808134 t lperfetto "Akt1 and akt2 are phosphorylated and activated by the protein kinase pdk1 at thr-308 or thr-309, respectively, in the activation t-loop, and further activation occurs through phosphorylation at ser-473 or ser-474, respectively. In this paper, we demonstrate that this is indeed the case, and report the purification and initial characterization of a 3 phosphoinositide-dependent protein kinase, pdk1, which activates pkb by phosphorylating it at thr308. Akt is directly phosphorylated and activated by pdk1. Akt/pkb activation requires the phosphorylation of thr308 in the activation loop by the phosphoinositide-dependent kinase 1 (pdk1)." SIGNOR-134477 PRKACG protein P22612 UNIPROT MYBPC3 protein Q14896 UNIPROT up-regulates phosphorylation Ser304 SLLKKRDsFRTPRDS 9606 BTO:0000887 20151718 t miannu "Phosphorylation of cmybp-c by pka speeds actomyosin interactions and contributes to increased cardiac contractility following _-adrenergic stimulation.7, 8 phosphorylation by pka is essential for proper cardiac function /for the human isoform, three pka sites were previously identified (ser275, ser284, and ser304) /our results indicate that pka phosphorylates up to four sites in both the murine and human m-domains including a novel site not previously described for either protein (ser307 for mouse and ser311 for human)." SIGNOR-163792 dothiepin chemical CHEBI:36798 ChEBI SLC6A4 protein P31645 UNIPROT "down-regulates activity" "chemical inhibition" 9606 BTO:0000007 9537821 t miannu "Among the antidepressants that we tested, paroxetine, which is a serotonin selective re-uptake inhibitor based on animal data, was the most potent for the human serotonin transporter with a KD=0.13±0.01 nM. Some tricyclic antidepressants (clomipramine, imipramine and amitriptyline), as well as some other antidepressants (sertraline, fluoxetine, citalopram and fluvoxamine) and some of their metabolites (norfluoxetine, desmethylsertraline and desmethylcitalopram) were also very potent at the human serotonin transporter." SIGNOR-258877 PRKACA protein P17612 UNIPROT ADD2 protein P35612 UNIPROT "down-regulates activity" phosphorylation Ser713 KKKFRTPsFLKKSKK -1 8810272 t miannu "Ser-726 and Ser-713 in the C-terminal MARCKS-related domains of - and -adducin, respectively, were identified as the major phosphorylation sites common for PKA and PKC. Phosphorylation by PKA, but not PKC, reduced the affinity of adducin for spectrin-F-actin complexes as well as the activity of adducin in promoting binding of spectrin to F-actin." SIGNOR-250332 RUNX2 protein Q13950 UNIPROT SNAI2 protein O43623 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 22641097 f miannu "Effective silencing of Runx2 by short interfering RNA (siRNA) demonstrated downregulation of EMT-related molecules (SNAI2, SNAI3 and TWIST1), MMP2 and vasculogenic factors (VEGFA and VEGFC) in thyroid carcinoma cells." SIGNOR-255080 PP2Ca_R1A_Bd complex SIGNOR-C133 SIGNOR GSK3B protein P49841 UNIPROT "up-regulates activity" dephosphorylation Ser9 SGRPRTTsFAESCKP 9606 BTO:0000007 20080667 t miannu "DAB2IP interacts via its C2 domain with GSK3β, recruiting phosphatase PP2A for S9 de-phosphorylation and leading to GSK3β activation." SIGNOR-254754 OPRL1 protein P41146 UNIPROT GNAZ protein P19086 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257117 IL6 protein P05231 UNIPROT IL6R protein P08887 UNIPROT up-regulates binding 9606 15895091 t gcesareni "We show that the augmentation of the il6 signal by recombinant il6 receptors (ril6r) delivery allows the functional recovery of phagocytes in a peritonitis mouse model." SIGNOR-137236 AKT1 protein P31749 UNIPROT ACLY protein P53396 UNIPROT unknown phosphorylation Ser455 PAPSRTAsFSESRAD 10116 BTO:0000443 12107176 t gcesareni "Taken together, these results demonstrate that serine 454 of ATP-citrate lyase is a novel and major in vivo substrate for protein kinase B." SIGNOR-245255 CSNK1D protein P48730 UNIPROT ZNF322 protein Q6U7Q0 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser396 ELSPPHAsEASQMS 9606 BTO:0002552 28581525 t lperfetto "CK1delta and GSK3beta kinases sequentially phosphorylate ZNF322A at serine-396 and then serine-391. Moreover, the doubly phosphorylated ZNF322A protein creates a destruction motif for the ubiquitin ligase FBXW7alpha leading to ZNF322A protein destruction." SIGNOR-264892 MAP2K6 protein P52564 UNIPROT MAPK14 protein Q16539 UNIPROT "up-regulates activity" phosphorylation Thr180 RHTDDEMtGYVATRW 9534 8622669 t lperfetto "These data indicate that mkk6 phosphorylates p38 map kinase on thr-180 and tyr-182, the sites of phosphorylation that activate p38 map kinase" SIGNOR-40423 GNB/GNG complex SIGNOR-C202 SIGNOR PLCB3 protein Q01970 UNIPROT up-regulates 23994464 t apalma "However, it was later shown that other PLCβ isoforms (particularly PLCβ2 and PLCβ3) can also be directly activated by Gβγ subunits" SIGNOR-255016 CSF2RB protein P32927 UNIPROT CSF2RA/CSF2RB complex SIGNOR-C212 SIGNOR "form complex" binding 9606 BTO:0000876 BTO:0001103 9680354 t apalma "The high-affinity GMR is known to be composed of a specific ligand-binding alpha subunit (GMRα) and a common beta subunit (βc), which is also a component of the interleukins-3 (IL-3) and -5 (IL-5) receptors." SIGNOR-255583 CACNA1G protein O43497 UNIPROT Excitatory_synaptic_transmission phenotype SIGNOR-PH133 SIGNOR up-regulates 9606 BTO:0000227 30849329 f miannu "Voltage-gated calcium channels mediate the influx of calcium in response to membrane depolarization in excitable cells. In presynaptic nerve terminals, this calcium influx triggers transmitter release for synaptic transmission. Several neurological and cardiac disorders are caused by pathogenic variants in genes encoding α1-subunits of voltage-gated calcium channels, including CACNA1A (MIM: 601011) (familial hemiplegic migraine [MIM: 141500], episodic ataxia [MIM: 108500], and epilepsy [MIM: 617106]),3, 4, 5 CACNA1C (MIM: 114205) (Timothy syndrome [MIM: 601005]),6, 7 CACNA1D (MIM: 114206) (primary aldosteronism, neurodevelopmental disorders [MIM: 615474]),8, 9 and CACNA1G (MIM: 604065) (spinocerebellar ataxia [MIM: 616795])." SIGNOR-264329 PRKCA protein P17252 UNIPROT RAF1 protein P04049 UNIPROT unknown phosphorylation Ser233 VSSQHRYsTPHAFTF 9606 12551925 t gcesareni "For example, PKCα phosphorylates Raf-1 at serine 499 (13), but mutation of this residue did not impede activation of Raf-1 by the physiological stimulators Ras and Lck. Similarly, both v-Src and phorbol esters were able to activate Raf-1 even though the PKC phosphorylation sites at serine 497 and serine 499 were mutated to alanine (14). Thus, although some PKC phosphorylation sites on Raf-1 have been identified, these sites do not appear to be required for activation of Raf-1." SIGNOR-37466 RICTOR protein Q6R327 UNIPROT mTORC2 complex SIGNOR-C2 SIGNOR "form complex" binding 9606 25628925 t lperfetto "Depending on their binding partners and sensitivities to rapamycin, mtor resides in at least two distinct complexes, termed mtor complex 1 (mtorc1, containing raptor, fkbp12, pras40 and mlst8) and mtor complex 2 (mtorc2, containing rictor, sin1, protor and mlst8)" SIGNOR-205624 CACNA1D protein Q01668 UNIPROT Excitatory_synaptic_transmission phenotype SIGNOR-PH133 SIGNOR up-regulates 9606 BTO:0000227 30849329 f miannu "Voltage-gated calcium channels mediate the influx of calcium in response to membrane depolarization in excitable cells. In presynaptic nerve terminals, this calcium influx triggers transmitter release for synaptic transmission. Several neurological and cardiac disorders are caused by pathogenic variants in genes encoding α1-subunits of voltage-gated calcium channels, including CACNA1A (MIM: 601011) (familial hemiplegic migraine [MIM: 141500], episodic ataxia [MIM: 108500], and epilepsy [MIM: 617106]),3, 4, 5 CACNA1C (MIM: 114205) (Timothy syndrome [MIM: 601005]),6, 7 CACNA1D (MIM: 114206) (primary aldosteronism, neurodevelopmental disorders [MIM: 615474]),8, 9 and CACNA1G (MIM: 604065) (spinocerebellar ataxia [MIM: 616795])." SIGNOR-264331 FBXL7 protein Q9UJT9 UNIPROT "Cullin 1-RBX1-Skp1" complex SIGNOR-C529 SIGNOR "up-regulates activity" binding 10090 BTO:0002268 25778398 t miannu "Fbxl7 targets survivin for polyubiquitylation and proteasomal degradation.these data suggest that the Skp1·Cul1·F-box protein complex subunit Fbxl7 modulates mitochondrial function by controlling the cellular abundance of survivin. These results suggest that both Lys-90 and Lys-91 are critical for Fbxl7-mediated polyubiquitylation." SIGNOR-272437 lenalidomide chemical CHEBI:63791 ChEBI IKZF1 protein Q13422 UNIPROT "down-regulates quantity by destabilization" "chemical inhibition" 9606 24328678 t gcesareni "Members of the Ikaros family of transcription factors, specifically Ikaros and Aiolos (encoded by the genes IKZF1 and IKZF3 respectively), are recruited as protein substrates for CRL4CRBN in T cells in response to lenalidomide or pomalidomide treatment." SIGNOR-236910 CACNA1C protein Q13936 UNIPROT Excitatory_synaptic_transmission phenotype SIGNOR-PH133 SIGNOR up-regulates 9606 BTO:0000227 30849329 f miannu "Voltage-gated calcium channels mediate the influx of calcium in response to membrane depolarization in excitable cells. In presynaptic nerve terminals, this calcium influx triggers transmitter release for synaptic transmission. Several neurological and cardiac disorders are caused by pathogenic variants in genes encoding α1-subunits of voltage-gated calcium channels, including CACNA1A (MIM: 601011) (familial hemiplegic migraine [MIM: 141500], episodic ataxia [MIM: 108500], and epilepsy [MIM: 617106]),3, 4, 5 CACNA1C (MIM: 114205) (Timothy syndrome [MIM: 601005]),6, 7 CACNA1D (MIM: 114206) (primary aldosteronism, neurodevelopmental disorders [MIM: 615474]),8, 9 and CACNA1G (MIM: 604065) (spinocerebellar ataxia [MIM: 616795])." SIGNOR-264330 PRKACA protein P17612 UNIPROT CAD protein P27708 UNIPROT down-regulates phosphorylation Ser1406 GAGGRRLsSFVTKGY 9606 17206380 t gcesareni "Protein kinase a phosphorylation at thr456 of the multifunctional protein cad antagonizes activation by the map kinase cascade." SIGNOR-151816 GSK3B protein P49841 UNIPROT MACF1 protein Q9UPN3 UNIPROT "down-regulates activity" phosphorylation Ser7234 RAASPTRsSSSASQS 9606 BTO:0004905 21295697 t lperfetto "We discovered that GSK3β, a kinase inhibited by Wnt signaling, directly phosphorylates ACF7, a > 500 kDa microtubule-actin crosslinking protein abundant in hair follicle stem cells (HF-SCs). We map ACF7's GSK3β sites to the microtubule-binding domain and show that phosphorylation uncouples ACF7 from microtubules." SIGNOR-264429 MYOG protein P15173 UNIPROT "Myog/SWI/SNF complex" complex SIGNOR-C94 SIGNOR "form complex" binding 9606 BTO:0001103 17194702 t miannu "Upon the expression of myogenin, myogenin, mef2d, and brg1 localize to the myogenin promoter to maintain myogenin expression./ Swi/snf chromatin-remodeling activity is required for myogenin expression in differentiated skeletal muscle" SIGNOR-151691 CLN8 protein Q9UBY8 UNIPROT SET protein Q01105 UNIPROT "down-regulates activity" binding 9606 BTO:0000007 30453012 t miannu "CLN8 interacts with ceramide binding proteins PP2A and I2PP2A. We showed that the phosphorylation levels of several substrates of PP2A, namely Akt, S6 kinase, and GSK3β, were decreased in CLN8 disease patient fibroblasts. This reduction can be reversed by inhibiting PP2A phosphatase activity with cantharidin, suggesting a higher PP2A activity in CLN8-deficient cells. The phosphorylation levels of PP2A substrates are decreased in the absence of CLN8." SIGNOR-265584 PTPRB protein P23467 UNIPROT MAPK3 protein P27361 UNIPROT up-regulates dephosphorylation 9606 12840032 t gcesareni "When cells are stimulated with various ligands such as growth factors, hormones, neurotransmitters, or tumor promoters, erk1/2 is activated through dualphosphorylation at the -ptepy-motif. Subsequently, p-erk1/2 translocates into the nucleus and phosphorylates elk-1, thereby acting as a transcription factor for cell proliferationthese data indicate that sa-p-erk1/2 might not only be regulated by mkp such as rvhr, but also by pp1 and ptp as well" SIGNOR-103165 EPHB2 protein P29323 UNIPROT EPHB2 protein P29323 UNIPROT "up-regulates activity" phosphorylation Tyr602 IYIDPFTyEDPNEAV -1 10572014 t "Our results demonstrate that autophosphorylation tyrosine 611 in the juxtamembrane region of chicken EphB2 is critical for the association of the Src SH2 domain." SIGNOR-251124 SNAI2 protein O43623 UNIPROT CDH1 protein P12830 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 15311212 f miannu "known E-cadherin transcriptional repressors, such as SLUG (SNAI2), SIP1 (ZEB2), TWIST1, SNAIL (SNAI1) and ZEB1 (TCF8), but not E12/E47 (TCF3), had a lack of upregulation in cells expressing mutated E-cadherin compared to WT." SIGNOR-255155 "monoisononyl phthalate" chemical CHEBI:132593 ChEBI PPARG protein P37231 UNIPROT "up-regulates activity" "chemical activation" 9534 BTO:0001538 27551952 t miannu "MEHP and MiNP exhibit potent activation of hCAR2 and hPXR with higher affinities for these receptors than for the hPPARs. The rank order potency for MEHP and MiNP was hCAR2 > hPXR > hPPARs." SIGNOR-268782 BTK protein Q06187 UNIPROT PLCG2 protein P16885 UNIPROT "up-regulates activity" phosphorylation Tyr1197 LESEEELySSCRQLR 9606 BTO:0000776 11507089 t lperfetto "These findings indicate that the phosphorylations of the tyrosine residues 753, 759, 1197, and 1217, which have been identified as btk-dependent phosphorylation sites in vitro, coordinately contribute to bcr-induced activation of plcgamma2." SIGNOR-109746 POU5F1 protein Q01860 UNIPROT NANOG protein Q9H9S0 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0001086 17068183 f miannu "To enhance our understanding of the molecular basis of this differentiation event in humans, we used a functional genomics approach involving RNA interference-mediated suppression of OCT4 function in a human ESC line and analysis of the resulting transcriptional profiles to identify OCT4-dependent genes in human cells. We detected altered expression of >1,000 genes, including targets regulated directly by OCT4 either positively (NANOG, SOX2, REX1, LEFTB, LEFTA/EBAF DPPA4, THY1, and TDGF1) or negatively (CDX2, EOMES, BMP4, TBX18, Brachyury [T], DKK1, HLX1, GATA6, ID2, and DLX5), as well as targets for the OCT4-associated stem cell regulators SOX2 and NANOG." SIGNOR-254939 AKT1 protein P31749 UNIPROT PIKFYVE protein Q9Y2I7 UNIPROT up-regulates phosphorylation Ser307 PARNRSAsITNLSLD 9606 BTO:0000887 15546921 t gcesareni "Here we report that serine318 on the fyve domain-containing ptdins3p 5-kinase (pikfyve) is a novel substrate for pkb, and show that phosphorylation stimulates the ptdins3p 5-kinase activity of the enzyme." SIGNOR-252474 ECM stimulus SIGNOR-ST20 SIGNOR "AX/b2 integrin" complex SIGNOR-C171 SIGNOR up-regulates 9606 30889378 t miannu "Upon binding to the extracellular matrix (ECM), the integrins organize the cytoskeleton and activate intracellular signaling, regulating complex cellular behaviors, including survival, proliferation, migration, and various cell fate transitions" SIGNOR-259053 Gbeta proteinfamily SIGNOR-PF4 SIGNOR POLR2A protein P24928 UNIPROT down-regulates phosphorylation 9606 14662762 t "inferred from 70% family members" lperfetto "Erk1/2 are major ser-5 kinases after h2o2 treatment. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination." SIGNOR-270039 CSNK2A1 protein P68400 UNIPROT SEC63 protein Q9UGP8 UNIPROT "up-regulates activity" phosphorylation Ser574 EEVSDKGsDSEEEET 9606 23287549 t lperfetto "Sec63 was identified as a novel substrate and binding partner of protein kinase CK2. We identified serine 574, serine 576 and serine 748 as CK2 phosphorylation sites. Phosphorylation of Sec63 by CK2 enhanced its binding to Sec62." SIGNOR-265269 "Ub:E1 (UBA6 substrate)" complex SIGNOR-C496 SIGNOR UBE2N protein P61088 UNIPROT "up-regulates activity" ubiquitination 9606 34199813 t miannu "The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t" SIGNOR-271354 PYGM protein P11217 UNIPROT glycogen smallmolecule CHEBI:28087 ChEBI "down-regulates quantity" "chemical modification" 9606 3346228 t "Mammalian glycogen phosphorylases are found in at least three isozymic forms that can be distinguished by functional and structural properties as well as by the tissues in which they are preferentially expressed [√¢‚Ǩ¬¶] Each phosphorylase isozyme fulfills different physiological requirements even though all forms of the enzyme catalyze the same reaction, the phosphorolysis of glycogen to yield glucose 1-phosphate." SIGNOR-267948 NfKb-p65/p50 complex SIGNOR-C13 SIGNOR Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 22021368 f apalma "In normal hematopoiesis, AML1 suppresses NF-κB signaling and thus may contribute to inhibition of excessive proliferation of hematopoietic cells." SIGNOR-255692 GOT1 protein P17174 UNIPROT oxaloacetate(2-) smallmolecule CHEBI:16452 ChEBI "up-regulates quantity" "chemical modification" 9606 26003525 t miannu "Glutamate oxaloacetate transaminase (GOT) catalyzes the reversible reaction of l-aspartate and √鬱-ketoglutarate into oxaloacetate and L-glutamate and plays a key role in carbon and nitrogen metabolism in all organisms. In human tissues, GOTs are pyridoxal 5'-phosphate-dependent (PLP) enzymes which exist in cytoplasm and mitochondrial forms, GOT1 and GOT2, respectively. GOT1 expression correlates with the growth of several tumors because cancer cells can utilize the amino acid glutamine to fuel anabolic processes, and therefore, GOT1 represents a new therapeutic target in cancer." SIGNOR-267509 DUSP1 protein P28562 UNIPROT MAPK3 protein P27361 UNIPROT "down-regulates activity" dephosphorylation Thr202 HDHTGFLtEYVATRW 10116 7535768 t "We demonstrate that ERK, JNK, and p38 are activated by distinct combinations of stimuli in T cells that simulate full or partial activation through the T cell receptor. These kinases are regulated by reversible phosphorylation on Tyr and Thr, and the dual specific phosphatases PAC1 and MKP-1 previously have been implicated in the in vivo inactivation of ERK or of ERK and JNK, respectively" SIGNOR-248462 NODAL protein Q96S42 UNIPROT ACVR1B protein P36896 UNIPROT "up-regulates activity" binding 9606 19874624 t Regulation miannu "Nodal effects are dependent upon interactions with Cripto, a small cysteine-rich extracellular protein that is attached to the plasma membrane through a glycosyl phosphatidyl inositol linkage. Cripto interacts with Nodal and ALK4, independently, and promotes the formation of a stable high affinity complex with activin type II receptors." SIGNOR-251939 SERPINA1 protein P01009 UNIPROT LRP1 protein Q07954 UNIPROT up-regulates binding 9606 8626456 t gcesareni "In vitro binding studies revealed that antithrombin iii (atiii)thrombin, heparin cofactor ii (hcii)thrombin, and ?1-antitrypsin (?1AT)trypsin bound to purified lrp" SIGNOR-41180 RRN3 protein Q9NYV6 UNIPROT "SL1 complex" complex SIGNOR-C464 SIGNOR "up-regulates activity" relocalization 9606 BTO:0000567 11250903 t lperfetto "HRRN3 is essential in the SL1-mediated recruitment of RNA Polymerase I to rRNA gene promoters|We conclude that hRRN3 functions to recruit initiation-competent Pol I to rRNA gene promoters. The essential role for hRRN3 in linking Pol I to SL1 suggests a mechanism for growth control of Pol I transcription." SIGNOR-269647 NTN3 protein O00634 UNIPROT NEO1 protein Q92859 UNIPROT "up-regulates activity" binding 9606 BTO:0001484 28245592 t miannu "Experiments have demonstrated that Neogenin also mediates Netrin-1 attractive functions. Both DCC and Neogenin are type I transmembrane receptors that belong to the immunoglobulin superfamily proteins." SIGNOR-268171 NTN1 protein O95631 UNIPROT NEO1 protein Q92859 UNIPROT "up-regulates activity" binding 9606 BTO:0001484 28245592 t miannu "Experiments have demonstrated that Neogenin also mediates Netrin-1 attractive functions. Both DCC and Neogenin are type I transmembrane receptors that belong to the immunoglobulin superfamily proteins." SIGNOR-268169 NRXN3 protein Q9Y4C0 UNIPROT DAG1 protein Q14118 UNIPROT "up-regulates activity" binding 9606 22626542 t miannu "The DGC is potentially recruited to the postsynaptic membrane though a direct neurexin–dystroglycan interaction and an indirect interaction with NL2 via the synaptic scaffolding protein S-SCAM." SIGNOR-265463 "nitric oxide" smallmolecule CHEBI:16480 ChEBI GUCY1A3-B2 complex SIGNOR-C139 SIGNOR "up-regulates activity" "chemical activation" 9606 15036565 t gcesareni "One of the most biologically relevant actions of NO is its binding to the heme moiety in the heterodimeric enzyme, soluble guanylyl cyclase (sGC). Activation of sGC by NO results in the production of the second messenger molecule, 3€²,5€²-cyclic guanosine monophosphate (cGMP)" SIGNOR-244113 CyclinA2/CDK2 complex SIGNOR-C83 SIGNOR ESR1 protein P03372 UNIPROT up-regulates phosphorylation Ser118 LHPPPQLsPFLQPHG 9606 10428798 t lperfetto "Within er af-1, serines 104, 106, and 118 represent potential cdk phosphorylation sites, and in this current study, we ascertain their importance in mediating cyclin a-cdk2-dependent enhancement of er transcriptional activity." SIGNOR-217292 Gbeta proteinfamily SIGNOR-PF4 SIGNOR ATF2 protein P15336 UNIPROT up-regulates phosphorylation 9606 12110590 t "inferred from 70% family members" gcesareni "Here, we show that in fibroblasts, insulin, epidermal growth factor (egf) and serum activate atf2 via a so far unknown two-step mechanism involving two distinct ras effector pathways: the raf-mek-erk pathway induces phosphorylation of atf2 thr71, whereas subsequent atf2 thr69 phosphorylation requires the ral-ralgds-src-p38 pathway." SIGNOR-270073 TACR3 protein P29371 UNIPROT GNAI1 protein P63096 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257066 PPP1CC protein P36873 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR "down-regulates activity" dephosphorylation Ser473 RPHFPQFsYSASGTA 9606 BTO:0002419 14633703 t "Here, we identify PP1 as a serine/threonine phosphatase that associates with and dephosphorylates AKT in breast cancer cells|The heat shock protein 90 inhibitor geldanamycin and the ErbB inhibitor ZD1839 promote rapid PP1 phosphatase-dependent inactivation of AKT in ErbB2 overexpressing breast cancer cells" SIGNOR-248502 AURKA protein O14965 UNIPROT "Histone H3" proteinfamily SIGNOR-PF69 SIGNOR unknown phosphorylation 10090 12234980 t gcesareni "In the present study, chromosome number instability and increased tumor invasiveness were noted in constitutively AIM-1-overexpressing cells in vivo. Increased mitotic Ser-10 phosphorylation was also observed in various colorectal tumor cells with high AIM-1 expression levels. These data suggest that increased H3 histone phosphorylation as a result of AIM-1 overexpression is a major precipitating factor of chromosome instability and, thus, may play a role in carcinogenesis." SIGNOR-265356 TTC3 protein P53804 UNIPROT AKT1 protein P31749 UNIPROT "down-regulates quantity by destabilization" ubiquitination 10090 BTO:0000944 20059950 t gcesareni "TTC3 is an Akt-specific E3 ligase that binds to phosphorylated Akt and facilitates its ubiquitination and degradation within the nucleus" SIGNOR-252436 DRD5 protein P21918 UNIPROT GNAZ protein P19086 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257311 CSK protein P41240 UNIPROT CSK protein P41240 UNIPROT "up-regulates activity" phosphorylation Tyr304 DVCEAMEyLEGNNFV -1 9148770 t llicata "Taken together these results indicate that Csk can be phosphorylated in vivo at Tyr-184 by an as yet unknown tyrosine kinase, and that autophosphorylation of Tyr-304 occurs only at abnormally high Csk concentrations in vitro. Furthermore, Tyr-304 is required for the maintenance of the structure of the Csk kinase domain." SIGNOR-250778 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR MYOD1 protein P15172 UNIPROT down-regulates phosphorylation Ser200 YSGDSDAsSPRSNCS 9606 BTO:0000222 14749395 t lperfetto "Myod is phosphorylated on ser5 and ser200 by cyclin b-cdc2, resulting in a decrease of its stability and down-regulation of both myod and p21." SIGNOR-216920 GOT1 protein P17174 UNIPROT L-aspartate(1-) smallmolecule CHEBI:29991 ChEBI "up-regulates quantity" "chemical modification" 9606 26003525 t miannu "Glutamate oxaloacetate transaminase (GOT) catalyzes the reversible reaction of l-aspartate and Œ±-ketoglutarate into oxaloacetate and L-glutamate and plays a key role in carbon and nitrogen metabolism in all organisms. In human tissues, GOTs are pyridoxal 5'-phosphate-dependent (PLP) enzymes which exist in cytoplasm and mitochondrial forms, GOT1 and GOT2, respectively. GOT1 expression correlates with the growth of several tumors because cancer cells can utilize the amino acid glutamine to fuel anabolic processes, and therefore, GOT1 represents a new therapeutic target in cancer." SIGNOR-267506 CDC14A protein Q9UNH5 UNIPROT MAPK6 protein Q16659 UNIPROT "down-regulates quantity by destabilization" dephosphorylation Ser705 TPSAMKSsPQIPHQT 9606 20236090 t "Reciprocally, we found that the phosphatases Cdc14A and Cdc14B (Cdc is cell-division cycle) bind to ERK3 and reverse its C-terminal phosphorylation in mitosis. Importantly, alanine substitution of the four C-terminal phosphorylation sites markedly decreased the half-life of ERK3 in mitosis, thereby linking phosphorylation to the stabilization of the kinase.|In vitro phosphorylation of a series of ERK3-deletion mutants by mitotic cell extracts revealed that phosphorylation is confined to the unique C-terminal extension of the protein. Using MS analysis, we identified four novel phosphorylation sites, Ser684, Ser688, Thr698 and Ser705, located at the extreme C-terminus of ERK3." SIGNOR-248833 ADP chemical CHEBI:16761 ChEBI AMPK complex SIGNOR-C15 SIGNOR up-regulates "chemical activation" 9606 21399626 t lperfetto "Amp binding to the gamma-regulatory domain promotes phosphorylation by the upstream kinase, protects the enzyme against dephosphorylation, as well as causing allosteric activation.Adp also stimulates phosphorylation, without stimulating already phosphorylated catalytic subunit. Atp promotes dephosphorylation of catalytic subunit, rendering the ampk enzyme inactive." SIGNOR-217475 serotonin smallmolecule CHEBI:28790 ChEBI HTR1A protein P08908 UNIPROT "up-regulates activity" "chemical activation" 10029 9550290 t miannu "Together, these data show that (i) [3H]-S 15535 is a highly selective 5-HT1A receptor ligand which labels both G-protein-coupled and uncoupled 5-HT1A receptors, (ii) antagonists, such as WAY 100,635, which yield monophasic isotherms in competition with both [3H]-agonists and [3H]-antagonists, are not sensitive to the G-protein coupling state of the receptor, but (iii) spiperone and methiothepin behaved as inverse agonists, their competition isotherms with [3H]-S 15535 being modulated in an opposite manner to those of agonists." SIGNOR-258889 NFS1 protein Q9Y697 UNIPROT "Mitochondrial Fe-S Cluster Assembly Complex" complex SIGNOR-C276 SIGNOR "form complex" binding -1 27519411 t lperfetto "As the architecture of the human machinery remains undefined, we co-expressed in Escherichia coli the following four proteins involved in the initial step of Fe-S cluster synthesis: FXN42-210 (iron donor); [NFS1]·[ISD11] (sulfur donor); and ISCU (scaffold upon which new clusters are assembled). We purified a stable, active complex consisting of all four proteins with 1:1:1:1 stoichiometry." SIGNOR-262127 MAPK1 protein P28482 UNIPROT NR5A1 protein Q13285 UNIPROT "up-regulates activity" phosphorylation Ser203 EYPEPYAsPPQPGLP 9534 BTO:0004055 10230405 t lperfetto "Here we show that maximal SF-1-mediated transcription and interaction with general nuclear receptor cofactors depends on phosphorylation of a single serine residue (Ser-203) located in a major activation domain (AF-1) of the protein. Moreover, phosphorylation-dependent SF-1 activation is likely mediated by the mitogen-activated protein kinase (MAPK) signaling pathway." SIGNOR-249431 Norbinaltorphimine chemical CHEBI:81529 ChEBI OPRK1 protein P41145 UNIPROT "down-regulates activity" "chemical inhibition" 10029 BTO:0000246 9686407 t miannu "Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors." SIGNOR-258819 DNAJC11 protein Q9NVH1 UNIPROT Mitochondrial_biogenesis phenotype SIGNOR-PH32 SIGNOR up-regulates 10090 BTO:0000312 25111180 f "Homozygous mutant mice developed locomotion defects, muscle weakness, spasticity, limb tremor, leucopenia, thymic and splenic hypoplasia, general wasting and early lethality. Neuropathological analysis showed severe vacuolation of the motor neurons in the spinal cord, originating from dilatations of the endoplasmic reticulum and notably from mitochondria that had lost their proper inner membrane organization. T" SIGNOR-261147 PRKN protein O60260 UNIPROT ZNF746 protein Q6NUN9 UNIPROT "down-regulates quantity by destabilization" ubiquitination 9606 BTO:0000793 28122242 t miannu "PINK1 is required for Parkin ubiquitination and degradation of PARIS. PINK1 interacts with and phosphorylates serines 322 and 613 of PARIS to control its ubiquitination and clearance by parkin." SIGNOR-273726 MAPK3 protein P27361 UNIPROT BCL6 protein P41182 UNIPROT down-regulates phosphorylation Ser343 KSDCQPNsPTESCSS 9606 BTO:0000782;BTO:0000785 9649500 t gcesareni "Here we show that antigen receptor activation leads to bcl-6 phosphorylation by mitogen-activated protein kinase (mapk). Phosphorylation, in turn, targets bcl-6 for rapid degradation by the ubiquitin/proteasome pathway." SIGNOR-58493 "Papain-like proteinase" protein P0C6X7-PRO_0000037311 UNIPROT TRAF6 protein Q9Y4K3 UNIPROT "down-regulates activity" deubiquitination 9606 31226023 t miannu "Also, SARS-CoVPLPro catalyzed deubiquitination ofTNF-receptor-associatedfactor3(TRAF3)and TRAF6, thereby suppressing IFN-I and proinflammatory cytokines induced by TLR7 agonist" SIGNOR-260248 ATF4 protein P18848 UNIPROT WARS2 protein Q9UGM6 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 33384352 t miannu "QRICH1 promotes the expression of translation-related genes. our combined ChIP-seq and RNA-seq analyses identified that QRICH1 and ATF4 were enriched at the promoters of these specific tRNA synthetases, and that ER stress positively regulated their transcription (Fig. 4I). Together, these findings suggest that QRICH1 and ATF4 modulate tRNA metabolic processes to promote secreted protein synthesis during ER stress." SIGNOR-269430 PRKACA protein P17612 UNIPROT RAP1B protein P61224 UNIPROT up-regulates phosphorylation Ser179 PGKARKKsSCQLL 9606 19651783 t llicata "These results provide a mechanistic explanation for the differential effects of rap1 phosphorylation by pka on effector protein interaction. camp is one among several pathways leading to rap1 activation" SIGNOR-187410 DNMT3B protein Q9UBC3 UNIPROT DPP6 protein P42658 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 23409053 t lperfetto "Dnmt3b was responsible for transcriptional silencing of Dpp6 gene as depletion of Dnmt3b resulted in increased mRNA and protein expression of Dpp6." SIGNOR-268963 IDH3A protein P50213 UNIPROT IDH complex SIGNOR-C396 SIGNOR "form complex" binding 9606 28139779 t miannu "Human NAD-dependent isocitrate dehydrogenase existing as the α2βγ heterotetramer, catalyzes the decarboxylation of isocitrate into α-ketoglutarate in the Krebs cycle, and is allosterically regulated by citrate, ADP and ATP." SIGNOR-266248 SOX2/POU5F1 complex SIGNOR-C73 SIGNOR SALL4 protein Q9UJQ4 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 31583686 t SimoneGraziosi "Both SOX2 and SOX17 are able to partner with OCT4 and, as a consequence, recognize and bind specific binding motifs.6, 7 In human and mouse ESCs, SOX2/OCT4 bind to canonical motifs (CTTTGTCATGCAAAT-like), which are composite SOX (CATTGTC-like) and OCT (ATGCAAAT-like) motifs|This way SOX17 and SOX2 regulate a common set of pluripotency and GC-related genes (PRDM14, DPPA4, TDGF1, NANOG, LIN28A, TRIM71, OTX2, PIM2) (Fig. 6). Additionally, in TCam-2 cells SOX17 binds to compressed motifs or SOX motifs (not bound by SOX2 in ECs), thereby regulating the PGC specifiers PRDM1 and TFAP2C, the GC-related genes NANOS3 and BMP7 and the cancer-related genes MYC and IGF1 (Fig. 6). In 2102EP cells, SOX2 further binds canonical elements or SOX motifs (not bound by SOX17 in TCam-2), regulating additional pluripotency genes (GDF3, LEFTY2, SALL4, SOX2 and POU5F1) (Fig. 6)." SIGNOR-269252 DDHD2 protein O94830 UNIPROT "phosphatidic acid" smallmolecule CHEBI:16337 ChEBI "down-regulates quantity" "chemical modification" 9606 22922100 t miannu "Members of the intracellular phospholipase A1 family of proteins have been implicated in organelle biogenesis and membrane trafficking. The mammalian family comprises three members: phosphatidic acid-preferring phospholipase A1 (PA-PIA1)/DDHD1, p125/Sec23ip and KIAA0725p/DDHD2, all of which have a DDHD domain." SIGNOR-269649 RNF128 protein Q8TEB7 UNIPROT CD83 protein Q01151 UNIPROT "down-regulates quantity by destabilization" polyubiquitination Lys177 SIFPDFSkAGMERAF 9606 BTO:0000007 19542455 t miannu "In this study, we show that GRAIL can down-modulate the expression of CD83 (previously described as a cell surface marker for mature dendritic cells) on CD4 T cells. GRAIL-mediated down-modulation of CD83 is dependent on an intact GRAIL extracellular protease-associated domain and an enzymatically active cytosolic RING domain, and proceeds via the ubiquitin-dependent 26S proteosome pathway. Ubiquitin modification of lysine residues K168 and K183, but not K192, in the cytoplasmic domain of CD83 was shown to be necessary for GRAIL-mediated degradation of CD83." SIGNOR-271850 HRC protein P23327 UNIPROT ATP2A2 protein P16615 UNIPROT "down-regulates activity" binding 10116 BTO:0001879 28784772 t miannu "Furthermore, a Ser96Asp HRC variant, which mimics constitutive phosphorylation of Ser96, diminished delayed aftercontractions in HRC null cardiac myocytes. This HRC phosphomimetic variant was also able to rescue the aftercontractions elicited by the Ser96Ala variant, demonstrating that phosphorylation of Ser96 is critical for the cardioprotective function of HRC. Phosphorylation of HRC on Ser96 regulated the interactions of HRC with both triadin and SERCA2a, suggesting a unique mechanism for regulation of SR Ca homeostasis. " SIGNOR-273662 TGFBR1 protein P36897 UNIPROT RAC1 protein P63000 UNIPROT "up-regulates activity" 9606 19726546 t lperfetto "Thus, TGF-_1 rapidly stimulates activity of both RhoA and Rac1 and this activation requires ALK5/T_RI kinase activity." SIGNOR-227496 OXTR protein P30559 UNIPROT GNAL protein P38405 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-256936 ATM protein Q13315 UNIPROT STK11 protein Q15831 UNIPROT up-regulates phosphorylation Thr367 IIYTQDFtVPGQVPE 9606 BTO:0000848 12234250 t gcesareni "We demonstrate that both dna-pk and atm efficiently phosphorylate lkb1 at thr-366 in vitro and provide evidence that atm mediates this phosphorylation in vivo." SIGNOR-92873 FLT1 protein P17948 UNIPROT FLT1 protein P17948 UNIPROT up-regulates phosphorylation Tyr1333 DYNSVVLySTPPI 9606 9722576 t lperfetto "Receptor tyrosine phosphorylation is crucial for signal transduction by creating high affinity binding sites for src homology 2 domain-containing molecules. By expressing the intracellular domain of flt-1/vascular endothelial growth factor receptor-1 in the baculosystem, we identified two major tyrosine phosphorylation sites at tyr-1213 and tyr-1242 and two minor tyrosine phosphorylation sites at tyr-1327 and tyr-1333 in this receptor." SIGNOR-59762 LAT protein O43561 UNIPROT PI3K complex SIGNOR-C156 SIGNOR "up-regulates activity" binding 9606 11368773 t lperfetto "By substituting these tyrosine residues in LAT with phenylalanine and by utilizing phosphorylated peptides derived from these sites, we mapped the tyrosine residues in LAT required for the direct interaction and activation of Vav, p85/p110alpha and phospholipase Cgamma1 (PLCgamma1). Our results indicate that Tyr(226) and Tyr(191) are required for Vav binding, whereas Tyr(171) and Tyr(132) are necessary for association and activation of phosphoinositide 3-kinase activity and PLCgamma1 respectively." SIGNOR-252734 MAPK1 protein P28482 UNIPROT EWSR1 protein Q01844 UNIPROT unknown phosphorylation Thr79 QPPTGYTtPTAPQAY 9606 19076070 t lperfetto "Here we report that ews and ews-fli1 become phosphorylated at thr79 in the n-terminal domain in response to mitogens or dna damage. Mitogen-induced phosphorylation of ews and ews-fli1 was weak and catalysed by erk1 (extracellular signal-regulated kinase 1) and erk2." SIGNOR-182770 CSNK2A1 protein P68400 UNIPROT ANP32B protein Q92688 UNIPROT up-regulates phosphorylation Thr244 GEKRKREtDDEGEDD 9606 19130553 t gcesareni "Here, we are able to report that casein kinase 2 (ck2) phosphorylates april on residue threonine244 (thr(244)) and demonstrate that the ck2-specific inhibitor 4,5,6,7-tetrabromo-2-azabenzimidazole abolishes cd83 expression in activated jurkat t cells by interfering with the nucleocytoplasmic translocation of cd83 mrna" SIGNOR-183158 PRTN3 protein P24158 UNIPROT F2RL1 protein P55085 UNIPROT "down-regulates activity" cleavage Val76 LTGKLTTvFLPIVYT -1 10978167 t lperfetto "PAR1E and PAR2E (10 microM) were incubated in the presence of the different proteases | The enzymes were used at the following concentrations: 0.5 unit/mL thrombin, 2.5 nM trypsin, 20 nM plasmin, 20 nM cathepsin G, 20 nM elastase, 20 nM proteinase 3, and 2 units/mL calpain I and II|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus.|Mass spectrometry studies of PAR2E predicted activation of PAR2 by trypsin through cleavage at the Arg36-Ser37 site, no effect of thrombin, and inactivation of the receptor by plasmin, calpain and leukocyte elastase, cathepsin G, and proteinase 3" SIGNOR-263601 CEBPB protein P17676 UNIPROT HSD11B1 protein P28845 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 19088256 t lperfetto "In conclusion, C/EBPalpha and C/EBPbeta control basal transcription, and TNF-alpha upregulates 11beta-HSD1, most likely by p38 MAPK-mediated increased binding of C/EBPbeta to the human HSD11B1 promoter." SIGNOR-268972 PLK1 protein P53350 UNIPROT SUZ12 protein Q15022 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser546 SMSEFLEsEDGEVEQ 25855382 t lperfetto "PLK1 and HOTAIR Accelerate Proteasomal Degradation of SUZ12 and ZNF198 during Hepatitis B Virus-Induced Liver Carcinogenesis|In SUZ12, residues 539, 541 and 546 phosphorylated by Plk1 in vitro" SIGNOR-275556 CIITA protein P33076 UNIPROT MYOG protein P15173 UNIPROT down-regulates binding 9606 BTO:0001103 28163303 t apalma "During early stages of myogenesis, CIITA binds directly to myogenin (MYOG) and inactivates it, preventing MYOG-mediated induction of myogenic genes that are required for muscle differentiation and function" SIGNOR-255111 TNFRSF1B protein P20333 UNIPROT MAPK14 protein Q16539 UNIPROT "up-regulates activity" 17151142 f "[...] TNF-alpha is critical for p38 activation during the early stages of myoblast differentiation" SIGNOR-253601 NPTX1 protein Q15818 UNIPROT BAX protein Q07812 UNIPROT "up-regulates activity" relocalization 10090 23069675 t lperfetto "Immunofluorescence staining and subcellular fractionation analyses revealed increased mitochondrial translocation of Bad and Bax proteins from cytoplasm following OGD (4 h) and simultaneously increased release of Cyt C from mitochondria followed by activation of caspase-3. NP1 protein was immunoprecipitated with Bad and Bax proteins; OGD caused increased interactions of NP1 with Bad and Bax, thereby, facilitating their mitochondrial translocation and dissipation of mitochondrial membrane potential" SIGNOR-261439 UBE3A protein Q05086 UNIPROT PSMB1 protein P20618 UNIPROT "down-regulates quantity by destabilization" ubiquitination 9606 BTO:0000007 28559284 t lperfetto "Our experiments collectively suggest that UBE3A stimulates Wnt pathway activation by interacting with, ubiquitinating, and reducing the levels of multiple (PSMB1, PSMC2, PSMD2, and PSMD7) proteasome subunits." SIGNOR-265131 NFIA protein Q12857 UNIPROT MYOD1 protein P15172 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 32991581 t brain lperfetto "NFIA binds to and activates the brown-fat-specific enhancers even before differentiation and later facilitates the binding of PPARgamma|NFIA has at least three functions on the transcriptional regulation of brown fat [2]. First, NFIA activates adipogenesis per se, through activating the transcription of Pparg, which encodes PPARgamma. Second, NFIA also activates the brown-fat-specific gene expression (such as Ucp1 and Ppargc1a) independent of the degree of adipocyte differentiation, through facilitating the binding of PPARgamma to the brown-fat-specific enhancers. Third, NFIA represses myogenesis through suppression of myogenic transcription factors such as Myod1 as well as Myog," SIGNOR-263982 AMPK complex SIGNOR-C15 SIGNOR MAPT protein P10636-5 UNIPROT "down-regulates activity" phosphorylation Ser262 NVKSKIGsTENLKHQ -1 21204788 t miannu "AMPK phosphorylation inhibits tau binding of microtubules. In order to study further the phosphorylation of tau by AMPK, we compared phosphorylation of tau by MARK4 or AMPK using a panel of phospho-tau antibodies (Figure 2A). Five phosphorylation sites common to both kinases were identified (Thr231, Ser262, Ser356, Ser396 and Ser422). In addition, AMPK, but not MARK4, was capable of phosphorylating Ser214 (Figure 2A)." SIGNOR-273928 MARK4 protein Q96L34 UNIPROT MAPT protein P10636-5 UNIPROT "down-regulates activity" phosphorylation Thr231 KKVAVVRtPPKSPSS -1 21204788 t miannu "AMPK phosphorylation inhibits tau binding of microtubules. In order to study further the phosphorylation of tau by AMPK, we compared phosphorylation of tau by MARK4 or AMPK using a panel of phospho-tau antibodies (Figure 2A). Five phosphorylation sites common to both kinases were identified (Thr231, Ser262, Ser356, Ser396 and Ser422). In addition, AMPK, but not MARK4, was capable of phosphorylating Ser214 (Figure 2A)." SIGNOR-273932 MARK4 protein Q96L34 UNIPROT MAPT protein P10636-5 UNIPROT "down-regulates activity" phosphorylation Ser262 NVKSKIGsTENLKHQ -1 21204788 t miannu "AMPK phosphorylation inhibits tau binding of microtubules. In order to study further the phosphorylation of tau by AMPK, we compared phosphorylation of tau by MARK4 or AMPK using a panel of phospho-tau antibodies (Figure 2A). Five phosphorylation sites common to both kinases were identified (Thr231, Ser262, Ser356, Ser396 and Ser422). In addition, AMPK, but not MARK4, was capable of phosphorylating Ser214 (Figure 2A)." SIGNOR-273933 AMPK complex SIGNOR-C15 SIGNOR MAPT protein P10636-4 UNIPROT "down-regulates activity" phosphorylation Ser352 PRHLSNVsSTGSIDM -1 21204788 t miannu "AMPK phosphorylation inhibits tau binding of microtubules. In order to study further the phosphorylation of tau by AMPK, we compared phosphorylation of tau by MARK4 or AMPK using a panel of phospho-tau antibodies (Figure 2A). Five phosphorylation sites common to both kinases were identified (Thr231, Ser262, Ser356, Ser396 and Ser422). In addition, AMPK, but not MARK4, was capable of phosphorylating Ser214 (Figure 2A)." SIGNOR-273929 MARK4 protein Q96L34 UNIPROT MAPT protein P10636-4 UNIPROT "down-regulates activity" phosphorylation Ser353 RHLSNVSsTGSIDMV -1 21204788 t miannu "AMPK phosphorylation inhibits tau binding of microtubules. In order to study further the phosphorylation of tau by AMPK, we compared phosphorylation of tau by MARK4 or AMPK using a panel of phospho-tau antibodies (Figure 2A). Five phosphorylation sites common to both kinases were identified (Thr231, Ser262, Ser356, Ser396 and Ser422). In addition, AMPK, but not MARK4, was capable of phosphorylating Ser214 (Figure 2A)." SIGNOR-273934 SCF-betaTRCP complex SIGNOR-C5 SIGNOR CEP68 protein Q76N32 UNIPROT "down-regulates quantity by destabilization" ubiquitination 25503564 t lperfetto "We show that the intercentrosomal linker protein Cep68 is degraded in prometaphase through the SCF(βTrCP) (Skp1-Cul1-F-box protein) ubiquitin ligase complex. Cep68 degradation is initiated by PLK1 phosphorylation of Cep68 on Ser 332, allowing recognition by βTrCP." SIGNOR-275622 SIRT5 protein Q9NXA8 UNIPROT LDHB protein P07195 UNIPROT "up-regulates activity" deacetylation Lys329 DTLWDIQkDLKDL 9606 BTO:0001615 34929314 t lperfetto "In colorectal cancer, SIRT5 binds to lactate dehydrogenase B (LDHB) to deacetylate it at Lysine 329, thereby increasing its enzymatic activity." SIGNOR-267645 AKT2 protein P31751 UNIPROT FOXO4 protein P98177 UNIPROT "down-regulates activity" phosphorylation Thr32 QSRPRSCtWPLPRPE 10090 BTO:0000944 11313479 t "Phosphorylation of AFX by PKB occurs in the nucleus. Phosphorylation of S193 reduces the rate of nuclear import. PKB-mediated phosphorylation of AFX, therefore, attenuates the import of the transcription factor, which shifts the localization of the protein from the nucleus to the cytoplasm and results in the inhibition of AFX transcriptional activity." SIGNOR-251491 putrescine smallmolecule CHEBI:17148 ChEBI Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 14617280 f apalma "Cell proliferation is highly dependent on the synthesis of polyamines, which are derived from arginine metabolism" SIGNOR-255551 NRF1 protein Q16656 UNIPROT RETREG3 protein Q86VR2 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 23939472 f miannu "We found that NRF-1 positively regulates FAM134C and ENOX1, but negatively regulates C3orf10 in human neuroblastoma IMR-32 cells and primary rat cortical neurons." SIGNOR-261367 DLG3 protein Q92796 UNIPROT "NMDA receptor_2B" complex SIGNOR-C348 SIGNOR "up-regulates activity" relocalization BTO:0000227 32904533 t lperfetto "DLG3 plays a critical role in clustering of NMDA receptors at excitatory synapses." SIGNOR-266007 PDPK1 protein O15530 UNIPROT SGK2 protein Q9HBY8 UNIPROT "up-regulates activity" phosphorylation Thr193 EPEDTTStFCGTPEY 10548550 t miannu "SGK2 and SGK3 are activated in vitro by PDK1, albeit more slowly than SGK1, and their activation is accompanied by the phosphorylation of Thr(193) and Thr(253) respectively. The PDK1-catalysed phosphorylation and activation of SGK2 and SGK3, like SGK1, is greatly potentiated by mutating Ser(356) and Ser(419) respectively to Asp, these residues being equivalent to the C-terminal phosphorylation site of PKB." SIGNOR-250277 FBXO27 protein Q8NI29 UNIPROT LAMP2 protein P13473 UNIPROT "down-regulates quantity by destabilization" binding 9606 BTO:0000007 28743755 t miannu "Here, we report the characterization of FBXO27, a glycoprotein-specific F-box protein that is part of the SCF (SKP1/CUL1/F-box protein) ubiquitin ligase complex, and demonstrate that SCFFBXO27 ubiquitinates glycoproteins in damaged lysosomes to regulate autophagic machinery recruitment.We found that the lysosomal protein LAMP2, which is ubiquitinated preferentially on lysosomal damage, enhances autophagic machinery recruitment to damaged lysosomes. Thus, we propose that SCFFBXO27 ubiquitinates glycoproteins exposed upon lysosomal damage to induce lysophagy." SIGNOR-272323 Ub:E2 complex SIGNOR-C497 SIGNOR TRIM34 protein Q9BYJ4 UNIPROT "up-regulates activity" ubiquitination 9606 34199813 t miannu "The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t" SIGNOR-270966 DZIP3 protein Q86Y13 UNIPROT H2AZ1 protein P0C0S5 UNIPROT "up-regulates activity" monoubiquitination Lys121 IHKSLIGkKGQQKTV 9606 18206970 t miannu " 2A-HUB catalyzes monoubiquitination of H2A at lysine 119, functioning as a combinatoric component of the repression machinery required for specific gene regulation programs. Thus, 2A-HUB mediates a selective repression of a specific set of chemokine genes in macrophages, critically modulating migratory responses to TLR activation. H2A monoubiquitination acts to prevent FACT recruitment at the transcriptional promoter region, blocking RNA polymerase II release at the early stage of elongation." SIGNOR-271748 AKT proteinfamily SIGNOR-PF24 SIGNOR DNMT1 protein P26358 UNIPROT up-regulates phosphorylation Ser143 RTPRRSKsDGEAKPE 9606 21151116 t lperfetto "Akt1 kinase colocalizes and directly interacts with dnmt1 and phosphorylates ser143. Phosphorylated dnmt1 peaks during dna synthesis, before dnmt1 methylation. Depletion of akt1 or overexpression of dominant-negative akt1 increases methylated dnmt1, resulting in a decrease in dnmt1 abundance. In mammalian cells, phosphorylated dnmt1 is more stable than methylated dnmt1." SIGNOR-244232 PPP3CC protein P48454 UNIPROT FLNA protein P21333 UNIPROT "down-regulates quantity by destabilization" dephosphorylation Ser2152 TRRRRAPsVANVGSH 9606 16442073 t "Filamin is a phosphoprotein that organizes actin filaments into networks. We report that a purified C-terminal recombinant region of filamin is a suitable substrate for calcineurin |Mutagenesis analysis showed that a dephosphorylation step occurred in Ser 2152, which was previously shown to provide resistance to calpain cleavage when endogenous PKA is activated. In contrast, phosphorylation of Ser 2152 was recently reported to be necessary for membrane dynamic changes. In this regard, we found that CsA protects filamin in platelets from calpain degradation." SIGNOR-248507 GRK3 protein P35626 UNIPROT TBXA2R protein P21731-2 UNIPROT "down-regulates activity" phosphorylation Ser357 RLPGSSDsRASASRA 9606 16956790 t done miannu " These data suggest a model whereby agonist-induced PKC phosphorylation of Ser(145) partially impairs TPbeta signalling while GRK2/3 phosphorylation at both Ser(239) and Ser(357) within its IC(3) and C-tail domains, respectively, sterically inhibits G-protein coupling, profoundly desensitizing signalling, and promotes beta-arrestin association and, in turn, facilitates TPbeta internalization." SIGNOR-274091 SRC protein P12931 UNIPROT YAP1 protein P46937-3 UNIPROT "up-regulates activity" phosphorylation Tyr394 QQNRFPDyLEAIPGT 11090 27013234 t done miannu "We found that YAP1, the pivotal effector of the Hippo signaling pathway, is a direct SRC phosphorylation target, and YAP1 phosphorylation at three sites in its transcription activation domain is necessary for SRC-YAP1-mediated transformation. " SIGNOR-274026 RPS6KA5 protein O75582 UNIPROT H3-4 protein Q16695 UNIPROT unknown phosphorylation Ser29 ATKVARKsAPATGGV 10090 12773393 t lperfetto "The results presented here show that MSK2 and, to a lesser extent, MSK1 are the major protein kinases required for the phosphorylation of histone H3 at both Ser10 and Ser28" SIGNOR-249214 KDM6A protein O15550 UNIPROT HOXC4 protein P09017 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 24561908 t miannu "Evidence for direct involvement of UTX in regulation of HOX gene activity was demonstrated through UTX knockdown experiments in HEK293T cells in which loss of UTX induced transcriptional repression of HOXA and HOXC clusters." SIGNOR-260030 IL1B protein P01584 UNIPROT GCH1 protein P30793 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000766 10435048 f miannu "IL-1 beta induces expression of GTP cyclohydrolase-1 which leads to increased generation of BH4 and activation of eNOS." SIGNOR-252224 pentazocine chemical CHEBI:7982 ChEBI OPRD1 protein P41143 UNIPROT "up-regulates activity" "chemical activation" 10029 BTO:0000246 9686407 t miannu "Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors." SIGNOR-258934 PRKCA protein P17252 UNIPROT EGFR protein P00533 UNIPROT "down-regulates activity" phosphorylation Thr678 RHIVRKRtLRRLLQE 9606 10816576 t lperfetto "Biochemical and morphological analyses indicate that threonine-phosphorylated EGFR molecules undergo normal internalization, but instead of sorting to lysosomal degradation, they recycle back to the cell surfaceThe inhibitory effects of pkc are mediated by a single threonine residue (threonine 654) of egfr" SIGNOR-77421 FBXO2 protein Q9UK22 UNIPROT BACE1 protein P56817 UNIPROT "down-regulates quantity by destabilization" binding 10090 BTO:0000938 20854419 t miannu "SCFFbx2-E3-ligase-mediated degradation of BACE1 attenuates Alzheimer’s disease amyloidosis and improves synaptic function. We report that the SCF(Fbx2) -E3 ligase is involved in the binding and ubiquitination of BACE1 via its Trp 280 residue of F-box-associated domain. we found that overexpression of Fbx2 in the primary cortical and hippocampal neurons derived from Tg2576 transgenic mice significantly promoted BACE1 degradation and reduced β-amyloid production." SIGNOR-271904 GRK2 protein P25098 UNIPROT TBXA2R protein P21731-2 UNIPROT "down-regulates activity" phosphorylation Ser239 AQQRPRDsEVEMMAQ 9606 16956790 t done miannu " These data suggest a model whereby agonist-induced PKC phosphorylation of Ser(145) partially impairs TPbeta signalling while GRK2/3 phosphorylation at both Ser(239) and Ser(357) within its IC(3) and C-tail domains, respectively, sterically inhibits G-protein coupling, profoundly desensitizing signalling, and promotes beta-arrestin association and, in turn, facilitates TPbeta internalization." SIGNOR-274088 CDH1 protein P12830 UNIPROT CTNNB1 protein P35222 UNIPROT "up-regulates activity" binding 9606 21255999 t miannu "At its C-terminus, cadherin interacts with β-catenin, which dynamically associates with α-catenin, a direct binding partner of filamentous actin" SIGNOR-265863 HCK protein P08631 UNIPROT BCR-ABL "fusion protein" SIGNOR-FP6 SIGNOR "up-regulates activity" phosphorylation Tyr730 PNLFVALyDFVASGD 9606 16912036 t Manara "Src family kinases phosphorylate the Bcr-Abl SH3-SH2 region and modulate Bcr-Abl transforming activity. | Tyrosine phosphorylation of the SH3-SH2 region is essential for full Bcr-Abl biological activity." SIGNOR-260810 PRKCQ protein Q04759 UNIPROT GRM5 protein P41594 UNIPROT "up-regulates activity" phosphorylation Thr841 RSAFTTStVVRMHVG -1 15894802 t lperfetto "Thus, we showed that it is phosphorylation of Ser-839, not Thr-840, that is absolutely required for the unique Ca2+ oscillations produced by mGluR5 activation. The Thr-840 residue is important only in that it is permissive for the PKC-dependent phosphorylation of Ser-839." SIGNOR-249290 MAPK11 protein Q15759 UNIPROT RUNX2 protein Q13950 UNIPROT up-regulates 9606 20551513 f gcesareni "Mechanistic analysis revealed that the tak1-mkk3/6-p38 mapk axis phosphorylated runx2, promoting its association with the coactivator creb-binding protein (cbp), which is re-quired to regulate osteoblast genetic programs." SIGNOR-166167 GRK2 protein P25098 UNIPROT TBXA2R protein P21731-2 UNIPROT "down-regulates activity" phosphorylation Ser357 RLPGSSDsRASASRA 9606 16956790 t done miannu " These data suggest a model whereby agonist-induced PKC phosphorylation of Ser(145) partially impairs TPbeta signalling while GRK2/3 phosphorylation at both Ser(239) and Ser(357) within its IC(3) and C-tail domains, respectively, sterically inhibits G-protein coupling, profoundly desensitizing signalling, and promotes beta-arrestin association and, in turn, facilitates TPbeta internalization." SIGNOR-274089 PRKCA protein P17252 UNIPROT TBXA2R protein P21731-2 UNIPROT "down-regulates activity" phosphorylation Ser145 FSRPAVAsQRRAWAT 9606 16956790 t done miannu " These data suggest a model whereby agonist-induced PKC phosphorylation of Ser(145) partially impairs TPbeta signalling while GRK2/3 phosphorylation at both Ser(239) and Ser(357) within its IC(3) and C-tail domains, respectively, sterically inhibits G-protein coupling, profoundly desensitizing signalling, and promotes beta-arrestin association and, in turn, facilitates TPbeta internalization." SIGNOR-274092 "Brain-specific SWI/SNF SMARCA4 variant" complex SIGNOR-C486 SIGNOR Epigenetic_regulation phenotype SIGNOR-PH203 SIGNOR up-regulates 9606 BTO:0000143 25195934 f miannu "The BAF (mammalian SWI/SNF) complexes are a family of multi-subunit ATP-dependent chromatin remodelers that use ATP hydrolysis to alter chromatin structure. Distinct BAF complex compositions are possible through combinatorial assembly of homologous subunit families and can serve non-redundant functions. In mammalian neural development, developmental stage-specific BAF assemblies are found in embryonic stem cells, neural progenitors and postmitotic neurons. In particular, the neural progenitor-specific BAF complexes are essential for controlling the kinetics and mode of neural progenitor cell division, while neuronal BAF function is necessary for the maturation of postmitotic neuronal phenotypes as well as long-term memory formation. " SIGNOR-270759 SNRPG protein P62308 UNIPROT "U4/U6.U5 snRNP complex" complex SIGNOR-C478 SIGNOR "form complex" binding 9606 30765414 t lperfetto "The major spliceosomal building blocks are the U1, U2, U4/U6, and U5 small nuclear ribonucleoproteins (snRNPs). Each consists of a small nuclear RNA (snRNA) (or two, in the case of U4/U6), seven Sm proteins that form a ring (or seven Lsm proteins in the case of U6), and a variable number of snRNP-specific proteins (Fig. 1F) (Will and Lührmann 2011). Under splicing conditions, the U4/U6 and U5 snRNPs form a 25S U4/U6.U5 tri-snRNP, in which the U4 and U6 snRNAs are base-paired, forming a three-way junction." SIGNOR-270632 PP2B proteinfamily SIGNOR-PF18 SIGNOR MEF2C protein Q06413 UNIPROT up-regulates 9606 BTO:0001103 11062529 f "inferred from 70% family members" gcesareni "The ca2+ dependent phosphatase calcineurin induces cardiac and skeletal muscle hypertrophy by a process that involves nf-at nuclear translocation, and activation of mef2c." SIGNOR-269993 CSF1R protein P07333 UNIPROT CSF1R protein P07333 UNIPROT down-regulates phosphorylation Tyr969 PLLQPNNyQFC 9606 BTO:0001271 15297464 t lperfetto "Csf-1r homodimerizes and autophosphorylates on six tyrosines in the cytoplasmic portion of the receptor. Tyr807 is located in the activation loop of the kinase domain (9) and its phosphorylation is important for kinase activity (10). The remaining tyrosines serve as binding sites for proteins containing src homology 2 (sh2) binding domains. Three sites are found in the ki: grb2/mona (tyr697) (11, 12), p85 subunit of phosphatidylinositol 3-kinase (tyr721) (13), and stat1 (tyr706) (14), the c-cbl binding site is in the cooh terminus (tyr974) following ligand binding, the csf-1r is rapidly internalized and degraded. This process begins with multiubiquitination of the csf-1r mediated by c-cbl (20), an e3-type ubiquitin ligase" SIGNOR-127626 CDK1 protein P06493 UNIPROT NPM1 protein P06748 UNIPROT "down-regulates activity" phosphorylation Thr199 VKKSIRDtPAKNAQK 9606 SIGNOR-C17 12058066 t llicata "However, under the experimental conditions used here, the t199 residue was the most likely candidate to be phosphorylated by cyclin b/cdc2 these results strongly support the concept that the rna binding activity of b23.1 is inactivated by cyclin b/cdc2-mediated phosphorylation." SIGNOR-89605 Ub:E2 complex SIGNOR-C497 SIGNOR TRIM68 protein Q6AZZ1 UNIPROT "up-regulates activity" ubiquitination 9606 34199813 t miannu "The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t" SIGNOR-271169 BCR-ABL "fusion protein" SIGNOR-FP6 SIGNOR RHOA protein P61586 UNIPROT "down-regulates activity" phosphorylation Tyr66 DTAGQEDyDRLRPLS 9606 BTO:0000567 23027962 t lperfetto "When these RhoA mutants were coexpressed with Bcr-Abl, phosphorylation levels of Y34F and Y66F RhoA mutants dramatically decreased to 32% and 17%, respectively. As expected, when Y34 and Y66 were both mutated to phenylalanine, phosphorylation was completely abolished. Together, these observations indicate that Y34 and Y66 are the two predominant phosphorylation sites, and that the Src kinase and Bcr-Abl are the two candidate kinases that may phosphorylate these sites.|In contrast to active RhoA, RhoAQ63L(Y34,66E) had a dramatic decrease in RBD binding. This binding fraction was even lower than that of WT RhoA, suggesting phosphorylation at these sites could have a negative effect on RhoA activity" SIGNOR-271699 HIP1 protein O00291 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR up-regulates 9606 11007801 f miannu "Huntingtin interacting protein 1 induces apoptosis via a novel caspase-dependent death effector domain." SIGNOR-82463 SNX9 protein Q9Y5X1 UNIPROT EGFR protein P00533 UNIPROT down-regulates 9606 11799118 f gcesareni "We have previously shown that sh3px1, phosphorylated by ack2 (activated cdc42-associated tyrosine kinase 2), regulates the degradation of egf (epidermal growth factor) receptor.The cdc42 target ack2 interacts with sorting nexin 9 (sh3px1) to regulate epidermal growth factor receptor degradation." SIGNOR-114167 SMARCC2 protein Q8TAQ2 UNIPROT "Brain-specific SWI/SNF SMARCA2 variant" complex SIGNOR-C485 SIGNOR "form complex" binding 9606 BTO:0000142 11790558 t miannu " Whereas chromatin-remodeling complexes are generally thought to promote gene expression, recent genetic and biochemical studies suggest that the SWI/SNF complex may also be involved in transcriptional repression . The subunit composition of the different human complexes that belong to this family is listed in Table 1. Several of the subunits, including SNF5/INI1, are common to all complexes and may constitute its core." SIGNOR-270746 KDM5D protein Q9BY66 UNIPROT H3-4 protein Q16695 UNIPROT "up-regulates activity" demethylation Lys5 kQTARKST 9606 30246379 t miannu "KDM5 subfamily is capable of removing tri‐ and di‐ methyl marks from lysine 4 on histone H3 (H3K4). Depending on the methylation site, its effect on transcription can be either activating or repressing." SIGNOR-264309 CLK1 protein P49759 UNIPROT RBM17 protein Q96I25 UNIPROT "up-regulates activity" phosphorylation Ser288 DATEKDAsKKSDSNP 9534 BTO:0001538 23519612 t miannu "In this work, we show that Cdc2-like kinase 1 (Clk1) phosphorylates SPF45 on eight serine residues." SIGNOR-262709 TTBK1 protein Q5TCY1 UNIPROT MAPT protein P10636 UNIPROT down-regulates phosphorylation Ser519 SGYSSPGsPGTPGSR 9606 BTO:0000938 16923168 t "The effect has been demonstrated using P10636-8" lperfetto "Direct tau phosphorylation by ttbk1 at ser198, ser199, ser202 and ser422, which are also phosphorylated in phfs. Ttbk1 also induces tau aggregation in human neuronal cells in a dose-dependent manner. We conclude that ttbk1 is a neuron-specific dual kinase involved in tau phosphorylation at ad-related sites and is also associated with tau aggregation." SIGNOR-148974 NRG1 protein Q02297 UNIPROT ERBB2 protein P04626 UNIPROT up-regulates binding 9606 BTO:0000150 7514177 t gcesareni "Direct interaction between heregulin and the two proteins was demonstrated by chemical cross-linking experiments using 125i-heregulin followed by immunoprecipitation with antibodies specific for erbb2 or erbb3." SIGNOR-26875 LPAR3 protein Q9UBY5 UNIPROT GNAO1 protein P09471 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257141 FLT3 protein P36888 UNIPROT PIK3R1 protein P27986 UNIPROT "up-regulates activity" 10090 BTO:0001516 23246379 f miannu "Grb10 transduces signal from FLT3 by direct interaction with p85 and Ba/F3-FLT3-ITD cells expressing Grb10 exhibits higher STAT5 activation. These results suggest that Grb10 binds to both normal and oncogenic FLT3 and induces PI3K-Akt and STAT5 signaling pathways resulting in an enhanced proliferation, survival and colony formation of hematopoietic cells." SIGNOR-260081 FERMT2 protein Q96AC1 UNIPROT FBLIM1 protein Q8WUP2 UNIPROT "up-regulates activity" binding 10090 BTO:0000944 24165133 t miannu "Kindlin binds migfilin tandem LIM domains and regulates migfilin focal adhesion localization and recruitment dynamics. Two integrin-binding proteins present in FAs, kindlin-1 and kindlin-2, are important for integrin activation, FA formation, and signaling. By binding filamin, migfilin provides a link between kindlin and the actin cytoskeleton." SIGNOR-266102 PPARG protein P37231 UNIPROT ACADM protein P11310 UNIPROT "down-regulates activity" binding 9606 BTO:0001370 28974683 t Federica "This truncated PPARγ translocates to mitochondria, where it directly interacts with medium-chain acyl-CoA dehydrogenase (MCAD). This binding event attenuates MCAD activity and inhibits fatty acid oxidation" SIGNOR-261264 "MSL acetyltransferase" complex SIGNOR-C344 SIGNOR H2BC1 protein Q96A08 UNIPROT "down-regulates activity" monoubiquitination Lys36 KKRKRTRkESYSIYI 9606 21726816 t miannu "MSL1/2 ubiquitylates histone H2B on K 34. Importantly, only mono-ubiquitylation of H2B by MSL1/2 was detected in cells (data not shown), suggesting that MSL1/2, like RNF20/RNF40, was mainly a mono-ubiquitylase under physiological conditions.the MOF-MSL complex functions to promote both H4 K16ac and H2B K34ub. H2B K34ub, in turn, promotes H2B K120ub, H3 K4me3 and K79me2 to facilitate transcription elongation." SIGNOR-271992 ACD protein Q96AP0 UNIPROT POT1/ACD complex SIGNOR-C64 SIGNOR "form complex" binding 9606 17237768 t miannu "We find that tpp1 and pot1 form a complex with telomeric dna that increases the activity and processivity of the human telomerase core enzyme." SIGNOR-152318 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR PGR protein P06401 UNIPROT down-regulates phosphorylation 9606 BTO:0000150 10655479 t "inferred from 70% family members" gcesareni "Specifically, down-regulation of mature prs occurs by a mechanism in which ligand binding activates pr phosphorylation by mapks at a unique serine residue, which then targets the receptors for degradation." SIGNOR-270157 CASP8 protein Q14790 UNIPROT CYCS protein P99999 UNIPROT "up-regulates activity" 9606 BTO:0000661 10364179 f "Translocation from Mitochondria to Cytosol" lperfetto "Caspase-8 triggered rapid cytochrome c release from mitochondria. The effect was indirect." SIGNOR-68225 MAPK1 protein P28482 UNIPROT SMAD1 protein Q15797 UNIPROT down-regulates phosphorylation Ser195 PNSSYPNsPGSSSST 9606 19914168 t lpetrilli "Phosphorylation of the linker region of smads mediated by erk2, gsk3?, And cdk2/4 negatively regulates smad activity by preventing their relocation to the nucleus, by inhibiting their interactions with coactivators, or by accelerating their degradation;in contrast, erk2 phosphorylated all four smad1 residues almost evenly, while showing a preference for s204 over s208 and s213 in smad3" SIGNOR-161686 U0126 chemical CHEBI:90693 ChEBI MAPK7 protein Q13164 UNIPROT down-regulates "chemical inhibition" 9606 BTO:0000938 BTO:0000142 11160424 t gcesareni "Pd98059, sl327, and u0126 have been extensively used to implicate erk1/2 in neuroplasticity and neuronal survival. Interestingly, erk5 activation by egf in cos7 cells is also blocked by these inhibitors suggesting that the erk5 pathway may also regulate cellular processes credited previously to erk1/2." SIGNOR-104945 NPTX1 protein Q15818 UNIPROT BAD protein Q92934 UNIPROT "up-regulates activity" relocalization 10090 BTO:0000938 23069675 t lperfetto "Immunofluorescence staining and subcellular fractionation analyses revealed increased mitochondrial translocation of Bad and Bax proteins from cytoplasm following OGD (4 h) and simultaneously increased release of Cyt C from mitochondria followed by activation of caspase-3. NP1 protein was immunoprecipitated with Bad and Bax proteins; OGD caused increased interactions of NP1 with Bad and Bax, thereby, facilitating their mitochondrial translocation and dissipation of mitochondrial membrane potential" SIGNOR-261483 "Urotensin II" smallmolecule CHEBI:80244 ChEBI UTS2R protein Q9UKP6 UNIPROT "up-regulates activity" "chemical activation" 9606 BTO:0002524 31160049 t "Ligand-GPCR dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257590 CSNK2A1 protein P68400 UNIPROT EIF4EBP1 protein Q13541 UNIPROT down-regulates phosphorylation Ser112 KRAGGEEsQFEMDI 9606 12588975 t gcesareni "Phosphorylation at s112 directly affects binding of 4e-bp1 to eif4e without influencing phosphorylation of other sites." SIGNOR-98280 TBX22 protein Q9Y458 UNIPROT MSX2 protein P35548 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9031 BTO:0005956 20033915 t miannu "the main function of TBX22 as shown in misexpression experiments is to decrease proliferation. We subsequently uncovered three targets of TBX22, DLX5, MSX2, and TBX22 itself. All are downregulated in the presence of viral-derived hTBX22." SIGNOR-265567 PAK2 protein Q13177 UNIPROT CASP7 protein P55210 UNIPROT down-regulates phosphorylation Ser30 DAKPDRSsFVPSLFS 9606 BTO:0000150 21555521 t gcesareni "Pak2 can bind with caspase-7 and phosphorylate caspase-7 at the ser-30, thr-173, and ser-239 sites. Functionally, the phosphorylation of caspase-7 decreases its activity, thereby inhibiting cellular apoptosis." SIGNOR-173659 AKT2 protein P31751 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR "down-regulates activity" phosphorylation Ser256 SPRRRAAsMDNNSKF 9606 10377430 t lperfetto "Our results demonstrate that pkb/akt directly phosphorylates fkhr1, a member of the closely related fkhr subclass of the forkhead family of transcription factors, on at least two residues (threonine-24 and serine-253). These results indicate that phosphorylation by pkbyakt negatively regulates fkhr1 by promoting export from the nucleus." SIGNOR-252871 PTPRT protein O14522 UNIPROT PXN protein P49023 UNIPROT "down-regulates activity" dephosphorylation Tyr88 PQSSSPVyGSSAKTS 9606 BTO:0000182 27447856 t brain lperfetto "To this end, using a phospho-proteomics approach, we identified and validated paxillin and STAT3 as the substrates of PTPRT [15, 16]|the PTPRT target site on paxillin is a previously uncharacterized tyrosine-88 residue (paxillin Y88)|In this study, we also show how pY88 paxillin transduces a signal to activate Akt" SIGNOR-263978 TUBA3C protein P0DPH7 UNIPROT Neuron_migration phenotype SIGNOR-PH67 SIGNOR up-regulates 9606 BTO:0000007 19185337 f miannu "We show here that Elongator regulates corticogenesis because an acute disruption of its activity in dorsal progenitors results in radial migration delays and defective terminal branching of projection neurons that come with a reduction in α-tubulin acetylation. Importantly, this complex interacts with the microtubule cytoskeleton, where Elp3 may directly acetylate α-tubulin, a posttranslational modification known to regulate the intracellular trafficking that is critical for cell shape remodeling during migration and terminal branching." SIGNOR-269724 MMP12 protein P39900 UNIPROT F12 protein P00748 UNIPROT "down-regulates quantity by destabilization" cleavage Gly376 SMTRVVGgLVALRGA -1 10930399 t lperfetto "The data presented in this study show for the first time the degradation of Factor XII of the blood clotting system by matrix metalloproteinases. MMP-12, MMP-13, and MMP-14 cleave at Gly376Leu377|However, no activity of Factor XII can be observed after MMPinduced cleavage." SIGNOR-263611 PKA proteinfamily SIGNOR-PF17 SIGNOR CAMKK2 protein Q96RR4 UNIPROT down-regulates phosphorylation Ser511 RREERSLsAPGNLLT 9606 22778263 t lperfetto "Pka phosphorylates ser-100, ser-495, and ser-511the camp/pka pathway can inhibit camkk2 activity" SIGNOR-198154 CEBPA protein P49715 UNIPROT MYC protein P01106 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 12032779 f miannu "Several different transcription factors have been implicated in the down-regulation of c-myc expression during differentiation, including C/EBPalpha, CTCF, BLIMP-1, and RFX1." SIGNOR-253830 PPP1R3A protein Q16821 UNIPROT GYS1 protein P13807 UNIPROT up-regulates dephosphorylation 9606 BTO:0000887;BTO:0001103 8250835 t gcesareni "In skeletal muscle, the activation of glycogen synthase by insulin involves the dephosphorylation of serine residues that are phosphorylated by gsk3 and dephosphorylated by the glycogen-associated form of protein phosphatase-l (pp1g)." SIGNOR-37301 HECTD4 protein Q9Y4D8 UNIPROT MYC protein P01106 UNIPROT "down-regulates quantity by destabilization" ubiquitination 9606 BTO:0001321 32814769 t miannu "We identified several E3 ligases as strong candidates responsible for AR and MYC protein loss as HECTD4, MYCBP2, and TRIM49. HECTD4 and MYCBP2 target AR and MYC for degradation while TRIM49 appears to promote AR and MYC stability. We have shown that these E3 ligases in turn are directly regulated by MYC. MYC in turn represses the expression of ubiquitin ligases, HECTD4 and MYCBP2 that promote AR and MYC protein degradation, further suppressing MYC and AR in a feed forward loop." SIGNOR-267146 PAK1 protein Q13153 UNIPROT MAP3K1 protein Q13233 UNIPROT "up-regulates activity" phosphorylation Ser67 RQLRKVRsVELDQLP 9606 BTO:0000007 12228228 t lperfetto "We found that pak1 phosphorylated mekk1 on serine 67 of its amino-terminal regulatory domain. mekk1 activity was increased modestly following pak phosphorylation." SIGNOR-236006 NF90-NF45 complex SIGNOR-C443 SIGNOR CDKN1A protein P38936 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 10116 BTO:0001221 25566957 t miannu "In the present study, we investigated the expression profiles of NF45 in the sciatic nerve of adult rats following crush injury.  in the TNF-α-induced Schwann cell proliferation assay, protein level of NF45 and cyclin E was elevated while expression of p21 was down-regulated. Further, when NF45 was knocked down, Schwann cell proliferation was interrupted and the expression of cyclin E was attenuated, while the expression of p21 was up-regulated. To repress the expression of p21 is one of the basic mechanisms for NF45-regulated cell proliferation." SIGNOR-268491 SRC protein P12931 UNIPROT SH3PXD2A protein Q5TCZ1 UNIPROT "up-regulates activity" phosphorylation 20943948 t lperfetto " Recently, we have shown that tyrosine kinase c-Src substrate Tks4 and Tks5 proteins are novel members of the organizer superfamily" SIGNOR-264706 metformin chemical CHEBI:6801 ChEBI NDUFS1 protein P28331 UNIPROT "down-regulates activity" "chemical inhibition" 9606 24843020 t Federica "In this study, we report that in human cancer cells, metformin inhibits mitochondrial complex I (NADH dehydrogenase) activity and cellular respiration" SIGNOR-261080 DPM3 protein Q9P2X0 UNIPROT "DPM complex" complex SIGNOR-C289 SIGNOR "form complex" binding 9606 10835346 t lperfetto "Human dolichol-phosphate-mannose synthase consists of three subunits, DPM1, DPM2 and DPM3." SIGNOR-262565 IL15 protein P40933 UNIPROT IL15RA protein Q13261 UNIPROT up-regulates binding 9606 BTO:0000887;BTO:0001103 17709786 t "Interleukin-15 specificity and high affinity binding are conferred by the IL-5-specific but nonsignaling IL-15R alpha subunit, which is structurally similar (but not homologous) to the alpha receptor subunit of IL-2" SIGNOR-157415 succinate(2-) smallmolecule CHEBI:30031 ChEBI fumarate(2-) smallmolecule CHEBI:29806 ChEBI "up-regulates quantity" "precursor of" 9606 16143825 t miannu "Mitochondrial succinate dehydrogenase (SDH) consists merely of four nuclearly encoded subunits. It participates in the electron transfer in the respiratory chain and in succinate catabolism in the Krebs cycle. The SDH enzyme, also known as respiratory chain complex II, faces the mitochondrial matrix and is bound to the inner membrane. The human enzyme readily oxidizes succinate to fumarate, while the reverse reaction is hardly detectable in most human cells and tissues under standard conditions." SIGNOR-266275 RXRB protein P28702 UNIPROT RARB protein P10826 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 1310351 f gcesareni "Here we report that the transcriptional activity of rar and rxr can be reciprocally modulated by direct interactions between the two proteins" SIGNOR-16680 Corticotropin protein P01189-PRO_0000024969 UNIPROT MC5R protein P33032 UNIPROT "up-regulates activity" binding 9606 BTO:0000142 20371771 t lperfetto "The melanocortin (MC) receptor family consists of five Gs-coupled receptors that control various physiological functions in response to four distinct agonists, adrenocorticotropic hormone (ACTH, also known as corticotrophin) and alpha, beta, and gamma melanocyte-stimulating hormone (MSH), which are derived from the proopiomelanocortin precursor protein, and two inverse agonists, agouti and agouti-related proteins" SIGNOR-268716 MC5R protein P33032 UNIPROT GNAS protein Q5JWF2 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-256798 "SAGA complex" complex SIGNOR-C465 SIGNOR Transcritpional_activation phenotype SIGNOR-PH205 SIGNOR up-regulates 9606 15970593 f lperfetto "Transcription initiation is a major regulatory step in eukaryotic gene expression. Co-activators establish transcriptionally competent promoter architectures and chromatin signatures to allow the formation of the pre-initiation complex (PIC), comprising RNA polymerase II (Pol II) and general transcription factors (GTFs).|this observation appears remarkably prevalent for chromatin-modifying and remodeling complexes. Here, we use the modular organization of the evolutionary conserved Spt-Ada-Gcn5 acetyltransferase (SAGA) complex as a paradigm to illustrate how co-activators share and combine a relatively limited set of functional tools." SIGNOR-269570 MAPK14 protein Q16539 UNIPROT MAPKAPK2 protein P49137 UNIPROT "up-regulates activity" phosphorylation Thr317 PTQRMTItEFMNHPW -1 7592979 t miannu "In Vitro Activation of MAPKAP Kinase 2 by p38/40. the constitutively active mutant T205E,T317E shows no changes in activity after treatment with the p38/40 fraction" SIGNOR-250102 MTHFR protein P42898 UNIPROT (6R)-5,10-methylenetetrahydrofolate(2-) smallmolecule CHEBI:15636 ChEBI "down-regulates quantity" "chemical modification" 9606 10720211 t lperfetto "Methylenetetrahydrofolate reductase (MTHFR) plays a central role in the folate cycle and contributes to the metabolism of the amino acid homocysteine. It catalyzes the reduction of 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate, thus generating the active form of folate required for remethylation of homocysteine to methionine." SIGNOR-268228 PIGF protein Q07326 UNIPROT PIGG protein Q5H8A4 UNIPROT "up-regulates quantity by stabilization" binding 10029 BTO:0000246 15632136 t miannu "We show that the human homolog of Gpi7p, termed hGPI7, binds to and is stabilized by PIG-F and that hGPI7 competes with PIG-O for binding to PIG-F. PIG-F Binds to and Stabilizes hGPI7 and PIG-O Independently. These results are consistent with the hypothesis that overexpression of hGPI7 decreases the biosynthetic activity of PIG-O by decreasing the available PIG-F, thereby destabilizing PIG-O." SIGNOR-261358 TLN1 protein Q9Y490 UNIPROT ITGB2 protein P05107 UNIPROT "up-regulates activity" binding 10090 BTO:0000132 19118207 t miannu "Over the past 10 years, the binding of talin to the cytoplasmic tail of integrin-β subunits has been established to have a key role in integrin activation. Binding of the phosphotyrosinebinding (PTB)-domain-like subdomain of the protein 4.1, ezrin, radixin, moesin (FERM) domain of talin to the conserved WxxxNP(I/L)Y motif of the β-integrin tail permits additional weaker interactions between talin and the membrane-proximal region of the tail that trigger integrin activation, probably through the disruption of inhibitory interactions between α- and β-subunit cytoplasmic tails." SIGNOR-257618 FGFR3 protein P22607 UNIPROT FGFR3 protein P22607 UNIPROT "up-regulates activity" phosphorylation Tyr760 TVTSTDEyLDLSAPF 9606 BTO:0000007 11294897 t lperfetto "Ligand stimulation leads to autophosphorylation of fgfr3taken together, these results clearly implicate y724 in the activation of stat proteins by constitutively activated mutants of fgfr3 and suggest that both y724 and y760 are required for maximal stat activation." SIGNOR-106742 TBX21 protein Q9UL17 UNIPROT IL4 protein P05112 UNIPROT down-regulates "transcriptional regulation" 9606 BTO:0000782 17541280 f "IL-4 gene transcription is inhibited by T-bet via the suppression of its promoter activity, independently of IFN-gamma. T-bet facilitates Th1 differentiation through not only upregulation of IFN-gamma, but also downregulation of IL-4 gene transcription" SIGNOR-254496 "N-[4-[(hydroxyamino)-oxomethyl]phenyl]carbamic acid [6-(diethylaminomethyl)-2-naphthalenyl]methyl ester" chemical CHEBI:94187 ChEBI HDAC7 protein Q8WUI4 UNIPROT "down-regulates activity" "chemical inhibition" -1 17868033 t Luana "Our findings suggest that hydroxamic acid-derived compounds such as TSA, NVP-LAQ824, panobinostat, ITF2357, vorinostat and belinostat act as potent pan-HDAC isoform inhibitors. A notable observation was the similarity between belinostat and vorinostat in the biochemical isoform assays; both compounds exhibit similar EC50 values in all but the HDAC8 assay." SIGNOR-257907 MDM2 protein Q00987 UNIPROT POLQ protein O75417 UNIPROT "down-regulates quantity by destabilization" polyubiquitination 9606 BTO:0001890 22056306 t miannu "DNA polymerase eta is targeted by Mdm2 for polyubiquitination and proteasomal degradation in response to ultraviolet irradiation" SIGNOR-272729 SERPINE1 protein P05121 UNIPROT Fibrinolysis phenotype SIGNOR-PH6 SIGNOR down-regulates 9606 19387897 f miannu "Plasma PAI-1 levels robustly fluctuate in a circadian manner and consequently contribute to hypofibrinolysis during the early morning. The circadian expression of PAI-1 gene is thought to be directly regulated by the circadian clock proteins such as CLOCK and BMAL1/BMAL2 which drive the endogenous biological clock. Plasma PAI-1 levels are increased in the beginning of the active phase in both diurnal humans and in nocturnal rodents, suggesting that the rhythmic PAI-1 expression is commonly indispensable for organisms." SIGNOR-267984 TGM2 protein P21980 UNIPROT "Histone H3" proteinfamily SIGNOR-PF69 SIGNOR unknown phosphorylation 9606 16407273 t gcesareni "Tg2 is able to phosphorylate purified histone proteins, and h3 and h1 in chromatin preparations, and it is associated with chromatin in breast cancer cells." SIGNOR-265369 SKOR1 protein P84550 UNIPROT LBX1 protein P52954 UNIPROT "down-regulates activity" binding 9606 BTO:0000007 15528197 t llicata "Furthermore, Corl1 interacted with Lbx1 and cooperatively repressed transcription, suggesting that it acts as a transcriptional corepressor for Lbx1 in regulating cell fate determination in the dorsal spinal cord." SIGNOR-238004 CASP8 protein Q14790 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR up-regulates 9606 14585074 f amattioni "Downstream of caspase-8 activation, apoptosis induction takes place" SIGNOR-90612 XRCC3 protein O43542 UNIPROT RAD51 protein Q06609 UNIPROT "up-regulates activity" relocalization 9606 BTO:0000567 SIGNOR-C301 23438602 t lperfetto "We examined the effect of XRCC3 depletion on redistribution of RAD51 upon IR damage|Interestingly, cells expressing the XRCC3 S225A phosphomutant showed compromised chromatin loading of RAD51 upon IR damage (Fig. 4G) while the nuclear and cytosolic fractions of RAD51 were largely unchanged|It is likely that BRCA2 may directly participate in RAD51 recruitment and XRCC3 may stabilize the RAD51 filament which is in part mediated by phosphorylation." SIGNOR-263258 TRBC1 protein P01850 UNIPROT TCR complex SIGNOR-C153 SIGNOR "form complex" binding 9606 12507424 t miannu "The T cell receptor-CD3 complex (TCR-CD3) serves a critical role in the differentiation, survival, and function of T cells, and receptor triggering elicits a complex set of biological responses that serve to protect the organism from infectious agents. The receptor is composed of six different chains that form the TCR heterodimer responsible for ligand recognition, as well as the CD3γε, CD3δε, and ζζ signaling modules.the TCRα-CD3δε and TCRβ-CD3γε interactions are similar since both require a lysine in the TM region of the respective TCR chain and both acidic TM residues in the relevant CD3 heterodimer. Nevertheless, formation of fully assembled αβ TCR-CD3 complexes containing the ζ-chain strictly required both CD3γ and δ" SIGNOR-255298 PPP2CA protein P67775 UNIPROT MAP2K1 protein Q02750 UNIPROT down-regulates dephosphorylation 9606 20626350 t gcesareni "In particular, p38 mapk activity stimulates the physical association between ppa2 and mkk1/2- erk1/2 complex, leading to mkk1/2 dephosphorilation by pp2a." SIGNOR-166649 CTDSPL protein O15194 UNIPROT SMAD2 protein Q15796 UNIPROT "down-regulates activity" dephosphorylation Ser250 TGSPAELsPTTLSPV 9606 BTO:0000007 17035229 t "Dephosphorylation of Smad2/3 Linkers by SCP2 and SCP3|MAPK-mediated linker phosphorylation appears to have a dual role in Smad2/3 regulation. Mitogens and hyperactive Ras result in extracellular signal-regulated kinase (ERK)-mediated phosphorylation of Smad3 at Ser-204, Ser-208, and Thr-179 and of Smad2 at Ser-245/250/255 and Thr-220. Mutation of these sites increases the ability of Smad3 to activate target genes, suggesting that MAPK phosphorylation of Smad3 is inhibitory (11, 12). However, in contrast, ERK-dependent phosphorylation of Smad2 at Thr-8 enhances its transcriptional activity" SIGNOR-248311 CREBBP protein Q92793 UNIPROT IFNAR2 protein P48551 UNIPROT "up-regulates activity" acetylation Lys399 SGPCERRkSPLQDPF 9606 BTO:0000007 17923090 t lperfetto "By binding to IFNalphaR2 within the region where two adjacent proline boxes bear phospho-Ser364 and phospho-Ser384, CBP acetylates IFNalphaR2 on Lys399, which in turn serves as the docking site for interferon regulatory factor 9 (IRF9)RF9 interacts with the acetyl-Lys399 motif by means of its IRF homology2 (IH2) domain, leading to formation of the ISGF3 complex that includes IRF9, STAT1, and STAT2." SIGNOR-217783 CDK2 protein P24941 UNIPROT MYBL2 protein P10244 UNIPROT "up-regulates activity" phosphorylation Ser393 RGELIPIsPSTEVGG BTO:0000007 10593981 t llicata "Ten phosphorylation sites carboxyl-terminal to the DNA-binding domain were identified by this method: threonines at positions 267, 408, 497, 519, 522, and 524 and serines at positions 283, 396, 455, and 581. | Our results indicate that B-Myb can be phosphorylated in a cell-free system by both cyclin A-Cdk2 and cyclin E-Cdk2 complexes. | These data suggest that B-Myb is a target for phosphorylation by cyclin-Cdk2 and that phosphorylation of B-Myb regulates its transcriptional activity." SIGNOR-250734 ATF4 protein P18848 UNIPROT AARS2 protein Q5JTZ9 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 33384352 t miannu "QRICH1 promotes the expression of translation-related genes. our combined ChIP-seq and RNA-seq analyses identified that QRICH1 and ATF4 were enriched at the promoters of these specific tRNA synthetases, and that ER stress positively regulated their transcription (Fig. 4I). Together, these findings suggest that QRICH1 and ATF4 modulate tRNA metabolic processes to promote secreted protein synthesis during ER stress." SIGNOR-269415 P300/PCAF complex SIGNOR-C7 SIGNOR SMAD3 protein P84022 UNIPROT up-regulates binding 9606 BTO:0000150 15009097 t lperfetto "Gcn5 functions like pcaf, in that it binds to tgf-beta-specific r-smads, and enhances transcriptional activity induced by tgf-beta. In addition, gcn5, but not pcaf, interacts with r-smads for bone morphogenetic protein (bmp) signalling pathways, and enhances bmp-induced transcriptional activity, suggesting that gcn5 and pcaf have distinct physiological functions in vivo." SIGNOR-217233 ASAP2 protein O43150 UNIPROT ARF5 protein P84085 UNIPROT "up-regulates activity" "gtpase-activating protein" -1 10022920 t miannu "Pap is a multidomain protein composed of an N-terminal alpha-helical region with a coiled-coil motif, followed by a pleckstrin homology domain, an Arf-GAP domain, an ankyrin homology region, a proline-rich region, and a C-terminal SH3 domain.  In addition, in vitro recombinant Pap exhibits strong GTPase-activating protein (GAP) activity towards the small GTPases Arf1 and Arf5 and weak activity towards Arf6.  Pap protein exhibits Arf GAP activity in vitro." SIGNOR-269707 PPP2CB protein P62714 UNIPROT PAK1 protein Q13153 UNIPROT "down-regulates activity" dephosphorylation Thr423 PEQSKRStMVGTPYW 10116 18586681 t "Both sites were dephosphorylated with the same kinetics; the anti-Ser(P)198 antibody was subsequently used as it exhibited lower background staining. Direct comparison of PP2Cα with purified PP1 and PP2A lead us to conclude that at the same molar ratio PP2Cα was the most efficient in dephosphorylating PAK1 (Fig. 1D). In this case we monitored two autophosphorylation sites in the Pak1 N-terminal regulatory region (Ser57 and Ser198/203) using phosphospecific antibodies: both sites showed the same kinetics of inactivation." SIGNOR-248600 FER protein P16591 UNIPROT PECAM1 protein P16284 UNIPROT "up-regulates activity" phosphorylation Tyr713 KKDTETVySEVRKAV 9606 BTO:0000007 12972546 t miannu "PECAM-1 Is Phosphorylated by Fer and, To a Lesser Extent, by Fes. These results suggest that Fer not only functions as a tyrosine kinase for PECAM-1 but also that Fer modulates the downstream signaling of PECAM-1 by inducing phosphorylation of SHP-2 and Gab1." SIGNOR-262866 AKT proteinfamily SIGNOR-PF24 SIGNOR BRAF protein P15056 UNIPROT down-regulates phosphorylation Thr440 EDRNRMKtLGRRDSS 9606 10869359 t lperfetto "We show that phosphorylation of b-raf by akt occurs at multiple residues within its amino terminal regulatory domain, at both the conserved and unique phosphorylation sites. Akt phosphorylated b-raf on s364 and s428 to inactivate its kinase activity b-raf contains three akt consensus sites, table i. One site, ser364 is conserved with c-raf;however, two sites, ser428 and thr439, are unique to b-raf" SIGNOR-244156 GSK3B protein P49841 UNIPROT MAPT protein P10636 UNIPROT "down-regulates activity" phosphorylation Ser717 VYKSPVVsGDTSPRH 9606 BTO:0000590 12387894 t lperfetto "Sequencing of 32P-labeled trypsin phosphopeptides from tau prephosphorylated by A-kinase (using unlabeled ATP) and further phosphorylated by GSK-3 in the presence of [gamma-32P]ATP revealed that Ser-195, Ser-198, Ser-199, Ser-202, Thr-205, Thr-231, Ser-235, Ser-262, Ser-356 and Ser-404 are phosphorylated, whereas if tau is not prephosphorylated by A-kinase, GSK-3 phosphorylates it at Thr-181, Ser-184, Ser-262, Ser-356 and Ser-400. These data suggest that (i) prephosphorylation of tau by A-kinase makes additional and different sites accessible for phosphorylation by GSK-3; (ii) phosphorylation of tau at these additional sites further inhibits the biological activity of tau in its ability to bind to microtubules and promote microtubule assembly." SIGNOR-249355 PYCARD protein Q9ULZ3 UNIPROT BAX protein Q07812 UNIPROT up-regulates relocalization 9606 16964285 t gcesareni "Asc directly induces bax-mediated apoptosis. Asc induces the translocation of bax to the mitochondria, bax-dependent cycs release from the mitochondria and casp9 activation." SIGNOR-149522 glycine smallmolecule CHEBI:15428 ChEBI Gly-tRNA(Gly) smallmolecule CHEBI:29156 ChEBI "up-regulates quantity" "precursor of" 9606 24898252 t miannu "Aminoacyl-tRNA synthetases are an ancient enzyme family that specifically charges tRNA molecules with cognate amino acids for protein synthesis. Glycyl- tRNA synthetase (GlyRS) is one of the most intriguing aminoacyl-tRNA synthetases due to its divergent quaternary structure and abnormal charging properties. . In this study we report crystal structures of wild type and mutant hGlyRS in complex with tRNA and with small substrates and describe the molecular details of enzymatic recognition of the key tRNA identity elements in the acceptor stem and the anticodon loop." SIGNOR-270484 ARP2/3 complex SIGNOR-C146 SIGNOR F-actin_assembly phenotype SIGNOR-PH18 SIGNOR "up-regulates quantity" binding 9606 BTO:0000132 27871158 t lperfetto "The Arp2/3 complex stimulates the assembly of actin filaments." SIGNOR-261838 WDR45 protein Q9Y484 UNIPROT ATG2A protein Q2TAZ0 UNIPROT "up-regulates activity" binding 9606 BTO:0001938 28561066 t miannu "WIPI4 interacts with ATG2, AMPK and ULK1. Upon starvation and AMPK activation, WIPI4-ATG2 dissociates from AMPK and ULK1 and localizes at nascent autophagosomes, potentially supporting further autophagosome maturation." SIGNOR-268483 HMGB1 protein P09429 UNIPROT HOXB3 protein P14651 UNIPROT "up-regulates activity" binding -1 8890171 t miannu "We show that HMG1 interacts with proteins encoded by the HOX gene family by establishing protein-protein contacts between the HMG box domains and the HOX homeodomain. The functional role of these interactions was studied using the transcriptional activity of the human HOXD9 protein as a model. HMG1 enhances, in a dose-dependent fashion, the sequence-specific DNA binding activity in vitro, and the transcriptional activation in a co-transfection assay in vivo, of the HOXD9 protein." SIGNOR-219902 MARK1 protein Q9P0L2 UNIPROT MAP4 protein P27816 UNIPROT "down-regulates activity" phosphorylation Ser1073 KAQAKVGsLDNVGHL -1 8631898 t miannu "Here we show that p110mark phosphorylates analogous KXGS sites in the microtubule binding domains of the neuronal MAP2 and the ubiquitous MAP4. Phosphorylation in vitro leads to the dissociation of MAP2 and MAP4 from microtubules and to a pronounced increase in dynamic instability." SIGNOR-250169 Ub:E2 complex SIGNOR-C497 SIGNOR RNF122 protein Q9H9V4 UNIPROT "up-regulates activity" ubiquitination 9606 34199813 t miannu "The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t" SIGNOR-271228 SOX2/POU5F1 complex SIGNOR-C73 SIGNOR TDGF1 protein P13385 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 31583686 t SimoneGraziosi "Both SOX2 and SOX17 are able to partner with OCT4 and, as a consequence, recognize and bind specific binding motifs.6, 7 In human and mouse ESCs, SOX2/OCT4 bind to canonical motifs (CTTTGTCATGCAAAT-like), which are composite SOX (CATTGTC-like) and OCT (ATGCAAAT-like) motifs|This way SOX17 and SOX2 regulate a common set of pluripotency and GC-related genes (PRDM14, DPPA4, TDGF1, NANOG, LIN28A, TRIM71, OTX2, PIM2) (Fig. 6). Additionally, in TCam-2 cells SOX17 binds to compressed motifs or SOX motifs (not bound by SOX2 in ECs), thereby regulating the PGC specifiers PRDM1 and TFAP2C, the GC-related genes NANOS3 and BMP7 and the cancer-related genes MYC and IGF1 (Fig. 6). In 2102EP cells, SOX2 further binds canonical elements or SOX motifs (not bound by SOX17 in TCam-2), regulating additional pluripotency genes (GDF3, LEFTY2, SALL4, SOX2 and POU5F1) (Fig. 6)." SIGNOR-269236 CyclinE/CDK2 complex SIGNOR-C16 SIGNOR NPM1 protein P06748 UNIPROT "down-regulates activity" phosphorylation Thr234 SFKKQEKtPKTPKGP 9606 12058066 t lperfetto "Both subtypes of B23 proteins were phosphorylated during mitosis by cyclin B/cdc2. The RNA binding activity of B23.1 was repressed through cyclin B/cdc2-mediated phosphorylation at specific sites in B23. Thus, the RNA binding activity of B23.1 is stringently modulated by its phosphorylation and subtype association." SIGNOR-216662 MFGE8 protein Q08431 UNIPROT IL1B protein P01584 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 10090 23454767 f Giorgia "We show that MFGE8 is an endogenous inhibitor of inflammasome-induced IL-1β production. MFGE8 inhibited necrotic cell–induced and ATP-dependent IL-1β production by macrophages through mediation of integrin β3 and P2X7 receptor interactions in primed cells. In conclusion, we demonstrated that MFGE8 regulates innate immunity through inhibition of inflammasome-induced IL-1β production." SIGNOR-260649 COL18A1 protein P39060 UNIPROT ECM_synthesis phenotype SIGNOR-PH8 SIGNOR up-regulates 9606 21949456 t "Muscle basement membrane consists primarily of a type IV collagen network, however types VI, XV, and XVIII are also present. Types XV and XVIII collagen are classified as multiplexins, which are heparan sulfate proteoglycans (HSPGs). The multiplexins can bind growth factors and also aid in linking the basement membrane to other basement membrane glycoproteins and endomysium" SIGNOR-254679 PTGDR protein Q13258 UNIPROT GNAS protein Q5JWF2 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-256755 MYO3A protein Q8NEV4 UNIPROT MYO3A protein Q8NEV4 UNIPROT "down-regulates activity" phosphorylation Thr908 INLAKGDtGEATRHA 9534 24214986 t Manara "We demonstrate by mass spectrometry that Thr-178 and Thr-184 in the kinase domain activation loop and two threonines in the loop 2 region of the motor domain are autophosphorylated (Thr-908 and Thr-919) | Thus, the phosphorylation sites in loop 2 (Thr-908 and Thr-919) are likely responsible for the down-regulation of MYO3A motor activity observed in our current and previous work" SIGNOR-260923 "NSL histone acetyltransferase" complex SIGNOR-C413 SIGNOR H4C1 protein P62805 UNIPROT "down-regulates activity" acetylation Lys9 SGRGKGGkGLGKGGA 9606 20018852 t miannu "Here we report an analysis of the subunit composition and substrate specificity of the NSL complex. Proteomic analyses of complexes purified through multiple candidate subunits reveal that NSL is composed of nine subunits. by comparing the substrate specificities of the MSL and NSL complexes, we obtain evidence that MOF HAT activity is differentially regulated by assembly into the MSL complex, where it acetylates nucleosomal histone H4 on lysine 16, and the NSL complex, where it also acetylates nucleosomal histone H4 on lysines 5 and 8." SIGNOR-267168 CSNK2A1 protein P68400 UNIPROT TLE1 protein Q04724 UNIPROT up-regulates phosphorylation Ser253 DNLVVDVsNEDPSSP 9606 22354967 t lperfetto "These results show that tle1 is necessary for the maintenance of neuronal survival. Experiments using pharmacological inhibitors as well as expression of point mutants indicate that phosphorylation of tle1 by casein kinase-2 (ck2) at ser-239 and ser-253 is necessary for its survival-promoting activity." SIGNOR-196146 PTEN protein P60484 UNIPROT GLI1 protein P08151 UNIPROT down-regulates 9606 17845852 f "PTEN is a suppressor of RAS-AKT function" gcesareni "Moreover, suppressors of ras akt function, such as the tumor-suppressor pten, and the attenuation of ras signaling involved in senescence, could be thus viewed as modulators of the gli code" SIGNOR-157776 CDK1 protein P06493 UNIPROT RAD9A protein Q99638 UNIPROT "up-regulates activity" phosphorylation Ser277 SHSQDLGsPERHQPV 9606 BTO:0000567 12734188 t lperfetto "Here we present evidence that thr292 of hrad9 is subject to cdc2-dependent phosphorylation in mitosis. Furthermore, our data are also consistent with four other hrad9 phosphorylation sites (ser277, ser328, ser336, and thr355) being regulated in part by cdc2. We also identify ser387 as a novel site of hrad9 constitutive phosphorylation and show that phosphorylation at ser387 is a prerequisite for one form of dna damage-induced hyperphosphorylation of hrad9." SIGNOR-101043 mTORC1 complex SIGNOR-C3 SIGNOR Autophagy phenotype SIGNOR-PH31 SIGNOR down-regulates 9606 23863160 f lperfetto "Historically, it was known that autophagy was switched off when mTORC1 was active and that inhibition of mTORC1 was a potent autophagy inducer." SIGNOR-209922 LRP6 protein O75581 UNIPROT GSK3B protein P49841 UNIPROT "up-regulates activity" 15229249 f "We speculate that DKK1 produced by βAP-treated neurons suppresses the canonical Wnt signaling pathway by interacting with LRP5/6 and therefore facilitates GSK3β activation." SIGNOR-255484 SRC protein P12931 UNIPROT GRB10 protein Q13322 UNIPROT down-regulates phosphorylation Tyr67 NASLESLySACSMQS 9606 10871840 t lperfetto "Grb10 tyrosine phosphorylation was stimulated by expression of constitutively active src or fyn in cells and by incubation with purified src or fyn in vitro. The insulin stimulated or src/fyn-mediated tyrosine phosphorylation in vivo was significantly reduced when grb10 tyrosine 67 was changed to glycine. This mutant form of grb10 bound with higher affinity to the ir in cells than that of the wild-type protein, suggesting that tyrosine phosphorylation of grb10 may normally negatively regulate its binding to the ir." SIGNOR-78706 LCK protein P06239 UNIPROT CD28 protein P10747 UNIPROT up-regulates phosphorylation Tyr191 SRLLHSDyMNMTPRR 9606 BTO:0000782;BTO:0001271 8992971 t lperfetto "We demonstrate that emt can phosphorylate all four tyrosines of the cd28 tail, in contrast to lck, which phosphorylates only tyrosine 173. Together with evidence that in vivo, tyrosines other than tyrosine 173 become phosphorylated following cd28 stimulation, this finding suggests that, like lck, one function of emt during cd28 signaling is phosphorylation of the receptor" SIGNOR-45524 phenylalanine smallmolecule CHEBI:28044 ChEBI Phe-tRNA(Phe) smallmolecule CHEBI:29153 ChEBI "up-regulates quantity" "precursor of" 9606 20223217 t miannu "Here we report crystal structure of hcPheRS complexed with phenylalanine at 3.3 Å resolution. An essential feature of hcPheRS is a novel fold formed by the N-terminal part of the α subunit, whose functional role in tRNAPhe binding and complex formation was studied by truncation mutagenesis. Phenylalanine activation and formation of Phe-tRNAPhe catalyzed by modified hcPheRS have been compared with those of the wild-type enzyme. HcPheRS is a heterotetramer built of two αβ heterodimers." SIGNOR-270444 AKT1 protein P31749 UNIPROT MTOR protein P42345 UNIPROT unknown phosphorylation Ser2448 RSRTRTDsYSAGQSV 9606 10910062 t lperfetto "Although AKT phosphorylated mTOR at two COOH-terminal sites (Thr2446 and Ser2448) in vitro, Ser2448 was the major phosphorylation site in insulin-stimulated or -activated AKT-expressing human embryonic kidney cells. Transient transfection assays with mTOR mutants bearing Ala substitutions at Ser2448 and/or Thr2446 indicated that AKT-dependent mTOR phosphorylation was not essential for either PHAS-I phosphorylation or p70S6K activation in HEK cells." SIGNOR-251099 SMARCA5 protein O60264 UNIPROT WICH complex SIGNOR-C449 SIGNOR "form complex" binding 9606 16603771 t miannu "We show here that the WICH complex (WSTF-SNF2h) interacts with several nuclear proteins as follows: Sf3b155/SAP155, RNA helicase II/Gualpha, Myb-binding protein 1a, CSB, the proto-oncogene Dek, and nuclear myosin 1 in a large 3-MDa assembly, B-WICH, during active transcription. Our results show that a WSTF-SNF2h assembly is involved in RNA polymerase III transcription, and we suggest that WSTF-SNF2h-NM1 forms a platform in transcription while providing chromatin remodeling." SIGNOR-268827 AKT1 protein P31749 UNIPROT IKK-complex complex SIGNOR-C14 SIGNOR up-regulates phosphorylation 9606 BTO:0001454 19609947 t lperfetto "Although there are likely to be multiple levels of crosstalk between the pi3k-akt and nf-kb pathways, one mechanism has been attributed to direct phosphorylation of the amino acid residue t23 on ikb kinase alfa (ikkalfa) by akt, thereby leading to activation of this kinase upstream of nf-kb akt mediates ikkalpha phosphorylation at threonine 23 akt transiently associates in vivo with ikk and induces ikk activation. Akt mediates ikkalfa phosphorylation at threonine 23.Akt phosphorylates ikkalpha on t23, and this phosphorylation event is a prerequisite for the phosphorylation of p65 at s534 by ikkalpha and beta" SIGNOR-217460 MYC protein P01106 UNIPROT HK2 protein P52789 UNIPROT "up-regulates quantity" "transcriptional regulation" 9606 17785433 t "Here, using the P493-6 Burkitt's lymphoma model with an inducible MYC, we demonstrate that HIF-1 cooperates with dysregulated c-Myc to promote glycolysis by induction of hexokinase 2, which catalyzes the first step of glycolysis, and pyruvate dehydrogenase kinase 1, which inactivates pyruvate dehydrogenase and diminishes mitochondrial respiration." SIGNOR-259986 MAPK14 protein Q16539 UNIPROT JUNB protein P17275 UNIPROT up-regulates phosphorylation Ser79 QGSDTGAsLKLASSE 9606 15308641 t lperfetto "These results clearly demonstrate that phosphorylation by p38 kinase is essential for the regulation of dmp1 transcription by junb and p300. phosphorylation of junb at ser-79 was found to be essential for its interaction with p300." SIGNOR-127545 CBFB protein Q13951 UNIPROT RUNX1 protein Q01196 UNIPROT "up-regulates quantity by stabilization" binding 10090 BTO:0002883 11179217 t "The RUNX genes encode the α subunit of the transcription factor PEBP2/CBF. The β subunit consists of the non-RUNX protein PEBP2β. We found that RUNX1/AML1, which is essential for hematopoiesis, is continuously subjected to proteolytic degradation mediated by the ubiquitin–proteasome pathway. When PEBP2β is present, however, the ubiquitylation of RUNX1 is abrogated and this causes a dramatic inhibition of RUNX1 proteolysis." SIGNOR-255742 IL10RA protein Q13651 UNIPROT JAK1 protein P23458 UNIPROT "up-regulates activity" binding 9606 BTO:0000801;BTO:0000776 10347215 t miannu "Specifically, il-10 effects the activation of jak1 (associated with the il-10 receptor alpha Chain) and tyk2 (associated with the il-10 receptor beta Chain) and induces the activation of stat1, stat3, and, in some cells, stat5." SIGNOR-68010 PRKCA protein P17252 UNIPROT ATP1A1 protein P05023 UNIPROT "down-regulates activity" phosphorylation Ser16 KYEPAAVsEQGDKKG 1792 BTO:0003069 14976217 t miannu "Parathyroid hormone (PTH) inhibits Na+,K+-ATPase activity through protein kinase C- (PKC) and extracellular signal-regulated kinase- (ERK) dependent pathways and increases serine phosphorylation of the α1-subunit. These results suggest that PTH regulates Na(+),K(+)-ATPase by PKC and ERK-dependent alpha(1)-subunit phosphorylation and that the phosphorylation requires the expression of a serine at the 11 position of the Na(+),K(+)-ATPase alpha(1)-subunit." SIGNOR-262941 EGR1 protein P18146 UNIPROT NAB2 protein Q15742 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000848 20506119 f miannu "In melanoma and carcinoma cells EGR1 activates NAB2 expression. we investigated the influence of EGR2 and EGR3 on NAB2 expression in melanoma and carcinoma cells. Here, we show that like EGR1, EGR2 and EGR3 induced NAB2 expression in these cells. EGR1 and EGR3 act in concert on the NAB2 promoter and are more potent activators of NAB2 transcription than EGR2." SIGNOR-253881 MAP1LC3B protein Q9GZQ8 UNIPROT SQSTM1 protein Q13501 UNIPROT up-regulates binding 9606 19250911 t gcesareni "Sqstm1/p62 (named a170 in the mouse;hereafter p62) is the first proposed example of such proteins (bj_?_?Rk_?_?Y et al.,2005). It binds polyubiquitinated protein aggregates via its uba domain and interacts with lc3 on the autophagosome/ this interaction is necessary for autophagic degradation of p62-positive cytoplasmic inclusion bodies containing ubiquitinated proteins. We also demonstrate that alis are indistinguishable from p62 inclusion bodies and that p62 is required for their formation." SIGNOR-184255 RPS6KA5 protein O75582 UNIPROT BAD protein Q92934 UNIPROT "down-regulates activity" phosphorylation Ser118 GRELRRMsDEFVDSF 12213813 t lperfetto "Phosphorylation of Bad at Ser112 in response to growth factors or cytokines is generally linked to cell survival. Knockdown of MSK1 suppressed Bad phosphorylation after calcium ionophore A23187 treatment in neuronal cells" SIGNOR-262990 PRKCD protein Q05655 UNIPROT RPS3 protein P23396 UNIPROT up-regulates phosphorylation Ser6 sKKRKFVA 9606 19059439 t llicata "Here we show that pkcdelta phosphorylates rps3 resulting in its mobilization in the nucleus to repair damaged dna. pkc? Kinase assay then indicated that at least two residues, serine 6 and threonine 221, are phosphorylated by pkc?" SIGNOR-182619 SETD1B protein Q9UPS6 UNIPROT "MLL/SET subcomplex" complex SIGNOR-C87 SIGNOR "form complex" binding 9606 24680668 t miannu "Dimethylation of h3k4 requires a sub-complex including wrad (wdr5, rbbp5, ash2l, and dpy-30), which binds to each set1 family member forming a minimal corecomplexthat is required for multiple lysine methylation." SIGNOR-268796 FNIP1 protein Q8TF40 UNIPROT HSP90AB1 protein P08238 UNIPROT "down-regulates activity" binding 9606 BTO:0000007 27353360 t miannu "FNIP1 and FNIP2 facilitate FLCN binding to Hsp90 chaperone. Our results suggest that FNIP1 is a potent inhibitor of Hsp90 ATPase activity, as 200 nM of FNIP1 inhibits Hsp90 ATPase activity by 50-fold. FNIP2 also has shown inhibitory activity towards Hsp90; however, it required 1.6 μM of FNIP2 to inhibit the ATPase activity by eightfold. Although we use the term ‘inhibition' here, FNIPs seem only to be slowing the chaperone cycle." SIGNOR-261415 RPS12 protein P25398 UNIPROT "40S cytosolic small ribosomal subunit" complex SIGNOR-C286 SIGNOR "form complex" binding -1 25901680 t lperfetto "Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins." SIGNOR-262440 DEPTOR protein Q8TB45 UNIPROT mTORC1 complex SIGNOR-C3 SIGNOR "down-regulates activity" binding 9606 BTO:0000007 19446321 t "DEPTOR is an mTOR inhibitor frequently overexpressed in multiple myeloma cells and required for their survival" SIGNOR-251658 KLF7 protein O75840 UNIPROT CDKN1A protein P38936 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9534 BTO:0004055 14729953 f miannu "KLF7 stimulates p21WAF1/Cip1 transcription" SIGNOR-224624 CALM1 protein P0DP23 UNIPROT PPP3CC protein P48454 UNIPROT up-regulates binding 9606 11796223 t gcesareni "Calcium-bound calmodulin associates with calcineurin (cn), releasing the phosphatase from the repressive effects on an autoinhibitory domain." SIGNOR-114104 STAT5A protein P42229 UNIPROT BCL2L1 protein Q07817 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 15626738 t "FLT3-ITD-TKD dual mutants induce hyperactivation of STAT5 and up-regulation of its downstream targets Bcl-x(L) and RAD51 in Ba/F3 cells" SIGNOR-261551 silodosin chemical CHEBI:135929 ChEBI ADRA1D protein P25100 UNIPROT "down-regulates activity" "chemical inhibition" 10029 7651358 t miannu "Membrane preparations from CHO cells stably transfected with the cloned human a1-AR genes showed saturable binding of [‘251]HEAT; Bm,,ı values were 1.3 ± 0.2, 5.5 ± 0.1, and 1.1 ± 0.1 pmol/mg of protein, with Kd values of 110 ± 21, 60 ± 1, and 300 ± 26 ıM (three experiments each), for the ala-, alb-, and ald-ARS, respectively. The potencies of a1-AR agonists and antagonists at the cloned human a1-ARs are shown in Table 1." SIGNOR-258451 TFIIH complex SIGNOR-C457 SIGNOR POLR2A protein P24928 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser1934 SPTYSPTsPKGSTYS 9606 14662762 t lperfetto "Although there is some inconsistency in the literature, it is generally thought that cdk7, a component of the transcription factor (tf) iih, is a major ser-5 kinase, whereas cdk9, a component of positive transcription elongation factor (p-tef) b, is a major ser-2 kinase within cells. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination." SIGNOR-269359 lidocaine chemical CHEBI:6456 ChEBI SCN5A protein Q14524 UNIPROT "down-regulates activity" "chemical inhibition" 8355 BTO:0000964 8786356 t miannu "Surprisingly, hH1-beta 1 Na channels were threefold more sensitive to rested-state block by lidocaine (402 +/- 36 microM, n = 4-22) than were mu 1-beta 1 Na channels (1,168 +/- 34 microM, n = 7-19)." SIGNOR-258499 CAMK1 protein Q14012 UNIPROT GCM1 protein Q9NP62 UNIPROT "up-regulates activity" phosphorylation Ser47 YAKHIYSsEDKNAQR 9606 BTO:0000007 21791615 t miannu "We show that Epac1 and Rap1, in response to cAMP, activate CaMKI to phosphorylate Ser47 in GCM1. This phosphorylation facilitates the interaction between GCM1 and the desumoylating enzyme SENP1 and thereby leads to GCM1 desumoylation and activation." SIGNOR-262680 CDK8 protein P49336 UNIPROT NOTCH1 protein P46531 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser2513 EHPFLTPsPESPDQW -1 25344755 t lperfetto "Mapping of cyclin C-dependent phosphosites on ICN1, using mass spectrometry revealed that several of them are located within the PEST-domain of Notch1, which controls ICN1 degradation38,39 (Fig. 5g and Supplementary Table 1). Three of them (T2512, S2514 and S2517) are localized within the consensus motif, “Cdc4 phosphodegron”, which is shared by most substrates of Fbw7 (Cdc4) ubiquitin ligase38. Two of these residues (S2514 and S2517) were previously shown by Fryer et al.20 to be phosphorylated by cyclin C-CDK8 in vitro, and all three were shown to play a role in controlling ICN1 stability via Fbw740. We verified that cyclin C-CDK8, C-CDK19 and C-CDK3 phosphorylate ICN1 on these three residues" SIGNOR-273176 FGB protein P02675 UNIPROT Platelet_aggregation phenotype SIGNOR-PH81 SIGNOR up-regulates 16418530 f lperfetto "In response to agonist stimulation, the αIIbβ3 integrin on platelets is converted to an active conformation that binds fibrinogen and mediates platelet aggregation." SIGNOR-253374 WNT6 protein Q9Y6F9 UNIPROT LRP5 protein O75197 UNIPROT up-regulates binding 9606 15578921 t gcesareni "Wnt proteins bind to the frizzled receptors and lrp5/6 co-receptors, and through stabilizing the critical mediator betBeta-catenin, initiate a complex signaling cascade that plays an important role in regulating cell proliferation and differentiation." SIGNOR-131894 KLHL12 protein Q53G59 UNIPROT "Cullin 3-RBX1-Skp1" complex SIGNOR-C526 SIGNOR "up-regulates activity" binding 9606 BTO:0000567 22358839 t miannu "By analyzing mouse embryonic stem cell (mESC) division, we have identified Cul3Klhl12 as a regulator of COPII coat formation. Cul3Klhl12 monoubiquitinates Sec31 and drives assembly of large COPII-coats. As a result, ubiquitination by Cul3Klhl12 is essential for collagen export, a step that is required for integrin-dependent mESC division." SIGNOR-272011 atropine chemical CHEBI:16684 ChEBI CHRM3 protein P20309 UNIPROT "down-regulates activity" "chemical inhibition" 10029 BTO:0000246 2704370 t miannu "In order to investigate the pharmacological properties of the individual muscarinic receptors, we have transfected each of these genes into Chinese hamster ovary cells (CHO-K1) and have established stable cell lines expressing each receptor. In the present study we have examined the antagonist binding properties of each muscarinic receptor. Antagonists were chosen that had previously been proposed to be selective for muscarinic receptor subtypes and included pirenzepine, AF-DX 116, methoctramine, dicyclomine, hexohydrodifenidol, hexahydrosiladifenidol, hexocyclium, and silahexocyclium." SIGNOR-258391 RXR proteinfamily SIGNOR-PF44 SIGNOR PPARG protein P37231 UNIPROT "up-regulates activity" binding 9606 11237216 t miannu "Although the three ppar subtypes are closely related and bind to similar dna response elements as heterodimers with the 9-cis retinoic acid receptor rxr, each subserves a distinct physiology" SIGNOR-259057 NFIA protein Q12857 UNIPROT ETV5 protein P41161 UNIPROT "down-regulates quantity" "transcriptional regulation" 10090 31838646 t Gianni "By integrating transcriptomic profiling (RNA-seq) of Nfia- and Nfix-deficient GNPs with epigenomic profiling (ChIP-seq against NFIA, NFIB and NFIX, and DNase I hypersensitivity assays), we reveal that these transcription factors share a large set of potential transcriptional targets, suggestive of complementary roles for these NFI family members in promoting neural development" SIGNOR-268874 PKA proteinfamily SIGNOR-PF17 SIGNOR GRK7 protein Q8WTQ7 UNIPROT "down-regulates activity" phosphorylation Ser23 YLQARKPsDCDSKEL 9606 15946941 t Luana "Phosphorylation of GRK1 and GRK7 by cAMP-dependent Protein Kinase Attenuates Their Enzymatic Activities | We also determined that cAMP-dependent protein kinase (PKA) phosphorylates GRK1 at Ser(21) and GRK7 at Ser(23) and Ser(36) in vitro. These sites are also phosphorylated when FLAG-tagged GRK1 and GRK7 are expressed in HEK-293 cells treated with forskolin to stimulate the endogenous production of cAMP and activation of PKA." SIGNOR-260839 HSBP1 protein O75506 UNIPROT "WASH complex" complex SIGNOR-C258 SIGNOR "up-regulates quantity" relocalization 9606 BTO:0000007 29844016 t lperfetto "The Trimeric Coiled-Coil HSBP1 Protein Promotes WASH Complex Assembly at Centrosomes" SIGNOR-261007 EPHB1 protein P54762 UNIPROT NRCAM protein Q92823 UNIPROT "up-regulates activity" phosphorylation Tyr1276 DGSFIGQySGKKEKE 9606 BTO:0000007 24023801 t miannu "EphB receptors were found to induce phosphorylation of NrCAM on the tyrosine residue within the FIGQY ankyrin binding motif, inhibiting ankyrin recruitment. Furthermore, NrCAM phospho-FIGQY levels in the SC were decreased in EphB1/3 and EphB1/2/3 null mice and increased in mutant mice overexpressing constitutively active EphB2 kinase." SIGNOR-262862 STAT5A protein P42229 UNIPROT FOXP3 protein Q9BZS1 UNIPROT up-regulates 9606 18270368 t "We demonstrate that the signal transducer and activator of transcription 5 (STAT5)-signaling cytokines, IL-2, IL-15 and to a lesser extent IL-7, induce FOXP3 up-regulation in vitro in activated human Teff cell" SIGNOR-254365 ABCA13 protein Q86UQ4 UNIPROT cholesterol smallmolecule CHEBI:16113 ChEBI "up-regulates quantity" relocalization 9606 33478937 t miannu "ATP-binding cassette subfamily A member 13 (ABCA13) is predicted to be the largest ABC protein, consisting of 5058 amino acids and a long N-terminal region. Mutations in the ABCA13 gene were reported to increase the susceptibility to schizophrenia, bipolar disorder, and major depression.Here, we examined the biochemical activity of ABCA13 using HEK293 cells transfected with mouse ABCA13. The expression of ABCA13 induced the internalization of cholesterol and gangliosides from the plasma membrane to intracellular vesicles. These findings suggest that ABCA13 accelerates cholesterol internalization by endocytic retrograde transport in neurons and that loss of this function is associated with the pathophysiology of psychiatric disorders." SIGNOR-265158 PCSK2 protein P16519 UNIPROT "Neurophysin 1" protein P01178-PRO_0000020496 UNIPROT "up-regulates quantity" cleavage 9606 BTO:0001073 11690596 t miannu "Oxytocin-extended form is further cleaved by enzymatic activity to yield the nine-amino-acid active peptide, OT. The proteolysis may involve several pro-hormone convertases, convertase 2 (PC2) (20p11-1-11.2) and convertase 5 (PC5) (9q21.3) (Gabreels et al 1998). Both enzymes are found in OT neurosecretory vesicles and are a part of a family of subtilisen/kexinlike convertases (Seidah et al 1994). It is a product of the OT gene located at human gene locus 20p13 (Rao et al 1992). The processing cascade results in the production of neurophysin I and OT extended form (OT-X), which is OT with a C-terminal, three-amino-acid extension." SIGNOR-270337 miR-29b mirna URS0000150A7D_9606 RNAcentral SP1 protein P08047 UNIPROT "down-regulates quantity by repression" "post transcriptional regulation" 10090 21730352 f miannu "We provide evidence that PU.1 directly controls expression of at least 4 of these miRs (miR-146a, miR-342, miR-338, and miR-155) through temporally dynamic occupation of binding sites within regulatory chromatin regions adjacent to their genomic coding loci. We conclude that PU.1 bound to open chromatin near 4 of its induced miR loci with 2 types of kinetics: (1) permanent (miR-146a, miR-342, and miR-338) and (2) transient (miR-155) during myeloid differentiation." SIGNOR-256244 LLGL1 protein Q15334 UNIPROT Scribble_complex_DLG5-LLGL1_variant complex SIGNOR-C508 SIGNOR "form complex" binding 9606 23397623 t miannu "The Scribble polarity complex or module is one of the three polarity modules that regulate cell polarity in multiple epithelia including blood-tissue barriers. This protein complex is composed of Scribble, Lethal giant larvae (Lgl) and Discs large (Dlg), which are well conserved across species from fruitflies and worms to mammals." SIGNOR-270899 MTOR protein P42345 UNIPROT RPS6KB1 protein P23443 UNIPROT "up-regulates activity" phosphorylation Thr412 NQVFLGFtYVAPSVL 9823 BTO:0004712 23486913 t lperfetto "Collectively, these results indicate that Arg, Leu, and Gln act coordinately to stimulate proliferation of pTr cells through activation of the MTOR-RPS6K-RPS6-EIF4EBP1 signal transduction pathway" SIGNOR-201538 MAPK1 protein P28482 UNIPROT DUSP6 protein Q16828 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser159 DGSCSSSsPPLPVLG 9606 15632084 t gcesareni "In vitro phosphorylation assays using glutathione S-transferase (GST)-MKP-3 fusion proteins indicated that ERK2 could phosphorylate MKP-3 on serines 159 and 197Double serine mutants of MKP-3 or MKP-3-GFP were more efficiently protected from degradation than single mutants or wild-type MKP-3, indicating that phosphorylation of either serine by ERK1/2 enhances proteasomal degradation of MKP-3." SIGNOR-132967 SNRPD1 protein P62314 UNIPROT "U2 snRNP complex" complex SIGNOR-C479 SIGNOR "form complex" binding 9606 30765414 t lperfetto "The major spliceosomal building blocks are the U1, U2, U4/U6, and U5 small nuclear ribonucleoproteins (snRNPs). Each consists of a small nuclear RNA (snRNA) (or two, in the case of U4/U6), seven Sm proteins that form a ring (or seven Lsm proteins in the case of U6), and a variable number of snRNP-specific proteins (Fig. 1F) (Will and Lührmann 2011). Under splicing conditions, the U4/U6 and U5 snRNPs form a 25S U4/U6.U5 tri-snRNP, in which the U4 and U6 snRNAs are base-paired, forming a three-way junction." SIGNOR-270660 RAPGEF6 protein Q8TEU7 UNIPROT HRAS protein P01112 UNIPROT up-regulates "guanine nucleotide exchange factor" 9606 19201597 t gcesareni "Gefs catalyse the transition from gdp-bound, inactive ras to gtp-bound, active ras." SIGNOR-183796 KAT6B protein Q8WYB5 UNIPROT RUNX2 protein Q13950 UNIPROT up-regulates binding 9606 BTO:0000782;BTO:0001271;BTO:0000785 SIGNOR-C54 11965546 t miannu "Moz and morf both interact with runx2 / while morf does not acetylate runx2, its sm domain potentiates runx2-dependent transcriptional activation." SIGNOR-117335 SNAI1 protein O95863 UNIPROT Epithelial-mesenchymal_transition phenotype SIGNOR-PH45 SIGNOR up-regulates 9606 BTO:0000567 29305973 f miannu "Our findings show that Snai1 mediates repression of PXDN and consolidate a role for this ECM-modifier during EMT." SIGNOR-265252 PRKCD protein Q05655 UNIPROT MARCKS protein P29966 UNIPROT unknown phosphorylation Ser159 KKKKKRFsFKKSFKL -1 8422248 t lperfetto "These results indicate that in vitro, PKC phosphorylates MARCKS only at three sites, but not at Ser160 as that reported previously, and there was no preferential phosphorylation of MARCKS by either PKC isozyme I, II or III." SIGNOR-248924 (6S)-5,6,7,8-tetrahydrofolate(2-) smallmolecule CHEBI:57453 ChEBI (6R)-5,10-methylenetetrahydrofolate(2-) smallmolecule CHEBI:15636 ChEBI "up-regulates quantity" "precursor of" 9606 32439610 t lperfetto "Serine catabolism initiated by serine hydroxymethyltransferase (SHMT) transfers thegamma-carbon amino acid side chain to THF, forming glycine and 5,10-methylene-THF (me-THF) (Fig. 1). The cytosolic (SHMT1) and mitochondrial (SHMT2) isoforms perform the same reactions." SIGNOR-268225 ILK protein Q13418 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR "up-regulates activity" phosphorylation Ser473 RPHFPQFsYSASGTA -1 11313365 t miannu "ILK Phosphorylates PKB/Akt on Serine 473 To become fully activated, PKB/Akt requires phosphorylation at two sites, threonine 308 and serine 473, in a phosphatidylinositol (PI) 3-kinase-dependent manner." SIGNOR-250261 CBLB protein Q13191 UNIPROT NCK1 protein P16333 UNIPROT "up-regulates activity" binding 9606 BTO:0000782 16503409 t lperfetto "Activated Cbl and Cbl-b interacted with Crk-L, Zap-70, Nck, PLC-gamma" SIGNOR-236054 SMURF1 protein Q9HCE7 UNIPROT DAB2IP protein Q5VWQ8 UNIPROT "down-regulates quantity by destabilization" ubiquitination 9606 27858941 t miannu "DAB2IP protein levels can be negatively regulated by the activity of the E3-ubiquitin ligases Fbw7, Skp2, and Smurf1" SIGNOR-254776 MIB1 protein Q86YT6 UNIPROT DLL4 protein Q9NR61 UNIPROT "up-regulates activity" ubiquitination 9606 16140393 t lperfetto "Mib physically interacts with Delta and promotes its ubiquitination and internalization [66], which have been shown to up-regulate Notch activity." SIGNOR-209626 RPS6KA3 protein P51812 UNIPROT BAD protein Q92934 UNIPROT down-regulates phosphorylation Ser75 EIRSRHSsYPAGTED 9606 19282669 t lperfetto "The rsks catalyze the phosphorylation of the pro-apoptotic protein bad at serine 112 to promote cell survival." SIGNOR-184595 D-threo-isocitrate(3-) smallmolecule CHEBI:15562 ChEBI IDH2 protein P48735 UNIPROT "up-regulates activity" "chemical activation" 9606 32943735 t "Wild-type IDH1 and IDH2 catalyze the reaction by converting isocitrate and NADP+ into α-KG and CO2 with the concomitant generation of NADPH in the cytosol and mitochondrial matrix" SIGNOR-267370 Exosome_Complex complex SIGNOR-C255 SIGNOR FUS protein P35637 UNIPROT "up-regulates activity" relocalization 9606 BTO:0000793 27460707 t "P35637:p.Arg495_Tyr526del (mutation increasing interaction)" "We hypothesized that FUS could be secreted via the exosome pathway. We tested and confirmed that FUS was indeed present in exosomes in both SH-SY5Y and N2A cells (Fig. 6 and Supplemental Fig. 2). It is also noted that the level of the R495X mutant in exosomes was significantly higher than that of WT or the R521G mutant. |It raises the possibility that the exosome-mediated secretion of FUS may contribute to the cell-to-cell propagation of FUS pathology." SIGNOR-262812 MAP3K11 protein Q16584 UNIPROT MAP3K11 protein Q16584 UNIPROT up-regulates phosphorylation Thr277 LAREWHKtTQMSAAG 9606 11053428 t gcesareni "These residues within the activation loop are critical for mlk-3 autophosphorylation and activation. In addition, when the thr277 and ser281 residues were mutated to negatively charged glutamic acid to mimic phosphorylated serine/threonine residues, the resulting mutants were fully functional, implying that these two residues may serve as the autophosphorylation sites." SIGNOR-83411 CDK5 protein Q00535 UNIPROT TP53 protein P04637 UNIPROT up-regulates phosphorylation Ser46 AMDDLMLsPDDIEQW 9606 BTO:0000938 17591690 t llicata "We show that cdk5 phosphorylates p53 on ser15, ser33 and ser46 cdk5-stabilized p53 protein is transcriptionally active" SIGNOR-156426 PAK2 protein Q13177 UNIPROT PAK2 protein Q13177 UNIPROT "up-regulates activity" phosphorylation Ser19 PAPPVRMsSTIFSTG -1 10075701 t miannu "Eight autophosphorylation sites were identified in Cdc42-activated gamma-PAK, six of which are in common with those previously reported in alpha-PAK, while Ser-19 and Ser-165 appear to be uniquely phosphorylated in the gamma-form. Further, the phosphorylation of Ser-141, Ser-165, and Thr-402 was found to correlate with gamma-PAK activation. The information resulting from manual Edman degradation and from automated sequencing clearly identified Ser-192, Ser-197, and Thr-402 as the phosphorylation sites" SIGNOR-250224 SKIL protein P12757 UNIPROT SMAD4 protein Q13485 UNIPROT "down-regulates activity" binding 9606 12793438 t lperfetto "The ski and snon protein family associate with and repress the activity of smad2, smad3, and smad4, three members of the tgf-fl signaling pathway" SIGNOR-236152 TRADD protein Q15628 UNIPROT CASP8 protein Q14790 UNIPROT "up-regulates activity" binding 9606 14585074 t amattioni "Tradd recruits caspase-8" SIGNOR-118591 NTRK1 protein P04629 UNIPROT FRS2 protein Q8WU20 UNIPROT up-regulates binding 9606 10092678 t gcesareni "The signaling adapter frs-2 competes with shc for binding to the nerve growth factor receptor trka:a model for discriminating proliferation and differentiation" SIGNOR-65955 quetiapine chemical CHEBI:8707 ChEBI HTR1E protein P28566 UNIPROT "up-regulates activity" "chemical activation" 9534 8935801 t miannu "Risperidone and its active metabolite 9-OH-risperidone were compared to reference antipsychotic drugs (haloperidol, pipamperone, fluspirilene, clozapine, zotepine) and compounds under development (olanzapine, seroquel, sertindole, ORG-5222, ziprasidone) for in vitro binding to neurotransmitter receptors in brain tissue and on membranes of recombinant cells expressing cloned human receptors and for in vivo occupancy of neurotransmitter receptors in rat and guinea-pig brain following acute treatment (2 h., s.c.). The binding affinities of the compounds for various neurotransmitter receptors were measured using membrane preparations of animal brain regions and of recombinant cells expressing cloned, mostly human receptors. Receptors, tissues and cells are indicated in Table I; results are shown in Table 4A-B." SIGNOR-258531 PAK1 protein Q13153 UNIPROT CTNNB1 protein P35222 UNIPROT up-regulates phosphorylation Ser675 QDYKKRLsVELTSSL 9606 21822311 t lperfetto "Pak1 directly phosphorylates _-catenin proteins at ser675 site and this leads to more stable and transcriptional active _-catenin" SIGNOR-175944 PIK3CG protein P48736 UNIPROT Survival phenotype SIGNOR-PH13 SIGNOR up-regulates 9534 BTO:0004055 14665640 f lperfetto "Signal transduction pathways triggered by Tie2 have been extensively examined. Tyr-1101of Tie2 directly associates in a phosphotyrosine (pTyr)-dependent manner with the p85 regulatory subunit of phosphatidylinositol (PI) 3-kinase, which in turn activate PI 3-kinase, leading to cell motility and survival" SIGNOR-242658 ETS1 protein P14921 UNIPROT MMP13 protein P45452 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000948 22270366 f miannu "VEGF-induced MMP-9 and MMP-13 promoter activities were down-regulated in ETS-1 siRNA-transfected cells. it is hypothesized that the activation of PI3K/AKT and p38 MAPK by VEGF results in ETS-1 gene expression, which activates MMP-9 and MMP-13, leading to the invasion and scattering of SKOV-3 cells." SIGNOR-254084 CNOT3 protein O75175 UNIPROT TNFRSF11A protein Q9Y6Q6 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 10090 BTO:0003292 24550297 t Luana "Our results reveal that CNOT3 is a critical regulator of bone mass acting on bone resorption through posttranscriptional down-regulation of RANK mRNA stability, at least in part, even in aging-induced osteoporosis." SIGNOR-261572 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR MRTFA protein Q969V6 UNIPROT down-regulates phosphorylation 9606 18694962 t "Translocation from Nuleus to Cytoplasm" gcesareni "Serum induces rhoa-dependent translocation of mkl1 from the cytoplasm to the nucleus and also causes a rapid increase in mkl1 phosphorylation. Serum-induced phosphorylation of the serum response factor coactivator mkl1 by the extracellular signal-regulated kinase 1/2 pathway inhibits its nuclear localization." SIGNOR-270131 ING2 protein Q9H160 UNIPROT AFP protein P02771 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0000599 14522900 f miannu "ING1b and ING2 also repressed the AFP promoter in Hep3B p53-null cell lines, and p53 coexpression enhanced this transcriptional repression. Suppression of AFP gene transcription by ING was strongly dependent on AT-motifs that bind to the hepatocyte nuclear factor 1 (HNF1) transcription factor." SIGNOR-254485 CSNK2A1 protein P68400 UNIPROT CARD9 protein Q9H257 UNIPROT down-regulates phosphorylation Thr531 NTTGSDNtDTEGS 9606 17936701 t lperfetto "Pvhl acts as an adaptor to promote the inhibitory phosphorylation of the nf-kappab agonist card9 by ck2. The card9 c terminus contains multiple serine and threonine residues that resemble ck2 phosphorylation sites. Mass spectrometry analysis of myc-card9 recovered from hela cells revealed that these sites, including t531 and t533, were phosphorylated in vivo" SIGNOR-158414 CSNK2A2 protein P19784 UNIPROT GTF2A1 protein P52655 UNIPROT "up-regulates activity" phosphorylation Ser321 LNSEDDVsDEEGQEL -1 11278496 t llicata "We now show that human TFIIA is phosphorylated in vivo on serine residues that are partially conserved between yeast and human TFIIA large subunits. Alanine substitution mutation of serine residues 316 and 321 in TFIIA alphabeta reduced TFIIA phosphorylation significantly in vivo. Additional alanine substitutions at serines 280 and 281 reduced phosphorylation to undetectable levels. Mutation of all four serine residues reduced the ability of TFIIA to stimulate transcription in transient transfection assays with various activators and promoters, indicating that TFIIA phosphorylation is required globally for optimal function." SIGNOR-250998 SMARCB1 protein Q12824 UNIPROT "SWI/SNF ACTL6B varian" complex SIGNOR-C476 SIGNOR "form complex" binding 9606 30397315 t miannu "Mammalian SWI/SNF (mSWI/SNF) complexes are ATP-dependent chromatin remodelers that modulate genomic architecture and DNA accessibility, enabling timely and appropriate control of gene expression. They are combinatorially assembled from the products of 29 total genes into three final-form complexes: canonical BAF, PBAF (polybromo-associated BAF complexes), and a newly-defined non-canonical BAF (ncBAF), with specific subunits specifying distinct complexes, such as PBRM1, ARID2, and BRD7 in PBAF complexes, ARID1A/ARID1B and DPF2 in canonical BAF (cBAF) complexes, and GLTSCR1/GLTSCR1L and BRD9 in ncBAF complexes" SIGNOR-270607 vorinostat chemical CHEBI:45716 ChEBI HDAC6 protein Q9UBN7 UNIPROT "down-regulates activity" "chemical inhibition" -1 20139990 t Luana "Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1)." SIGNOR-257949 CTDSP1 protein Q9GZU7 UNIPROT POLR2A protein P24928 UNIPROT "up-regulates activity" dephosphorylation Ser1651 SPTSPSYsPTSPSYS -1 22137580 t "Phosphorylation and dephosphorylation of the C-terminal domain (CTD) of RNA polymerase II (Pol II) represent a critical regulatory checkpoint for transcription. Transcription initiation requires Fcp1/Scp1-mediated dephosphorylation of phospho-CTD. | This combined structure-function analysis discloses the residues in Scp1 involved in CTD binding and its preferential dephosphorylation of P.Ser5 of the CTD heptad repeat." SIGNOR-248782 MAP2K4 protein P45985 UNIPROT MAPK8 protein P45983 UNIPROT "up-regulates activity" phosphorylation Tyr185 TSFMMTPyVVTRYYR -1 11062067 t "Stress-activated protein kinase 1 (SAPK1), also called c-Jun N-terminal kinase (JNK), becomes activated in vivo in response to pro-inflammatory cytokines or cellular stresses. Its full activation requires the phosphorylation of a threonine and a tyrosine residue in a Thr-Pro-Tyr motif, which can be catalysed by the protein kinases mitogen-activated protein kinase kinase (MKK)4 and MKK7. Here we report that MKK4 shows a striking preference for the tyrosine residue (Tyr-185), and MKK7 a striking preference for the threonine residue (Thr-183) in three SAPK1/JNK1 isoforms tested (JNK1 alpha 1, JNK2 alpha 2 and JNK3 alpha 1)." SIGNOR-251419 PDK2 protein Q15119 UNIPROT PDHA1 protein P08559 UNIPROT down-regulates phosphorylation Ser300 SMSDPGVsYRTREEI 9606 17474719 t gcesareni "Regulation of mammalian pdc activity is accomplished in large part by phosphorylation (resulting in inactivation) of the e1 component by a family of pyruvate dehydrogenase kinases (pdk 14 isozymes) and dephosphorylation (leading to activation) of phosphorylated e1 by a set of specific phosphatases (phosphopyruvate dehydrogenase phosphatase 12 isozymes) (1, 3-6). The subunit of the e1 component has three phosphorylation sites, named site 1 (ser-264), site 2 (ser-271), and site 3 (ser-203), and phosphorylation of any one of these three sites results in inactivation" SIGNOR-154640 ILK protein Q13418 UNIPROT AKT1 protein P31749 UNIPROT up-regulates phosphorylation Ser473 RPHFPQFsYSASGTA 9606 9736715 t acerquone "Ilk can phosphorylate pkb-akt on serine-473, whereas kinase-deficient ilk severely inhibits endogenous phosphorylation of pkb-akt on serine-473, demonstrating that ilk is involved in agonist stimulated, pi(3)k-dependent, pkb-akt activation." SIGNOR-252597 CLOCK/BMAL1 complex SIGNOR-C195 SIGNOR VWF protein P04275 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 10090 BTO:0000394 20658528 t lperfetto "We also show that major circadian transcriptional regulators CLOCK and Bmal1 directly regulate the activity of vWF promoter and that lack of Bmal1 results in upregulation of vWF both at mRNA and protein level. Here we report a direct regulation of vWF expression in endothelial cells by biological clock gene Bmal1. This study establishes a mechanistic connection between Bmal1 and cardiovascular phenotype." SIGNOR-253703 CDKN2B protein P42772 UNIPROT CDK4 protein P11802 UNIPROT down-regulates binding 9606 BTO:0000763 9042862 t gcesareni "We present evidence that the different subcellular location of p15 and p27 ensures the prior access of p15 to cdk4. In the cell, p15 is localized mostly in the cytoplasm, whereas p27 is nuclear. p15 prevails over p27 or a p27 construct consisting of the cdk inhibitory domain tagged with a nuclear localization signal. However, when p15 and p27 are forced to reside in the same subcellular location, either the cytoplasm or the nucleus, p15 no longer prevents p27 from binding to cdk4. These properties allow p15 and p27 to coordinately inhibit cdk4 and cdk2." SIGNOR-46758 CBFbeta-MYH11 "fusion protein" SIGNOR-FP3 SIGNOR TP53 protein P04637 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 10090 9834241 f miannu "CBFbeta-SMMHC, Expressed in M4eo Acute Myeloid Leukemia, Reduces p53 Induction and Slows Apoptosis in Hematopoietic Cells Exposed to DNA-damaging Agents Reduced p53 induction may be caused in part by direct inhibition of p53 gene transcription, because p53 mRNA levels were reduced by CBFβ-SMMHC. Attenuated p53 induction and slowed apoptosis may contribute to leukemogenesis by CBFβ-SMMHC." SIGNOR-256132 PRKACA protein P17612 UNIPROT KCNH2 protein Q12809 UNIPROT up-regulates phosphorylation Ser283 CASVRRAsSADDIEA 9606 10488078 t lperfetto "Deletion of protein kinase a phosphorylation sites in the herg potassium channel inhibits activation shift by protein kinase afour consensus pka phosphorylation sites (s283a, s890a, t895a, s1137a)" SIGNOR-70722 PRKCD protein Q05655 UNIPROT CREBBP protein Q92793 UNIPROT unknown phosphorylation Ser437 CLPLKNAsDKRNQQT 11463380 t lperfetto "This study demonstrates that transcriptional control of mitogen-responsive genes by AP-1 and Pit-1 response elements involves direct phosphorylation of CBP and that growth factor€“dependent phosphorylation of CBP within the GF box is indispensable for signaling via these sites. " SIGNOR-249104 AKT1 protein P31749 UNIPROT TIFA protein Q96CG3 UNIPROT "up-regulates activity" phosphorylation Thr9 TSFEDADtEETVTCL 9606 BTO:0000007 27965388 t miannu "For the activation of signal 2, Akt is involved in TIFA Thr9 phosphorylation, which is essential for TIFA-TIFA homophilic oligomerization. Thr9 phosphorylation-dependent TIFA oligomerization facilitates the higher-order assembly of NLRP3 inflammasome, as indicated by the interaction between TIFA and caspase-1 in the activated ECs." SIGNOR-273542 MRPS7 protein Q9Y2R9 UNIPROT "28S mitochondrial small ribosomal subunit" complex SIGNOR-C266 SIGNOR "form complex" binding 9606 25838379 t miannu "The mammalian mitochondrial ribosome (mitoribosome) has a highly protein-rich composition with a small sedimentation coefficient of 55 S, consisting of 39 S large and 28 S small subunits. . We report here the identification of 28 S small subunit proteins." SIGNOR-267730 F11 protein P03951 UNIPROT "GPIb-IX-V complex" complex SIGNOR-C270 SIGNOR "up-regulates activity" binding 9606 BTO:0000132 25297919 t lperfetto "Besides VWF as a main ligand, GPIbα also binds multiple ligands such as thrombospondin, Factor XII, Factor XI, thrombin, High Molecular Weight kininogen, P-selectin and Mac-1." SIGNOR-261857 "CCAN complex" complex SIGNOR-C365 SIGNOR Chromosome_segregation phenotype SIGNOR-PH44 SIGNOR up-regulates 9606 BTO:0000567 18007590 f lperfetto "Based on our results, we propose that the cooperative action of CENP-A NAC/CAD subunits and the KMN network drives efficient chromosome segregation and bipolar spindle assembly during mitosis." SIGNOR-265219 GTF2F2 protein P13984 UNIPROT GTF2F1 protein P35269 UNIPROT "up-regulates activity" binding 9534 11278533 t miannu "Direct Interaction Between the Subunit RAP30 of Transcription Factor IIF (TFIIF) and RNA Polymerase Subunit 5, Which Contributes to the Association Between TFIIF and RNA Polymerase II. we showed that RPB5 binds RAP30 but not RAP74 and associates to TFIIF through the binding to RAP30." SIGNOR-261180 PAK2 protein Q13177 UNIPROT MYL12A protein P19105 UNIPROT "up-regulates activity" phosphorylation Ser19 KRPQRATsNVFAMFD -1 10047984 t miannu "In this study we report that gamma-PAK, which is activated by the GTP-binding proteins Cdc42 and Rac, catalyses phosphorylation of intact non-muscle myosin II and isolated recombinant RLC. Phosphopeptide maps and phosphoamino acid analysis revealed that gamma-PAK phosphorylates Ser-19 but does not phosphorylate Thr-18.Taken together, these data suggest that myosin II activation by the p21-activated family of kinases may be physiologically important in regulating cytoskeletal organization." SIGNOR-263020 TCF7L2 protein Q9NQB0 UNIPROT Adipogenesis phenotype SIGNOR-PH26 SIGNOR "down-regulates activity" "transcriptional regulation" 20492721 f FFerrentino "These findings suggested that miR-210 could promote adipogenesis by repressing WNT signaling through targeting Tcf7l2." SIGNOR-253519 MLL-AF9 "fusion protein" SIGNOR-FP5 SIGNOR MECOM protein Q03112 UNIPROT "up-regulates quantity by expression" methylation 10090 BTO:0001271 22553314 t irozzo "We hypothesize, based on our ChIP data, that MLL-AF9 up-regulates EVI1 transcription via H3K79 methylation, which is known to be a major gene regulatory mechanism used by some MLL-fusion proteins in leukemia." SIGNOR-255858 TNFRSF1A protein P19438 UNIPROT MAPK14 protein Q16539 UNIPROT up-regulates 9606 BTO:0000567 11672426 f lperfetto "Conversely, only activation of the TNFR1 could stimulate mitogen-activated protein kinase (MAPK) or p38 MAPK activities in a time-dependent manner." SIGNOR-226637 PAX3-FOXO1 "fusion protein" SIGNOR-FP12 SIGNOR IGF1R protein P08069 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 25211658 t miannu "Several deregulated signalling pathways enhance cell growth by modulating cell-cycle regulatory factors in RMS. The most frequently affected signalling pathways include the insulin-like growth factor (IGF), fibroblast growth factor (FGF), hepatocyte growth factor, and platelet-derived growth factor. In ARMS, PAX-FOXO1 activates these pathways by transcriptional activation of receptor genes including IGFR1, FGFR4, MET (c-Met), and PDGFRA." SIGNOR-251568 MTOR protein P42345 UNIPROT ULK1 protein O75385 UNIPROT "down-regulates activity" phosphorylation 9606 BTO:0000007 21460634 t lperfetto "mTORC1, which is often referred to as the gatekeeper to autophagy, is a key regulator of the Ulk1-Atg13-FIP200 kinase complex.11,14,25 Under nutrient-rich conditions, active mTORC1 associates with and inactivates the Ulk1-Atg13-FIP200 complex by phosphorylating Ulk1 and Atg13." SIGNOR-183903 ARPC5 protein O15511 UNIPROT ARP2/3 complex SIGNOR-C146 SIGNOR "form complex" binding 9606 12479800 t "The subunits in mammalian cells are named Arp3, Arp2, p41-Arc, p34-Arc, p21-Arc, p20-Arc and p16-Arc" SIGNOR-251518 "Rigosertib sodium" chemical CID:23696523 PUBCHEM PLK1 protein P53350 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-195028 PPP3CC protein P48454 UNIPROT NFATC2 protein Q13469 UNIPROT "up-regulates activity" dephosphorylation Ser174 LSPASSGsSASFISD 9606 BTO:0000567 11030334 t "NFAT1 is phosphorylated on fourteen conserved phosphoserine residues in its regulatory domain, thirteen of which are dephosphorylated upon stimulation. Dephosphorylation of all thirteen residues is required to mask a nuclear export signal (NES), cause full exposure of a nuclear localization signal (NLS), and promote transcriptional activity" SIGNOR-248512 10-formyltetrahydrofolate(2-) smallmolecule CHEBI:57454 ChEBI (6S)-5,6,7,8-tetrahydrofolate(2-) smallmolecule CHEBI:57453 ChEBI "up-regulates quantity" "precursor of" 9606 11381136 t miannu "The third step is catalyzed by the enzyme glycinamide ribonucleotide transformylase (GAR Tfase). The two folate-requiring reactions, glycinamide ribonucleotide transformylase (GAR Tfase) and aminoimidazole ribonucleotide transformylase (AICAR Tfase), have attracted particular attention because some of the most successful anticancer drugs to date have been folate antimetabolites such as methotrexate (3). These two enzymes carry out similar chemistry in catalyzing the transfer of a formyl group from 10-formyltetrahydrofolate to the amino group of the substrates GAR and AICAR to form fGAR and fAICAR." SIGNOR-267302 AKT proteinfamily SIGNOR-PF24 SIGNOR BMI1 protein P35226 UNIPROT "up-regulates activity" phosphorylation Ser316 ANRPRKSsVNGSSAT 9606 BTO:0001033 22505453 t lperfetto "The polycomb group silencing protein Bmi1 can be phosphorylated by AKT, which enhances its oncogenic potential in PCa. Overexpression of Bmi1 can act in combination with PTEN haploinsufficiency to induce invasive carcinogenic formation in the prostate" SIGNOR-249581 TRIP13 protein Q15645 UNIPROT EGFR protein P00533 UNIPROT "up-regulates quantity by stabilization" binding 9606 BTO:0000007 32860853 t lperfetto "Mechanistically, TRIP13 enhanced EGFR protein abundance in part by preventing Cbl-mediated ubiquitination and proteasomal degradation." SIGNOR-265084 SPI1 protein P17947 UNIPROT Monocyte_differentiation phenotype SIGNOR-PH101 SIGNOR "up-regulates activity" 10090 BTO:0000725 8079170 f "Mice carrying a mutation in the PU.1 locus were generated by gene targeting. Homozygous mutant embryos died at a late gestational stage. [...]An invariant consequence of the mutation was a multilineage defect in the generation of progenitors for B and T lymphocytes, monocytes, and granulocytes. Thus, the developmental programs of lymphoid and myeloid lineages require a common genetic function likely acting at the level of a multipotential progenitor." SIGNOR-259954 LRRK2 protein Q5S007 UNIPROT LRRK2 protein Q5S007 UNIPROT unknown phosphorylation Ser1403 AGREEFYsTHPHFMT 9606 BTO:0000938 19824698 t lperfetto "We identified ser1403, thr1404, thr1410, thr1491 located within the roc domain, as well as thr1967 and thr1969 in the kinase domain, as the autophosphorylation sites." SIGNOR-188429 CBP/p300 complex SIGNOR-C6 SIGNOR DDX5 protein P17844 UNIPROT up-regulates binding 9606 12527917 t miannu "Cbp/p300 interact with p68 rna helicase / the atpase activity of p68 is required for the specific transcriptional activation of cbp" SIGNOR-97274 "Neural progenitor-specific SWI/SNF" complex SIGNOR-C477 SIGNOR Epigenetic_regulation phenotype SIGNOR-PH203 SIGNOR up-regulates 9606 25195934 f miannu "The BAF (mammalian SWI/SNF) complexes are a family of multi-subunit ATP-dependent chromatin remodelers that use ATP hydrolysis to alter chromatin structure. Distinct BAF complex compositions are possible through combinatorial assembly of homologous subunit families and can serve non-redundant functions. In mammalian neural development, developmental stage-specific BAF assemblies are found in embryonic stem cells, neural progenitors and postmitotic neurons. In particular, the neural progenitor-specific BAF complexes are essential for controlling the kinetics and mode of neural progenitor cell division, while neuronal BAF function is necessary for the maturation of postmitotic neuronal phenotypes as well as long-term memory formation. " SIGNOR-270621 MAPK13 protein O15264 UNIPROT TP53BP1 protein Q12888 UNIPROT "down-regulates activity" phosphorylation Thr1609 LGPYEAVtPLTKAAD -1 24703952 t lperfetto "Here we show that 53BP1 is phosphorylated during mitosis on two residues, T1609 and S1618, located in its well-conserved ubiquitination-dependent recruitment (UDR) motif.|Dephosphorylation enables the recruitment of 53BP1 to double-strand DNA breaks |phosphorylation of T1609 is likely to be mediated by p38 MAPK" SIGNOR-264449 PKA proteinfamily SIGNOR-PF17 SIGNOR "SMN complex" complex SIGNOR-C158 SIGNOR "up-regulates quantity by stabilization" phosphorylation 9606 BTO:0000007 19103745 t lperfetto "PKA increases SMN complex formation and SMN stability." SIGNOR-253122 TIMM10 protein P62072 UNIPROT "TIM22 complex" complex SIGNOR-C424 SIGNOR "form complex" binding 9606 BTO:0000007 32901109 t lperfetto "Cryo-EM structure of the human mitochondrial translocase TIM22 complex|In humans, TIM22 is a 440-kDa complex comprising at least six components: the hypothetical channel-forming protein Tim22, three small Tim proteins (Tim9, Tim10a and Tim10b), Tim29 and acylglycerol kinase (AGK)." SIGNOR-267701 SKIL protein P12757 UNIPROT SMAD4 protein Q13485 UNIPROT "down-regulates activity" binding 9606 10531062 t lperfetto "Thus, SnoN can interact with Smad4 and Smad2 and inhibit their abilities to activate transcription." SIGNOR-71633 "dasatinib (anhydrous)" chemical CHEBI:49375 ChEBI BCR-ABL "fusion protein" SIGNOR-FP6 SIGNOR "down-regulates activity" "chemical inhibition" 9606 BTO:0001056 23409026 t miannu "Pre-existing BCR-ABL mutations can be detected in a substantial number of chronic-phase CML patients by sensitive allele-specific PCR technique using CD34+ cells. These mutations are associated with imatinib resistance if affecting drug binding directly or indirectly. After the recent approval of nilotinib, dasatinib, bosutinib and ponatinib for treatment of chronic myeloid leukemia along with imatinib, all of which vary in their effectiveness against mutated BCR-ABL forms, detection of pre-existing BCR-ABL mutations can help in selection of appropriate first-line drug therapy." SIGNOR-259270 Ub:E2 complex SIGNOR-C497 SIGNOR RNF7 protein Q9UBF6 UNIPROT "up-regulates activity" ubiquitination 9606 34199813 t miannu "The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t" SIGNOR-271116 GUCY1B1 protein Q02153 UNIPROT GUCY1A2-B3 complex SIGNOR-C138 SIGNOR "form complex" binding 9606 10977868 t gcesareni "This enzyme is a heterodimeric protein consisting of - and ²-subunits, and expression of both subunits is required for catalytic activity" SIGNOR-243980 clozapine chemical CHEBI:3766 ChEBI HTR1B protein P28222 UNIPROT "up-regulates activity" "chemical activation" 10116 BTO:0001311 8935801 t miannu "Risperidone and its active metabolite 9-OH-risperidone were compared to reference antipsychotic drugs (haloperidol, pipamperone, fluspirilene, clozapine, zotepine) and compounds under development (olanzapine, seroquel, sertindole, ORG-5222, ziprasidone) for in vitro binding to neurotransmitter receptors in brain tissue and on membranes of recombinant cells expressing cloned human receptors and for in vivo occupancy of neurotransmitter receptors in rat and guinea-pig brain following acute treatment (2 h., s.c.). The binding affinities of the compounds for various neurotransmitter receptors were measured using membrane preparations of animal brain regions and of recombinant cells expressing cloned, mostly human receptors. Receptors, tissues and cells are indicated in Table I; results are shown in Table 4A-B." SIGNOR-258519 PTPN2 protein P17706 UNIPROT SRC protein P12931 UNIPROT down-regulates dephosphorylation 9606 22080863 t gcesareni "We found that tcptp dephosphorylates and inactivates src family kinases to regulate t cell responses._" SIGNOR-177116 IL20RA protein Q9UHF4 UNIPROT JAK1 protein P23458 UNIPROT up-regulates binding 9606 15120645 t gcesareni "Each r1-type chain (il-10r1, il-20r1, il-22r1, ifn-_r1 and ifn-_r1) is associated with jak1 tyrosine kinase and mediates recruitment of a variety of signaling molecules after being phosphorylated on its intracellular domain." SIGNOR-124486 MLLT11 protein Q13015 UNIPROT TCF7 protein P36402 UNIPROT "up-regulates activity" binding -1 26079538 t irozzo "Here, we show that AF1q specifically binds to T-cell-factor-7 (TCF7) in the Wnt signaling pathway and results in transcriptional activation of CD44 as well as multiple downstream targets of the TCF7/LEF1. Super-shift and electrophoretic mobility shift assay (EMSA) further confirmed that AF1q directly interacted with TCF7 and enhanced the binding affinity of the complex" SIGNOR-259108 TWIST1 protein Q15672 UNIPROT HGF protein P14210 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0003879 20646316 f miannu "Individual genes upregulated by TWIST1 known to promote EMT and/or GBM invasion included SNAI2, MMP2, HGF, FAP and FN1." SIGNOR-255522 F2RL3 protein Q96RI0 UNIPROT GNAO1 protein P09471 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257245 PAK2 protein Q13177 UNIPROT PAK2 protein Q13177 UNIPROT "up-regulates activity" phosphorylation Ser141 TVKQKYLsFTPPEKD -1 10075701 t miannu "Eight autophosphorylation sites were identified in Cdc42-activated gamma-PAK, six of which are in common with those previously reported in alpha-PAK, while Ser-19 and Ser-165 appear to be uniquely phosphorylated in the gamma-form. Further, the phosphorylation of Ser-141, Ser-165, and Thr-402 was found to correlate with gamma-PAK activation. Autophosphorylation of γ-PAK with MgATP alone takes place at Ser-19, Ser-20, Ser-55, Ser-192, and Ser-197." SIGNOR-250228 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR CDCA5 protein Q96FF9 UNIPROT "up-regulates activity" phosphorylation Ser79 AVQSPRRsPRISFFL 9606 BTO:0000567 20551060 t miannu "Phosphorylation and activation of cell division cycle associated 5 by mitogen-activated protein kinase play a crucial role in human lung carcinogenesis. Our data suggest that transactivation of CDCA5 and its phosphorylation at Ser209 by ERK play an important role in lung cancer proliferation, and that the selective suppression of the ERK-CDCA5 pathway could be a promising strategy for cancer therapy." SIGNOR-262969 NAALAD2 protein Q9Y3Q0 UNIPROT L-glutamate(1-) smallmolecule CHEBI:29985 ChEBI "up-regulates quantity" "chemical modification" 9606 10085079 t miannu "The neuropeptide N-acetyl-L-aspartate-L-glutamate (NAAG)1 is expressed both in the central nervous system and in the periphery. Hydrolysis of the neuropeptide N-acetyl-L-aspartyl-L-glutamate (NAAG) by N-acetylated alpha-linked acidic dipeptidase (NAALADase) to release glutamate may be important in a number of neurodegenerative disorders in which excitotoxic mechanisms are implicated." SIGNOR-267542 CSNK2A1 protein P68400 UNIPROT SET protein Q01105-2 UNIPROT down-regulates phosphorylation Ser9 SAPAAKVsKKELNSN 9606 BTO:0000938 BTO:0000142 23374587 t "The effect has been demonstrated using Q01105-2" miannu "Ckii-mediated phosphorylation at ser9 hinders nuclear import of set" SIGNOR-200798 Ub:E2 complex SIGNOR-C497 SIGNOR RNF213 protein Q63HN8 UNIPROT "up-regulates activity" ubiquitination 9606 34199813 t miannu "The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t" SIGNOR-271097 AV412 chemical CID:11700696 PUBCHEM EGFR protein P00533 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-190050 AKT1 protein P31749 UNIPROT LONP1 protein P36776 UNIPROT "up-regulates activity" phosphorylation Ser181 NESDVVEsLDEIYHT 9606 BTO:0001061 31406245 t lperfetto "In mitochondria, LonP1 is phosphorylated by Akt on Ser173 and Ser181, enhancing its protease activity." SIGNOR-265725 PLK1 protein P53350 UNIPROT PLEKHG6 protein Q3KR16 UNIPROT up-regulates phosphorylation Thr574 HLVVTEDtDEDAPLV 9606 BTO:0000567 18694934 t lperfetto "We reported previously that a guanine nucleotide exchange factor, myogef, localizes to the central spindle, activates rhoa, and is required for cytokinesis. In this study, we have found that plk1 (polo-like kinase 1) can phosphorylate myogef, thereby recruiting myogef to the central spindle as well as enhancing myogef activity toward rhoa. The in vitro kinase assay shows that plk1 can phosphorylate myogef on threonine 574." SIGNOR-179954 Sin3B_complex complex SIGNOR-C409 SIGNOR H3-5 protein Q6NXT2 UNIPROT "down-regulates activity" binding 9606 BTO:0000007 21041484 t miannu "We report here the identification of a mammalian complex containing the corepressor Sin3B, the histone deacetylase HDAC1, Mrg15, and the PHD finger-containing Pf1 and show that this complex plays important roles in regulation of transcription. Sin3B, Pf1, Mrg15, and HDAC1 associate within a stable complex that binds H3K4me3/H3K36me3-enriched nucleosomes. We identify mammalian Pf1, a PHD finger protein, as a homologue of Rco1, and show that all four components, Sin3B, HDAC1, Mrg15, and Pf1, can form a stable complex, which is recruited downstream of the transcriptional start site through complex interactions with histones. these results indicate that the Pf1/Sin3B-containing complex is recruited at discrete sites within actively transcribed loci, likely through its interaction with H3K4me3/H3K36me3-enriched chromatin." SIGNOR-266972 FZD3 protein Q9NPG1 UNIPROT GNA12 protein Q03113 UNIPROT up-regulates binding 9606 14977528 t gcesareni "Gpcrs signal through four relatively small families of galfa proteins (galfas, galfai/o, galfaq, and galfa12/13), and if fzd receptors are classic gpcrs, they should signal through one of these four galfa families." SIGNOR-122889 PAK3 protein O75914 UNIPROT CALD1 protein Q05682 UNIPROT down-regulates phosphorylation Ser744 GLKVGVSsRINEWLT 9606 BTO:0000887;BTO:0001260 20858431 t gcesareni "We investigated the effects of phosphorylation by p(21)-activated kinase 3 (pak) and calmodulin on the 22 kda c-terminal fragment of caldesmon (cad22). We substituted the major pak sites, ser-672 and ser-702, with either alanine or aspartic acid to mimic nonphosphorylated and constitutively phosphorylated states of caldesmon, respectively. Phosphorylation at these sites weakened ca(2+)-calmodulin binding further and reduced the inhibitory activity of cad22 in the absence of ca(2+)-calmodulin." SIGNOR-167980 FBXO33 protein Q7Z6M2 UNIPROT SCF-betaTRCP complex SIGNOR-C5 SIGNOR "up-regulates activity" binding 9606 BTO:0000007 16797541 t miannu "Here we identify FBX33 as a component of an SCF E3-ubiquitin ligase that targets the multifunctional regulator Y-box binding protein 1 (YB-1)/dbpB/p50 for polyubiquitination and destruction by the proteasome. By targeting YB-1 for proteasomal degradation, FBX33 negatively interferes with YB-1 mediated functions.  FBX33 recruits Skp-1/Cul1 to YB-1" SIGNOR-271605 TRIM2 protein Q9C040 UNIPROT NEFL protein P07196 UNIPROT "down-regulates quantity by destabilization" ubiquitination 9606 BTO:0000567 18687884 t miannu "Here, we show that TRIM RING finger protein TRIM2, highly expressed in the nervous system, is an UbcH5a-dependent ubiquitin ligase. We further demonstrate that TRIM2 binds to neurofilament light subunit (NF-L) and regulates NF-L ubiquitination." SIGNOR-271776 CSNK2A1 protein P68400 UNIPROT XRCC1 protein P18887 UNIPROT up-regulates phosphorylation Thr519 EDPYAGStDENTDSE 9606 20471329 t lperfetto "Xrcc1 phosphorylation by ck2 is required for its stability and efficient dna repair. Rcc1 is phosphorylated in vivo and in vitro by ck2, and ck2 phosphorylation of xrcc1 on s518, t519, and t523" SIGNOR-165431 TCF20 protein Q9UGU0 UNIPROT MMP3 protein P08254 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 7760812 t Luana "This result indicates that expression of SPBP is sufficient to transactivate a minimal promoter containing a single copy of the SPRE, as well as the full-length stromelysin promoter." SIGNOR-266223 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR BANP protein Q8N9N5 UNIPROT "down-regulates activity" phosphorylation Thr337 VKSFSRRtPNSSSYC 9606 BTO:0000567 26080397 t miannu "ERK-MAPK pathway that regulates alternative splicing facilitates ERK-1/2-mediated phosphorylation of SMAR1 at threonines 345 and 360 and localizes SMAR1 to the cytoplasm, preventing its interaction with Sam68." SIGNOR-266203 NFIL3 protein Q16649 UNIPROT CYP3A4 protein P08684 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0000599 18004209 f miannu "The oscillation in the expression of the CYP3A4 gene seemed to be the underlying cause of the rhythmic change in its metabolic activity. Luciferase reporter gene analysis and electrophoretic mobility shift assay revealed that the circadian transcriptional factor, D-site-binding protein (DBP), activated the transcription of the CYP3A4 gene by binding to the DNA sequence near the upstream of the transcriptional start site. The transactivation of the CYP3A4 gene by DBP was repressed by the E4 promoter-binding protein-4 (E4BP4), a negative component of the circadian clock." SIGNOR-253836 TRAF2 protein Q12933 UNIPROT TICAM1 protein Q8IUC6 UNIPROT up-regulates polyubiquitination 9606 20047764 t miannu "Here, we show that the TRAF family proteins directly bind TICAM-1 and demonstrate that TRAF2 and TRAF6 bind different sites of the N-terminal TICAM-1 and accelerate its polyubiquitination. we speculate that polyubiquitination of TICAM-1 by TRAF2 and TRAF6 is required for TICAM-1 to induce IRF-3 and NF-κB activation. This is supported by the observation that polyubiquitination of TICAM-1 was required for TRAF3-binding to TICAM-1" SIGNOR-271427 MAPK1 protein P28482 UNIPROT RPS3 protein P23396 UNIPROT up-regulates phosphorylation Thr42 SGVEVRVtPTRTEII 9606 15950189 t lperfetto "Erk phosphorylates threonine 42 residue of ribosomal protein s3." SIGNOR-137955 AKT proteinfamily SIGNOR-PF24 SIGNOR YBX1 protein P67809 UNIPROT up-regulates phosphorylation Ser102 NPRKYLRsVGDGETV 9606 BTO:0000150 19036157 t lperfetto "Phosphorylation of yb-1 at the serine 102 residue is required for transcriptional activation of growth-enhancing genes, such as egfr. Herein, we illustrate that activated akt binds to and phosphorylates the yb-1 cold shock domain at ser102" SIGNOR-182493 STOML2 protein Q9UJZ1 UNIPROT CD3E protein P07766 UNIPROT "up-regulates activity" binding 9606 BTO:0000661 18641330 t Giorgia "We observed that SLP-2 steadily associated with the CD3-epsilon chain of the TCR complex under resting conditions and during the 60 min of stimulation|The SLP-2-associated pool of these molecules became phosphorylated/activated in a sequential manner, a profile compatible with their temporal involvement in early TCR signalling." SIGNOR-260375 LBX1 protein P52954 UNIPROT ZEB1 protein P37275 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0002181 19651985 t Luana "Compared with the empty vector, LBX1 induced increased promoter activity of threefold to fourfold and fivefold to sixfold for ZEB1 and Snail1, respectively " SIGNOR-266054 ATR protein Q13535 UNIPROT MCC protein P23508 UNIPROT "up-regulates activity" phosphorylation Ser118 SELRSELsQSQHEVN 9606 BTO:0001109 21779472 t miannu "MCC is phosphorylated at the ATM/ATR consensus sites Ser118 and Ser120.  Finally, mutation of S118/120 to alanine did not affect MCC nuclear shuttling following UV but did impair MCC G2/M checkpoint activity." SIGNOR-273514 estrone smallmolecule CHEBI:17263 ChEBI 17beta-estradiol smallmolecule CHEBI:16469 ChEBI "up-regulates quantity" "precursor of" -1 8099587 t Luana "17 beta-HSD type 2 was capable of catalyzing the interconversion of testosterone and androstenedione as well as estradiol and estrone. " SIGNOR-269763 JAK2 protein O60674 UNIPROT JAK2 protein O60674 UNIPROT "up-regulates activity" phosphorylation Tyr637 KFGSLDTyLKKNKNC 9606 BTO:0000007 19364823 t "16705160:The effect of Ser523 on Jak2 function was independent of Tyr570-mediated inhibition." lperfetto "Analysis of in vitro autophosphorylated jak2while cytokine receptor stimulation mediates the phosphorylation of both tyr317 and tyr637, these residues oppositely regulate jak2-dependent signaling: the mutation of tyr317 enhances jak2 function, suggesting a role for the phosphorylation of tyr317 in the inhibition of jak2. Conversely, mutation of tyr637 reduces jak2 signaling, suggesting a role for the phosphorylation of this residue in the activation of jak2." SIGNOR-235885 ATR protein Q13535 UNIPROT MCC protein P23508 UNIPROT "up-regulates activity" phosphorylation Ser120 LRSELSQsQHEVNED 9606 BTO:0001109 21779472 t miannu "MCC is phosphorylated at the ATM/ATR consensus sites Ser118 and Ser120.  Finally, mutation of S118/120 to alanine did not affect MCC nuclear shuttling following UV but did impair MCC G2/M checkpoint activity." SIGNOR-273515 MAPK3 protein P27361 UNIPROT TOB1 protein P50616 UNIPROT down-regulates phosphorylation Ser154 SSVSSSPsPPFGHSA 9606 12050114 t gcesareni "Tob is rapidly phosphorylated at Ser 152, Ser 154, and Ser 164 by Erk1 and Erk2 upon growth-factor stimulation." SIGNOR-88732 Ub:E2 complex SIGNOR-C497 SIGNOR TRIM36 protein Q9NQ86 UNIPROT "up-regulates activity" ubiquitination 9606 34199813 t miannu "The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t" SIGNOR-271229 CSNK2A2 protein P19784 UNIPROT GTF2A1L protein Q9UNN4 UNIPROT "up-regulates activity" phosphorylation Ser356 VDGSGDTsSNEEIGS -1 12107178 t llicata "ALF was able to stabilize the binding of TBP to DNA, but it could not stabilize TBP mutants A184E, N189E, E191R, and R205E nor could it facilitate binding of the TBP-like factor TRF2/TLF to a consensus TATA element. However, phosphorylation of ALF with casein kinase II resulted in the partial restoration of complex formation using mutant TBPs. | Because the residues involved (Ser-280, Ser-281, Ser-316, and Ser-321) are conserved in ALF (Ser-356, Ser-357, Ser-418, and Ser-423), we tested whether its activity might also be affected by this modification. We first showed that ALF and TFIIAα/β polypeptides incubated with casein kinase II and [γ-32P]ATP could be labeled." SIGNOR-250991 GLI3 protein P10071 UNIPROT PTCH1 protein Q13635 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 17419683 f lperfetto "Binding of n-shh to ptch1 inhibits repression of smo, leading to activationof some genes and de-repression of others through the effects of smo on the gli family of transcription factors." SIGNOR-154240 taurine smallmolecule CHEBI:15891 ChEBI GlyR proteinfamily SIGNOR-PF62 SIGNOR "up-regulates activity" "chemical activation" 9606 BTO:0000007 9009272 t "inferred from family member" miannu "For each mutant GlyR we examined the agonist efficacies of taurine and Œ≤-alanine relative to glycine, the concentration of each agonist required for half-maximal current activation (EC50) and, in mutant GlyRs where Œ≤-alanine and taurine exhibited partial or no agonist efficacy, the concentration required for half-maximal inhibition of glycine-gated currents (IC50).experiments described in this report were performed on human Œ±1 homomeric GlyRs recombinantly expressed in mammalian HEK 293 cells. Taurine and Œ≤-alanine act as full agonists of human Œ±1 GlyRs when expressed in this system." SIGNOR-270259 NFIL3 protein Q16649 UNIPROT Cell_death phenotype SIGNOR-PH109 SIGNOR down-regulates 10090 BTO:0003104 10082541 f lperfetto "NFIL3 inhibits apoptosis without affecting Bcl-xL expression." SIGNOR-256653 PRKAA1 protein Q13131 UNIPROT SLC2A4 protein P14672 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 17609368 f gcesareni "Several in vivo studies using aicar to activate ampk chronically determined that mitochondrial enzymes [e.g., cytochrome c, uncoupling protein 3 (ucp-3)] and proteins involved in glucose uptake (glut4)are increased at the transcriptional level in skeletal muscle." SIGNOR-156786 PIGS protein Q96S52 UNIPROT PIGK protein Q92643 UNIPROT "up-regulates activity" binding 10090 BTO:0000095 11483512 t miannu "To determine roles for PIG-S and PIG-T, we disrupted these genes in mouse F9 cells by homologous recombination. PIG-S and PIG-T knockout cells were defective in transfer of GPI to proteins, particularly in formation of the carbonyl intermediates. We also demonstrate that PIG-S and PIG-T form a protein complex with GAA1 and GPI8, and that PIG-T maintains the complex by stabilizing the expression of GAA1 and GPI8." SIGNOR-261362 levomethadone chemical CHEBI:136003 ChEBI OPRD1 protein P41143 UNIPROT "up-regulates activity" "chemical activation" 10029 BTO:0000246 9686407 t miannu "Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors." SIGNOR-258809 "N-[4-[(hydroxyamino)-oxomethyl]phenyl]carbamic acid [6-(diethylaminomethyl)-2-naphthalenyl]methyl ester" chemical CHEBI:94187 ChEBI HDAC9 protein Q9UKV0 UNIPROT "down-regulates activity" "chemical inhibition" -1 20139990 t Luana "Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1)." SIGNOR-257970 RET/PTC2 protein Q15300 UNIPROT STAT3 protein P40763 UNIPROT "up-regulates activity" phosphorylation Tyr705 DPGSAAPyLKTKFIC 9606 12637586 t Manara "In addition, RET/PTC-mediated cellular transformation and proliferation of transformed cells require tyrosine 705 phosphorylation of STAT3 in NIH3T3 cells. We conclude that STAT3 activation by the RET/PTC tyrosine kinase is one of the critical signaling pathways for the regulation of specific genes, such as cyclin D1, vascular endothelial growth factor, and intercellular adhesion molecule 1, and for cellular transformation." SIGNOR-260917 Gbeta proteinfamily SIGNOR-PF4 SIGNOR RPS6KA1 protein Q15418 UNIPROT "up-regulates activity" phosphorylation 10090 BTO:0000938 8387505 t "inferred from 70% family members" lperfetto "The pp90rsk phosphothreonine content paralleled the ERK1 activity more closely than the phosphoserine level. These results provide compelling evidence that in fibroblasts and PC12 cells ERK1 plays a direct role in the phosphorylation of pp90rsk and that pp90rsk represents a physiologically relevant substrate of extracellular-regulated kinases" SIGNOR-270002 ACE protein P12821 UNIPROT bradykinin smallmolecule CHEBI:3165 ChEBI "down-regulates quantity by destabilization" binding 9606 16219810 t "The angiotensin-converting enzyme (ACE) is a membrane-bound peptidyl dipeptidase known to act on a variety of peptide substrates in the extracellular space. Its most notable functions are the formation of angiotensin II and the degradation of bradykinin." SIGNOR-253341 IDH2 protein P48735 UNIPROT 2-oxoglutarate(2-) smallmolecule CHEBI:16810 ChEBI "up-regulates quantity" "chemical modification" 9606 29090344 t miannu "Two of the most commonly mutated genes in AML encode for two isoforms of isocitrate dehydrogenase (IDH), IDH1 and IDH2. IDH1 and IDH2 are two isoforms of isocitrate dehydrogenase that perform crucial roles in cellular metabolism. Somatic mutations in either of these two genes impart a neomorphic enzymatic activity upon the encoded enzymes resulting in the ability to convert √鬱-ketoglutarate (√鬱KG) into the oncometabolite R2-hydroxyglutarate (R2-HG), which can competitively inhibit multiple √鬱KG-dependent dioxygenases." SIGNOR-253134 ALPK1 protein Q96QP1 UNIPROT TIFA protein Q96CG3 UNIPROT "up-regulates activity" phosphorylation Thr9 TSFEDADtEETVTCL -1 30111836 t miannu "Infection-induced activation of NF-κB and formation of eGFP–TIFA foci required ALPK1-dependent phosphorylation of TIFA at T9 (Extended Data Fig. 3a–e). Upon phosphorylation at T9, TIFA forms foci to activate TRAF6-dependent NF-κB signalling" SIGNOR-273543 EP300 protein Q09472 UNIPROT KPNA2 protein P52292 UNIPROT up-regulates acetylation Lys22 HRFKNKGkDSTEMRR 9606 15342649 t lperfetto "Ampk triggered the acetylation of importin alpha1 on lys(22), a process dependent on the acetylase activity of p300" SIGNOR-128625 CREB5 protein Q02930 UNIPROT MX1 protein P20591 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0002807 21132541 f miannu "Our result verified CREB5 biological regulation module in the upstream of frontal cortex of HIVE-control patients (MAPKAPK3 activation; DGKG, LY96, TNFRSF11B inhibition) and downstream (ATP6V0E1, CFB, DGKG, MX1, TGFBR3 activation; LGALS3BP, RASGRP3, RDX, STAT1 inhibition)," SIGNOR-253800 GATA6 protein Q92908 UNIPROT CDX2 protein Q99626 UNIPROT "up-regulates quantity by expression" 9606 BTO:0000195 24317510 f lperfetto "Many GATA6-dependent genes lacked nearby binding sites but several strongly dependent, synexpressed and GATA6-bound genes encode TFs such as MYC, HES1, RARB and CDX2." SIGNOR-253155 CDK18 protein Q07002 UNIPROT PTK2 protein Q05397 UNIPROT "down-regulates activity" 9606 BTO:0000567 28361970 f lperfetto "PCTK3/CDK18 regulates cell migration and adhesion by negatively modulating FAK activity" SIGNOR-264561 CTDSP1 protein Q9GZU7 UNIPROT SMAD2 protein Q15796 UNIPROT "down-regulates activity" dephosphorylation Ser250 TGSPAELsPTTLSPV 9606 BTO:0000007 17035229 t "SCP1 Dephosphorylates Smad2/3 in the Linkers|MAPK-mediated linker phosphorylation appears to have a dual role in Smad2/3 regulation. Mitogens and hyperactive Ras result in extracellular signal-regulated kinase (ERK)-mediated phosphorylation of Smad3 at Ser-204, Ser-208, and Thr-179 and of Smad2 at Ser-245/250/255 and Thr-220. Mutation of these sites increases the ability of Smad3 to activate target genes, suggesting that MAPK phosphorylation of Smad3 is inhibitory (11, 12). However, in contrast, ERK-dependent phosphorylation of Smad2 at Thr-8 enhances its transcriptional activity" SIGNOR-248796 AURKA protein O14965 UNIPROT SPIN1 protein Q9Y657 UNIPROT "up-regulates activity" phosphorylation Ser109 LNKDERVsALEVLPD 9606 BTO:0000567 22258766 t miannu "The Ser84 and Ser99 amino acids within SPINDLIN1 were further identified as the key functional sites in WNT/TCF-4 signaling activation. Mutation of these two sites of SPINDLIN1 abolished its effects on promoting WNT/TCF-4 signaling and cancer cell proliferation. We further found that Aurora-A could interact with and phosphorylate SPINDLIN1 at its key functional sites, Ser84 and Ser99, suggesting that phosphorylation of SPINDLIN1 is involved in its oncogenic function." SIGNOR-273549 IGF1R protein P08069 UNIPROT AKT1 protein P31749 UNIPROT "up-regulates activity" 10090 11715022 f lperfetto "We show that IGF-1 unexpectedly acts via Akt to antagonize calcineurin signalling during myotube hypertrophy." SIGNOR-235373 CDK11A protein Q9UQ88 UNIPROT CDK11B protein P21127 UNIPROT up-regulates phosphorylation Thr726 KHEYFREtPLPIDPS 9606 21078675 t lperfetto "Overall, our data indicated that thr-370 is responsible for the autophosphorylation, dimerization, and kinase activity of cdk11(p58)" SIGNOR-169628 TFDP1 protein Q14186 UNIPROT MYBL2 protein P10244 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000972 14618416 f miannu "To assess transactivating activity of E2F1/DP-1, we also analyzed expression of ten putative transcriptional targets of this complex in HCCs. Expression levels of TFDP1 and E2F1 correlated with those of seven transcriptional targets ( TYMS, DHFR, PCNA, RRM1, CCNE1, CDC2, and MYBL2) that play important roles in the G1/S transition, and down-regulation of TFDP1 inhibited growth of Hep3B cells." SIGNOR-253862 GRIP1 protein Q9Y3R0 UNIPROT MEF2C protein Q06413 UNIPROT up-regulates binding 9606 11062529 t gcesareni "The cofactors grip-1, cbp/p300 and pcaf have hat activity and function as co-activators for mef-2c during myogenesis." SIGNOR-83883 Ub:E2 complex SIGNOR-C497 SIGNOR DTX1 protein Q86Y01 UNIPROT "up-regulates activity" ubiquitination 9606 34199813 t miannu "The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t" SIGNOR-271106 RELA protein Q04206 UNIPROT B2M protein P61769 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 12480693 f miannu "The nuclear factor kappa B (NF-kappa B) subunits p50 and p65 bind to the kappa B box and p65 transactivates beta(2)m." SIGNOR-254657 HDLBP protein Q00341 UNIPROT HDL_assembly phenotype SIGNOR-PH61 SIGNOR up-regulates 9606 9925647 f miannu "HBP/vigilin binds HDL and apoA-I on ligand blots; conceivably therefore apoA-I may interact with cytoplasmic vigilin promoting changes in cholesterol flux." SIGNOR-266692 FBN1 protein P35555 UNIPROT SMAD2 protein Q15796 UNIPROT "up-regulates activity" 9606 17242066 f Regulation miannu "Fibrillin-1 sequence encoded by exons 44-49 releases endogenous TGFbeta1, thereby stimulating TGFbeta receptor-mediated Smad2 signaling." SIGNOR-251889 PTPN5 protein P54829 UNIPROT GRIN2B protein Q13224 UNIPROT "down-regulates activity" dephosphorylation Tyr1474 GSSNGHVyEKLSSIE 10090 BTO:0004102 20427654 t lperfetto " These previous results, together with the present findings, indicate that STEP61 dephosphorylates the NR2B subunit at its regulatory tyr1472 site, and dephosphorylation of this site leads to internalization of the NMDAR complex from neuronal surface membranes." SIGNOR-265744 9-(1-Methyl-4-pyrazolyl)-1-[1-(1-oxoprop-2-enyl)-2,3-dihydroindol-6-yl]-2-benzo[h][1,6]naphthyridinone chemical CID:71748056 PUBCHEM ITK protein Q08881 UNIPROT "down-regulates activity" "chemical inhibition" -1 24556163 t miannu "This analysis revealed that QL47 also potently inhibits BMX with an IC50 of 6.7 nM but impressively displays more than 100-fold selectivity against EGFR, HER2, JAK3, BLK, TEC, and ITK that possess an equivalently placed cysteine" SIGNOR-262236 LFNG protein Q8NES3 UNIPROT DLL1 protein O00548 UNIPROT up-regulates binding 9606 11346656 t gcesareni "The modification of notch by fringe would influence binding between the notch receptor and its ligand. It was reported previously that mfng and lfng inhibited notch1-mediated signaling triggered by jagged1 and enhanced that triggered by delta1, and either jagged1- or delta1-triggered notch2 signaling was enhanced by lfng" SIGNOR-107699 RXRA protein P19793 UNIPROT PPARG protein P37231 UNIPROT up-regulates binding 9606 11237216 t gcesareni "Although the three ppar subtypes are closely related and bind to similar dna response elements as heterodimers with the 9-cis retinoic acid receptor rxr, each subserves a distinct physiology" SIGNOR-105445 HTR3E protein A5X5Y0 UNIPROT Excitatory_synaptic_transmission phenotype SIGNOR-PH133 SIGNOR up-regulates 9606 BTO:0000142 18761359 f miannu "The 5-hydroxytryptamine type-3 (5-HT3) receptor is a cation-selective ion channel of the Cys-loop superfamily. 5-HT3 receptor activation in the central and peripheral nervous systems evokes neuronal excitation and neurotransmitter release. " SIGNOR-264318 PIP3 smallmolecule CHEBI:16618 ChEBI AKT3 protein Q9Y243 UNIPROT up-regulates "chemical activation" 9606 21779497 t gcesareni "When active, pi3k converts phosphatidylinositol (4,5)-bisphosphate (pip2) into phosphatidylinositol (3,4,5)-trisphosphate (pip3). Pip3, in turn, binds the pleckstrin homology (ph) domain of akt/pkb, stimulating its kinase activity, resulting in the phosphorylation of a host of other proteins that affect cell growth, cell cycle entry, and cell survival." SIGNOR-175250 CDK2 protein P24941 UNIPROT CDK2 protein P24941 UNIPROT up-regulates phosphorylation Thr160 GVPVRTYtHEVVTLW 9606 17361108 t gcesareni "Our results demonstrate that cdk2 is capable of autophosphorylation at thr160." SIGNOR-153636 EEF1A1 protein P68104 UNIPROT Trp-tRNA(Trp) smallmolecule CHEBI:29159 ChEBI up-regulates relocalization 9606 23699257 t lperfetto "During protein synthesis, eEF1A binds to and delivers aminoacylated tRNAs (aa-tRNAs) to the elongating ribosome (Fig. 1). GTP bound to eEF1A is hydrolyzed upon codon-anticodon match between an aa-tRNA in the A site of the ribosome and mRNA bound to the ribosome." SIGNOR-269517 LYN protein P07948 UNIPROT GCSAM protein Q8N6F7 UNIPROT "up-regulates activity" phosphorylation Tyr128 LGGTETEySLLHMPS -1 31362927 t miannu "Herein, we demonstrate phosphorylation of HGAL by Syk and Lyn kinases at tyrosines Y80, Y86, Y106Y107, Y128, and Y148.  Y148 (in black) was already phosphorylated before the addition of kinases. We demonstrate that Grb2 facilitates HGAL and Syk binding following BCR stimulation but does not affect the HGAL-mediated increase in Syk kinase activity. Previous studies showed that Grb2 inhibits BCR signaling by decreasing the activation of Syk by Lyn.11 Thus, while HGAL and Grb2 oppositely affect Syk kinase activity, this is not due to direct Grb2 effects on HGAL-mediated Syk kinase activation." SIGNOR-273559 KLF2 protein Q9Y5W3 UNIPROT RELN protein P78509 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 21530336 t Luana "KLF2 transactivates the reelin promoter in K562 cells." SIGNOR-266048 CDK1 protein P06493 UNIPROT NCOA3 protein Q9Y6Q9 UNIPROT down-regulates phosphorylation Ser728 VVKQEQLsPKKKENN 9606 SIGNOR-C17 22163316 t gcesareni "We demonstrate that aib1 is phosphorylated on ser728 and ser867 by cdk1/cyclin b at the onset of mitosis and remains phosphorylated until exit from m phase." SIGNOR-195233 TEC protein P42680 UNIPROT STAP1 protein Q9ULZ2 UNIPROT "up-regulates activity" phosphorylation 9606 BTO:0000007 10518561 t miannu "In 293 cells expressing recombinant BRDG1 and various PTKs, Tec and Pyk2, but not Btk, Bmx, Lyn, Syk, or c-Abl, induced marked phosphorylation of BRDG1 on tyrosine residues. BRDG1 was also phosphorylated by Tec directly in vitro. Efficient phosphorylation of BRDG1 by Tec required the PH and SH2 domains as well as the kinase domain of the latter. Furthermore, BRDG1 was shown to participate in a positive feedback loop by increasing the activity of Tec. BRDG1 transcripts are abundant in the human B cell line Ramos, and the endogenous protein underwent tyrosine phosphorylation in response to BCR stimulation. BRDG1 thus appears to function as a docking protein acting downstream of Tec in BCR signaling." SIGNOR-261817 SCF-betaTRCP complex SIGNOR-C5 SIGNOR COMMD1 protein Q8N668 UNIPROT "down-regulates quantity by destabilization" ubiquitination 9606 BTO:0001321 20068069 t miannu "CLU-2 is a ubiquitin binding protein (UBP) that enhances proteasome activity. sCLU promotes degradation of COMMD1. sCLU interacts with the SCF-βTrCP E3 ligase complex, serving as a scaffolding chaperone to form a multimeric protein complex that facilitates COMMD1 and I-κB ubiquitination and proteasomal degradation." SIGNOR-271430 RB1 protein P06400 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR down-regulates 9606 21524151 f miannu "Consistent with this, the magnitude of the response (i.e. the fraction of cells undergoing arrest) appears to diminish the closer the cells are to the time of S-phase entry. The existence of a time gap between full pRb phosphorylation and S-phase entry is also consistent with the notion that E2F, once released from pRb, transcriptionally activates factors needed for S-phase entry, a process which likely requires a significant amount of time." SIGNOR-262533 SLC35A2 protein P78381 UNIPROT UDP-D-galactose smallmolecule CHEBI:18307 ChEBI "up-regulates quantity" relocalization 9606 34384782 t miannu "The CMP-sialic acid transporter SLC35A1 and UDP-galactose transporter SLC35A2 are two well-characterized nucleotide sugar transporters with distinctive substrate specificities. Nucleotide sugar transporters (NSTs) transport nucleotide sugars from the cytosol into the lumen of the endoplasmic reticulum or the Golgi apparatus, where the nucleotide sugars serve as substrates for protein glycosylation and glycosphingolipid synthesis." SIGNOR-268465 CDK7 protein P50613 UNIPROT POLR2A protein P24928 UNIPROT down-regulates phosphorylation Ser1944 GSTYSPTsPGYSPTS 9606 14662762 t lperfetto "Although there is some inconsistency in the literature, it is generally thought that cdk7, a component of the transcription factor (tf) iih, is a major ser-5 kinase, whereas cdk9, a component of positive transcription elongation factor (p-tef) b, is a major ser-2 kinase within cells. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination." SIGNOR-120076 CSNK2A1 protein P68400 UNIPROT ANP32B protein Q92688 UNIPROT up-regulates phosphorylation Thr244 GEKRKREtDDEGEDD 9606 17178712 t gcesareni "Here, we are able to report that casein kinase 2 (ck2) phosphorylates april on residue threonine244 (thr(244)) and demonstrate that the ck2-specific inhibitor 4,5,6,7-tetrabromo-2-azabenzimidazole abolishes cd83 expression in activated jurkat t cells by interfering with the nucleocytoplasmic translocation of cd83 mrna" SIGNOR-151261 MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR MAPK3 protein P27361 UNIPROT up-regulates phosphorylation 9606 12270934 t lperfetto "Mek1 as indicated by extensive phosphorylation of erk1 and erk2 during the initial 2 h of adipogenesis." SIGNOR-244798 PYGM protein P11217 UNIPROT "alpha-D-glucose 1-phosphate(2-)" smallmolecule CHEBI:58601 ChEBI "up-regulates quantity" "chemical modification" 9606 3346228 t miannu "Mammalian glycogen phosphorylases are found in at least three isozymic forms that can be distinguished by functional and structural properties as well as by the tissues in which they are preferentially expressed [√¢‚Ǩ¬¶] Each phosphorylase isozyme fulfills different physiological requirements even though all forms of the enzyme catalyze the same reaction, the phosphorolysis of glycogen to yield glucose 1-phosphate." SIGNOR-267390 CASZ1 protein Q86V15 UNIPROT EGFL7 protein Q9UHF1 UNIPROT "up-regulates quantity" "transcriptional regulation" 9606 BTO:0001176 24150064 t miannu "We have recently demonstrated that a novel transcriptional pathway involving activation of the Epidermal Growth Factor-like Domain 7 (Egfl7) gene by the transcription factor CASTOR (CASZ1) is required for blood vessel assembly and lumen morphogenesis." SIGNOR-266858 CDK2 protein P24941 UNIPROT FOXM1 protein Q08050 UNIPROT "up-regulates activity" phosphorylation Thr611 ETLPISStPSKSVLP BTO:0001938 15024056 t llicata "We demonstrated that FoxM1B transcriptional activity requires binding of either S-phase or M-phase Cdk-cyclin complexes to mediate efficient Cdk phosphorylation of the FoxM1B Thr 596 residue, which is essential for recruitment of p300/CBP coactivator proteins." SIGNOR-250731 MBOAT7 protein Q96N66 UNIPROT 2-acyl-sn-glycero-3-phospho-D-myo-inositol smallmolecule CHEBI:62746 ChEBI "down-regulates quantity" "chemical modification" -1 18772128 t miannu "The cycle of deacylation and reacylation of phospholipids plays a critical role in regulating availability of arachidonic acid for eicosanoid production. The major yeast lysophospholipid acyltransferase, Ale1p, is related to mammalian membrane-bound O-acyltransferase (MBOAT) proteins. MBOAT7 is a lysophosphatidylinositol acyltransferase with remarkable specificity for arachidonoyl-CoA. MBOAT5 and MBOAT7 are particularly susceptible to inhibition by thimerosal. Human neutrophils express mRNA for these four enzymes, and neutrophil microsomes incorporate arachidonoyl chains into phosphatidylinositol, phosphatidylcholine, PS, and phosphatidylethanolamine in a thimerosal-sensitive manner. These results strongly implicate MBOAT5 and MBOAT7 in arachidonate recycling, thus regulating free arachidonic acid levels and leukotriene synthesis in neutrophils." SIGNOR-267246 AKT2 protein P31751 UNIPROT FOXO4 protein P98177 UNIPROT "down-regulates activity" phosphorylation 9606 21620960 t lperfetto "Akt phosphorylates members of the foxo factors (forkhead family of transcription factors), leading to binding of 14-3-3 proteins and cytoplasmic localisation. In particular, akt phosphorylates foxo1 on thr24, ser256 and ser319. Foxo 3alfa and foxo4 are phosphorylated on equivalent sites. In addition, phosphorylation of afx by protein kinase b inhibits its transcriptional activity." SIGNOR-233529 SMAD1 protein Q15797 UNIPROT Differentiation phenotype SIGNOR-PH37 SIGNOR up-regulates 10090 BTO:0002729 23993924 f flangone "Engagement of BMP4-mediated signaling in adult mouse ovary-derived OSCs cultured in vitro drives differentiation of these cells into IVD oocytes through Smad1/5/8 activation and transcriptional up-regulation of key meiosis-initiating genes." SIGNOR-255259 DNMT1 protein P26358 UNIPROT ESR1 protein P03372 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0001570 23242655 f "Our previous studies demonstrated that mutant p53 along with repression complex proteins including DNMT1, HDAC1 and MeCP2 is associated with ER-negative promoter in MDA-MB-468 cells." SIGNOR-254027 CDK2 protein P24941 UNIPROT MYBL2 protein P10244 UNIPROT up-regulates phosphorylation Thr487 SQKVVVTtPLHRDKT 9606 SIGNOR-C83 9840932 t lperfetto "The cell-cycle regulated transcription factor b-myb is phosphorylated by cyclin a/cdk2 at sites that enhance its transactivation properties. we show that b-myb is phosphorylated at thr447, thr490, thr497 and ser581 by cyclin a/cdk2" SIGNOR-62361 ATM protein Q13315 UNIPROT PAN2 protein Q504Q3 UNIPROT "up-regulates activity" phosphorylation Ser1003 TKSTIKPsQMSVARI 9606 BTO:0000007 33097710 t miannu "Here, we identify that USP52 directly interacts with and deubiquitinates CtIP, thereby promoting DNA end resection and HR. Mechanistically, USP52 removes the ubiquitination of CtIP to facilitate the phosphorylation and activation of CtIP at Thr-847. In addition, USP52 is phosphorylated by ATM at Ser-1003 after DNA damage, which enhances the catalytic activity of USP52. " SIGNOR-273508 "ginkgolide B" chemical CHEBI:5356 ChEBI PTAFR protein P25105 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-192684 PIAS4 protein Q8N2W9 UNIPROT STAT1 protein P42224 UNIPROT down-regulates binding 9606 11248056 t gcesareni "First, piasy interacts with stat1 both in vitro and in vivo. The in vivo piasy__stat1 interaction is dependent on cytokine stimulation. Second, piasy can inhibit stat1-mediated gene activation without blocking the dna binding activity of stat1." SIGNOR-105723 "Ub:E1 (UBA1 substrate)" complex SIGNOR-C495 SIGNOR UBE2N protein P61088 UNIPROT "up-regulates activity" ubiquitination 9606 34199813 t miannu "The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t" SIGNOR-271320 EEF1A2 protein Q05639 UNIPROT Val-tRNA(Val) smallmolecule CHEBI:29164 ChEBI up-regulates relocalization 9606 23699257 t lperfetto "During protein synthesis, eEF1A binds to and delivers aminoacylated tRNAs (aa-tRNAs) to the elongating ribosome (Fig. 1). GTP bound to eEF1A is hydrolyzed upon codon-anticodon match between an aa-tRNA in the A site of the ribosome and mRNA bound to the ribosome." SIGNOR-269539 MAPK3 protein P27361 UNIPROT FOS protein P01100 UNIPROT up-regulates phosphorylation Thr232 GGLPEVAtPESEEAF 9606 7816602 t lperfetto "Phosphorylation of the c-fos and c-jun hob1 motif stimulates its activation capacity here we show that the hob1-containing activation domain of c-fos is stimulated by ha-ras in vivo and phosphorylated by a map kinase family member in vitro and that mutating t232 to ala abolishes both functions." SIGNOR-33909 NEK2 protein P51955 UNIPROT NEK2 protein P51955 UNIPROT up-regulates phosphorylation Thr175 HDTSFAKtFVGTPYY 9606 17197699 t gcesareni "Enzymatic activity, induced;" SIGNOR-151763 FBLIM1 protein Q8WUP2 UNIPROT FLNB protein O75369 UNIPROT "up-regulates activity" binding 10090 BTO:0000944 24165133 t miannu "Kindlin binds migfilin tandem LIM domains and regulates migfilin focal adhesion localization and recruitment dynamics. Two integrin-binding proteins present in FAs, kindlin-1 and kindlin-2, are important for integrin activation, FA formation, and signaling. By binding filamin, migfilin provides a link between kindlin and the actin cytoskeleton." SIGNOR-266106 DOK1 protein Q99704 UNIPROT "AIIB/b3 integrin" complex SIGNOR-C173 SIGNOR "down-regulates activity" binding 9606 19118207 t miannu "Integrins also bind to many PTBdomain-containing proteins (Calderwood et al., 2003) – including Dok1 and integrincytoplasmic-domain-associated protein 1 (ICAP1) – and these can compete with talin for binding to integrin and so can impair activation" SIGNOR-257686 CARM1 protein Q86X55 UNIPROT PAX7 protein P23759 UNIPROT up-regulates methylation 10090 BTO:0002314 BTO:0001103 29681515 t apalma "Carm1 specifically methylates Pax7 at multiple arginine residues in the N terminus of Pax7" SIGNOR-255898 ABL1 protein P00519 UNIPROT NCOA3 protein Q9Y6Q9 UNIPROT up-regulates phosphorylation Tyr1357 HPQAASIyQSSEMKG 9606 18765637 t lperfetto "Tyrosine phosphorylation of the nuclear receptor coactivator aib1/src-3 is enhanced by abl kinase and is required for its activity in cancer cellstyrosine kinase directly phosphorylates aib1/src-3 at y1357 and modulates the association of aib1 with c-abl, eralpha, the transcriptional cofactor p300," SIGNOR-180571 ULK1 protein O75385 UNIPROT ATG13 protein O75143 UNIPROT up-regulates phosphorylation 9606 19211835 t gcesareni "Ulks directly phosphorylate atg13" SIGNOR-183957 CASP4 protein P49662 UNIPROT GSDMD protein P57764 UNIPROT "up-regulates activity" cleavage Asp275 CLHNFLTdGVPAEGA 9606 BTO:0000007 26375003 t lperfetto "Co-expression of GSDMD with caspase-1, 4, 5 or 11 but not apoptotic caspases (caspase-2, 8 and 9) in 293T cells induced the same cleavage of GSDMD|inflammatory caspases specifically cleave GSDMD after the 272FLTD275 (or 273LLSD276) sequence |" SIGNOR-256417 SNX6 protein Q9UNH7 UNIPROT IGF1R protein P08069 UNIPROT "down-regulates quantity" binding 9606 BTO:0000567 32150533 t miannu "Here, we discovered that the binding between SNX-BARs and CI-MPR or IGF1R is mediated by the phox-homology (PX) domain of SNX5 or SNX6 and a bipartite motif, termed SNX-BAR-binding motif (SBM), in the cargoes. our studies establish that SNX-BARs function as a direct cargo-selecting module for a large set of transmembrane proteins transiting the endosome, in addition to their roles in phospholipid recognition and biogenesis of tubular structures." SIGNOR-269445 UHMK1 protein Q8TAS1 UNIPROT SYN1 protein P17600 UNIPROT unknown phosphorylation Ser438 GSHGQTPsPGALPLG 9606 10880969 t lperfetto "We also identified a tryptic peptide of synapsin i phosphorylated by kis" SIGNOR-78899 "MLL3 complex" complex SIGNOR-C446 SIGNOR H3C1 protein P68431 UNIPROT "down-regulates activity" methylation Lys5 kQTARKST 9606 34156443 t miannu "MLL3/KMT2C and MLL4/KMT2D are two paralogous histone modifiers that belong to the SET1/MLL (also named COMPASS) family of lysine methyltransferases and play critical roles in enhancer-regulated gene activation. MLL3 and MLL4 form identical multi-protein complexes for modifying mono-methylation of histone H3 lysine 4 (H3K4) at enhancers, which together with the p300/CBP-mediated H3K27 acetylation can generate an active enhancer landscape for long-range target gene activation." SIGNOR-268810 RAGAC complex SIGNOR-C113 SIGNOR mTORC1 complex SIGNOR-C3 SIGNOR "up-regulates activity" relocalization 9606 20381137 t gcesareni "The Rag GTPases interact with mTORC1 and are proposed to activate it in response to amino acids by promoting mTORC1 translocation to a membrane-bound compartment that contains the mTORC1 activator, Rheb" SIGNOR-228158 PHLPP2 protein Q6ZVD8 UNIPROT PRKCB protein P05771 UNIPROT "down-regulates quantity by destabilization" dephosphorylation Ser661 QNEFAGFsYTNPEFV 9606 18162466 t "These data reveal that PHLPP controls the cellular levels of PKC by specifically dephosphorylating the hydrophobic motif, thus destabilizing the enzyme and promoting its degradation.|n contrast, results from siRNA depletion and overexpression experiments indicate that the hydrophobic motif site (Ser660) is regulated by PHLPP isoforms," SIGNOR-248727 PRKCB protein P05771 UNIPROT protein Q5T7P8 UNIPROT "up-regulates activity" phosphorylation Thr283 DRKCKLQtRVHRKTL 9606 BTO:0001277 16111671 t miannu "We found by site-directed mutagenesis that Thr418 and/or Thr419 in the polybasic region (KKKTTIK) of the C2B domain--a key region for the function of synaptotagmins--are the PKC target that regulates its inhibitory effect on acrosomal exocytosis. Similarly, we showed that Thr284 in the polybasic region of C2A (KCKLQTR) is the target for PKC-mediated phosphorylation in this domain." SIGNOR-273565 "SEC61 complex" complex SIGNOR-C368 SIGNOR HSPA5 protein P11021 UNIPROT "up-regulates activity" binding 33925740 t lperfetto "This is where allosteric effectors of the Sec61 complex (BiP together with Sec62/Sec63 complex or TRAP complex) (Figure 2 and Figure 5) and auxiliary membrane protein insertases (EMC and TMCO1 complex) join the game" SIGNOR-265276 TP53 protein P04637 UNIPROT MDM2 protein Q00987 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 7958853 f gcesareni "The p53 tumor suppressor protein trans-activates mdm2 itself, which is therefore considered a component of a p53 negative feedback loop." SIGNOR-34962 Ub:E2 complex SIGNOR-C497 SIGNOR TRIM75 protein A6NK02 UNIPROT "up-regulates activity" ubiquitination 9606 34199813 t miannu "The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t" SIGNOR-271139 PBX3 protein P40426 UNIPROT FGF8 protein P55075 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 10090 BTO:0003560 10026229 t miannu "Our results in ES cells suggest that Engrailed inhibits Fgf8 expression in the absence of Pbx1. We identified single Engrailed- and Pbx-binding sites in the Fgf8 intron that inhibit expression of Fgf8 in mouse ES cells, but that together can allow full Fgf8 expression. Our data support the model that Engrailed heterodimerized with Pbx might activate transcription, while Engrailed or Pbx proteins alone might repress transcription" SIGNOR-265779 CAMK2G protein Q13555 UNIPROT SYN1 protein P17600 UNIPROT unknown phosphorylation Ser605 AGPTRQAsQAGPVPR 3118371 t llicata "Sites 2 and 3 are serine residues phosphorylated by calcium/calmodulin-dependent protein kinase II." SIGNOR-250708 PAN2 protein Q504Q3 UNIPROT RBBP8 protein Q99708 UNIPROT "up-regulates activity" deubiquitination 9606 BTO:0000007 33097710 t miannu "Here, we identify that USP52 directly interacts with and deubiquitinates CtIP, thereby promoting DNA end resection and HR. Mechanistically, USP52 removes the ubiquitination of CtIP to facilitate the phosphorylation and activation of CtIP at Thr-847. In addition, USP52 is phosphorylated by ATM at Ser-1003 after DNA damage, which enhances the catalytic activity of USP52. " SIGNOR-273509 SRC protein P12931 UNIPROT EGFR protein P00533 UNIPROT "up-regulates activity" phosphorylation Tyr869 LGAEEKEyHAEGGKV 9606 BTO:0000452 11983694 t lperfetto "In summary, this study describes a novel mechanism for metal-induced egfr transactivation, which is likely to be mediated by src through the phosphorylation site of tyr-845 on egfr. emanating from a variety of growth factor receptors, including egfry845 (e-e-k-e-y845-h-a-e)" SIGNOR-235921 PNCK protein Q6P2M8 UNIPROT EIF4G3 protein O43432 UNIPROT up-regulates phosphorylation Ser1156 NTFMRGGsSKDLLDN 9606 22514323 t lperfetto "Here we report that activity-dependent translational initiation in cultured rat hippocampal neurons is enhanced by camki-mediated phosphorylation of ser1156 in eukaryotic initiation factor eif4gii (4gii)." SIGNOR-197190 EGFR protein P00533 UNIPROT CALM1 protein P0DP23 UNIPROT down-regulates phosphorylation Tyr100 FDKDGNGyISAAELR 9606 3415247 t lperfetto "Phosphorylation of calmodulin by the epidermal-growth-factor-receptor tyrosine kinase. Phosphorylated calmodulin does not exhibit the characteristic ca2+ shift normally observed with calmodulin in electrophoretic gels, an observation that is consistent with this modification affecting the biological activity of the molecule." SIGNOR-24778 RALA protein P11233 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR "up-regulates activity" phosphorylation Thr451 PIPKALGtPVLTPPT 10090 11689711 t gcesareni "We conclude that Ral-mediated phosphorylation of threonines 447 and 451 is required for proper activity of AFX-WT." SIGNOR-252984 PPP2CB protein P62714 UNIPROT PRKCB protein P05771-2 UNIPROT "down-regulates activity" dephosphorylation Ser660 QSEFEGFsFVNSEFL 10116 15880462 t "Inhibition of PP2A increased phosphorylation at Ser660 that determines calcium sensitivity and activity of PKCbetaII isoform" SIGNOR-248586 "Multiaminoacyl-tRNA synthetase" complex SIGNOR-C472 SIGNOR alpha-aminoacyl-tRNA smallmolecule CHEBI:2651 ChEBI "up-regulates quantity" "chemical modification" 9606 14660560 t miannu "Aminoacyl-tRNA synthetases (aaRSs)1 are a family of ancient enzymes that catalyze amino acid activation by ATP and the subsequent aminoacylation to its cognate tRNA." SIGNOR-270796 STAT3 protein P40763 UNIPROT FBXO32 protein Q969P5 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 22669242 f miannu "Thus we infected C2C12 myofibers with a recombinant adenovirus expressing a mutant, constitutively activated STAT3 (cSTAT3) known to possess increased DNA binding/transcriptional activity. Consistent with wasting, atrogin-1 expression was also markedly increased (Fig. 3A). Thus STAT3 activation is by itself sufficient to induce muscle fiber wasting in cell culture." SIGNOR-255331 ADRB3 protein P13945 UNIPROT GNAL protein P38405 UNIPROT "up-regulates activity" binding 9606 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-256896 8-[4,4-bis(4-fluorophenyl)butyl]-1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one chemical CHEBI:93369 ChEBI HTR1A protein P08908 UNIPROT "down-regulates activity" "chemical inhibition" 10116 BTO:0000601 8935801 t miannu "Risperidone and its active metabolite 9-OH-risperidone were compared to reference antipsychotic drugs (haloperidol, pipamperone, fluspirilene, clozapine, zotepine) and compounds under development (olanzapine, seroquel, sertindole, ORG-5222, ziprasidone) for in vitro binding to neurotransmitter receptors in brain tissue and on membranes of recombinant cells expressing cloned human receptors and for in vivo occupancy of neurotransmitter receptors in rat and guinea-pig brain following acute treatment (2 h., s.c.). The binding affinities of the compounds for various neurotransmitter receptors were measured using membrane preparations of animal brain regions and of recombinant cells expressing cloned, mostly human receptors. Receptors, tissues and cells are indicated in Table I; results are shown in Table 4A-B." SIGNOR-258540 NFIB protein O00712 UNIPROT EPHA5 protein P54756 UNIPROT "up-regulates quantity" "transcriptional regulation" 10090 31838646 t Gianni "For example, within the NFI targetome, we identified 6 collagen genes, 13 genes encoding potassium channel or glutamate receptor subunits and a range of factors related to axon guidance (e.g. Slit1, Robo1, Epha4, Epha5, Epha8)" SIGNOR-268902 POGZ protein Q7Z3K3 UNIPROT AURKB protein Q96GD4 UNIPROT "up-regulates activity" binding 9606 BTO:0000932 20562864 t miannu "POGZ is required for the correct activation and dissociation of Aurora B kinase from chromosome arms during M phase. These results reveal POGZ as an essential protein that links HP1alpha dissociation with Aurora B kinase activation during mitosis." SIGNOR-264497 Fibrinolysis phenotype SIGNOR-PH6 SIGNOR Fibrin complex SIGNOR-C317 SIGNOR down-regulates 9606 BTO:0000131 1447176 f lperfetto "The fibrinolytic system is sequentially composed of plasminogen activation and fibrin degradation [1, 2]. Three distinct inhibitors of the fibrinolytic system that differently regulate these two steps are plasminogen activator inhibitor type-1 (PAI-1), α2-antiplasmin (α2AP) and thrombin activatable fibrinolysis inhibitor (TAFI) [3]. PAI-1 limits the amount of free tissue-type plasminogen activator (tPA) both in plasma and on vascular endothelial cells (VECs), and regulates plasminogen activation potential to dissolve fibrin" SIGNOR-263532 GRK2 protein P25098 UNIPROT OPRM1 protein P35372 UNIPROT "down-regulates activity" phosphorylation Ser358 EFCIPTSsNIEQQNS 9606 BTO:0000007 12123746 t gcesareni "These results suggest that two C-terminal amino acids, Ser(355) and Thr(357), are required for short-term homologous desensitization and agonist-induced phosphorylation of mu-opioid receptors expressed in HEK 293 cells" SIGNOR-249661 DAB2IP protein Q5VWQ8 UNIPROT AR protein P10275 UNIPROT "down-regulates activity" binding 9606 27858941 t miannu "DAB2IP acts as a scaffold protein for PP2A to suppress DHT-elicited S81 phosphorylation of the AR, preventing its nuclear translocation and binding to androgen response elements. In addition, DAB2IP can compete with the AR for binding to c-Src, thus blocking the non-genomic AR pathway" SIGNOR-254758 MAPK3 protein P27361 UNIPROT MAGEA11 protein P43364 UNIPROT up-regulates phosphorylation Ser174 ESPSPPQsPQEESFS 9606 BTO:0000848 19828458 t llicata "Mage-11 ser-174 appears to be a post-translational regulatory site phosphorylated by erk1, based on the inhibitory effect of the s174a mutation in the context of shorter ar nh2-terminal fragments (19), and the greater transcriptional activity of gal-mage-11 fusion proteins containing the s174d phosphomimetic." SIGNOR-188466 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR SMAD2 protein Q15796 UNIPROT up-regulates phosphorylation Ser245 NQSMDTGsPAELSPT 9606 BTO:0000763;BTO:0000149 10197981 t lperfetto "These results suggest that oncogenic ras, acting through mek1 and erk kinases, induces the phosphorylation of smad2 and smad3 .we show that phosphorylation of smad2, a mediator of the activin/transforming growth factor-beta signal, by activated extracellular signal-regulated kinase 1 (erk1) increases the amount of smad2 protein and leads to enhanced transcriptional activity" SIGNOR-244719 vorinostat chemical CHEBI:45716 ChEBI HDAC2 protein Q92769 UNIPROT "down-regulates activity" "chemical inhibition" -1 20139990 t Luana "Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1)." SIGNOR-257951 KDM5C protein P41229 UNIPROT BDNF protein P23560 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 10090 31691806 f miannu "The KDM5C decrease was associated with a lack of repression of downstream target genes Scn2a, Syn1 and Bdnf in the embryonic brain of Arx-null mice." SIGNOR-264315 NFYA protein P23511 UNIPROT NFY complex SIGNOR-C1 SIGNOR "form complex" binding 9606 9885213 t lperfetto "Nf-y is one of the best characterized ccaat binding proteins, and its unique structure and evolutionary conservation suggest that it plays a crucial role in transcription of eukaryotic genes.It Is a ubiquitous heteromeric transcription factor, composed of three subunits, nf-ya, nf-yb, and nf-yc, all necessary for dna binding." SIGNOR-63013 CARS1 protein P49589 UNIPROT ATP(4-) smallmolecule CHEBI:30616 ChEBI "down-regulates quantity" "chemical modification" 9606 11347887 t miannu "Cysteinyl-tRNA synthetase catalyzes the addition of cysteine to its cognate tRNA. Here we report the isolation of a fulllength cDNA that encodes a protein of 748 amino acids. The predicted protein sequence shows considerable similarity to other eukaryotic cysteinyltRNA synthetases in the carboxylterminus. Expression of the fulllength and alternative forms of the enzyme in E. coli generated functional proteins that were active in aminoacylation of human cytoplasmic tRNA with cysteine." SIGNOR-270471 PLK2 protein Q9NYY3 UNIPROT FBXW7 protein Q969H0 UNIPROT down-regulates phosphorylation Ser176 KRKLDHGsEVRSFSL 9606 22399798 t lperfetto "Plk2 regulates centriole duplication through phosphorylation-mediated degradation of fbxw7 (human cdc4).Plk2 phosphorylates fbxw7 on serine 176" SIGNOR-196448 PAX2/TLE4 complex SIGNOR-C152 SIGNOR WT1 protein P19544 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 10090 BTO:0002295 16631587 t "Recruitment of the groucho-related protein TLE4 may be involved in converting Pax2 into a transcriptional repressor of Wt1." SIGNOR-252291 PRKACA protein P17612 UNIPROT PPP1R8 protein Q12972 UNIPROT "down-regulates activity" phosphorylation Ser178 TAHNKRIsTLTIEEG -1 9407077 t miannu "NIPP-1 is the RNA-binding subunit of a major species of protein phosphatase-1 in the nucleus. The purified recombinant protein was a potent (Ki = 9.9 +/- 0.3 pM) and specific inhibitor of protein phosphatase-1 and was stoichiometrically phosphorylated by protein kinases A and CK2. At physiological ionic strength, phosphorylation by these protein kinases drastically decreased the inhibitory potency of free NIPP-1. Sequencing and phosphoamino acid analysis of tryptic phosphopeptides enabled us to identify Ser178 and Ser199 as the phosphorylation sites of protein kinase A" SIGNOR-250032 Riluzole chemical CHEBI:8863 ChEBI KCNN1 protein Q92952 UNIPROT "up-regulates activity" "chemical activation" 9606 BTO:0000007 18955585 t Luana "Here, we used the neuroprotectant riluzole as a template for the design of KCa2/3 channel activators that are potent enough for in vivo studies. Of a library of 41 benzothiazoles, we identified 2 compounds, anthra[2,1-d]thiazol-2-ylamine (SKA-20) and naphtho[1,2-d]thiazol-2-ylamine (SKA-31), which are 10 to 20 times more potent than riluzole and activate KCa2.1 with EC50 values of 430 nM and 2.9 μM, KCa2.2 with an EC50 value of 1.9 μM, KCa2.3 with EC50 values of 1.2 and 2.9 μM, and KCa3.1 with EC50 values of 115 and 260 nM. " SIGNOR-258021 DIO proteinfamily SIGNOR-PF83 SIGNOR 3,3',5'-triiodo-L-thyronine smallmolecule CHEBI:11684 ChEBI "up-regulates quantity" "small molecule catalysis" 20978344 t "inferred from family member" "The deiodinase family of enzymes controls the tissue-specific activation and inactivation of the prohormone thyroxine (T4)" SIGNOR-270305 ATM protein Q13315 UNIPROT ZNF420 protein Q8TAQ5 UNIPROT "down-regulates activity" phosphorylation Ser68 NTYETELsQWEMSDR 9606 BTO:0001109 19377469 t done miannu "These results indicate that Apak is a genuine substrate of ATM kinase. Apak phosphorylation on Ser 68 is critical for p53-mediated apoptosis. in response to DNA damage, ATM is rapidly activated by autophosphorylation and mediates p53 activation through disruption of the Apak–p53 complex by phosphorylating Apak on Ser 68." SIGNOR-273513 SMAD8/SMAD4 complex SIGNOR-C206 SIGNOR RUNX2 protein Q13950 UNIPROT up-regulates "transcriptional regulation" 9606 27563484 f ggiuliani "Smad1/5/8-Smad4 complex transcribed Runx2 expression, as they complex with Runx2 to initiate other osteoblast gene expression." SIGNOR-255784 lysine smallmolecule CHEBI:25094 ChEBI Lys-tRNA(Lys) smallmolecule CHEBI:16047 ChEBI "up-regulates quantity" "precursor of" 9606 28271488 t miannu "Aminoacyl-tRNA synthetases (AARSs) are essential enzymes that specifically aminoacylate one tRNA molecule by the cognate amino acid. In mammals, nine synthetases, those specific for amino acids Arg, Asp, Gln, Glu, Ile, Leu, Lys, Met and Pro, associate into a multi-aminoacyl-tRNA synthetase complex, an association which is believed to play a key role in the cellular organization of translation, but also in the regulation of the translational and nontranslational functions of these enzymes." SIGNOR-270410 CSNK2A1 protein P68400 UNIPROT HSF1 protein Q00613 UNIPROT "up-regulates activity" phosphorylation Thr142 DSVTKLLtDVQLMKG -1 12659875 t llicata "Transcriptional activity and DNA binding of heat shock factor-1 involve phosphorylation on threonine 142 by CK2." SIGNOR-250898 "Cullin 3-RBX1-Skp1" complex SIGNOR-C526 SIGNOR AURKB protein Q96GD4 UNIPROT "up-regulates activity" polyubiquitination 9606 BTO:0000567 17543862 t miannu "Aurora B Interacts with the Cul3 Complex during Mitosis and Is Ubiquitylated in a Cul3-Dependent Manner In Vivo and In Vitro. our results suggest that Cul3/KLHL9/KLHL13 activity is required to remove the chromosomal passenger protein Aurora B from mitotic chromosomes, and that Aurora B is ubiquitylated in vivo and in vitro in a KLHL9/13-dependent manner. We conclude that the Cul3/KLHL9/KLHL13 E3 ligase is an important cell-cycle regulator which, in addition to the anaphase-promoting complex (APC), coordinates mitotic progression and completion of cytokinesis." SIGNOR-271661 MAPK1 protein P28482 UNIPROT NUP153 protein P49790 UNIPROT unknown phosphorylation Ser529 SPMFKFSsPIVKSTE 9606 19767751 t llicata "These results indicate that phosphorylation of nup153 and nup214 by erk strongly reduces their affinity for importin-. nup153 depletion caused a strong inhibition of nuclear accumulation of gfp?importin-beta in both erk-inhibited and erk-activated cells (fig. 8b,c), indicating that nup153 is essential for the efficient importin-beta transport." SIGNOR-188123 CSNK2A1 protein P68400 UNIPROT SRF protein P11831 UNIPROT "up-regulates activity" phosphorylation Ser79 AGALYSGsEGDSESG -1 2046671 t llicata "Casein kinase II (CKII) phosphorylates the mammalian transcription factor serum response factor (SRF) on a serine residue(s) located within a region of the protein spanning amino acids 70 to 92, thereby enhancing its DNA-binding activity in vitro.| Nevertheless, additional mutation of serines 77 and 79 was required before phosphorylation and enhanced binding were completely abolished. Thus, serines 77 and 79 could also be recognized by CKII if serines 83 and 85 were mutated." SIGNOR-250956 HOXA10 protein P31260 UNIPROT MEF2C protein Q06413 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0000661 21261500 f miannu "Overexpression of HOXA9 or HOXA10 in JURKAT cells by lentiviral transduction resulted in decreased expression of MEF2C, indicating repression by these homeodomain proteins. HOXA9/10 inhibits expression of MEF2C via NMYC" SIGNOR-254212 Ub:E2 complex SIGNOR-C497 SIGNOR SIAH3 protein Q8IW03 UNIPROT "up-regulates activity" ubiquitination 9606 34199813 t miannu "The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t" SIGNOR-271264 ATF4 protein P18848 UNIPROT FGF19 protein O95750 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000195 23205607 t lperfetto "Reporter gene analyses using the 5'-promoter region of FGF19 revealed that a functional AARE (amino-acid-response element) was localized in this region, and this site was responsible for inducing its transcription through ATF4 (activating transcription factor 4), which is activated in response to ER stress" SIGNOR-253727 CDK2 protein P24941 UNIPROT CCP110 protein O43303 UNIPROT "down-regulates activity" phosphorylation Ser516 ASSQCIAsPNFGTVS -1 12361598 t miannu "GST-tagged recombinant CP110 (GST-wt) was robustly phosphorylated by cyclin E/CDK2 (Figure 2A). Expression of a mutant derivative of CP110 refractory to CDK phosphorylation provokes marked polyploidy. We localized the majority (nine of ten) of potential CDK2 phosphorylation sites in CP110 to an amino-terminal fragment (GST-ΔN1; Figure 1B)" SIGNOR-265963 PAK2 protein Q13177 UNIPROT MYLK protein Q15746 UNIPROT "down-regulates activity" phosphorylation Ser1208 MKSRRPKsSLPPVLG -1 10748018 t miannu "PAK2 can directly phosphorylate MLCK, inhibiting its activity and limiting the development of isometric tension. PAK2 catalyzes MLCK phosphorylation on serine residues 439 and 991." SIGNOR-250222 GSK3A protein P49840 UNIPROT ARHGAP31 protein Q2M1Z3 UNIPROT "up-regulates activity" phosphorylation Thr789 PPAPPPPtPLEESTP 10090 BTO:0000944 17158447 t miannu "We show that GSK-3alpha and -beta interact with CdGAP in mammalian cells. We also demonstrate that GSK-3 phosphorylates CdGAP both in vitro and in vivo on Thr-776, which we have previously shown to be an ERK 1/2 phosphorylation site involved in CdGAP regulation." SIGNOR-262878 SUFU protein Q9UMX1 UNIPROT GLI3 protein P10071 UNIPROT "up-regulates quantity by stabilization" binding 9606 BTO:0000007 20463034 t Gianni "We show that loss of suppressor of fused (Sufu; an inhibitory effector for Gli proteins) results in destabilization of Gli2 and Gli3 full-length activators but not of their C-terminally processed repressors, whereas overexpression of Sufu stabilizes them." SIGNOR-268868 "bisindolylmaleimide i" chemical CID:2396 PUBCHEM PRKCG protein P05129 UNIPROT down-regulates "chemical inhibition" 9606 Other t CellSignaling gcesareni SIGNOR-190356 FBXO8 protein Q9NRD0 UNIPROT ARF6 protein P62330 UNIPROT "down-regulates quantity by destabilization" binding 9534 BTO:0000298 18094045 t miannu "Fbx8 Is a Component of the SCF Complex and Mediates Ubiquitination of Arf6. We first examined whether Fbx8 makes a complex with Cul1, through its binding to Skp1. We expressed GST-tagged Fbx8 together with FLAG-tagged Skp1 and Myc-tagged Cul1 in Cos-7 cells and found that Myc-Cul1 is coprecipitated with GST-Fbx8 in the presence of FLAG-Skp1 (Figure 1A)." SIGNOR-271764 serotonin smallmolecule CHEBI:28790 ChEBI HTR1F protein P30939 UNIPROT "up-regulates activity" "chemical activation" 9606 BTO:0000938 25601315 t miannu "Serotonin or 5-hydroxytryptamine (5-HT) remains one of the most widely studied chemical messengers. Serotonin produces a myriad of physiological effects in humans, mediated through 14 distinct receptor subtypes, of which 13 are G protein coupled receptors (GPCRs), and one ligand-gated cation channel" SIGNOR-264297 "Phenylalanyl-tRNA synthetase" complex SIGNOR-C473 SIGNOR AMP smallmolecule CHEBI:456215 ChEBI "up-regulates quantity" "chemical modification" 9606 20223217 t miannu "Here we report crystal structure of hcPheRS complexed with phenylalanine at 3.3 Å resolution. An essential feature of hcPheRS is a novel fold formed by the N-terminal part of the α subunit, whose functional role in tRNAPhe binding and complex formation was studied by truncation mutagenesis. Phenylalanine activation and formation of Phe-tRNAPhe catalyzed by modified hcPheRS have been compared with those of the wild-type enzyme. HcPheRS is a heterotetramer built of two αβ heterodimers." SIGNOR-270441 SAR1A protein Q9NR31 UNIPROT SEC23B protein Q15437 UNIPROT "up-regulates quantity" binding SIGNOR-C370 30605680 t lperfetto "Biogenesis of COPII vesicles is initiated by the activation of the small guanosine triphosphate (GTP)-binding protein secretion-associated Ras-related protein 1 (Sar1) at specialized subdomains of the ER, called ER exit sites (ERES) or transitional ER (tER). Membrane-bound Sar1 then recruits the inner COPII coat subcomplex, the Sec23/24 heterodimer." SIGNOR-265298 NSD1 protein Q96L73 UNIPROT RELA protein Q04206 UNIPROT up-regulates methylation Lys218 EIFLLCDkVQKEDIE 9606 SIGNOR-C13 20080798 t miannu "Fbxl11 and nsd1 have opposite effects on nf-kb; both bind to p65 subunit after activation of nf-kb. / nsd1 activates nf-kb and reverses the inhibitory effect of fbxl11 / these data confirm that fbxl11 and nsd1 constitute an enzyme pair that methylates and demethylates p65 on k218 and 221 in response to cytokine stimulation." SIGNOR-163454 Ub:E2 complex SIGNOR-C497 SIGNOR BIRC7 protein Q96CA5 UNIPROT "up-regulates activity" ubiquitination 9606 34199813 t miannu "The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t" SIGNOR-271113 SYK protein P43405 UNIPROT GCSAM protein Q8N6F7 UNIPROT "up-regulates activity" phosphorylation Tyr107 GNSAEEYyENVPCKA -1 31362927 t miannu "Herein, we demonstrate phosphorylation of HGAL by Syk and Lyn kinases at tyrosines Y80, Y86, Y106Y107, Y128, and Y148.  Y148 (in black) was already phosphorylated before the addition of kinases. We demonstrate that Grb2 facilitates HGAL and Syk binding following BCR stimulation but does not affect the HGAL-mediated increase in Syk kinase activity. Previous studies showed that Grb2 inhibits BCR signaling by decreasing the activation of Syk by Lyn.11 Thus, while HGAL and Grb2 oppositely affect Syk kinase activity, this is not due to direct Grb2 effects on HGAL-mediated Syk kinase activation." SIGNOR-273571 AMPK complex SIGNOR-C15 SIGNOR MAPT protein P10636-5 UNIPROT "down-regulates activity" phosphorylation Thr231 KKVAVVRtPPKSPSS -1 21204788 t miannu "AMPK phosphorylation inhibits tau binding of microtubules. In order to study further the phosphorylation of tau by AMPK, we compared phosphorylation of tau by MARK4 or AMPK using a panel of phospho-tau antibodies (Figure 2A). Five phosphorylation sites common to both kinases were identified (Thr231, Ser262, Ser356, Ser396 and Ser422). In addition, AMPK, but not MARK4, was capable of phosphorylating Ser214 (Figure 2A)." SIGNOR-273927 "D-glyceraldehyde 3-phosphate(2-)" smallmolecule CHEBI:59776 ChEBI "β-D-fructose 6-phosphate" smallmolecule CHEBI:57634 ChEBI "up-regulates quantity" "precursor of" 9606 19401148 t miannu "Transaldolase (TAL, sedoheptulose 7-phosphate: d-glyceraldehyde 3-phosphate dihydroxyacetone transferase; EC number 2.2.1.2) is a cofactor-less enzyme of the pentose phosphate pathway (PPP) (Fig. 1A and B). It catalyzes the reversible transfer of a three carbon unit (“dihydroxyacetone”) between various sugar phosphates (from 3 to 8 carbon atoms in length). Physiological donor compounds are ketose sugar phosphates as fructose 6-phosphate or sedoheptulose 7-phosphate. Acceptor compounds are aldose sugar phosphates as glyceraldehyde 3-phosphate and erythrose 4-phosphate." SIGNOR-268134 (6R)-5,10-methenyltetrahydrofolate smallmolecule CHEBI:57455 ChEBI 10-formyltetrahydrofolate(2-) smallmolecule CHEBI:57454 ChEBI "up-regulates quantity" "precursor of" 9606 18767138 t lperfetto "Methylenetetrahydrofolate dehydrogenase)methenyltetrahydrofolate cyclohydrolase)formyltetrahydrofolate synthetase (MTHFD1) is a trifunctional enzyme that interconverts tetrahydrofolate (THF) derivatives for nucleotide synthesis.|The Arg653Gln substitution is located in the synthetase domain, which catalyzes the magnesium adenosine triphosphate (MgATP)-dependent production of formylTHF from THF and formate" SIGNOR-268247 SLC12A7 protein Q9Y666 UNIPROT chloride smallmolecule CHEBI:17996 ChEBI "down-regulates quantity" relocalization 21613606 t lperfetto "Eukaryotic cells regulate their volume in the long term through the coordinated function of the Na+-coupled chloride (NKCC1/2 and NCC) and K+-coupled chloride (KCC1–4) cotransporters, which encompass two branches of the SLC12|The K+-Cl− cotransporters move chloride outside the cell, are inhibited by phosphorylation, and are activated by dephosphorylation. In contrast, the Na+-K+-2Cl− cotransporters introduce chloride into the cell, are inhibited by dephosphorylation, and are activated by phosphorylation gene family of solute transporters (12). " SIGNOR-264639 MAPK14 protein Q16539 UNIPROT MAPKAPK3 protein Q16644 UNIPROT "up-regulates activity" phosphorylation 10090 BTO:0000944 11157753 t lperfetto "These results, taken together, suggest the importance of the docking interaction in the efficient phosphorylation and activation of 3pk by p38." SIGNOR-235451 metyrapone chemical CHEBI:44241 ChEBI CYP11B1 protein P15538 UNIPROT "down-regulates activity" "chemical inhibition" -1 21129965 t Luana "In an effort to develop and evaluate new classes of compounds as CYP inhibitors, we based our investigations on the structure of the well-known CYP inhibitor Metyrapone 2, which has been used for the treatment of hypercortisolism and Cushing’ssyndrome for several decades." SIGNOR-257884 SYK protein P43405 UNIPROT LAT2 protein Q9GZY6 UNIPROT "up-regulates activity" phosphorylation Tyr233 EEDGEPDyVNGEVAA 10090 BTO:0001930 14722116 t miannu "Our results indicated that human LAB was primarily phosphorylated on three membrane-distal tyrosines, Tyr(136), Tyr(193), and Tyr(233). Mutation of these three tyrosines abolished Grb2 binding and LAB function. Our data suggested that these tyrosines are the most important tyrosines for LAB function.The dramatic reduction in phosphorylation of the LAB Y233F mutant suggested that Tyr233 is a primary target of the Syk family kinases." SIGNOR-273577 VRK2 protein Q86Y07 UNIPROT USP25 protein Q9UHP3 UNIPROT "down-regulates activity" phosphorylation Thr727 QKLRESEtSVTTAQA 9606 BTO:0000007 25755282 t miannu "Here, we report that USP25 is a novel TRiC interacting protein that is also phosphorylated by VRK2. USP25 catalyzed deubiquitination of the TRiC protein and stabilized the chaperonin, thereby reducing accumulation of misfolded polyglutamine protein aggregates. Notably, USP25 deubiquitinating activity was suppressed when VRK2 phosphorylated the Thr(680), Thr(727), and Ser(745) residues. " SIGNOR-273578 sunitinib chemical CHEBI:38940 ChEBI FLT1 protein P17948 UNIPROT down-regulates "chemical inhibition" 9606 BTO:0000776 20185585 t gcesareni "The vegfr/pdgfr inhibitor sunitinib (selleck) was used at 35 mg/kg in citrate-buffered water and administered daily by oral gavage for 7 days." SIGNOR-163938 VRK2 protein Q86Y07 UNIPROT USP25 protein Q9UHP3 UNIPROT "down-regulates activity" phosphorylation Ser745 PEYLEQPsRSDFSKH 9606 BTO:0000007 25755282 t miannu "Here, we report that USP25 is a novel TRiC interacting protein that is also phosphorylated by VRK2. USP25 catalyzed deubiquitination of the TRiC protein and stabilized the chaperonin, thereby reducing accumulation of misfolded polyglutamine protein aggregates. Notably, USP25 deubiquitinating activity was suppressed when VRK2 phosphorylated the Thr(680), Thr(727), and Ser(745) residues. " SIGNOR-273579 VRK2 protein Q86Y07 UNIPROT USP25 protein Q9UHP3 UNIPROT "down-regulates activity" phosphorylation Thr680 QPLVGIEtLPPDLRD 9606 BTO:0000007 25755282 t miannu "Here, we report that USP25 is a novel TRiC interacting protein that is also phosphorylated by VRK2. USP25 catalyzed deubiquitination of the TRiC protein and stabilized the chaperonin, thereby reducing accumulation of misfolded polyglutamine protein aggregates. Notably, USP25 deubiquitinating activity was suppressed when VRK2 phosphorylated the Thr(680), Thr(727), and Ser(745) residues. " SIGNOR-273580 BTRC protein Q9Y297 UNIPROT EZH2 protein Q15910 UNIPROT down-regulates ubiquitination 9606 BTO:0000785 24469040 t lperfetto "_-trcp ubiquitinates ezh2 and jak2-mediated phosphorylation on y641 directs _-trcp-mediated ezh2 degradation." SIGNOR-204481 AURKA protein O14965 UNIPROT RASSF1 protein Q9NS23 UNIPROT down-regulates phosphorylation Thr206 GTSVRRRtSFYLPKD 9606 17563743 t llicata "AuroraT-a appears to phosphorylate rassf1a at threonine202 and/or serine203 that reside within the known microtubule-binding domain of rassf1a. Substitutions of these residues with glutamic acid at both positions, mimicking constitutive phosphorylation of rassf1a, disrupt rassf1a interactions with microtubules and abolish its ability to induce m-phase cell cycle arrest." SIGNOR-155819 ZW10 protein O43264 UNIPROT "NRZ complex" complex SIGNOR-C358 SIGNOR "form complex" binding 25364732 t lperfetto "NRZ complex, which comprises NAG, RINT1, and ZW10, is also involved in Golgi-to-ER retrograde transport, but each component of the complex has diverse cellular functions including endosome-to-Golgi transport, cytokinesis, cell cycle checkpoint, autophagy, and mRNA decay." SIGNOR-265023 CDK5 protein Q00535 UNIPROT ERBB3 protein P21860 UNIPROT "up-regulates activity" phosphorylation Thr873 LLYSEAKtPIKWMAL 10116 BTO:0004102 12824184 t llicata "We demonstrated that Cdk5 phosphorylated Ser-1176 in the neuregulin receptor ErbB2 and phosphorylated Thr-871 and Ser-1120 in the ErbB3 receptor. We identified the Ser-1120 sequence RSRSPR in ErbB3 as a novel phosphorylation consensus sequence of Cdk5. Finally, we found that Cdk5 activity is involved in neuregulin-induced Akt activity and neuregulin-mediated neuronal survival. " SIGNOR-250664 CDK5 protein Q00535 UNIPROT CORO1A protein P31146 UNIPROT "up-regulates activity" phosphorylation Thr424 AAPEASGtPSSDAVS 9606 BTO:0001588 26823173 t lperfetto "We here show that phosphorylation of coronin 1 on Thr(418/424) by cyclin-dependent kinase (CDK) 5 activity was responsible for coronin 1-G_s association and the modulation of cAMP production. Together these results show an essential role for CDK5 activity in promoting the coronin 1-dependent cAMP/PKA pathway." SIGNOR-245187 ALDOC protein P09972 UNIPROT "glycerone phosphate(2-)" smallmolecule CHEBI:57642 ChEBI "up-regulates quantity" "chemical modification" 9606 16051738 t miannu "Aldolase catalyzes the reversible conversion of FBP to glyceraldehyde-3-phosphate and dihydroxyacetone phosphate (DHAP; Figure 1). Aldolase is a tetramer of identical subunits of 40 kDa each, and 3 distinct isoenzymes have been identified: aldolase A, B, and C." SIGNOR-266485 CDK1 protein P06493 UNIPROT ODF2 protein Q5BJF6 UNIPROT "up-regulates activity" phosphorylation Ser820 YSTFLTSsPIRSRSP 9606 19386263 t miannu "Phosphorylation of hCenexin1 at S796 is critical for the hCenexin1-Plk1 interaction.Here we show that a splice variant of hODF2 called hCenexin1, but not hODF2 itself, efficiently localizes to somatic centrosomes via a variant-specific C-terminal extension and recruits Plk1 through a Cdc2-dependent phospho-S796 motif within the extension. This interaction and Plk1 activity were important for proper recruitment of pericentrin and gamma-tubulin, and, ultimately, for formation of normal bipolar spindles." SIGNOR-273584 CD3 complex SIGNOR-C432 SIGNOR TCR complex SIGNOR-C153 SIGNOR "form complex" binding 9606 12507424 t miannu "The T cell receptor-CD3 complex (TCR-CD3) serves a critical role in the differentiation, survival, and function of T cells, and receptor triggering elicits a complex set of biological responses that serve to protect the organism from infectious agents. The receptor is composed of six different chains that form the TCR heterodimer responsible for ligand recognition, as well as the CD3Œ≥Œµ, CD3Œ¥Œµ, and Œ∂Œ∂ signaling modules.the TCRŒ±-CD3Œ¥Œµ and TCRŒ≤-CD3Œ≥Œµ interactions are similar since both require a lysine in the TM region of the respective TCR chain and both acidic TM residues in the relevant CD3 heterodimer. Nevertheless, formation of fully assembled Œ±Œ≤ TCR-CD3 complexes containing the Œ∂-chain strictly required both CD3Œ≥ and Œ¥" SIGNOR-269472 AHCYL1 protein O43865 UNIPROT SLC4A4 protein Q9Y6R1 UNIPROT "up-regulates activity" binding 9606 BTO:0000007 21317537 t miannu "IRBIT opposed the effects of WNKs and SPAK by recruiting PP1 to the complex to dephosphorylate CFTR and NBCe1-B, restoring their cell surface expression, in addition to stimulating their activities." SIGNOR-263135 AKT proteinfamily SIGNOR-PF24 SIGNOR MAP3K8 protein P41279 UNIPROT "up-regulates activity" phosphorylation Ser413 LERKRLLsRKELELP 9606 BTO:0000007 12138205 t "Akt-dependent phosphorylation of Cot occurs exclusively on serines 400 and 413. Akt to phosphorylate Cot at two sites in the carboxy-terminal domain, at least one of which may promote binding of substrates or coactivators to Cot, or alternatively may relieve binding of a negative regulator." SIGNOR-251481 INPP5D protein Q92835 UNIPROT TRAF6 protein Q9Y4K3 UNIPROT "down-regulates activity" binding 9606 BTO:0000007 24817116 t lperfetto "Of note, SHIP1 was associated with TRAF6 in co-transfected HEK293T cells (Fig. 6A). Moreover, SHIP1 overexpression suppressed TRAF6 autoubiquitination in a dose-dependent manner" SIGNOR-261429 TBXA2R protein P21731 UNIPROT GNAI1 protein P63096 UNIPROT "up-regulates activity" binding 9606 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-256744 "prostaglandin E2(1-)" smallmolecule CHEBI:606564 ChEBI PTGER4 protein P35408 UNIPROT "up-regulates activity" "chemical activation" 9606 BTO:0002524 31160049 t "Ligand-GPCR dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257572 ADP chemical CHEBI:16761 ChEBI P2RY13 protein Q9BPV8 UNIPROT "up-regulates activity" "chemical activation" 9606 BTO:0002524 31160049 t "Ligand-GPCR dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257561 FGR protein P09769 UNIPROT ACO2 protein Q99798 UNIPROT unknown phosphorylation Tyr544 FDPGQDTyQHPPKDS -1 17997986 t miannu "Here, we provide evidence that the flavoprotein of succinate dehydrogenase and aconitase are ""in vitro"" substrates of Fgr tyrosine kinase. Fgr phosphorylates flavoprotein of succinate dehydrogenase at Y535 and Y596 and aconitase at Y71, Y544 and Y665. Further experiments will be necessary to verify if Fgr is the tyrosine kinase responsible for the tyrosine phosphorylation of these proteins in vivo and to elucidate the role of these phosphorylations." SIGNOR-262869 UTS2R protein Q9UKP6 UNIPROT GNAI3 protein P08754 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257164 EFNA4 protein P52798 UNIPROT EPHA5 protein P54756 UNIPROT up-regulates binding 9606 9330863 t tpavlidou "Receptors of the epha group preferentially interact with glycosylphosphatidylinositol (gpi)-linked ligands (of the ephrin-a subclass, which comprises five ligands), while receptors of the ephb group preferentially interact with transmembrane ligands (of the ephrin-b subclass, which comprises three ligands) (table 1). In either case, binding of a ligand results in eph receptor autophosphorylation on tyrosine residues and activation of the kinase activity of the eph receptor" SIGNOR-52430 RET protein P07949 UNIPROT GFRA1 protein P56159 UNIPROT up-regulates binding 9606 10829012 t gcesareni "Gdnfr-alpha-ligand complex, together with the tyrosine kinase receptor (cret) forms a functional receptor that activates downstream signal transduction pathways" SIGNOR-77587 CDK2 protein P24941 UNIPROT SMAD3 protein P84022 UNIPROT down-regulates phosphorylation Thr8 MSSILPFtPPIVKRL 9606 19114991 t lpetrilli "In the nucleus cdk2/4-mediated phosphorylation of smad3 occurs mostly at thr8, thr179, and ser213. Cdk-dependent phosphorylation of smad3 inhibits its transcriptional activity" SIGNOR-182975 PTPN3 protein P26045 UNIPROT GHR protein P10912 UNIPROT "down-regulates activity" dephosphorylation Tyr534 NFLMDNAyFCEADAK 10029 12907755 t "PTPH1 only bound Tyr534, whereas PTP1B and TC-PTP bound multiple phosphopeptides. Earlier work suggests that Tyr332, Tyr487, Tyr534, Tyr566, and Tyr627 are all phosphorylated after GH stimulation (21). Apart from Tyr627, all of these also appear good PTP substrates" SIGNOR-248459 MAPKAPK2 protein P49137 UNIPROT PLK1 protein P53350 UNIPROT up-regulates phosphorylation Ser326 LTIPPRFsIAPSSLD 9606 18695677 t llicata "Here, we have identified mk2 as a major plk1 kinase toward ser326, whose phosphorylation is critical to recruit ?-Tubulin to centrosomes and subsequent establishment of functional bipolar spindles. To our knowledge, this is the first direct evidence to demonstrate that the essential function of plk1 in centrosome maturation and bipolar spindle formation is controlled by its upstream kinase." SIGNOR-179968 YAP1 protein P46937 UNIPROT TP73 protein O15350 UNIPROT up-regulates binding 9606 21808241 t "The WW domain of YAP binds to PPXY-containing p73 family members." gcesareni "Yap also interacts with p73, a p53 family pro-apoptotic transcription factor, to induce expression of genes such as bax, puma and pml." SIGNOR-175934 MAVS protein Q7Z434 UNIPROT TBK1 protein Q9UHD2 UNIPROT "up-regulates activity" binding 9606 25636800 t miannu "After ligand binding, cGAS and RIG-I signal through respective adaptor proteins STING and MAVS to recruit the kinases IKK and TBK1, which then activate the transcription factors NF-κB and interferon regulatory factor 3 (IRF3), respectively." SIGNOR-260145 ULK1 protein O75385 UNIPROT ATG9A protein Q7Z3C6 UNIPROT "up-regulates activity" phosphorylation Ser14 EYQRLEAsYSDSPPG 9606 27934868 t miannu "Src phosphorylates mATG9 at Tyr8 to maintain its endocytic and constitutive trafficking in unstressed conditions. In response to starvation, phosphorylation of mATG9 at Tyr8 by Src and at Ser14 by ULK1 functionally cooperate to promote interactions between mATG9 and the AP1/2 complex, leading to redistribution of mATG9 from the plasma membrane and juxta-nuclear region to the peripheral pool for autophagy initiation." SIGNOR-266369 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR CEBPA protein P49715 UNIPROT up-regulates "transcriptional regulation" 10090 BTO:0000011 12270934 f lperfetto "We demonstrate that exposure of post-confluent 3T3-L1 preadipocytes to insulin, isobutylmethylxanthine (MIX), dexamethasone (DEX), and fetal bovine serum induces a rapid but transient activation of MEK1 as indicated by extensive phosphorylation of ERK1 and ERK2 during the initial 2 h of adipogenesis. We further show that activation of MEK1 significantly enhances the transactivation of the C/EBPalpha minimal promoter during the early phase of the differentiation process." SIGNOR-235322 IL15RA protein Q13261 UNIPROT TIMP3 protein P35625 UNIPROT up-regulates 9606 30029643 f areggio "Since recent study demonstrated desert Hedgehog (DHH) signaling can repressed FAP-derived adipocyte differentiation through Timp3 [30], we tested the mRNA expression of DHH and Timp3 in injured muscle with injection of IL-15. As expected, mRNA levels of DHH and Timp3 were both upregulated (Fig. 2f)." SIGNOR-256232 FYN protein P06241 UNIPROT GRIN2A protein Q12879 UNIPROT up-regulates phosphorylation Tyr1325 RLLEGNFyGSLFSVP 9606 19834457 t gcesareni "The nr2a subunit of the nmda receptor is tyrosine-phosphorylated, with tyr 1325 as its one of the major phosphorylation site. Tyr 1325 phosphorylation site is required for src-induced potentiation of the nmda receptor channel in the striatum. Tyr 1325 was most prominently phosphorylated by fyn in vitro." SIGNOR-188527 PDK1 protein Q15118 UNIPROT PDH complex SIGNOR-C402 SIGNOR "down-regulates activity" phosphorylation 9606 BTO:0003291 16517405 t miannu "PDK1 is a direct HIF-1 target gene. We found that the gene encoding pyruvate dehydrogenase kinase 1 (PDK1) is a direct target of HIF-1. PDK1 phosphorylates the pyruvate dehydrogenase (PDH) E1α subunit and inactivates the PDH enzyme complex that converts pyruvate to acetyl-coenzyme A, thereby inhibiting pyruvate metabolism via the tricarboxylic acid (TCA) cycle" SIGNOR-267445 MAPK10 protein P53779 UNIPROT BCL2L11 protein O43521 UNIPROT "up-regulates activity" phosphorylation Ser59 GDSCPHGsPQGPLAP 10090 12818176 t miannu "JNKs specifically phosphorylate BIMEL at Ser55, 65, and/or 73. several observations demonstrate that the phosphorylation of BIMEL is a physiologically important mechanism for enhancing its proapoptotic activity." SIGNOR-250130 FBXL5 protein Q9UKA1 UNIPROT DCTN1 protein Q14203 UNIPROT "down-regulates quantity by destabilization" binding 9606 BTO:0000567 17532294 t miannu "FBXL5 binds to p150(Glued)in vitro and in vivo. FBXL5 and p150(Glued) co-localize primarily in the cytoplasm with peri-nuclear enrichment in HeLa cells. Overexpression of FBXL5 promotes poly-ubiquitination of p150(Glued) and protein turnover of p150(Glued). Our findings provide a potential mechanism by which p150(Glued) protein function is regulated by SCFs." SIGNOR-271652 PTPN5 protein P54829 UNIPROT MAPK14 protein Q16539 UNIPROT up-regulates binding 9606 BTO:0000938 23932588 t "A study conducted by Zhang et al. showed that STEP is significantly less efficient than PTPSL and HePTP at dephosphorylating p38a." gcesareni "First [] step prevents upstream activating kinases from promiscuously binding and activating p38a. Second, by blocking access to the mapk insert pocket, through the stepcat interaction, step can prevent the binding of allosteric signaling molecules that induce autoactivation of p38a." SIGNOR-194829 androst-4-ene-3,17-dione smallmolecule CHEBI:16422 ChEBI estrone smallmolecule CHEBI:17263 ChEBI "up-regulates quantity" "precursor of" 9606 BTO:0000975 27702664 t lperfetto "The cytochrome P450 aromatase is involved in the last step of sex hormones biosynthesis by converting androgens into estrogens. |Human aromatase (CYP19A1) is a membrane-bound class II cytochrome P450 that converts androgens into estrogens [1], [2], [3], [4]. Specifically, the enzyme is involved sex hormones biosynthesis where it is responsible for the conversion of androstenedione, testosterone and 16alpha-hydroxytestosterone into estrone, estradiol and estriol, respectively" SIGNOR-268668 Gbeta proteinfamily SIGNOR-PF4 SIGNOR TSC2 protein P49815 UNIPROT "down-regulates activity" phosphorylation 10090 BTO:0000944 15851026 t "inferred from 70% family members" lperfetto "Here, we show that Erk may play a critical role in TSC progression through posttranslational inactivation of TSC2. Erk-dependent phosphorylation leads to TSC1-TSC2 dissociation and markedly impairs TSC2 ability to inhibit mTOR signaling, cell proliferation, and oncogenic transformation. |Serine to alanine substitution at S664 or double S664A/S540A mutagenesis resulted in a marked reduction in TSC2 phosphorylation to a similar extent. In contrast, S540A substitution only moderately impaired TSC2 phosphorylation (Figure 3D), corroborating the notion that in vivo S664 is the most relevant residue for Erk-mediated phosphorylation." SIGNOR-270108 PMS2 protein P54278 UNIPROT DNA_repair phenotype SIGNOR-PH57 SIGNOR "up-regulates activity" 10090 9500552 f "Germline mutations in the human MSH2, MLH1, PMS2 and PMS1 DNA mismatch repair (MMR) gene homologues appear to be responsible for most cases of hereditary non-polyposis colorectal cancer" SIGNOR-257596 HTR6 protein P50406 UNIPROT GNAL protein P38405 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-256944 AKT proteinfamily SIGNOR-PF24 SIGNOR mTORC1 complex SIGNOR-C3 SIGNOR "up-regulates activity" phosphorylation 10090 BTO:0000011 19593385 t lperfetto "In examining the requirements for different Akt-mediated phosphorylation sites on TSC2, we find that only TSC2 mutants lacking all five previously identified Akt sites fully block insulin-stimulated mTORC1 signaling in reconstituted Tsc2 null cells, and this mutant also inhibits adipogenesis" SIGNOR-252817 MAP3K20 protein Q9NYL2 UNIPROT MAP2K4 protein P45985 UNIPROT "up-regulates activity" phosphorylation 9606 11416147 t gcesareni "We show here that members of the mixed-lineage kinase (MLK) family (including MLK1, MLK2, MLK3, and dual leucine zipper kinase [DLK]) are expressed in neuronal cells and are likely to act between Rac1/Cdc42 and MKK4 and -7 in death signaling." SIGNOR-243348 PRKCG protein P05129 UNIPROT CD5 protein P06127 UNIPROT unknown phosphorylation Thr434 MSFHRNHtATVRSHA 9606 11123317 t lperfetto "Here, we present a selective mutagenesis analysis of two conserved threonine residues (T410 and T412) located at the membrane-proximal cytoplasmic region of CD5. These residues are contained within consensus phosphorylation motifs for protein kinase C and are shown here to be critical for in vivo protein kinase C-mediated phosphorylation of CD5. " SIGNOR-249072 PDGFRB protein P09619 UNIPROT PDGFRB protein P09619 UNIPROT "up-regulates activity" phosphorylation Tyr716 RPPSAELySNALPVG -1 8940081 t miannu "The SH2 domain of Grb7 can directly bind to the autophosphorylated PDGF beta-receptor in vitro. Grb7 association to the PDGF beta-receptor was dramatically reduced by replacement of tyrosine residues 716 or 775 with phenylalanine residues." SIGNOR-250256 PI4K2B protein Q8TCG2 UNIPROT ATP(4-) smallmolecule CHEBI:30616 ChEBI "down-regulates quantity" "chemical modification" 9606 10101268 t miannu "The enzymes PtdIns 4-kinase (PI4K, for nomenclature see [3]) and PtdIns(4)P 5-kinase (PI4P5K) catalyse the phosphorylation of PtdIns at the D4 and consecutively at the D5 position." SIGNOR-269100 BRD2 protein P25440 UNIPROT ZMYND8 protein Q9ULU4 UNIPROT "up-regulates activity" relocalization 9606 BTO:0000007 29018219 t lperfetto "ZMYND8 and BRD2 therefore work together to protect H4Ac domains from HDAC activity.|Further, when BRD2 was depleted, ZMYND8 accumulation was lost (Fig. 2e), indicating that either BRD2, or the underlying H4Ac, is required for ZMYND8 loading." SIGNOR-262036 CDK1 protein P06493 UNIPROT DNMT1 protein P26358 UNIPROT up-regulates phosphorylation Ser154 AKPEPSPsPRITRKS 9606 21565170 t gcesareni "We report that cyclin-dependent kinases (cdks) 1, 2 and 5 can phosphorylate ser154 of human dnmt1 in vitro. Further evidence of phosphorylation of endogenous dnmt1 at position 154 by cdks is also found in 293 cells treated with roscovitine, a specific inhibitor of cdk1, 2 and 5" SIGNOR-173677 CDK1 protein P06493 UNIPROT NDE1 protein Q9NXR1 UNIPROT up-regulates phosphorylation 9606 16682949 t gcesareni "We found that nde1 is subjected to phosphorylation in vivo. In particular, we identified six putative cdc2 phosphorylation sites in nde1 and found that alteration of these sites diminishes phosphorylation by cdc2 in vitro and affects the stability of su48-nde1 interactions and the centrosomal localization of nde1." SIGNOR-146734 PRKAA2 protein P54646 UNIPROT CRTC2 protein Q53ET0 UNIPROT down-regulates phosphorylation Ser171 SALNRTSsDSALHTS 9606 SIGNOR-C15 16308421 t gcesareni "Phosphorylation on the ser171 residue of crtc2 by ampk and ampk-related kinases, including the salt-inducible kinases (siks), is critical for determining the activity, cellular localization, and degradation of crtc2" SIGNOR-142211 MAPK1 protein P28482 UNIPROT HIF1A protein Q16665 UNIPROT up-regulates phosphorylation Ser641 DIKILIAsPSPTHIH 9606 BTO:0000567 18519666 t lperfetto "We show that at least two different nuclear protein kinases, one of them identified as p42/p44 mapk, can modify hif-1_. Analysis of in vitro phosphorylated hif-1_ by mass spectroscopy revealed residues ser-641 and ser-643 as possible mapk phosphorylation sites these data suggest that phosphorylation of ser-641/643 by mapk promotes the nuclear accumulation and transcriptional activity of hif-1_" SIGNOR-178723 MYOD1 protein P15172 UNIPROT CDKN1A protein P38936 UNIPROT up-regulates "transcriptional regulation" 9606 25211658 t "P21 is regulated by MyoD and myogenin in normal muscle cells and the inactivation of these factors in RMS cells contributes to the silencing of p21 in RMS cells" SIGNOR-251574 palmitoyl-CoA smallmolecule CHEBI:15525 ChEBI 3-hydroxyoctadecanoyl-CoA smallmolecule CHEBI:50583 ChEBI "up-regulates quantity" "precursor of" 9606 31616255 t miannu "The ELOVL family of enzymes in mammals is comprised of seven members that all reside in the endoplasmic reticulum (ER) and are thought to form a multimeric complex. Together, the ELOVL family is responsible for the elongation of saturated and unsaturated fatty acids.Fatty acid elongation occurs by cycling through a four step process (condensation, reduction, dehydration, and reduction), with two carbon atoms added through each cycle." SIGNOR-267882 EGF protein P01133 UNIPROT HBA1 protein P69905 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 9168989 f Regulation miannu "We describe the roles of Stat5 and of these tyrosine residues in the EPOR in the erythroid differentiation of murine hematopoietic cell line SKT6 which produces hemoglobin in response to EPO. Chimeric receptors carrying the extracellular domain of the EGF receptor and the intracellular domain of the EPOR were introduced into SKT6 cells. Like EPO, EGF equally activated Stat5 and induced hemoglobin." SIGNOR-251785 TBCK protein Q8TEA7 UNIPROT mTORC1 complex SIGNOR-C3 SIGNOR "up-regulates activity" 9606 BTO:0000142 33240423 f miannu "TBCK included two types of alternatively spliced isoforms (long TBCK and short TBCK). Although there is a long way to go to fully understand the function of TBCK, recent research indicates that TBCK plays an important role in brain development. BCK deficiency would disturb activation of the mTOR complex 1 (mTORC1), thus, affecting the autophagy process and further leading to autophagosomal-lysosomal dysfunction" SIGNOR-266699 CDK4 protein P11802 UNIPROT RB1 protein P06400 UNIPROT down-regulates phosphorylation Ser249 AVIPINGsPRTPRRG 9606 15809340 t gcesareni "Phosphorylated by cdk6 and cdk4, and subsequently by cdk2 at ser-567 in g1, thereby releasing e2f1 which is then able to activate cell growth. Here we show that although these cdks phosphorylate multiple residues in prb, they do so with different residue selectivities in vitro;thr821 and thr826 are preferentially phosphorylated by cdk6 and cdk4, respectively." SIGNOR-135181 serotonin smallmolecule CHEBI:28790 ChEBI HTR1D protein P28221 UNIPROT "up-regulates activity" "chemical activation" 9606 BTO:0000938 25601315 t miannu "Serotonin or 5-hydroxytryptamine (5-HT) remains one of the most widely studied chemical messengers. Serotonin produces a myriad of physiological effects in humans, mediated through 14 distinct receptor subtypes, of which 13 are G protein coupled receptors (GPCRs), and one ligand-gated cation channel" SIGNOR-264287 3,3',5'-triiodothyronine smallmolecule CHEBI:28774 ChEBI THR proteinfamily SIGNOR-PF84 SIGNOR "up-regulates activity" binding 9606 29407449 t scontino "T3 binds its receptor (TR) in the nucleus. TRs are ligand-dependent transcription factors belonging to the type II group of NHRs. TRs are encoded by two genes, Thra and Thrb." SIGNOR-267276 DUSP26 protein Q9BV47 UNIPROT TP53 protein P04637 UNIPROT down-regulates dephosphorylation Ser37 NVLSPLPsQAMDDLM 9606 20562916 t miannu "We found that dusp26 promotes the resistance of human neuroblastoma to doxorubicin-induced apoptosis by acting as a p53 phosphatase to downregulate p53 tumor suppressor function in neuroblastoma cells. / we found that dusp26 binds to p53 and dephosphorylates p53 at ser20 and ser37." SIGNOR-166262 SSU72 protein Q9NP77 UNIPROT POLR2A protein P24928 UNIPROT "up-regulates activity" dephosphorylation Ser1675 SPSYSPTsPSYSPTS -1 15125841 t "Phosphorylation of serine-2 (S2) and serine-5 (S5) of the C-terminal domain (CTD) of RNA polymerase II (RNAP II) is a dynamic process that regulates the transcription cycle and coordinates recruitment of RNA processing factors. The Fcp1 CTD phosphatase catalyzes dephosphorylation of S2-P.| Depletion of Ssu72 impairs transcription in vitro" SIGNOR-248809 VEGFC protein P49767 UNIPROT Angiogenesis phenotype SIGNOR-PH46 SIGNOR up-regulates 17326328 f lperfetto "More than a dozen different proteins have been identified as angiogenic activators, including vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), angiogenin, transforming growth factor (TGF)-α, TGF-β, tumor necrosis factor (TNF)-α, platelet-derived endothelial growth factor, granulocyte colony-stimulating factor, placental growth factor, interleukin-8, hepatocyte growth factor, and epidermal growth factor" SIGNOR-252277 UBR4 protein Q5T4S7 UNIPROT TRPV5 protein Q9NQA5 UNIPROT "down-regulates quantity by destabilization" ubiquitination 10090 BTO:0003913 23747339 t miannu "Cytomix induced interaction between TRPV5 and UBR4 (Ubiquitin recoginition 4), an E3 ubiquitin ligase; knockdown of UBR4 with small interfering RNAs prevented cytomix-induced degradation of TRPV5.  UBR4/p600 ubiquitin ligase is responsible for TRPV5 ubiquitination and proteasomal degradation in response to cytomix" SIGNOR-272117 NAT8L protein Q8N9F0 UNIPROT "coenzyme A(4-)" smallmolecule CHEBI:57287 ChEBI "up-regulates quantity" "chemical modification" 9606 19524112 t miannu "The biosynthetic enzyme, aspartate-N-acetyltransferase (Asp-NAT; EC 2.3.1.17) is a CNS specific enzyme that catalyzes the transfer of acetate from acetyl-CoA to L-aspartate forming NAA." SIGNOR-267524 PRKCG protein P05129 UNIPROT VTN protein P04004 UNIPROT "up-regulates quantity by stabilization" phosphorylation Ser381 RNRKGYRsQRGHSRG -1 9030777 t lperfetto "Phosphorylation of vitronectin on Ser362 by protein kinase C attenuates its cleavage by plasmin." SIGNOR-248964 "mono(2-ethylhexyl) phthalate" chemical CHEBI:17243 ChEBI NR1I2 protein O75469 UNIPROT "up-regulates activity" "chemical activation" 9534 BTO:0001538 27551952 t miannu "MEHP and MiNP exhibit potent activation of hCAR2 and hPXR with higher affinities for these receptors than for the hPPARs. The rank order potency for MEHP and MiNP was hCAR2 > hPXR > hPPARs." SIGNOR-268777 SF3b complex SIGNOR-C442 SIGNOR Spliceosomal_snRNP_assembly phenotype SIGNOR-PH79 SIGNOR up-regulates 9606 32140746 f lperfetto "The SF3b complex is an intrinsic component of the functional U2 small nuclear ribonucleoprotein (snRNP). As U2 snRNP enters nuclear pre-mRNA splicing, SF3b plays key roles in recognizing the branch point sequence (BPS) and facilitating spliceosome assembly and activation." SIGNOR-268414 MAP3K14 protein Q99558 UNIPROT NFKB2 protein Q00653 UNIPROT "up-regulates activity" phosphorylation Ser870 KEDSAYGsQSVEQEA 9606 BTO:0000007 11239468 t lperfetto "NIK-induced p100 processing requires phosphorylation of p100 at serines 866 and 870" SIGNOR-105557 FGF12 protein P61328 UNIPROT SCN8A protein Q9UQD0 UNIPROT "down-regulates activity" binding 9606 BTO:0000938 20679355 t miannu "Sodium channel fast inactivation is modulated by alpha subunit interaction with a family of cytoplasmic proteins termed fibroblast growth factor homologous factors (FHFs). In this paper, we report that all A-type FHFs exert rapid onset long-term inactivation on Nav1.6 and other sodium channels." SIGNOR-253412 MSL2 protein Q9HCI7 UNIPROT TP53 protein P04637 UNIPROT "down-regulates activity" ubiquitination 9606 BTO:0002552 19033443 t miannu "Here we describe MSL2, a novel E3 ligase for p53 that promotes ubiquitin-dependent cytoplasmic p53 localization. Unlike Mdm2 or most other p53 E3 ligases, MSL2-mediated p53 ubiquitination does not affect the stability of p53. Moreover, the MSL2-mediated effect on p53 is Mdm2-independent. Thus, our study identifies an important ubiquitin-ligase for modulating p53 subcellular localization. MSL2 ubiquitination of p53 is required for p53 cytoplasmic localization." SIGNOR-271774 PRKCA protein P17252 UNIPROT LRP1 protein Q07954 UNIPROT up-regulates phosphorylation Ser4523 GSRHSLAsTDEKREL 9606 15272003 t lperfetto "Serine and threonine phosphorylation of the low density lipoprotein receptor-related protein by protein kinase calpha regulates endocytosis and association with adaptor moleculesthese results indicate that elimination of serine and threonine phosphorylation sites in the lrp cytoplasmic domain reduces the extent of tyr63 phosphorylation and leads to impaired association with the adaptor protein shc." SIGNOR-127211 KCNJ8 protein Q15842 UNIPROT NLRP3 protein Q96P20 UNIPROT "down-regulates activity" binding 9606 31387986 t lperfetto "We further show that Kir6.1 physically associates with NLRP3 and thus inhibits the interactions between the NLRP3 inflammasome subunits. Our results reveal a previously unrecognized function of Kir6.1 as a negative regulator of the NLRP3 inflammasome" SIGNOR-262034 atenolol chemical CHEBI:2904 ChEBI ADRB2 protein P07550 UNIPROT "down-regulates activity" "chemical inhibition" 10030 BTO:0000246 10079020 t Luana "In our CHO cells transfected with the human β1- and β2-adrenoceptors, the binding affinities of atenolol, metoprolol, betaxolol and practolol correlate with previously published β1- (P=0.03) and β2-adrenoceptor (P=0.03) binding affinities in human lung tissue" SIGNOR-258335 THBS2 protein P35442 UNIPROT CD47 protein Q08722 UNIPROT up-regulates binding 9606 8550562 t gcesareni "We report here that iap is a receptor for the ts1 cbd and its vvm-containing peptides and that a function-blocking anti-iap mab inhibits the chemotactic response to ts1 and its cbd peptides in endothelial cells." SIGNOR-39749 MAPK7 protein Q13164 UNIPROT MEF2A protein Q02078 UNIPROT up-regulates phosphorylation Thr312 QATQPLAtPVVSVTT 9606 BTO:0000567 10849446 t lperfetto "We have previously shown that bmk1 regulates c-jun gene expression through direct phosphorylation and activation of transcription factor mef2c.Here, we demonstrate that, in addition to mef2c, bmk1 phosphorylates and activates mef2a and mef2d but not mef2b.The sites phosphorylated by activated bmk1 were mapped to ser-355, thr-312, and thr-319 of mef2a and ser-179 of mef2d both in vitro and in vivo." SIGNOR-236583 ITK protein Q08881 UNIPROT CD28 protein P10747 UNIPROT "up-regulates activity" phosphorylation Tyr206 PGPTRKHyQPYAPPR 8992971 t "EMT can phosphorylate all four tyrosines of the CD28 tail. in vivo, tyrosines other than tyrosine 173 become phosphorylated following CD28 stimulation, this finding suggests that, like LCK, one function of EMT during CD28 signaling is phosphorylation of the receptor." SIGNOR-251334 Ub:E2 complex SIGNOR-C497 SIGNOR MARCHF11 protein A6NNE9 UNIPROT "up-regulates activity" ubiquitination 9606 34199813 t miannu "The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t" SIGNOR-271244 IRF2BP2 protein Q7Z5L9 UNIPROT IRF2 protein P14316 UNIPROT "up-regulates activity" binding 9606 BTO:0000567 12799427 t miannu "We have identified two novel proteins that interact specifically with the C-terminal repression domain of Interferon Regulatory Factor-2 (IRF-2). These proteins, which we term IRF-2 binding proteins 1 and 2 (IRF-2BP1 and IRF-2BP2, the latter having two splicing isoforms, A and B), are nuclear proteins, and have the properties of IRF-2-dependent transcriptional co-repressors that can inhibit both enhancer-activated and basal transcription in a manner that is not dependent upon histone deacetylation." SIGNOR-224073 Ub:E2 complex SIGNOR-C497 SIGNOR "RING E3 ligase" proteinfamily SIGNOR-PF106 SIGNOR "up-regulates activity" ubiquitination 9606 34199813 t miannu "The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t" SIGNOR-270944 PLK1 protein P53350 UNIPROT BRCA2 protein P51587 UNIPROT "down-regulates activity" phosphorylation Thr203 SSLATPPtLSSTVLI 9606 12815053 t lperfetto "M phase-specific phosphorylation of brca2 by polo-like kinase 1 correlates with the dissociation of the brca2-p/caf complex.Plk1 interacts with brca2 in vivo, and mutation of ser193, ser205/206, and thr203/207 to ala in br-n1 abolished plk1 phosphorylation, suggesting that brca2 is the substrate of plk1" SIGNOR-102498 PDPK1 protein O15530 UNIPROT AHCYL1 protein O43865 UNIPROT "down-regulates activity" phosphorylation Ser68 RSLSRSIsQSSTDSY 9534 17635105 t lperfetto "Residue 68 resides in a consensus phosphorylation site for PKD (Figure 1A) [22,23]. Interestingly, phosphorylation of Ser68 could allow for subsequent phosphorylation of Ser71, Ser74, Ser77 and Ser80 by CK1, for which the consensus phosphorylation site is pS/T-X-X-S/T| We found that phosphorylation of Ser71 and Ser74 were sufficient to enable inhibition of IP3 binding to the IP3R" SIGNOR-249174 CSNK2A1 protein P68400 UNIPROT PPP1R2 protein P41236 UNIPROT up-regulates phosphorylation Ser121 YRIQEQEsSGEEDSD 9606 9405437 t gcesareni "Recombinant inh2 was phosphorylated by kinases in cytosols prepared from g1 and s phase cells. The amount of inh2 kinase attributed to casein kinase 2, based on inhibition by heparin, increased 2.6-fold from g1 to s phase" SIGNOR-53857 RAB6B protein Q9NRW1 UNIPROT Neurite_outgrowth phenotype SIGNOR-PH134 SIGNOR up-regulates 10116 25492866 f miannu "Cohen syndrome-associated protein COH1 physically and functionally interacts with the small GTPase RAB6 at the Golgi complex and directs neurite outgrowth. COH1 and RAB6 regulate neurite outgrowth in primary neurons" SIGNOR-266874 MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR GSK3B protein P49841 UNIPROT "up-regulates activity" phosphorylation Tyr216 RGEPNVSyICSRYYR 9606 BTO:0001253 15020233 t lperfetto "In vitro kinase assay was carried out using a recombinant human active mek1 and we found that gsk-3beta was phosphorylated on tyr(216) by this kinase in a dose- and time-dependent manner. Further, the pretreatment of fibroblasts with u0126 inhibited serum-induced nuclear translocation of gsk-3beta. These results suggested that mek1/2 induces tyrosine phosphorylation of gsk-3beta and this cellular event might induce nuclear translocation of gsk-3beta." SIGNOR-244780 SNRPA protein P09012 UNIPROT "U1 snRNP complex" complex SIGNOR-C480 SIGNOR "form complex" binding 9606 30765414 t lperfetto "The major spliceosomal building blocks are the U1, U2, U4/U6, and U5 small nuclear ribonucleoproteins (snRNPs). Each consists of a small nuclear RNA (snRNA) (or two, in the case of U4/U6), seven Sm proteins that form a ring (or seven Lsm proteins in the case of U6), and a variable number of snRNP-specific proteins (Fig. 1F) (Will and Lührmann 2011). Under splicing conditions, the U4/U6 and U5 snRNPs form a 25S U4/U6.U5 tri-snRNP, in which the U4 and U6 snRNAs are base-paired, forming a three-way junction." SIGNOR-270678 HDAC3 protein O15379 UNIPROT SMAD7 protein O15105 UNIPROT up-regulates binding 9606 23213415 t gcesareni "We show here that smad7 can form a complex with endogenous histone deacetylase proteins hdac-1 and hdac-3 in nih 3t3 mouse fibroblast cells" SIGNOR-199967 SRC protein P12931 UNIPROT EGFR protein P00533 UNIPROT up-regulates phosphorylation Tyr1125 APSRDPHyQDPHSTA 9606 8845374 t lperfetto "The c-terminal autophosphorylation domain of egfr was extensively phosphorylated by c-src./These studies revealed that y1086 was phosphorylated to a significantly higher extent by c-src than by egfr. Additionally, y1101 was identified as a unique c-src phosphorylation site" SIGNOR-44247 GSK3B protein P49841 UNIPROT MAP3K4 protein Q9Y6R4 UNIPROT down-regulates binding 9606 17726008 t gcesareni "Gsk3beta binding to mekk4 blocks mekk4 dimerization that is required for mekk4 activation, effectively inhibiting mekk4 stimulation of the jnk and p38 mapk pathways" SIGNOR-157541 CUL1 protein Q13616 UNIPROT SCF-SKP2 complex SIGNOR-C136 SIGNOR "form complex" binding 9606 15340381 t gcesareni "The F-box family of proteins €” which are the substrate-recognition components of the Skp1€“Cul1€“F-box-protein (SCF) ubiquitin ligase €” are important players in many mammalian functions." SIGNOR-243557 CDC20 protein Q12834 UNIPROT APC-c complex SIGNOR-C150 SIGNOR "up-regulates activity" binding 16896351 t lperfetto "In addition to E2 enzymes, APC/C activity is also strictly dependent on one of several co-activator proteins that associate with APC/C during specific periods of the cell cycle. The best studied of these are Cdc20 and Cdh1" SIGNOR-252014 CACNA1D protein Q01668 UNIPROT calcium(2+) smallmolecule CHEBI:29108 ChEBI "up-regulates quantity" relocalization 9606 30849329 t miannu "Voltage-gated calcium channels mediate the influx of calcium in response to membrane depolarization in excitable cells. In presynaptic nerve terminals, this calcium influx triggers transmitter release for synaptic transmission. Several neurological and cardiac disorders are caused by pathogenic variants in genes encoding α1-subunits of voltage-gated calcium channels, including CACNA1A (MIM: 601011) (familial hemiplegic migraine [MIM: 141500], episodic ataxia [MIM: 108500], and epilepsy [MIM: 617106]),3, 4, 5 CACNA1C (MIM: 114205) (Timothy syndrome [MIM: 601005]),6, 7 CACNA1D (MIM: 114206) (primary aldosteronism, neurodevelopmental disorders [MIM: 615474]),8, 9 and CACNA1G (MIM: 604065) (spinocerebellar ataxia [MIM: 616795])." SIGNOR-264326 EIF2AK1 protein Q9BQI3 UNIPROT EIF2S1 protein P05198 UNIPROT up-regulates phosphorylation Ser49 IEGMILLsELSRRRI 9606 10563826 t lperfetto "The wild-type and ser-48 mutant proteins became extensively phosphorylated by eif-2 kinases present in the reticulocyte lysate. These findings support the hypothesis that the serine 48 residue is required for high-affinity interaction between eif2 alpha(p) and eif2b." SIGNOR-72152 RNF144A protein P50876 UNIPROT PRKDC protein P78527 UNIPROT "down-regulates quantity by destabilization" polyubiquitination 9606 BTO:0000007 24979766 t miannu "We show that RNF144A induces ubiquitination of DNA-PKcs in vitro and in vivo and promotes its degradation." SIGNOR-272213 STAG3 protein Q9UJ98 UNIPROT "RAD21L Cohesin complex" complex SIGNOR-C355 SIGNOR "form complex" binding 10090 BTO:0000534 21242291 t miannu "RAD21L associates with SMC3, STAG3, and either SMC1α or SMC1β. Our results suggest that cohesin complexes containing RAD21L may be involved in synapsis initiation and crossover recombination between homologous chromosomes. In mice, RAD21L is expressed exclusively in early meiosis: it apparently replaces RAD21 in premeiotic S phase, becomes detectable on the axial elements in leptotene, and stays on the axial/lateral elements until mid pachytene. RAD21L then disappears, and is replaced with RAD21." SIGNOR-264536 PRKCE protein Q02156 UNIPROT PRKD2 protein Q9BZL6 UNIPROT up-regulates phosphorylation Ser876 QGLAERIsVL 9606 12058027 t gcesareni "Furthermore, we show that pkd2 can be activated by classical and novel members of the protein kinase c (pkc) family such as pkc alpha, pkc epsilon, and pkc eta. These pkcs are activated by gastrin in ags-b cells. Thus, pkd2 is likely to be a novel downstream target of specific pkcs upon the stimulation of ags-b cells with gastrin." SIGNOR-89419 HDLBP protein Q00341 UNIPROT CTCF protein P49711 UNIPROT "up-regulates activity" binding 9606 BTO:0000599 24725430 t miannu "Vigilin interacts with CCCTC-binding factor (CTCF) and is involved in CTCF-dependent regulation of the imprinted genes Igf2 and H19. vigilin is present at several known CTCF target sites, such as the promoter regions of c-myc and BRCA1, the locus control region of β-globin, and several regions within the Igf2/H19 locus. These results reveal the functional relevance of vigilin and CTCF, and show that the CTCF-vigilin complex contributes to regulation of Igf2/H19." SIGNOR-266693 CDK9 protein P50750 UNIPROT TP53 protein P04637 UNIPROT unknown phosphorylation Ser33 LPENNVLsPLPSQAM 9606 16552184 t llicata "Here, we report for the first time that cyclin dependent kinase 9, whose well-known substrate is rna polymerase ii, can also phosphorylate p53. Specifically, ser33 on the n-terminus and, ser315 and ser392 on the c-terminus of p53 were found to be phosphorylated. The precise biological role of this phosphorylation remains to be elucidated." SIGNOR-145315 CSNK2A1 protein P68400 UNIPROT DDHD1 protein Q8NEL9 UNIPROT "down-regulates activity" phosphorylation Ser92 SDENYDFsSAESGSS -1 11328814 t miannu "Here we incubated a recombinant preparation of the phospholipase in vitro with several enzymes including protein kinase CK2 (CK2), extracellular signal-regulated kinase 2 (ERK2), and protein phosphatase 2A (PP2A) to identify effects that might be of regulatory importance in vivo.Major findings were that 1) CK2 phosphorylated the phospholipase on serines 93, 105, and 716; 2) ERK2 phosphorylated the enzyme on serine 730; 3) there was cross-antagonism between the reactions that phosphorylated serines 716 and 730; 4) PP2A selectively hydrolyzed phosphate groups that were esterified to serines 716 and 730. The results of two independent experiments with each type of assay indicated that the incubation caused a 50% loss of phospholipase activity (TableV). These results differed from those of corresponding incubation experiments with PA-PLA1α plus ERK2 and MgATP (see “Experimental Procedures”), which provided no evidence for complex formation or phosphorylation-dependent loss of phospholipase activity" SIGNOR-262973 NR5A1 protein Q13285 UNIPROT CYP11B2 protein P19099 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0002588 21169726 f miannu "Inhibitory SF-1 was found to decrease the sensitivity of CYP11B2 and aldosterone to Ang II stimulation, whereas a down-regulation of SF-1 enhanced basal CYP11B2 expression and aldosterone production in H295R cells." SIGNOR-254867 "perfluorodecanoic acid" chemical CHEBI:35546 ChEBI AR protein P10275 UNIPROT "down-regulates activity" "chemical inhibition" -1 23764977 t miannu "Seven PFCs [perfluorohexane sulfonate (PFHxS), perfluorooctane sulfonate (PFOS), perfluorooctanoate (PFOA), perfluorononanoate (PFNA), perfluorodecanoate (PFDA), perfluoroundecanoate (PFUnA), and perfluorododecanoate (PFDoA)] were analyzed in vitro for their potential to affect estrogen receptor (ER) and androgen receptor (AR) transactivity as well as aromatase enzyme activity. The PFCs were assessed as single compounds and in an equimolar mixture. PFHxS, PFOS and PFOA significantly induced the ER transactivity, whereas PFHxS, PFOS, PFOA, PFNA and PFDA significantly antagonized the AR activity in a concentration-dependent manner. " SIGNOR-268770 DAMPS stimulus SIGNOR-ST18 SIGNOR NLRP1 protein Q9C000 UNIPROT "up-regulates activity" 16037825 f lperfetto "Among these sensors, members of the evolutionary conserved NLRs, together with AIM2 and pyrin, can assemble into a multimeric protein complex that is called the inflammasome (see poster).| An inflammasome assembles in response to a diverse range of pathogen-associated or danger-associated molecular patterns (PAMPs or DAMPs). The inflammasome platform leads to activation of caspase-1 through proximity-induced self-cleavage" SIGNOR-256421 "Complement C1 complex" complex SIGNOR-C309 SIGNOR C2 protein P06681 UNIPROT "up-regulates activity" cleavage Ser20 LYPGLADsAPSCPQN 31331124 t lperfetto "C1s subsequently activate serum proteins C4 and C2. C4 is cleaved to fragment C4a, which is an anaphylatoxin, and to fragment C4b, which is deposited on the adjacent surfaces. C2 is cleaved to a fragment C2b, and larger fragment C2a, which binds noncovalently to C4b on the target cell membrane. This forms the C4b2a complex" SIGNOR-263421 PRKAA1 protein Q13131 UNIPROT PRKAB1 protein Q9Y478 UNIPROT up-regulates phosphorylation Ser108 SKLPLTRsHNNFVAI 9606 SIGNOR-C15 SIGNOR-C15 17728241 t gcesareni "Mutation of serine 108 to alanine, an autophosphorylation site within the glycogen binding domain of the beta1 subunit, almost completely abolishes activation of ampk by a-769662 in cells and in vitro, while only partially reducing activation by amp" SIGNOR-157553 MAPK1 protein P28482 UNIPROT DOCK1 protein Q14185 UNIPROT unknown phosphorylation Thr1772 QQTPPPVtPRAKLSF 10090 BTO:0000944 22028470 t miannu "We have optimized a chemical genetic system using analog-sensitive ERK2, a form of ERK2 engineered to use an analog of adenosine 5'-triphosphate (ATP), to tag and isolate ERK2 substrates in vitro. This approach identified 80 proteins phosphorylated by ERK2, 13 of which are known ERK2 substrates. With this improved methodology, we detected 98 sites directly phosphorylated by ERK2 on 80 proteins from NIH 3T3-L1 fibroblasts. Thirteen of these proteins are known substrates and the rest represent previously unknown kinase/substrate interactions. (table1)" SIGNOR-262769 RNF216 protein Q9NWF9 UNIPROT TLR4 protein O00206 UNIPROT "down-regulates quantity by destabilization" ubiquitination 9606 15107846 t miannu "Here we describe how a RING finger protein, Triad3A, acts as an E3 ubiquitin-protein ligase and enhances ubiquitination and proteolytic degradation of some TLRs. Triad3A overexpression promoted substantial degradation of TLR4 and TLR9 with a concomitant decrease in signaling, but did not affect TLR2 expression or signaling. " SIGNOR-271504 PRKCD protein Q05655 UNIPROT LIMK2 protein P53671 UNIPROT down-regulates phosphorylation Ser283 EGTLRRRsLRRSNSI 9606 15923181 t "Translocation from Cytosol to Nucleus" flangone "Activation of pkc by phorbol ester treatment of endothelial cells stimulated limk2 phosphorylation at ser-283 and inhibited nuclear import of limk2" SIGNOR-137927 STK11 protein Q15831 UNIPROT MARK3 protein P27448 UNIPROT "up-regulates activity" phosphorylation Thr211 TVGGKLDtFCGSPPY 9606 BTO:0000568 12879020 t lperfetto "Regulation of the wnt signalling component par1a by the peutz-jeghers syndrome kinase lkb1. Lkb1 is a master kinase that activates 13 kinases of the ampk subfamily, including mark/par-1. Mark3 is activated by phosphorylation on thr-211." SIGNOR-104063 FFAR3 protein O14843 UNIPROT GNA12 protein Q03113 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-256957 CHUK protein O15111 UNIPROT NFKB1 protein P19838 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser923 DELRDSDsVCDSGVE 10090 BTO:0000944 SIGNOR-C14 SIGNOR-C13 11297557 t lperfetto "The i b kinase (ikk) complex rapidly phosphorylates nf- b1 p105 on serine 927 in the pest region romashkova et al. demonstrated that akt binds to and activates inhibitor of kappa b kinase-alfa (ikkalfa), which in turn phosphorylates and thereby promotes the degradation of the inhibitory cofactor of nf-kb, i-kb the scf-betatrcp complex is responsible for the ubiquitination of p100 and p105 following their phosphorylation by ikk." SIGNOR-235434 PTPRF protein P10586 UNIPROT LRRC4B protein Q9NT99 UNIPROT "up-regulates activity" binding 9606 19467332 t miannu "The NGL (netrin-G ligand; LRRC4) family of synaptic cell adhesion molecules belongs to the superfamily of leucine-rich repeat (LRR) proteins. The three known members of the NGL family, NGL-1, NGL-2, and NGL-3, are mainly localized to the postsynaptic side of excitatory synapses, and interact with the presynaptic ligands, netrin-G1, netrin-G2, and LAR, respectively." SIGNOR-264049 adenosine smallmolecule CHEBI:16335 ChEBI ADORA2B protein P29275 UNIPROT "up-regulates activity" "chemical activation" 9606 BTO:0002524 31160049 t "Ligand-GPCR dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257448 GGCX protein P38435 UNIPROT "vitamin K epoxide" smallmolecule CHEBI:28371 ChEBI "up-regulates activity" "chemical modification" 9606 31226734 t lperfetto "GGCX carboxylates the glutamic acid residues of vitamin K-dependent proteins (VKDP) to Gla using reduced vitamin K, while simultaneously oxidizing the reduced form of vitamin K to an epoxide form." SIGNOR-265917 "sorafenib tosylate" chemical CHEBI:50928 ChEBI KDR protein P35968 UNIPROT "down-regulates activity" "chemical inhibition" -1 16757355 t miannu "Further characterization of sorafenib revealed that this molecule was a multikinase inhibitor that targeted the vascular endothelial growth factor receptor family (VEGFR-2 and VEGFR-3) and platelet-derived growth factor receptor family (PDGFR-beta and Kit), which play key roles in tumor progression and angiogenesis. The in vitro and cellular profile of sorafenib is summarized in Table I." SIGNOR-259225 PSMC4 protein P43686 UNIPROT "26S Proteasome" complex SIGNOR-C307 SIGNOR "form complex" binding 9606 BTO:0000007 29636472 t lperfetto "Here, we report near-atomic resolution cryo-EM structures of the activated human proteasome|The proteasome is composed of a 28-subunit barrel-shaped core particle (CP) and two 19- subunit regulatory particles (RP)5–8 capped at both sides of the CP|Human proteasomes were purified through affinity chromatography on a large scale from a stable HEK293 cell line" SIGNOR-263371 GSK3B protein P49841 UNIPROT SPAG5 protein Q96R06 UNIPROT up-regulates phosphorylation Ser974 EESLAEMsIMTTELQ 9606 18055457 t lperfetto "Astrin acts as a substrate for gsk3beta and is phosphorylated at thr-111, thr-937 ((s/t)p motif) and ser-974/thr-978 ((s/t)xxx(s/t)-p motif;p is a phosphorylatable residue). Inhibition of gsk3beta impairs spindle and kinetochore accumulation of astrin and spindle formation at mitosis, suggesting that astrin association with the spindle microtubule and kinetochore may be dependent on phosphorylation by gsk3beta" SIGNOR-159574 PRKACA protein P17612 UNIPROT CFTR protein P13569 UNIPROT "up-regulates activity" phosphorylation Ser660 FSAERRNsILTETLH -1 1377674 t miannu "CFTR is phosphorylated directly by PKA and PKC in vivo. phosphorylation by PKA is necessary to allow ATP hydrolysis by CFTR and that ATP hydrolysis is necessary for channel opening. CF-2 was phosphorylated by PKA in vitro on serines 660,700, 737, 813 and most likely on both serines 768 and 795." SIGNOR-250349 FOXO1 protein Q12778 UNIPROT IDH1 protein O75874 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 25648147 t miannu "We identify FOXOs as transcriptional activators of IDH1. FOXOs promote IDH1 expression and thereby maintain the cytosolic levels of α-ketoglutarate and NADPH." SIGNOR-260090 KRAS protein P01116 UNIPROT NFE2L2 protein Q16236 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 29731393 f miannu "Oncogenic proteins that regulate proliferation, such as KRAS, BRAF, and MYC increase the transcription of NRF2" SIGNOR-267361 EIF2B1 protein Q14232 UNIPROT EIF2S2 protein P20042 UNIPROT "up-regulates activity" "guanine nucleotide exchange factor" 9606 15054402 t lperfetto "EIF2B converts the protein synthesis initiation factor 2 (eIF2) from an inactive GDP-bound form to an active eIF2-GTP complex owing to its guanine nucleotide exchange factor (GEF) activity." SIGNOR-269129 PTPRH protein Q9HD43 UNIPROT INSR protein P06213 UNIPROT down-regulates dephosphorylation Tyr999 YASSNPEyLSASDVF 9606 10734133 t gcesareni "These results, combined with secondary dephosphorylation tests, confirm and extend earlier findings that ptp-1b and t-cell ptp are physiological enzymes for the insulin receptor kinase" SIGNOR-76084 ACVR2A protein P27037 UNIPROT ACVR1B protein P36896 UNIPROT up-regulates phosphorylation 9606 BTO:0000007 12682303 t acerquone "In this complex, the actrii??/Iib kinase phosphorylates alk4 within a glycine- and serine-rich region called the gs domain, and this phosphorylation event activates the alk4 kinase" SIGNOR-99995 SH3BP4 protein Q9P0V3 UNIPROT TFRC protein P02786 UNIPROT down-regulates binding 9606 16325581 t miannu "Here, we report that ttp (sh3bp4), a sh3-containing protein, specifically regulates the internalization of the transferrin receptor (tfr). / overexpression of ttp specifically inhibits tfr internalization" SIGNOR-142840 taurine smallmolecule CHEBI:15891 ChEBI GLRA1 protein P23415 UNIPROT "up-regulates activity" "chemical activation" 9606 BTO:0000007 9009272 t miannu "For each mutant GlyR we examined the agonist efficacies of taurine and β-alanine relative to glycine, the concentration of each agonist required for half-maximal current activation (EC50) and, in mutant GlyRs where β-alanine and taurine exhibited partial or no agonist efficacy, the concentration required for half-maximal inhibition of glycine-gated currents (IC50).experiments described in this report were performed on human α1 homomeric GlyRs recombinantly expressed in mammalian HEK 293 cells. Taurine and β-alanine act as full agonists of human α1 GlyRs when expressed in this system." SIGNOR-258579 ILK protein Q13418 UNIPROT NACA protein E9PAV3 UNIPROT up-regulates phosphorylation Ser1906 PELEEQDsTQATTQQ 9606 15299025 t lperfetto "The inactivation of gsk3? In response to adhesion and ilk activation (6) would then result in a thr-159-hypophosphorylated ?-Nac that would become unavailable for proteasome degradation but would become a substrate for the ilk kinase activity on residue ser-43. The ser-43-phosphorylated ?-Nac would preferentially interact with c-jun (30), translocate to the nucleus, and potentiate transcription" SIGNOR-127631 C5AR2 protein Q9P296 UNIPROT Chemotaxis phenotype SIGNOR-PH93 SIGNOR up-regulates 9606 9108406 f lperfetto "We report here that the anaphylatoxins C3a and C5a are chemotactic factors for the human mast cell line HMC-1, human cord blood-derived mast cells (CBMC) and cutaneous mast cells in vitro." SIGNOR-263459 PTBP2 protein Q9UKA9 UNIPROT HNRNPH1 protein P31943 UNIPROT "up-regulates activity" binding 9606 BTO:0000567 11003644 t lperfetto "Splicing of the c-src N1 exon in neuronal cells depends in part on an intronic cluster of RNA regulatory elements called the downstream control sequence (DCS). |nPTB binds more stably to the DCS RNA than PTB does but is a weaker repressor of splicing in vitro. nPTB also greatly enhances the binding of two other proteins, hnRNP H and KSRP, to the DCS RNA." SIGNOR-261269 GSK3B protein P49841 UNIPROT H1-5 protein P16401 UNIPROT up-regulates phosphorylation Thr11 TAPAETAtPAPVEKS 9606 BTO:0000567 19136008 t lperfetto "We found that threonine 10 of h1.5 can be phosphorylated by glycogen synthase kinase-3 in vitro. We have generated an antiserum specific for human h1.5 phosphorylated at threonine 10. Immunofluorescence labeling of hela cells with this antiserum revealed that the phosphorylation at this site appears in prometaphase and disappears in telophase, and that this hyperphosphorylated form of h1.5 is mainly chromatin-bound in metaphase when chromatin condensation is maximal." SIGNOR-183325 MAPK14 protein Q16539 UNIPROT MYOD1 protein P15172 UNIPROT "up-regulates activity" 9606 BTO:0000887;BTO:0001103 15466486 f lperfetto "Here, we show that p38 activity facilitates myod and mef2 binding at a subset of late-activated promoters, and the binding of mef2d recruits pol ii." SIGNOR-129702 U50488 chemical CHEBI:73358 ChEBI OPRK1 protein P41145 UNIPROT "up-regulates activity" "chemical activation" 10029 9262330 t miannu "We recently cloned a human kappa opioid receptor and stably expressed it in Chinese hamster ovary (CHO) cells. In this study, the effects of activation of the human kappa receptor by agonists on [35S]GTPgammaS binding to CHO cell membranes were examined.. The rank order of potencies of opioid ligands tested in stimulating [35S]GTPgammaS binding was dynorphin A 1-17 > (+/-)-ethylketocyclazocine > beta-funaltrexamine, (-)-U50,488H, tifluadom > nalorphine > pentazocine, nalbuphine > buprenorphine." SIGNOR-258666 KDM6A protein O15550 UNIPROT HOXA5 protein P20719 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 24561908 t miannu "Evidence for direct involvement of UTX in regulation of HOX gene activity was demonstrated through UTX knockdown experiments in HEK293T cells in which loss of UTX induced transcriptional repression of HOXA and HOXC clusters." SIGNOR-260023 FADD protein Q13158 UNIPROT CASP10 protein Q92851 UNIPROT up-regulates binding 9606 11717445 t gcesareni "The death-effector domains ofcasp8and -10 bothinteractwith the death-effector domain offadd. Therefore, caspase-10 is recruited into the fas signaling complex and becomes activated like caspase-8" SIGNOR-112058 AKT proteinfamily SIGNOR-PF24 SIGNOR CDKN1B protein P46527 UNIPROT "down-regulates activity" phosphorylation Thr198 PGLRRRQt 9606 12042314 t lperfetto "Because Thr198-phosphorylated p27Kip1 was localized only in the cytoplasm, Akt might promote 14-3-3 binding to p27Kip1 by phosphorylation at Thr198, allowing its cytoplasmic localization and degradation." SIGNOR-244194 "Multiaminoacyl-tRNA synthetase" complex SIGNOR-C472 SIGNOR Glu-tRNA(Glu) smallmolecule CHEBI:29157 ChEBI "up-regulates quantity" "chemical modification" 9606 28271488 t miannu "Aminoacyl-tRNA synthetases (AARSs) are essential enzymes that specifically aminoacylate one tRNA molecule by the cognate amino acid. In mammals, nine synthetases, those specific for amino acids Arg, Asp, Gln, Glu, Ile, Leu, Lys, Met and Pro, associate into a multi-aminoacyl-tRNA synthetase complex, an association which is believed to play a key role in the cellular organization of translation, but also in the regulation of the translational and nontranslational functions of these enzymes." SIGNOR-270382 paroxetine chemical CHEBI:7936 ChEBI SLC6A4 protein P31645 UNIPROT "down-regulates activity" "chemical inhibition" 9606 BTO:0000007 9537821 t miannu "Among the antidepressants that we tested, paroxetine, which is a serotonin selective re-uptake inhibitor based on animal data, was the most potent for the human serotonin transporter with a KD=0.13±0.01 nM. Some tricyclic antidepressants (clomipramine, imipramine and amitriptyline), as well as some other antidepressants (sertraline, fluoxetine, citalopram and fluvoxamine) and some of their metabolites (norfluoxetine, desmethylsertraline and desmethylcitalopram) were also very potent at the human serotonin transporter." SIGNOR-258739 USP6 protein P35125 UNIPROT MMP9 protein P14780 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 20418905 f miannu "In this study we show that tre17 is sufficient to induce expression of mmp-9 and mmp-10, in a manner requiring its usp activity, but not its ability to bind arf6. Tre17 induces transcription of mmp-9 through activation of nuclear factor-kappab (nf-kappab), mediated in part by the gtpase rhoa and its effector kinase, rock." SIGNOR-164946 DPF2 protein Q92785 UNIPROT ESRRA protein P11474 UNIPROT "down-regulates activity" binding 10090 BTO:0000165 25713408 t 1 miannu "DPF2 directly bound to ERRalpha and suppressed the transactivation function of nuclear receptors such as androgen receptor. DPF2 was recruited to ERR target gene promoters in myoblast cells, and knockdown of DPF2 derepressed the level of mRNA expressed by target genes of ERRalpha. These results show that DPF2 acts as a nuclear receptor-selective co-repressor for ERRalpha by associating with both acetylated histone H3 and HDAC1." SIGNOR-239539 benazepril chemical CHEBI:3011 ChEBI ACE protein P12821 UNIPROT "down-regulates activity" "chemical inhibition" 9606 16407508 t "Angiotensin-converting-enzyme inhibitors provide renal protection in patients with mild-to-moderate renal insufficiency (serum creatinine level, 3.0 mg per deciliter or less). We assessed the efficacy and safety of benazepril in patients without diabetes who had advanced renal insufficiency." SIGNOR-253343 Ubiquitin proteinfamily SIGNOR-PF89 SIGNOR Ubiquitinated-Viral_Protein complex SIGNOR-C427 SIGNOR "form complex" binding 9606 25688236 t scontino "MHC class I antigen presentation pathway. Proteins with ubiquitin tags (red spheres) are degraded by proteasomes and the resulting peptides are transported into the endoplasmic reticulum (ER) by TAP|Many viruses have mechanisms of interfering with MHC class I processing, including direct interaction of viral proteins with immunoproteasome subunits." SIGNOR-267766 WNT3A protein P56704 UNIPROT Frizzled proteinfamily SIGNOR-PF11 SIGNOR "up-regulates activity" binding 18697834 t "Simone Vumbaca" "Wnt1, Wnt3a and Wnt5a all induced a statistically greater degree of proliferation than control cells" SIGNOR-255650 Ternary_GTP_eIF2_tRNA_complex complex SIGNOR-C452 SIGNOR 43S_pre_initiation_complex complex SIGNOR-C453 SIGNOR "form complex" binding 9606 35489072 t lperfetto "In eukaryotes, mRNA is recruited to the 43S pre-initiation complex (43S PIC), which consists of the 40S ribosomal subunit, translation initiation factors eIF1, eIF1A, eIF3, eIF5, and a ternary complex (TC) composed of eIF2, GTP and Met-tRNAiMet. 43S PIC binds to the 5′ end of the mRNA and scans along the 5′ untranslated region (5′UTR) in the 3′ direction to find the start codon (AUG) within the context of an optimal Kozak sequence. Start codon recognition stabilizes the 48S initiation complex (48S IC), initiates dissociation of eIF1, eIF1A, eIF2 and eIF5, and promotes recruitment of the 60S ribosomal subunit to form 80S IC ready to enter the elongation cycle of protein synthesis." SIGNOR-269159 CEP68 protein Q76N32 UNIPROT PCNT protein O95613 UNIPROT "up-regulates activity" relocalization 25503564 t lperfetto "We also found that Cep68 forms a complex with Cep215 (also known as Cdk5Rap2) and PCNT (also known as pericentrin), two PCM (pericentriolar material) proteins involved in centriole engagement. |Cep68 stabilization increases the amount of PCNT at metaphase centrosomes, but does not affect its removal at the end of mitosis" SIGNOR-275623 AKT1 protein P31749 UNIPROT RNF11 protein Q9Y3C5 UNIPROT "down-regulates quantity" phosphorylation Thr135 DWLMRSFtCPSCMEP 9606 BTO:0003474 16123141 t gcesareni "Upon inhibition of the AKT pathway or mutation of T135, the phosphorylation at one of these sites is virtually eliminated, suggesting that AKT may phosphorylate RNF11 at T135. Moreover, RNF11 is phosphorylated by AKT in vitro and is recognized by phospho-AKT substrate antibodies. RNF11 shows enhanced binding to 14-3-3 in WM239 cells compared with that seen in the parental WM35 cells which have low AKT activity" SIGNOR-252558 CSNK2A1 protein P68400 UNIPROT PIP4K2A protein P48426 UNIPROT up-regulates phosphorylation Ser304 DGEEEGEsDGTHPVG 9606 BTO:0000567 10508590 t lperfetto "Here, we demonstrate the partial purification of a protein kinase that phosphorylates the type iialpha pip kinase at a single site unique to that isoform - ser304. This kinase was identified as protein kinase ck2 (formerly casein kinase 2). Mutation of ser304 to aspartate to mimic its phosphorylation had no effect on pip kinase activity, but promoted both redistribution of the green fluorescent protein (gfp)-tagged enzyme in hela cells from the cytosol to the plasma membrane, and membrane ruffling." SIGNOR-71014 "2-Hydroxy-3-[N-[4-[methyl-[2-(4-methylpiperazin-1-yl)acetyl]amino]phenyl]-C-phenylcarbonimidoyl]-1H-indole-6-carboxylic acid" chemical CID:135461425 PUBCHEM PDGFRB protein P09619 UNIPROT "down-regulates activity" "chemical inhibition" -1 22037378 t miannu "Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here." SIGNOR-259707 CSNK2A1 protein P68400 UNIPROT L1CAM protein P32004 UNIPROT unknown phosphorylation Ser1181 GEYRSLEsDNEEKAF 10116 BTO:0000142 8592152 t llicata "Serine to alanine substitutions in these peptides indicate that the CKII phosphorylation site is at Ser1,181. | Finally, in vivo radiolabeling indicates that Ser1,181 is phosphorylated in newborn rat brain. These data show that CKII is associated with and able to phosphorylate L1." SIGNOR-250913 MIB1 protein Q86YT6 UNIPROT CEP131 protein Q9UPN4 UNIPROT down-regulates ubiquitination 9606 BTO:0001938 24121310 t miannu " We demonstrate that the E3 ubiquitin ligase MIB1 is a new component of centriolar satellites, which interacts with and ubiquitylates AZI1 and PCM1 and suppresses primary cilium formation. Whereas these proteins are degraded prior to the ciliation process, MIB1 appears to maintain its targets in a latent state through inhibitory ubiquitylation that is reversed during ciliogenesis and in response to cell stress.The precise mechanism by which MIB1 inhibits primary cilium formation through ubiquitylation of ciliogenesis-promoting target proteins such as AZI1 and PCM1 remains to be determined." SIGNOR-272876 RUNX3 protein Q13761 UNIPROT FADD protein Q13158 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0002384 17956589 f miannu "Comprehensive analysis using a cDNA microarray showed that RUNX3 upregulated 17 apoptosis-related genes (including FADD, TRAF6, caspase-2, ING1, ING4, Calpain 10, and DNase1) and downregulated 135 apoptosis-related genes (including FLIP, PEA15, TXN2, HSPD1, IKK, and TIAL1) in MKN-1 cells." SIGNOR-255095 ATM protein Q13315 UNIPROT ATM protein Q13315 UNIPROT "up-regulates activity" phosphorylation Ser367 DTRSLEIsQSYTTTQ 9606 21149446 t gcesareni "In human cells, the activation process involves autophosphorylation on three sites (ser367, ser1893, and ser1981) and acetylation on lys3016. We now describe the identification of a new atm phosphorylation site, thr(p)1885 and an additional autophosphorylation site, ser(p)2996, that is highly dna damage-inducible." SIGNOR-170477 KAT6A protein Q92794 UNIPROT TP53 protein P04637 UNIPROT up-regulates acetylation Lys120 FLHSGTAkSVTCTYS 9606 BTO:0001271 SIGNOR-C54 23431171 t miannu "We show here that moz is an acetyltransferase of p53 at k120 and k382 and colocalizes with p53 in promyelocytic leukemia (pml) nuclear bodies following cellular stress. The moz-pml-p53 interaction enhances moz-mediated acetylation of p53, and this ternary complex enhances p53-dependent p21 expression" SIGNOR-201482 testosterone smallmolecule CHEBI:17347 ChEBI 17beta-estradiol smallmolecule CHEBI:16469 ChEBI "up-regulates quantity" "precursor of" 9606 BTO:0000975 27702664 t lperfetto "The cytochrome P450 aromatase is involved in the last step of sex hormones biosynthesis by converting androgens into estrogens. |Human aromatase (CYP19A1) is a membrane-bound class II cytochrome P450 that converts androgens into estrogens [1], [2], [3], [4]. Specifically, the enzyme is involved sex hormones biosynthesis where it is responsible for the conversion of androstenedione, testosterone and 16alpha-hydroxytestosterone into estrone, estradiol and estriol, respectively" SIGNOR-268667 PPM1B protein O75688 UNIPROT IKBKB protein O14920 UNIPROT down-regulates dephosphorylation Ser177 AKELDQGsLCTSFVG 9606 18930133 t lperfetto "Using a functional genomic approach, we have identified two protein serine/threonine phosphatases, ppm1a and ppm1b, as ikkbeta phosphatases. Overexpression of ppm1a or ppm1b results in dephosphorylation of ikkbeta at ser177 and ser181 and termination of ikkbeta-induced nf-kappab activation" SIGNOR-181663 Gbeta proteinfamily SIGNOR-PF4 SIGNOR CALD1 protein Q05682 UNIPROT down-regulates phosphorylation 9606 BTO:0001260 10514499 t "inferred from 70% family members" lperfetto "Extracellular signal-regulated kinases (erks) phosphorylate the high molecular mass isoform of the actin-binding protein caldesmon (h-cad) at two sites (ser(759) and ser(789)) during smooth muscle stimulation. Nmr spectroscopy shows that the actin binding properties of the minimal inhibitory region of caldesmon, residues 750-779, alter upon map kinase phosphorylation of ser-759, a residue not involved in actin binding. This phosphorylation leads to markedly diminished actin affinity as a result of the loss of interaction at one of the two sites that bind to f-actin." SIGNOR-270049 GTF2H2C protein Q6P1K8 UNIPROT TFIIH complex SIGNOR-C457 SIGNOR "form complex" binding 9606 30860024 t lperfetto "Transcription factor IIH (TFIIH) is a heterodecameric protein complex critical for transcription initiation by RNA polymerase II and nucleotide excision DNA repair.|The TFIIH core complex is composed of the seven subunits XPB, XPD, p62, p52, p44, p34, and p8, and is the form of TFIIH active in DNA repair|and additionally the CdK activating kinase (CAK) complex, which harbors the kinase activity of CDK7 as well as the Cyclin H and MAT1 subunits" SIGNOR-269317 "Cullin 3-RBX1-Skp1" complex SIGNOR-C526 SIGNOR INF2 protein Q27J81 UNIPROT "down-regulates quantity by destabilization" polyubiquitination Lys666 IRAGDTTkFDVEVLK 9606 BTO:0000007 28448495 t miannu "SPOP acts as an adaptor protein of the CUL3-RBX1 E3 ubiquitin ligase complex that generally recruits substrates for ubiquitination and subsequent degradation. Here, we revealed that SPOP recognizes a Ser/Thr (S/T)-rich motif in the C-terminal region of INF2 and triggers atypical polyubiquitination of INF2. These ubiquitination modifications do not lead to INF2 instability, but rather reduces INF2 localization in ER and mitochondrially associated DRP1 puncta formation, therefore abrogates its ability to facilitate mitochondrial fission. It revealed that INF2 was ubiquitinated at least at 7 lysine residues (Fig 2I). Interestingly, 5 of 7 ubiquitin attachment sites are localized in a short stretch of sequence (amino acids 612–682) within the FH2 domain of INF2 (Fig 2J)." SIGNOR-272803 PRKCA protein P17252 UNIPROT LRP1 protein Q07954 UNIPROT up-regulates phosphorylation Thr4460 GFQHQRMtNGAMNVE 9606 15272003 t lperfetto "Serine and threonine phosphorylation of the low density lipoprotein receptor-related protein by protein kinase calpha regulates endocytosis and association with adaptor moleculesthese results indicate that elimination of serine and threonine phosphorylation sites in the lrp cytoplasmic domain reduces the extent of tyr63 phosphorylation and leads to impaired association with the adaptor protein shc." SIGNOR-127215 RNF111 protein Q6ZNA4 UNIPROT SKIL protein P12757 UNIPROT "down-regulates quantity by destabilization" polyubiquitination 9606 BTO:0000007 23530057 t miannu "Upon TGF-β induction, interaction of Arkadia with phosphorylated Smad2 triggers degradation of SnoN, whereas upon arsenic treatment, interaction of Arkadia with poly-SUMO in PML nuclear bodies induces degradation of polysumoylated PML together with RNF4." SIGNOR-272885 PGM1 protein P36871 UNIPROT "alpha-D-glucose 1-phosphate(2-)" smallmolecule CHEBI:58601 ChEBI "up-regulates quantity" "chemical modification" 9606 32898648 t miannu "Human PGM1 deficiency is an inborn error of metabolism (OMIM: 614921), affecting cellular glucose homeostasis, the storage of glucose as glycogen, and the N-glycosylation of proteins. Like other PGM enzymes, the human protein catalyzes the Mg2+-dependent interconversion of glucose 1-phosphate (G1P) and glucose 6-phosphate (G6P)." SIGNOR-267929 USP36 protein Q9P275 UNIPROT "RNA Polymerase I" complex SIGNOR-C390 SIGNOR "up-regulates quantity by stabilization" deubiquitination 22902402 t lperfetto "USP36, the human ortholog of Ubp10, complements the ubp10Δ allele for RNAPI stability, pre-rRNA processing, and cell growth in yeast, suggesting that deubiquitination of RNAPI may be conserved in eukaryotes. Our work implicates Ubp10/USP36 as a key regulator of rRNA production through control of RNAPI stability.|Human USP36 complements ubp10delta for RNA polymerase I deubiquitination and stability" SIGNOR-272292 GSK3B/Axin/APC complex SIGNOR-C110 SIGNOR ROR2 protein Q01974 UNIPROT "down-regulates activity" phosphorylation Ser864 PKPSSHHsGSGSTST 9606 21078818 t gcesareni "We identify ror2 ser 864 as a critical residue phosphorylated by gsk3 and required for noncanonical receptor activation by wnt5a, analogous to the priming phosphorylation of low-density receptor-related protein 6 (lrp6) in response to wnt3a." SIGNOR-228026 EEF1A1 protein P68104 UNIPROT Ser-tRNA(Ser) smallmolecule CHEBI:29162 ChEBI up-regulates relocalization 9606 23699257 t lperfetto "During protein synthesis, eEF1A binds to and delivers aminoacylated tRNAs (aa-tRNAs) to the elongating ribosome (Fig. 1). GTP bound to eEF1A is hydrolyzed upon codon-anticodon match between an aa-tRNA in the A site of the ribosome and mRNA bound to the ribosome." SIGNOR-269515 FYN protein P06241 UNIPROT TXK protein P42681 UNIPROT "up-regulates activity" phosphorylation Tyr420 RYVLDDEyVSSFGAK 11353545 t lperfetto "We further demonstrate that Rlk can be phosphorylated and activated by Src kinases, leading to a decrease in its half-life. A specific tyrosine in the activation loop of Rlk, Y420, is required for phosphorylation and activation, as well as for decreased stability, but is not required for lipid RAFT association." SIGNOR-249341 CSNK2A1 protein P68400 UNIPROT CTNNB1 protein P35222 UNIPROT "up-regulates activity" phosphorylation Thr393 RNLSDAAtKQEGMEG 9534 BTO:0000298 12700239 t llicata "The major CK2 phosphorylation site in this domain is Thr393, a solvent-accessible residue in a key hinge region of the molecule. Mutation of this single amino acid reduces beta-catenin phosphorylation, cotranscriptional activity, and stability." SIGNOR-250849 STK3 protein Q13188 UNIPROT LATS1 protein O95835 UNIPROT up-regulates phosphorylation Ser909 HQRCLAHsLVGTPNY 9606 BTO:0000007 15688006 t "Two of these, S909 and T1079, were required for Lats1 activation." milica "Since the N-terminal half of Lats1 (residues 1–588) was dispensable for the activation of Lats1 by Mst2, mass spectrometry was used to identify phosphorylation sites within the C-terminal domain of Lats1." SIGNOR-133544 Endothelin-1 smallmolecule CHEBI:80240 ChEBI EDNRA protein P25101 UNIPROT "up-regulates activity" "chemical activation" 9606 BTO:0002524 31160049 t "Ligand-GPCR dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257482 DOK1 protein Q99704 UNIPROT "Av/b5 integrin" complex SIGNOR-C178 SIGNOR "down-regulates activity" binding 9606 19118207 t miannu "Integrins also bind to many PTBdomain-containing proteins (Calderwood et al., 2003) – including Dok1 and integrincytoplasmic-domain-associated protein 1 (ICAP1) – and these can compete with talin for binding to integrin and so can impair activation" SIGNOR-257692 TRAF2 protein Q12933 UNIPROT MAP3K5 protein Q99683 UNIPROT "up-regulates activity" binding 9606 9774977 t lperfetto "Traf2 is a strong activator of ask1" SIGNOR-60747 MAPK8 protein P45983 UNIPROT ITCH protein Q96J02 UNIPROT up-regulates phosphorylation 9606 16469705 t gcesareni "Here we show that tnfalpha-mediated jnk activation accelerates turnover of the nf-kappab-induced antiapoptotic protein c-flip, an inhibitor of caspase-8. This is not due to direct c-flip phosphorylation but depends on jnk-mediated phosphorylation and activation of the e3 ubiquitin ligase itch, which specifically ubiquitinates c-flip and induces its proteasomal degradation." SIGNOR-144456 DUSP9 protein Q99956 UNIPROT MAPK14 protein Q16539 UNIPROT down-regulates dephosphorylation 9606 BTO:0000887 11988087 t "This interaction is observed for Mus musculus Pyst3 gene, which encodes for DUSP9" gcesareni "These properties define the ability of this enzyme to dephosphorylate and inactivate erk1/2 and p38a, but not jnk (c-jun n-terminal kinase) in vivo." SIGNOR-87150 STK38 protein Q15208 UNIPROT PANX2 protein Q96RD6 UNIPROT "up-regulates activity" phosphorylation Ser514 KKHARHFsLDVHPYI 10090 BTO:0000142 22445341 t miannu "We identified 5 potential NDR1 substrates in the mouse brain and chose two for functional validation. We show that one NDR1 substrate is another kinase, AP-2 associated kinase-1 (AAK1) which regulates dendritic branching as a result of NDR1 phosphorylation. Another substrate is the Rab8 guanine nucleotide exchange factor (GEF) Rabin8 (a Sec2p homolog) which we find is involved in spine synapse formation." SIGNOR-263032 ROS stimulus SIGNOR-ST2 SIGNOR ATF4 protein P18848 UNIPROT up-regulates "transcriptional regulation" 9606 19439225 f lperfetto "Oxidative and ER stress conditions induce rapid and significant activation of ATF4 downstream of eIF2alpha phosphorylation, which is responsible for Redd1 expression" SIGNOR-253729 SCF-SKP2 complex SIGNOR-C136 SIGNOR CCNE1 protein P24864 UNIPROT "down-regulates quantity by destabilization" ubiquitination -1 phosphorylation:Ser399;Thr395 GLLTPPQsGKKQSSG;PLPSGLLtPPQSGKK 11533444 t lperfetto "The amount of cyclin E protein present in the cell is tightly controlled by ubiquitin-mediated proteolysis. Here we identify the ubiquitin ligase responsible for cyclin E ubiquitination as SCFFbw7 and demonstrate that it is functionally conserved in yeast, flies, and mammals. Fbw7 associates specifically with phosphorylated cyclin E, and SCFFbw7 catalyzes cyclin E ubiquitination in vitro" SIGNOR-267558 MET protein P08581 UNIPROT PTK2 protein Q05397 UNIPROT up-regulates phosphorylation Tyr194 ALEKKSNyEVLEKDV 9606 20802513 t gcesareni "In this study, we demonstrate that growth factor receptors including hepatocyte growth factor receptor met, epidermal growth factor receptor, and platelet-derived growth factor receptor directly phosphorylate fak on tyr194 in the ferm domain (band 4.1 and ezrin/radixin/moesin homology domain)." SIGNOR-167654 WT1 protein P19544 UNIPROT Urogenital_tract phenotype SIGNOR-PH71 SIGNOR "up-regulates activity" 10090 10101119 f "The Wilms' Tumour gene WT1 has important functions during development. Knock-out mice were shown to have defects in the urogenital system and to die at embryonic day E13.5, probably due to heart failure." SIGNOR-252302 EIF2AK2 protein P19525 UNIPROT EIF2AK2 protein P19525 UNIPROT up-regulates phosphorylation Thr88 AVSPLLLtTTNSSEG 9606 11152499 t tpavlidou "Taken together, these results show that pkr is autophosphorylated on serine 83 and threonines 88, 89, and 90, that this autophosphorylation may enhance kinase activation, and that the inhibition of pkr by hcv e2 is not solely due to duplication of and competition with these autophosphorylation sites." SIGNOR-85781 NTRK2 protein Q16620 UNIPROT FRS3 protein O43559 UNIPROT "up-regulates activity" phosphorylation Tyr417 EPPRQLNyIQVELKG 9606 11432792 t miannu "The tyrosine phosphoryla tion of FRS2/SNT2 was stimulated dependently on the TrkB activation. to explore the possibility that tyrosine residues 417 and 455 on FRS2/SNT2 function as the binding sites for Shp2, we coexpressed Y417F or Y455F phenylalanine mutants and the Y417/455F double phenylalanine mutant of Myc/Histagged FRS2/SNT2 with TrkB. The active TrkB induced somewhat reduced tyrosine phosphorylation of all of the phenylalanine mutants of FRS2/SNT2 in comparison with tyrosine phosphorylation of the wild type" SIGNOR-250202 AMPK complex SIGNOR-C15 SIGNOR FOXO3 protein O43524 UNIPROT "up-regulates activity" phosphorylation Ser399 DNITLPPsQPSPTGG 9606 BTO:0000007 17711846 t gcesareni "Phosphorylation by AMPK leads to the activtion of FOXO3 transcriptional activity without affecting FOXO3 subcellular localization." SIGNOR-249668 pazopanib chemical CHEBI:71219 ChEBI FGFR1 protein P11362 UNIPROT "down-regulates activity" "chemical inhibition" 9606 BTO:0001949 18620382 t Luana "Pyrimidine 13 showed good potency against all the human VEGFR receptors with an IC50 of 10, 30, and 47 nM for VEGFR-1, -2, and -3, respectively. Significant activity was also seen against the closely related tyrosine receptor kinases PDGFRβ, c-Kit, FGF-R1, and c-fms with IC50’s of 84, 74, 140, and 146 nM, respectively." SIGNOR-257735 KAT2A protein Q92830 UNIPROT "Histone H3" proteinfamily SIGNOR-PF69 SIGNOR "down-regulates activity" acetylation 9606 SIGNOR-C465 34811519 t lperfetto "The HAT module within the SAGA and ADA complexes acetylates histone H3, mainly on residues K9 and K14." SIGNOR-269593 "A9/b1 integrin" complex SIGNOR-C166 SIGNOR TNF protein P01375 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000801 24241034 f lperfetto "Importantly, autocrine and paracrine interactions of alpha9beta1 integrin and tenascin-C induced the expression of MMPs and IL-6 in synovial fibroblasts, as well as TNF-alpha± and IL-1beta in synovial macrophages." SIGNOR-253315 "BRCA1-C complex" complex SIGNOR-C299 SIGNOR TP53BP1 protein Q12888 UNIPROT "up-regulates activity" relocalization 25400280 t lperfetto "Additional to the role of the BRCA1–C complex in 53BP1 repositioning and initiation of resection, end resection is extended to facilitate RPA loading and subsequent RPA‐Rad51 exchange prior to sister strand invasion" SIGNOR-263230 GSK3B protein P49841 UNIPROT CTNNB1 protein P35222 UNIPROT "down-regulates activity" phosphorylation Ser33 QQQSYLDsGIHSGAT 9606 SIGNOR-C110 23151663 t gcesareni "Beta-catenin phosphorylation in vivo is sequentially carried out by two distinct kinases, ckialfa and gsk-3. Ckialfa phosphorylation of s45 proceeds and is required for subsequent gsk-3 phosphorylation of t41, s37, and s33 one key substrate of gsk3 is the transcriptional co-activator beta catenin, whichis inactivated by gsk3 mediated phosphorylation and targeted for proteasomal degradation in unstimulated cells." SIGNOR-199504 STK24 protein Q9Y6E0 UNIPROT STK38L protein Q9Y2H1 UNIPROT up-regulates phosphorylation Thr442 DWVFLNYtYKRFEGL 9606 BTO:0000007 16314523 t lperfetto "Ndr1/ndr2 protein kinase is activated by phosphorylation on the activation loop phosphorylation site ser281/ser282 and the hydrophobic motif phosphorylation site thr444/thr442. Autophosphorylation of ndr is responsible for phosphorylation on ser281/ser282, whereas thr444/thr442 is targeted by an upstream kinase. Here we show that mst3, a mammalian ste20-like protein kinase, is able to phosphorylate ndr protein kinase at thr444/thr442. In vitro, mst3 selectively phosphorylated thr442 of ndr2, resulting in a 10-fold stimulation of ndr activity." SIGNOR-142510 ANAPC4 protein Q9UJX5 UNIPROT APC-c complex SIGNOR-C150 SIGNOR "form complex" binding 16896351 t lperfetto "The anaphase promoting complex/cyclosome (APC/C) is a ubiquitin ligase that has essential functions in and outside the eukaryotic cell cycle. It is the most complex molecular machine that is known to catalyse ubiquitylation reactions, and it contains more than a dozen subunits that assemble into a large 1.5-MDa complex." SIGNOR-252004 "Cullin 7-RBX1-Skp1" complex SIGNOR-C528 SIGNOR AICDA protein Q9GZX7 UNIPROT "down-regulates quantity by destabilization" ubiquitination 9606 BTO:0000007 31092637 t miannu " Further analysis indicated that CUL7 mediated AID ubiquitination by forming a complex with FBXW11. In a CUL7 fl/fl CD19 cre+ mouse model, we demonstrated that CUL7 knockout significantly enhanced AID protein levels in B cells in the germinal center and increased both the IgG1 and IgA class switching. Collectively, our results reveal a subtle regulation mechanism for tightly controlling AID protein levels. F-box proteins are components of SCF ubiquitin-ligase complexes that contain Skp1, CUL1, or CUL7, and an F-box protein" SIGNOR-272026 FGF6 protein P10767 UNIPROT FGFR4 protein P22455 UNIPROT up-regulates binding 9606 1385111 t gcesareni "Our results establish an fgf binding profile for fgfr-4 with afgf having the highest affinity, followed by k-fgf/hst-1 and bfgf. In addition, fgf-6 was found to bind to fgfr-4 in ligand competition experiments. Ligands binding to fgfr-4 induced receptor autophosphorylation and phosphorylation of a set of cellular polypeptides." SIGNOR-18570 EGFR protein P00533 UNIPROT EGFR protein P00533 UNIPROT "up-regulates activity" phosphorylation Tyr869 LGAEEKEyHAEGGKV 10090 BTO:0002882 16122376 t "Dimerization mediated by a beta hairpin, which protudes from the S1 domains of each ligand bound monomer" lperfetto "EGFR possesses three major and two minor tyrosine autophosphorylation sites located at Y1068, Y1148, Y1173, and at Y992 and Y1086 respectively. In addition, EGFR Y1114 is preceded by glutamic acid (Figure 1), which should be preferred by the EGFR kinase as indicated in previous work" SIGNOR-235956 AKT1 protein P31749 UNIPROT SKI protein P12755 UNIPROT down-regulates phosphorylation Thr458 QPRKRKLtVDTPGAP 9606 19875456 t llicata "The phosphorylation of ski at threonine 458 is induced by akt pathway activators including insulin, insulin-like growth factor-1, and hepatocyte growth factor. The phosphorylation of ski causes its destabilization and reduces ski-mediated inhibition of expression of another negative regulator of tgf-beta, smad7" SIGNOR-252527 DKK1 protein O94907 UNIPROT WNT3A protein P56704 UNIPROT down-regulates 9606 19874086 f "Antagonizes canonical Wnt signaling by inhibiting LRP5/6 interaction with Wnt and by forming a ternary complex with the transmembrane protein KREMEN that promotes internalization of LRP5/6." gcesareni "It has been shown that both sclerostin and dkk1 act physiologically as downstream molecules of bmp signaling to inhibit canonical wnt signaling and therefore negatively regulate bone mass." SIGNOR-188961 NFY complex SIGNOR-C1 SIGNOR CCNB2 protein O95067 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 10086339 f gcesareni "In this study, we analysed the mechanisms leading to activation of the cyclin b2 ccaat boxes: a combination of (i) genomic footprinting, (ii) transfections with single, double and triple mutants, (iii) emsas with nuclear extracts, antibodies and nf-y recombinant proteins and (iv) transfections with an nf-ya dominant negative mutant established the positive role of the three ccaat sequences and proved that nf-y plays a crucial role in their activation." SIGNOR-65638 TIMM21 protein Q9BVV7 UNIPROT "MITRAC complex" complex SIGNOR-C538 SIGNOR "form complex" binding 9606 23260140 t "TIM21 is a constituent of MITRAC and presequence translocase complexes ► TIM21 ushers imported subunits of complexes I and IV to assembly intermediates" SIGNOR-272488 SLC9A9 protein Q8IVB4 UNIPROT hydron chemical CHEBI:15378 ChEBI "down-regulates quantity" relocalization 9606 BTO:0000938 31507243 t miannu "Na+/H+ exchangers play pivotal roles in the control of cell and tissue pH by mediating the electroneutral exchange of Na+ and H+ across cellular membranes. " SIGNOR-265599 "Dynorphin A" smallmolecule CHEBI:4727 ChEBI OPRM1 protein P35372 UNIPROT "up-regulates activity" "chemical activation" 10029 BTO:0000246 9686407 t miannu "Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors." SIGNOR-258793 SREBF2 protein Q12772 UNIPROT ABCG5 protein Q9H222 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 21123766 f miannu "these results indicate that HMG-CoAR inhibition with atorvastatin stimulates intestinal expression of NPC1L1 and PCSK9, increases cholesterol absorption, and reduces ABCG5/8 expression; these effects are mediated most likely by stimulation of the transcription factors SREBP-2 and HNF-4α." SIGNOR-254455 PRKACA protein P17612 UNIPROT ADD2 protein P35612 UNIPROT "down-regulates activity" phosphorylation Ser726 KKKEKVEs -1 8810272 t miannu "Ser-726 and Ser-713 in the C-terminal MARCKS-related domains of - and -adducin, respectively, were identified as the major phosphorylation sites common for PKA and PKC. Phosphorylation by PKA, but not PKC, reduced the affinity of adducin for spectrin-F-actin complexes as well as the activity of adducin in promoting binding of spectrin to F-actin." SIGNOR-250333 EXOC1 protein Q9NV70 UNIPROT "Exocyst_EXOC6 variant" complex SIGNOR-C492 SIGNOR "form complex" binding 9606 26240175 t miannu "The exocyst is an octameric protein complex that is implicated in the tethering of secretory vesicles to the plasma membrane prior to SNARE-mediated fusion." SIGNOR-270784 SLC9A6 protein Q92581 UNIPROT hydron chemical CHEBI:15378 ChEBI "down-regulates quantity" relocalization 9606 BTO:0000938 31507243 t miannu "Na+/H+ exchangers play pivotal roles in the control of cell and tissue pH by mediating the electroneutral exchange of Na+ and H+ across cellular membranes. " SIGNOR-265596 "alpha-D-ribose 1-phosphate(2-)" smallmolecule CHEBI:57720 ChEBI "D-ribofuranose 5-phosphate(2-)" smallmolecule CHEBI:78346 ChEBI "up-regulates quantity" "precursor of" 9606 17804405 t miannu "Phosphopentomutase catalyzes the conversion of the nucleoside breakdown products ribose 1-phosphate and deoxyribose 1-phosphate to the corresponding 5-phosphopentoses. The role of phosphopentomutase is to utilize ribose 1-phosphate and deoxyribose 1-phosphate, which are formed by purine nucleoside phosphorylase and uridine phosphorylase. Using catalytic efficiency as a criterion, PGM2 acted more than 10-fold better as a phosphopentomutase (both on deoxyribose 1-phosphate and on ribose 1-phosphate) than as a phosphoglucomutase." SIGNOR-267074 NEDD4 protein P46934 UNIPROT KIF26B protein Q2KJY2 UNIPROT "down-regulates quantity by destabilization" polyubiquitination 9606 phosphorylation:Thr1855 PSPYSKItPPRRPHR 22768111 t miannu "We find that Kif26b interacts with an E3 ubiquitin ligase, neural precursor cell expressed developmentally down-regulated protein 4 (Nedd4) in developing kidney. Phosphorylation of Kif26b at Thr-1859 and Ser-1962 by the cyclin-dependent kinases (CDKs) enhances the interaction of Kif26b with Nedd4. Nedd4 polyubiquitinates Kif26b and thereby promotes degradation of Kif26b via the ubiquitin-proteasome pathway. " SIGNOR-272906 HRK protein O00198 UNIPROT BCL2L1 protein Q07817 UNIPROT down-regulates binding 9606 9130713 t gcesareni "Hrk, physically interacts with the death-repressor proteins bcl2 and bcl2l1. Hrk activates cell death at least in part by interacting with and inhibiting the protection afforded by bcl2 and bcl2l1." SIGNOR-47797 "gamma-aminobutyric acid" smallmolecule CHEBI:16865 ChEBI "GABA-A (a4-b3-d) receptor" complex SIGNOR-C327 SIGNOR "up-regulates activity" "chemical activation" 9606 18790874 t brain lperfetto "Gamma-Aminobutyric acid (GABA1), the major inhibitory neurotransmitter in the brain, exerts its action via ionotropic GABAA and metabotropic GABAB receptors. GABAA receptors (GABAA-Rs) are the major inhibitory receptors in the central nervous system (CNS)." SIGNOR-263785 PRKAA2 protein P54646 UNIPROT BAIAP2 protein Q9UQB8 UNIPROT down-regulates phosphorylation Ser366 KTLPRSSsMAAGLER 9606 SIGNOR-C15 19933840 t lperfetto "Using this approach for ppp1r12c, baiap2, and cdc27, we found that mutation of a single serine to alanine (s452, s366, and s379 respectively) resulted in almost a complete loss of ampk phosphorylation in these proteins. Termination of irsp53 function is suggested to occur following cdc42 dissociation, kinase phosphorylation of t340 and t360, and subsequent 14-3-3 binding, which competes for sh3 partners, thus allowing filopodial retraction" SIGNOR-161810 CCT2 protein P78371 UNIPROT TRiC complex SIGNOR-C539 SIGNOR "form complex" binding 9606 36185250 t miannu "Mammalian cells contain an evolutionarily conserved type II chaperonin called chaperonin containing tailless complex polypeptide 1 (CCT) or tailless complex polypeptide 1 ring complex (TRiC). The CCT complex is composed of eight subunits [CCT1-8 (yeast) or CCTα-θ (mammals)] and folds substrates needed for cell invasion and proliferation, such as actin, tubulin, and cell division cycle protein 20 homolog (cdc20), as well as oncoproteins like signal transducer and activator of transcription 3 (STAT3), Kirsten rat sarcoma viral oncogene homolog (KRAS), and Myelocytomatosis (MYC)." SIGNOR-272860 VAV3 protein Q9UKW4 UNIPROT RHOA protein P61586 UNIPROT "up-regulates activity" "guanine nucleotide exchange factor" 9606 BTO:0000007 32203420 t Luana "We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2)." SIGNOR-260584 CDK1 protein P06493 UNIPROT CDC23 protein Q9UJX2 UNIPROT up-regulates phosphorylation Thr565 NQGETPTtEVPAPFF 9606 14657031 t lperfetto "Apc activation is thought to depend on apc phosphorylation and cdc20 binding. We have identified 43 phospho_sites on apc of which at least 34 are mitosis specific. Of these, 32 sites are clustered in parts of apc1 and the tetratricopeptide repeat (tpr) subunits cdc27, cdc16, cdc23 and apc7. In vitro, at least 15 of the mitotic phospho_sites can be generated by cyclin_dependent kinase 1 (cdk1), and 3 by polo_like kinase 1 (plk1). Apc phosphorylation by cdk1, but not by plk1, is sufficient for increased cdc20 binding and apc activation" SIGNOR-119821 DUOX1 protein Q9NRD9 UNIPROT superoxide smallmolecule CHEBI:18421 ChEBI "up-regulates quantity" "chemical modification" 9606 17237347 t lperfetto "Over the last years, six homologs of the cytochrome subunit of the phagocyte NADPH oxidase were found: NOX1, NOX3, NOX4, NOX5, DUOX1, and DUOX2. Together with the phagocyte NADPH oxidase itself (NOX2/gp91phox), the homologs are now referred to as the NOX family of NADPH oxidases. These enzymes share the capacity to transport electrons across the plasma membrane and to generate superoxide and other downstream reactive oxygen species (ROS)." SIGNOR-264726 CFAP53 protein Q96M91 UNIPROT DNAH5 protein Q8TE73 UNIPROT "up-regulates activity" binding 10090 BTO:0000379 33347437 t miannu "CFAP53 likely facilitates the transport of TTC25 and the dyneins into cilia. CFAP53 at the centriolar satellites may form a complex with TTC25 and ODAs, including DNAH5 and DNAH11, and regulate their trafficking into the cilium (Fig 10B)." SIGNOR-265544 STK39 protein Q9UEW8 UNIPROT SLC12A1 protein Q13621 UNIPROT "up-regulates activity" phosphorylation Thr105 LQTFGHNtMDAVPKI 9606 BTO:0000007 21321328 t miannu "We establish that the SPAK and OSR1 kinases activated by WNK interact with an RFQV motif on NKCC2 and directly phosphorylate Thr95, Thr100, Thr105 and, possibly, Ser91. Our data indicate that a SPAK-OSR1-independent kinase, perhaps AMP-activated protein kinase (AMPK), phosphorylates Ser130 and that phosphorylation of Thr105 and Ser130 plays the most important roles in stimulating NKCC2 activity." SIGNOR-263131 TLK1 protein Q9UKI8 UNIPROT H3C1 protein P68431 UNIPROT "up-regulates activity" phosphorylation Ser11 TKQTARKsTGGKAPR -1 11314006 t "The effect has been demonstrated using Q9UKI8-2|Ser 11 phosphorylation of H3 is either activatory and inhibitory as promotes DNA condensation (activatory) and induce transcription (inhibitory)." lperfetto "Purified tlk1b phosphorylated histone h3 at s(10) with high specificity both in a mix of core histones and in isolated chromatin, suggesting that histone h3 is a physiological substrate for tlk1b. Phosphorylation of H3 has been linked to the activation of the immediate-early genes upon mitogenic stimulation, and to chromatin condensation during mitotic/meiotic events." SIGNOR-107037 MACF1 protein Q9UPN3 UNIPROT GSK3B/Axin/APC complex SIGNOR-C110 SIGNOR "down-regulates quantity by destabilization" 9606 BTO:0000938 16815997 f lperfetto "In the absence of wnt, macf1 associated with a complex that contained axin, betBeta-catenin, gsk3beta, and apc. Upon wnt stimulation, macf1 appeared to be involved in the translocation and subsequent binding of the axin complex to lrp6 at the cell membrane. Macf1 is involved in the translocation of the complex containing axin, Beta-catenin, and gsk3_ but not apc from the cytosol to the cell membrane, where axin and macf1 bind to lrp-5/6. Subsequently, gsk3_ is inactivated by phosphorylation, axin is degraded, and Beta-catenin is released and enters the nucleus, where it can activate the wnt-responsive genes." SIGNOR-227997 ziprasidone chemical CHEBI:10119 ChEBI HRH1 protein P35367 UNIPROT "down-regulates activity" "chemical inhibition" -1 8935801 t miannu "Risperidone and its active metabolite 9-OH-risperidone were compared to reference antipsychotic drugs (haloperidol, pipamperone, fluspirilene, clozapine, zotepine) and compounds under development (olanzapine, seroquel, sertindole, ORG-5222, ziprasidone) for in vitro binding to neurotransmitter receptors in brain tissue and on membranes of recombinant cells expressing cloned human receptors and for in vivo occupancy of neurotransmitter receptors in rat and guinea-pig brain following acute treatment (2 h., s.c.). The binding affinities of the compounds for various neurotransmitter receptors were measured using membrane preparations of animal brain regions and of recombinant cells expressing cloned, mostly human receptors. Receptors, tissues and cells are indicated in Table I; results are shown in Table 4A-B." SIGNOR-258504 CDK1 protein P06493 UNIPROT TK1 protein P04183 UNIPROT down-regulates phosphorylation Ser13 LPTVLPGsPSKTRGQ 9606 BTO:0000567 12435275 t gcesareni "Given that the dimeric form of tk1 is less active than the tetrameric, we propose that mitotic phosphorylation of serine-13 is of physiological importance, in that it may counteract atp-dependent activation of tk1 by affecting its quaternary structure, thus attenuating its enzymatic function at the g2/m phase." SIGNOR-95574 PRKCE protein Q02156 UNIPROT BAD protein Q92934 UNIPROT down-regulates phosphorylation Ser75 EIRSRHSsYPAGTED 9606 20179209 t lperfetto "Pkcs phosphorylate bad under in vitro conditions, and the association of phosphorylated bad with pkc-mu or pkc-epsilon, as shown by immunoprecipitation, indicated direct involvement of pkcs in bad phosphorylation. To confirm these results, cells overexpressing pegfp-n1, wt-bad, or bad with a single site mutated (ser112ala;ser136ala;ser155ala), two sites mutated (ser(112/136)ala;ser(112/155)ala;ser(136/155)ala), or the triple mutant were tested. Igf-i protected completely against rapamycin-induced apoptosis in cells overexpressing wt-bad and mutants having either one or two sites of phosphorylation mutated" SIGNOR-163912 CASP1 protein P29466 UNIPROT "Caspase 1 complex" complex SIGNOR-C220 SIGNOR "form complex" binding cleavage:Asp119 PAPQAVQdNPAMPTS 7721861 t lperfetto "The interleukin-1 beta-converting enzyme is a heterodimeric cysteine protease that is produced as a 45-kDa precursor. The full-length precursor form of the enzyme was expressed in Escherichia coli as insoluble inclusion bodies. Following solubilization and refolding of the 45-kDa protein, autoproteolytic conversion to a heterodimeric form containing 10- and 20-kDa subunits was observed." SIGNOR-256386 MAP3K3 protein Q99759 UNIPROT MAP3K3 protein Q99759 UNIPROT up-regulates phosphorylation Ser526 MSGTGMRsVTGTPYW 9606 BTO:0000007 16407301 t lperfetto "Phosphorylation of serine 526 is required for mekk3 activity, and association with 14-3-3 blocks dephosphorylationautophosphorylation of mekk3 at ser526" SIGNOR-143647 HLX protein Q14774 UNIPROT CCNB1 protein P14635 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0003980 20008130 t Luana "In this study, we have identified cell cycle regulatory genes as downstream targets of the homeobox gene HLX in cultured trophoblast cells, namely RB1, MYC, EGR1, CDKN1C, ELK1, CCNB1, and JUN. RB1 and MYC mRNA expression was increased with HLX inactivation, whereas EGR1, CDKN1C, ELK1, CCNB1, and JUN mRNA expression was decreased compared with mock-transfected control cells." SIGNOR-261619 "MLL Fusion" "fusion protein" SIGNOR-FP14 SIGNOR RUNX1 protein Q01196 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 24449215 f miannu "However, the functional consequence of MLL fusions on RUNX1/CBFβ activity has not been fully understood. In this report, we show that MLL fusion proteins and the N-terminal MLL portion of MLL fusions downregulate RUNX1 and CBFβ protein expression via the MLL CXXC domain and flanking regions." SIGNOR-260129 PLN protein P26678 UNIPROT ATP2A2 protein P16615 UNIPROT "down-regulates activity" binding 10090 12838339 t "Heart failure can be traced, in part, to alterations in the activity of the sarcoplasmic reticulum Ca2+ pump that are induced by its interactions with phospholamban, a reversible inhibitor." SIGNOR-252031 ALDH1A3 protein P47895 UNIPROT retinal smallmolecule CHEBI:15035 ChEBI "down-regulates quantity" "chemical modification" 9606 21621639 t lperfetto "All-trans-retinoic acid (atRA) provides essential support to diverse biological systems and physiological processes.| An accrual of biochemical, physiological and genetic data have identified specific functional outcomes for the retinol dehydrogenases, RDH1, RDH10, and DHRS9, as physiological catalysts of the first step in atRA biosynthesis, and for the retinal dehydrogenases RALDH1, RALDH2, and RALDH3, as catalysts of the second and irreversible step." SIGNOR-265128 KATNA1 protein O75449 UNIPROT KATNB1 protein Q9BVA0 UNIPROT "up-regulates activity" binding 9606 BTO:0000567 10751153 t miannu "In its active ATP-bound state, KATNA1 forms hexameric rings capable of binding to and severing microtubule polymers. Typically, KATNA1 binding to KATNB1 enhances severing, likely due to KATNB1 increasing the stability of the KATNA1 hexamer" SIGNOR-267174 GOT1 protein P17174 UNIPROT oxaloacetate(2-) smallmolecule CHEBI:16452 ChEBI "down-regulates quantity" "chemical modification" 9606 26003525 t miannu "Glutamate oxaloacetate transaminase (GOT) catalyzes the reversible reaction of l-aspartate and √É≈Ω√Ǭ±-ketoglutarate into oxaloacetate and L-glutamate and plays a key role in carbon and nitrogen metabolism in all organisms. In human tissues, GOTs are pyridoxal 5'-phosphate-dependent (PLP) enzymes which exist in cytoplasm and mitochondrial forms, GOT1 and GOT2, respectively. GOT1 expression correlates with the growth of several tumors because cancer cells can utilize the amino acid glutamine to fuel anabolic processes, and therefore, GOT1 represents a new therapeutic target in cancer." SIGNOR-268061 G6PC3 protein Q9BUM1 UNIPROT "alpha-D-glucose 6-phosphate(2-)" smallmolecule CHEBI:58225 ChEBI "down-regulates quantity" "chemical modification" 9606 12093795 t miannu "Glucose-6-phosphatase (G6Pase), a key enzyme in glucose homeostasis, is anchored to the endoplasmic reticulum by nine transmembrane helices. The amino acids comprising the catalytic center of G6Pase include Lys(76), Arg(83), His(119), Arg(170), and His(176). During catalysis, a His residue in G6Pase becomes phosphorylated generating an enzyme-phosphate intermediate. Glucose-6-phosphatase (G6Pase,1 EC 3.1.3.9), a key enzyme in glucose homeostasis, catalyzes the hydrolysis of glucose 6-phosphate (G6P) to glucose and phosphate, the terminal steps in gluconeogenesis and glycogenolysis" SIGNOR-266570 C4B protein P0C0L5 UNIPROT "C3 convertase complex" complex SIGNOR-C310 SIGNOR "form complex" binding -1 cleavage:Arg756;Gly1446 KGQAGLQrALEILQE;TPLQLFEgRRNRRRR 17204478 t "complement C4b fragment:PRO_0000042703" lperfetto "However, following cleavage of C4, C2 binds tightly to C4b to form the C4b2 complex" SIGNOR-263398 PRKAA1 protein Q13131 UNIPROT PIAS1 protein O75925 UNIPROT "up-regulates activity" phosphorylation Ser510 SPVSRTPsLPAVDTS 9606 27256105 t Luana "Mechanically, we found that AMPKα1 directly phosphorylated protein inhibitor of activated STAT-1 (PIAS1), the SUMO E3-ligase of Runx2, at serine 510, to promote its SUMO E3-ligase activity. Finally, mutation of protein inhibitor of activated STAT-1 at serine 510 suppressed m" SIGNOR-259866 GTF2A2 protein P52657 UNIPROT TFIIA complex SIGNOR-C395 SIGNOR "form complex" binding 9606 BTO:0000567 7724559 t lperfetto "TFIIA purified from HeLa extracts consists of 35-, 19-, and 12-kDa subunits. Here we describe the isolation of a cDNA clone (hTFIIA gamma) encoding the 12-kDa subunit." SIGNOR-266196 "Ub:E1 (UBA6 substrate)" complex SIGNOR-C496 SIGNOR UBE2U protein Q5VVX9 UNIPROT "up-regulates activity" ubiquitination 9606 34199813 t miannu "The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t" SIGNOR-271371 XBP1 protein P17861-2 UNIPROT Unfolded_Proteins stimulus SIGNOR-ST22 SIGNOR down-regulates 9606 15598891 f miannu "ATF6 and XBP1 are transcription factors activated specifically in response to endoplasmic reticulum (ER) stress. Three cis-acting elements capable of binding to ATF6, XBP1 or both have been identified to date, namely ER stress-response element (ERSE), unfolded protein response element (UPRE) and ERSE-II. ERSE controls the expression of ER-localized molecular chaperones such as BiP that can refold unfolded proteins in the ER; transcription from ERSE is fully activated by ATF6 even in the absence of XBP1. In contrast, transcription from UPRE depends solely on XBP1 and it has been suggested that UPRE may control the expression of components of the ER-associated degradation system that can degrade unfolded proteins in the ER." SIGNOR-260186 TAOK2 protein Q9UL54 UNIPROT MAP2K4 protein P45985 UNIPROT "up-regulates activity" binding 9606 BTO:0001130 10660600 t lperfetto "Immunoprecipitated psk phosphorylates myelin basic protein and transfected psk stimulates mkk4 and mkk7 and activates the c-jun n-terminal kinase mitogen-activated protein kinase pathway." SIGNOR-74864 GOLPH3 protein Q9H4A6 UNIPROT MTOR protein P42345 UNIPROT "up-regulates activity" 9606 BTO:0000018;BTO:0005011 19553991 f "Mechanistically, GOLPH3 regulates cell size, enhances growth factor-induced mTOR signaling in human cancer cells and alters response to mTOR inhibitor in vivo." SIGNOR-253554 CSNK1A1 protein P48729 UNIPROT SMO protein Q99835 UNIPROT up-regulates phosphorylation 9606 21695114 t gcesareni "We demonstrate that mammalian Smo (mSmo) is activated through multi-site phosphorylation of its carboxyl-terminal tail by CK1α and GRK2. Phosphorylation of mSmo induces its active conformation and simultaneously promotes its ciliary accumulation." SIGNOR-174542 MACF1 protein Q9UPN3 UNIPROT GSK3B/Axin/APC complex SIGNOR-C110 SIGNOR "down-regulates activity" 9606 BTO:0000938 16815997 f lperfetto "In the absence of wnt, macf1 associated with a complex that contained axin, betBeta-catenin, gsk3beta, and apc. Upon wnt stimulation, macf1 appeared to be involved in the translocation and subsequent binding of the axin complex to lrp6 at the cell membrane. Macf1 is involved in the translocation of the complex containing axin, Beta-catenin, and gsk3_ but not apc from the cytosol to the cell membrane, where axin and macf1 bind to lrp-5/6. Subsequently, gsk3_ is inactivated by phosphorylation, axin is degraded, and Beta-catenin is released and enters the nucleus, where it can activate the wnt-responsive genes." SIGNOR-228000 TLX1 protein P31314 UNIPROT PPP2CA protein P67775 UNIPROT "down-regulates activity" binding 9606 BTO:0000661 15897879 t 2 miannu "HOX11 also inhibited PP2A serine/threonine phosphatase activity concomitant with stimulation of the AKT/PKB signaling cascade." SIGNOR-240719 BAK1 protein Q16611 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR up-regulates 9606 23567751 f miannu "The mitochondrial pathway of apoptosis proceeds when the outer mitochondrial membrane (OMM) is compromised by the pro-apoptotic BCL-2 family members, BAK and BAX. Once activated, BAK and BAX form proteolipid pores in the OMM leading to mitochondrial outer membrane permeabilization (MOMP), and the release of inner membrane space proteins, such as cytochrome c, which promotes caspase activation." SIGNOR-261493 FZD5 protein Q13467 UNIPROT LRP5 protein O75197 UNIPROT "up-regulates activity" binding 9606 25902418 t areggio "Here we report that Wnt receptor Frizzled (Frz) and theco-receptors LRP5 and LRP6 (LRP5/6) directly interact with each other and this interaction is regulated by the LRP6 ectodomain." SIGNOR-258969 BTK protein Q06187 UNIPROT BMX protein P51813 UNIPROT up-regulates phosphorylation Tyr224 DSNSKKIyGSQPNFN 9606 12573241 t lperfetto "Tec family protein tyrosine kinases (tfks) play a central role in hematopoietic cellular signaling. Initial activation takes place through specific tyrosine phosphorylation situated in the activation loop. Further activation occurs within the sh3 domain via a transphosphorylation mechanism. For bmx, we obtained two phosphorylated sites, y215 and y223 (fig. 6c). The bmx-y215 is a conserved tyrosine, which is homologous to btk-y223 and itk-y180" SIGNOR-98032 WNT5B protein Q9H1J7 UNIPROT LRP6 protein O75581 UNIPROT up-regulates binding 9606 15578921 t gcesareni "Wnt proteins bind to the frizzled receptors and lrp5/6 co-receptors, and through stabilizing the critical mediator betBeta-catenin, initiate a complex signaling cascade that plays an important role in regulating cell proliferation and differentiation." SIGNOR-131888 nalbuphine chemical CHEBI:7454 ChEBI OPRM1 protein P35372 UNIPROT "up-regulates activity" "chemical activation" 10030 BTO:0000246 19282177 t Luana "A series of novel high affinity opioid receptor ligands have been made whereby the phenolic-OH group of nalbuphine, naltrexone methiodide, 6-desoxonaltrexone, hydromorphone and naltrindole was replaced by a carboxamido group and the furan ring was opened to the corresponding 4-OH derivatives. These furan ring “open” derivatives display very high affinity for μ and κ receptors and much less affinity for δ." SIGNOR-258041 BIRC3 protein Q13489 UNIPROT RIPK2 protein O43353 UNIPROT "up-regulates activity" polyubiquitination 9606 BTO:0000007 21931591 t miannu "CIAP1/2 are direct E3 ligases conjugating diverse types of ubiquitin chains to receptor interacting proteins kinases 1 to 4 (RIP1-4).Together, our results demonstrate that depleting cIAP1/2 inhibits RIP1-4 mediated NF-kB activation without affecting RIP auto-phosphorylation." SIGNOR-272715 CTR9 protein Q6PD62 UNIPROT PAF1C complex SIGNOR-C471 SIGNOR "form complex" binding 9606 BTO:0000567 20178742 t miannu "Human PAF1C was affinity purified from a FLAG-hPAF1 HeLa cell line and found to contain homologues (hCTR9, hLEO1, hPAF1, hCDC73 and hRTF1) of the five yeast PAF1C subunits, as well as the SKI8 subunit unique to hPAF1C (Figure 1A). " SIGNOR-269834 GRM5 protein P41594 UNIPROT Excitatory_synaptic_transmission phenotype SIGNOR-PH133 SIGNOR up-regulates 9606 BTO:0000938 24564659 f miannu "Excitatory synaptic transmission in the mammalian brain is mediated primarily by the amino acid glutamate, activating two different groups of glutamate receptors: ionotropic and metabotropic." SIGNOR-264348 PRKAA1 protein Q13131 UNIPROT CYCS protein P99999 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000887;BTO:0001103 17609368 f gcesareni "Severalin vivostudies using aicar to activate ampk chronically determined that mitochondrial enzymes [e.g., cytochromec, uncoupling protein 3 (ucp-3)] (1518) and proteins involved in glucose uptake (glut4) (1820) are increased at the transcriptional level in skeletal muscle." SIGNOR-156772 PML protein P29590 UNIPROT ZFYVE9 protein O95405 UNIPROT up-regulates binding 9606 15356634 t gcesareni "Cytoplasmic pml physically interacts with smad2/3 and sara (smad anchor for receptor activation) and is required for association of smad2/3 with sara and for the accumulation of sara and tgf-beta receptor in the early endosome." SIGNOR-128744 Ub:E2 complex SIGNOR-C497 SIGNOR TRIM49D1 protein C9J1S8 UNIPROT "up-regulates activity" ubiquitination 9606 34199813 t miannu "The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t" SIGNOR-271270 "Glycine cleavage system" complex SIGNOR-C437 SIGNOR (6R)-5,10-methylenetetrahydrofolate(2-) smallmolecule CHEBI:15636 ChEBI "up-regulates quantity" "chemical modification" 9606 16051266 t lperfetto "The glycine cleavage system is a mitochondrial multienzyme system composed of four proteins termed P, H, T and L-protein, and catalyzes the reversible oxidation of glycine yielding carbon dioxide, ammonia, 5,10-methylenetetrahydrofolate (5,10-CH2-H4folate), and reduced pyridine nucleotide." SIGNOR-268239 MAPK8 protein P45983 UNIPROT SP1 protein P08047 UNIPROT up-regulates phosphorylation Thr739 SEGSGTAtPSALITT 9606 19245816 t gcesareni "In addition, for mutation of the jnk-1 phosphorylated residues of sp1, namely, sp1(t278/739a) and sp1(t278/739d), the effect of ga on sp1 stability was reversed." SIGNOR-184194 "Class II MHC:Antigen" complex SIGNOR-C429 SIGNOR CD4 protein P01730 UNIPROT "up-regulates activity" binding 9606 31001252 t scontino "Extracellular domain of¬†CD4, which is responsible for the recognition of its ligands, is composed of four globular Ig-like domains (D1-D4). The N-terminal D1 domain binds to a segment of the non-polymorphic Œ≤2 domain of MHC class II. CD4 is required for the recognition of most antigens in vivo. The presence of the CD4 coreceptor enhances T cell sensitivity to antigens" SIGNOR-267990 ERO1B protein Q86YB8 UNIPROT ERP44 protein Q9BS26 UNIPROT "up-regulates quantity by stabilization" binding 9606 BTO:0000567 11847130 t Simone "Here, we report the functional characterization of a novel UPR-induced ER resident protein (ERp44) that forms mixed disulfides with both hEROs, as well as with partially unfolded Ig subunits." SIGNOR-261048 MAPK8 protein P45983 UNIPROT RCSD1 protein Q6JBY9 UNIPROT "down-regulates activity" phosphorylation Ser68 GQNGEEKsPPNASHP -1 15850461 t miannu "CapZIP was also phosphorylated rapidly by SAPK3/p38γ and SAPK4/p38δ, and even faster and more extensively by JNK1α1, these protein kinases phosphorylating CapZIP in vitro to >3, approx. 2 and >5 mol of phosphate/mol of protein respectively within a few minutes. Following tryptic digestion and C18 chromatography, further sites phosphorylated by JNK1α1 were identified as Ser-68, Ser-83 and Ser-216 (results not shown), and are highlighted in Figure 3.Using this antibody, we showed by immunoblotting that bacterially expressed CapZIP was phosphorylated at Ser-108 by SAPK4/p38δ, JNK1α1 and ERK2 in vitro, as well as by SAPK3/p38γ (results not shown).An important clue to the function of CapZIP and its phosphorylation came from the finding that it binds to the actin-capping protein CapZ (Figure 7A), and that cellular stresses trigger the dissociation of these two proteins (Figure 7B).Such an effect is presumably lost when CapZIP is phosphorylated and dissociates from CapZ." SIGNOR-263085 MMP17 protein Q9ULZ9 UNIPROT ECM stimulus SIGNOR-ST20 SIGNOR down-regulates 17318226 f lperfetto "Historically, MMPs were thought to function mainly as enzymes that degrade structural components of the ECM." SIGNOR-272385 EREG protein O14944 UNIPROT "ErbB receptor family" proteinfamily SIGNOR-PF36 SIGNOR up-regulates binding 9606 16829981 t "inferred from 70% of family members" gcesareni "For example, betacellulin binds to and activates both erbb1 and erbb4, whereas epiregulin binds to erbb1, erbb3 and erbb4." SIGNOR-269873 "CCR4-NOT complex" complex SIGNOR-C439 SIGNOR PUM2 protein Q8TB72 UNIPROT "down-regulates quantity by repression" "post transcriptional regulation" 9606 31320642 t lperfetto "In addition to its role in bulk mRNA decay, CCR4-NOT can also catalyze the deadenylation or promote translational repression of specific mRNA targets to which it is recruited by RNA binding proteins, such as Nanos, Roquin and Puf/Pumilio proteins" SIGNOR-268347 CTSG protein P08311 UNIPROT C3 protein P01024 UNIPROT "up-regulates activity" cleavage Arg748 ASHLGLArSNLDEDI 9606 BTO:0001412 1861080 t miannu "Plasma membrane elastase and cathepsin G from U937 cells cleave C3 into C3a- and C3b-like fragments; further incubation leads to C3c- and C3dg-like fragments, as judged from SDS-PAGE analysis of the digests. Sequencing of the C3b-like fragment purified by reverse phase chromatography indicates that initial cleavage of C3 by purified cathepsin G occurs at two positions in the amino-terminal part of the alpha-chain, at a Arg-Ser bond located between residues 748 and 749 and at a Leu-Asp bond between residues 751 and 752. These proteases are, thus, able to generate, on the U937 surface, active fragments of C3, which are likely to be involved in cell-protein and cell-cell interactions." SIGNOR-256347 1-(3-chlorophenyl)piperazine chemical CHEBI:10588 ChEBI HTR2B protein P41595 UNIPROT "up-regulates activity" "chemical activation" 10036 BTO:0000452 9459568 t miannu "The data in Table 2 show the affinity of a number of compounds for the [3H]rauwolscine labeled human 5-HT2B receptor. All of the competition curves for these compounds yielded slope values that were near unity, i.e, they did not significantly fit a two-site binding model better than a one-site binding model. sured against [3H]rauwolscine (Fig. 4), as would be expected since antagonists typically do not discriminate between the agonist high- and low-affinity states. Note that the correlation line is about 0.25 log units from the line of identity, while still having a slope near unity. In fact many compounds, including haloperidol, m-CPP, rauwolscine, ritanserin, spiroxatrine, yohimbine and 1-NP displayed significantly higher affinity for the [3H]rauwolscine than for the [3H]5-HT labeled human 5-HT2B receptor. measured against [3H]5-HT versus the pKi when mea-" SIGNOR-258684 RPL37A protein P61513 UNIPROT "60S cytosolic large ribosomal subunit" complex SIGNOR-C287 SIGNOR "form complex" binding -1 25901680 t lperfetto "Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins." SIGNOR-262462 EP300 protein Q09472 UNIPROT MEF2C protein Q06413 UNIPROT up-regulates binding 9606 11796223 t lperfetto "Once released from associated repressors, MEF2 is bound by the p300 coactivator, which possesses histone acetyltransferase activity. Thus, the net result of CaMK signaling to MEF2 complexes is increased histone acetylation (Ac), which relaxes chromatin and stimulates MEF2 target gene transcription." SIGNOR-232159 zotepine chemical CHEBI:32316 ChEBI SLC6A2 protein P23975 UNIPROT "down-regulates activity" "chemical inhibition" 9606 20223878 t Luana "These results collectively demonstrate that norZTP exerts more potent inhibitory action than ZTP on norepinephrine transporters both in vitro and in vivo, presumably accounting for its antidepressant-like effect and low EPS propensity." SIGNOR-257828 CDK4 protein P11802 UNIPROT FOXM1 protein Q08050 UNIPROT up-regulates phosphorylation Ser4 sPRRPLIL 9606 22094256 t lperfetto "We identified the forkhead box m1 (foxm1) transcription factor as a common critical phosphorylation target. Cdk4/6 stabilize and activate foxm1these data identify five overlapping in vivo and in vitro cdk4/6 target sites in foxm1 (s4, s35, t611, t620 and t627)" SIGNOR-177251 GDNF protein P39905 UNIPROT ID3 protein Q02535 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10116 BTO:0002881 15212950 f miannu "We characterize the network of 43 genes induced by GDNF overproduction of neuronal progenitor cells (ST14A), which mainly regulate migration and differentiation of neuronal progenitor cells.Laminin, Mpl3, Alcam, Bin1, Id1, Id2, Id3, neuregulin1, the ephrinB2-receptor, neuritin, focal adhesion kinase (FAK), Tc10, Pdpk1, clusterin, GTP-cyclooxygenase1, and follistatin are genes up-regulated by GDNF overexpression." SIGNOR-252181 PTPN22 protein Q9Y2R2 UNIPROT CD247 protein P20963 UNIPROT "down-regulates activity" dephosphorylation 9606 BTO:0000007 16461343 t "In vitro experiments with purified recombinant proteins demonstrated that PTPN22-D195A/C227S interacted directly with activated Lck, Zap70, and TCRzeta, confirming the initial substrate trap results. Native PTPN22 dephosphorylated Lck and Zap70 at their activating tyrosine residues Tyr-394 and Tyr-493, respectively, but not at the regulatory tyrosines Tyr-505 (Lck) or Tyr-319 (Zap70). Native PTPN22 also dephosphorylated TCRzeta in vitro and in cells, and its substrate trap variant co-immunoprecipitated with TCRzeta when both were coexpressed in 293T cells, establishing TCRzeta as a direct substrate of PTPN22." SIGNOR-248837 ALDH1A3 protein P47895 UNIPROT "all-trans-retinoic acid" smallmolecule CHEBI:15367 ChEBI "up-regulates quantity" "chemical modification" 9606 21621639 t lperfetto "All-trans-retinoic acid (atRA) provides essential support to diverse biological systems and physiological processes.| An accrual of biochemical, physiological and genetic data have identified specific functional outcomes for the retinol dehydrogenases, RDH1, RDH10, and DHRS9, as physiological catalysts of the first step in atRA biosynthesis, and for the retinal dehydrogenases RALDH1, RALDH2, and RALDH3, as catalysts of the second and irreversible step." SIGNOR-265129 CyclinE/CDK2 complex SIGNOR-C16 SIGNOR NPM1 protein P06748 UNIPROT "down-regulates activity" phosphorylation Thr199 VKKSIRDtPAKNAQK 11278991 t llicata "Here, we identified that threonine 199 (Thr(199)) of NPM/B23 is the major phosphorylation target site of CDK2-cyclin E in vitro, and the same site is phosphorylated in vivo.|NPM/B23 binds specifically to unduplicated centrosomes and loses its centrosome binding activity when phosphorylated by CDK2-cyclin E" SIGNOR-250744 MAPK1 protein P28482 UNIPROT CTTN protein Q14247 UNIPROT up-regulates phosphorylation Ser405 KTQTPPVsPAPQPTE 9606 BTO:0000938 20444238 t gcesareni "Cortactin is regulated by multiple phosphorylation events, including phosphorylation of s405 and s418 by extracellular regulated kinases (erk)1/2. Erk1/2 phosphorylation of cortactin has emerged as an important positive regulatory modification, enabling cortactin to bind and activate the arp2/3 regulator neuronal wiskott-aldrich syndrome protein (n-wasp), promoting actin polymerization and enhancing tumor cell movement." SIGNOR-165200 SATB1 protein Q01826 UNIPROT HSPA6 protein P17066 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0000664 17343824 f miannu "We found 59 up-regulated and 75 down-regulated genes in the K562-SATB1 cells that were not observed in the K562 cells. Partial genes that have special biological functions are listed in Table 1." SIGNOR-255134 "Tandospirone citrate" chemical CHEBI:32182 ChEBI HTR1A protein P08908 UNIPROT "up-regulates activity" "chemical activation" 10029 BTO:0000246 9760039 t miannu "A range of serotonergic agonists and partial agonists were tested for their capacity to stimulate 5-HT1A receptor mediated GTPg binding in CHO-h5-HT1A membranes. The methoxynaphtylpiperazine ligand, S 14671,was the most potent agonist tested, with virtually full agonist activity, relative to 5-HT Table 1; Fig. 2C consistent with its exceptionally potent and efficacious actions in in vivo functional paradigms. Its analogue, S 14506 was also a highly potent and efficacious ligand (Emax90%) in agreement with previous in vivo studies ( Schreiber et al., 1994 ). (+)UH 301 exhibited partial agonist activity at 5-HT1A receptors" SIGNOR-258861 PRPS1 protein P60891 UNIPROT Nucleotide_synthesis phenotype SIGNOR-PH179 SIGNOR up-regulates 9606 BTO:0006038 29074724 f lperfetto "We demonstrate here that glucose deprivation or hypoxia results in the AMPK-mediated phosphorylation of phosphoribosyl pyrophosphate synthetase 1 (PRPS1) S180 and PRPS2 S183, leading to conversion of PRPS hexamers to monomers and thereby inhibiting PRPS1/2 activity, nucleotide synthesis, and nicotinamide adenine dinucleotide (NAD) production." SIGNOR-265733 GSK3B protein P49841 UNIPROT SMAD1 protein Q15797 UNIPROT down-regulates phosphorylation 9606 18045539 t gcesareni "Phosphorylation at the gsk3 sites represses the transcriptional activity of smad1 by enhancing proteasomal degradation of psmad1cter" SIGNOR-159484 PRKDC protein P78527 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR "up-regulates activity" phosphorylation Ser473 RPHFPQFsYSASGTA 9606 BTO:0001949 18439899 t gcesareni "DNA-PK phosphorylates HM Ser473 of PKB. However, we also noted similar patterns in T loop Thr308 phosphorylation after _-IR []his function is apparently restricted to the PKBalpha isoform" SIGNOR-252447 DBP protein Q10586 UNIPROT Gluconeogenesis phenotype SIGNOR-PH35 SIGNOR up-regulates 9606 21633182 f miannu "In addition to NHRs, Dbp, a known clock target gene, regulates expression of key metabolic genes involved in gluconeogenesis and lipogenesis (60). Because DBP levels change 100-fold in response to CLOCK/BMAL1 activation, it is conceivable that DBP generates circadian oscillation in metabolic processes such as gluconeogenesis." SIGNOR-268028 "Daunorubicin hydrochloride" chemical CHEBI:31456 ChEBI TOP2A protein P11388 UNIPROT "down-regulates activity" "chemical inhibition" 9606 1963303 t miannu "DNA topoisomerase II as the primary target of anti-tumor anthracyclines.Such studies have also given evidence of the peculiar features of the drug interference with DNA topoisomerase II activity. In contrast to other cytotoxic topoisomerase II inhibitors (acridines, epipodophyllotoxins), anthracyclines produce persistent DNA cleavable complexes. This property is more evident with doxorubicin derivatives than with daunorubicin derivatives." SIGNOR-259322 PRKCD protein Q05655 UNIPROT NCF1 protein P14598 UNIPROT up-regulates phosphorylation Ser370 PAVPPRPsADLILNR 9606 BTO:0000130 12056906 t esanto "Pkc alpha, beta ii, delta, and zeta expressed in human neutrophils can individually phosphorylate p47(phox) and induce both its translocation and nadph oxidase activation. The use of p47phox mutants identified serines 303, 304, 315, 320, 328, 359, 370, and 379 as targets of pkc?, ???, And ?." SIGNOR-89241 XAV939 chemical CHEBI:62878 ChEBI AXIN2 protein Q9Y2T1 UNIPROT up-regulates 9606 19759537 f gcesareni "Using a quantitative chemical proteomic approach, we discovered that xav939 stabilizes axin by inhibiting the poly-adp-ribosylating enzymes tankyrase 1 and tankyrase 2" SIGNOR-188048 CEP68 protein Q76N32 UNIPROT CDK5RAP2 protein Q96SN8 UNIPROT "up-regulates activity" relocalization 25503564 t lperfetto "We also found that Cep68 forms a complex with Cep215 (also known as Cdk5Rap2) and PCNT (also known as pericentrin), two PCM (pericentriolar material) proteins involved in centriole engagement. |Retention of Cep68 or PCNT in late mitosis prevents the removal of Cep215" SIGNOR-275624 UBE2D3 protein P61077 UNIPROT ZSWIM2 protein Q8NEG5 UNIPROT "up-regulates activity" binding 9606 BTO:0000007 16522193 t miannu "MEX can act as an E3, Ub (ubiquitin) ligase, through the E2, Ub-conjugating enzymes UbcH5a, UbcH5c or UbcH6. A region of MEX that contains the RING fingers and the ZZ zinc finger was required for interaction with UbcH5a and MEX self-association, whereas the SWIM domain was critical for MEX ubiquitination. The expression of MEX promoted apoptosis that was induced through Fas, DR (death receptor) 3 and DR4 signalling, but not that mediated by the BH3 (Bcl-2 homology 3)-only protein BimEL or the chemotherapeutic drug adriamycin. " SIGNOR-271557 PDPK1 protein O15530 UNIPROT RPS6KB2 protein Q9UBS0 UNIPROT "up-regulates activity" phosphorylation Ser370 TRQTPVDsPDDTALS -1 11733037 t miannu " Mutational analysis revealed that the phosphorylation of Thr241 and Thr401 in p70beta1 was indispensable for the kinase activity. In contrast, a p70beta1 mutant in which Ser383 was substituted with Gly (S383G) still retained nearly the half maximal activity. Sequential phosphorylation of wild-type and S383G mutant of p70beta1 with mTOR and 3-phosphoinositide-dependent protein kinase 1 (PDK1) in vitro synergistically activated their kinase activities." SIGNOR-250371 AKT1 protein P31749 UNIPROT ACOT4 protein Q8N9L9 UNIPROT "up-regulates quantity by stabilization" phosphorylation Ser392 GGEPRAHsKAQEDAW 9606 BTO:0001861 33148467 t lperfetto "HSPA1A was found to associate with ACOT4. Furthermore, we found that phosphorylation of ACOT4 at S392 by AKT decreased the binding of ACOT4 to HSPA1A, resulting in ACOT4 accumulation. |AKT phosphorylates ACOT4 at S392 and promotes ACOT4 stability" SIGNOR-271820 STAP1 protein Q9ULZ2 UNIPROT TEC protein P42680 UNIPROT "up-regulates activity" binding 9606 BTO:0000007 10518561 t miannu "In 293 cells expressing recombinant BRDG1 and various PTKs, Tec and Pyk2, but not Btk, Bmx, Lyn, Syk, or c-Abl, induced marked phosphorylation of BRDG1 on tyrosine residues. BRDG1 was also phosphorylated by Tec directly in vitro. Furthermore, BRDG1 was shown to participate in a positive feedback loop by increasing the activity of Tec. BRDG1 thus appears to function as a docking protein acting downstream of Tec in BCR signaling. BRDG1 may activate Tec by disrupting an intramolecular interaction." SIGNOR-261819 PTEN protein P60484 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR "down-regulates activity" 9606 BTO:0001271 20596030 f lperfetto "Exposure of eol-1r cells to imatinib failed to dephosphorylate akt, erk and stat5, although pdgfralpha was effectively inactivated. The forced expression of pten negatively regulated these signal pathways and sensitized eol-1r cells to imatinib." SIGNOR-166478 GOT2 protein P00505 UNIPROT L-glutamate(1-) smallmolecule CHEBI:29985 ChEBI "up-regulates quantity" "chemical modification" 9606 31422819 t miannu "This is a pyridoxal 5‚Ä≤-phosphate (PLP)-dependent enzyme that exists as cytosolic (GOT1) and intramitochondrial (GOT2) isoforms. Both isoforms catalyze the reversible interconversion of oxaloacetate and glutamate into aspartate and Œ±-ketoglutarate. These enzymes are part of the malate-aspartate shuttle (MAS), a key player in intracellular NAD(H) redox homeostasis (Figure 1)." SIGNOR-267518 CHEK2 protein O96017 UNIPROT CDC25A protein P30304 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser279 VLKRPERsQEESPPG 9606 12676583 t "Phosphorylation is the signal for ubiquitination" gcesareni "We show that ir-induced destruction of cdc25a requires both atm and the chk2-mediated phosphorylation of cdc25a on serine 123. the basal turnover of cdc25a operating in unperturbed s phase required chk1-dependent phosphorylation of serines 123, 178, 278, and 292. Ir-induced acceleration of cdc25a proteolysis correlated with increased phosphate incorporation into these residues generated by a combined action of chk1 and chk2 kinases." SIGNOR-99729 CYP11B2 protein P19099 UNIPROT 11-deoxycortisol smallmolecule CHEBI:28324 ChEBI "down-regulates quantity" "chemical modification" 9606 BTO:0000050 9814482 t lperfetto "Recombinant CYP11B genes encode enzymes that can catalyze conversion of 11-deoxycortisol to cortisol, 18-hydroxycortisol, and 18-oxocortisol." SIGNOR-268677 SRCAP protein Q6ZRS2 UNIPROT AR protein P10275 UNIPROT "up-regulates activity" binding 9606 20432434 t miannu "The SNF2-related CBP activator protein (SRCAP) serves as a coactivator for several nuclear receptors including the androgen receptor (AR). SRCAP is an ATPase that is the core subunit of a large multiprotein complex and was shown to incorporate the histone variant H2A.Z into nucleosomes. In this report, we demonstrate that SRCAP is expressed in the epithelium of normal prostate and in prostate carcinoma cells, and is associated with AR in the nucleus" SIGNOR-255221 SRPK1 protein Q96SB4 UNIPROT SRPK1 protein Q96SB4 UNIPROT up-regulates phosphorylation Thr326 ENPPNKMtQEKLEES 9606 22727668 t llicata "We found that activated akt binds and induces srpk1 autophosphorylation because akt-mediated phosphorylation depends on the kinase activity of srpk1" SIGNOR-197993 CSNK2A1 protein P68400 UNIPROT EIF2B5 protein Q13144 UNIPROT "up-regulates activity" phosphorylation Ser717 LKEAEEEsSEDD 9606 BTO:0000007 11500362 t llicata "Two conserved sites (Ser712/713) are phosphorylated by casein kinase 2. They lie at the extreme C-terminus and are required for the interaction of eIF2Bepsilon with its substrate, eIF2, in vivo and for eIF2B activity in vitro. " SIGNOR-250859 SRC protein P12931 UNIPROT NOS2 protein P35228 UNIPROT up-regulates phosphorylation Tyr151 IEFVNQYyGSFKEAK 9606 19875457 t llicata "We identify human inos residue tyr(1055) as a target for src-mediated phosphorylation. src kinase-mediated phosphorylation stabilizes inducible nitric-oxide synthase in normal cells and cancer cells." SIGNOR-188974 TIMP3 protein P35625 UNIPROT Adipogenesis phenotype SIGNOR-PH26 SIGNOR "down-regulates activity" 10090 BTO:0005300 28709001 f "Hh signaling through FAP cilia regulated the expression of TIMP3, a secreted metalloproteinase inhibitor, that inhibited MMP14 to block adipogenesis. A pharmacological mimetic of TIMP3 blocked the conversion of FAPs into adipocytes" SIGNOR-255906 AGT protein P01019 UNIPROT AGTR1 protein P30556 UNIPROT up-regulates binding 9606 BTO:0001130 16597412 t gcesareni "Endothelin-1 (et-1) and angiotensin ii (angii), two potent vasoactive peptides involved in the regulation of cardiovascular homeostasis, also induce mitogenic and pro-angiogenic responses in vitro and in vivo. Both peptides are produced by cleavage of inactive precursors by metalloproteases (endothelin-converting enzyme and angiotensin-converting enzyme, respectively) and activate two subtypes of membrane receptors (eta-r and etb-r for et-1, at1r and at2r for angii) that all belong to the superfamily of g-protein coupled receptors." SIGNOR-145677 GBE1 protein Q04446 UNIPROT α-D-glucosyl-glycogenin complex SIGNOR-C430 SIGNOR "down-regulates quantity" "chemical modification" 9606 26199317 t miannu "Glycogen branching enzyme 1 (GBE1) plays an essential role in glycogen biosynthesis by generating α-1,6-glucosidic branches from α-1,4-linked glucose chains, to increase solubility of the glycogen polymer. In eukaryotes, glycogenin (EC 2.4.1.186) initiates the synthesis of the linear glucan chain (2), which is elongated by glycogen synthase (GYS, EC 2.4.1.11) (3), functioning in concert with glycogen branching enzyme (GBE, EC 2.4.1.18) to introduce side chains" SIGNOR-267941 miR-155 mirna URS000062749E_9606 RNAcentral TRIB2 protein Q92519 UNIPROT "up-regulates quantity by expression" "post transcriptional regulation" 9606 20516212 t Luisa "ZEB2 is upregulated by serum and downregulates GAX, while the expression of miR-221 upregulates GAX and downregulates ZEB2." SIGNOR-268956 DLGAP3 protein O95886 UNIPROT SHANK1 protein Q9Y566 UNIPROT "up-regulates activity" relocalization 9606 BTO:0000938 28179641 t miannu "SHANK proteins are ‘master’ scaffolding proteins that tether and organize intermediate scaffolding proteins. They are located at excitatory synapses, where they are crucial for proper synaptic development and function. SAPAP proteins subsequently bind to the PDZ domain of members of the SHANK protein family. SHANK proteins then bind to the actin cytoskeleton and to Homer protein, which in turn interacts with mGluRs. Through these extended links, PSD95, SAPAP, SHANK and Homer proteins form a quaternary complex that brings together mGluR and NMDAR complexes in the PSD (FIG. 3)." SIGNOR-264592 zotepine chemical CHEBI:32316 ChEBI HTR1A protein P08908 UNIPROT "down-regulates activity" "chemical inhibition" 10116 8935801 t miannu "Risperidone and its active metabolite 9-OH-risperidone were compared to reference antipsychotic drugs (haloperidol, pipamperone, fluspirilene, clozapine, zotepine) and compounds under development (olanzapine, seroquel, sertindole, ORG-5222, ziprasidone) for in vitro binding to neurotransmitter receptors in brain tissue and on membranes of recombinant cells expressing cloned human receptors and for in vivo occupancy of neurotransmitter receptors in rat and guinea-pig brain following acute treatment (2 h., s.c.). The binding affinities of the compounds for various neurotransmitter receptors were measured using membrane preparations of animal brain regions and of recombinant cells expressing cloned, mostly human receptors. Receptors, tissues and cells are indicated in Table I; results are shown in Table 4A-B." SIGNOR-258558 CREB1 protein P16220 UNIPROT NR4A3 protein Q92570 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000782 17668895 f gcesareni "Phosphorylation of creb by msk has been linked to the transcription of nur77, nor1 and c-fos downstream of mapk signalling in various cell types." SIGNOR-157154 CDK1 protein P06493 UNIPROT BRCA1 protein P38398 UNIPROT up-regulates phosphorylation Ser1189 QKGELSRsPSPFTHT 9606 BTO:0000150 10550055 t gcesareni "However, shrna-mediated depletion of cdk1 alone or small molecule cdk1 inhibition abrogated s phase cell-cycle arrest and the phosphorylation of a subset of atr/atm targets after dna damage. Loss of dna damage-induced checkpoint control was caused by a reduction in formation of brca1-containing foci. Mutation of brca1 at s1497 and s1189/s1191 resulted in loss of cdk1-mediated phosphorylation and also compromised formation of brca1-containing foci." SIGNOR-72083 ITGB6 protein P18564 UNIPROT "Av/b6 integrin" complex SIGNOR-C179 SIGNOR "form complex" binding 16988024 t lperfetto "Integrins are one of the major families of cell adhesion receptors (Humphries, 2000; Hynes, 2002). All integrins are non-covalently-linked, heterodimeric molecules containing an α and a β subunit. Both subunits are type I transmembrane proteins, containing large extracellular domains and mostly short cytoplasmic domains (Springer and Wang, 2004; Arnaout et al., 2005). Mammalian genomes contain 18 α subunit and 8 β subunit genes, and to date 24 different α,β combinations have been identified at the protein level. Although some subunits only appear in a single heterodimer, twelve integrins contain the β1 subunit, and five contain αV." SIGNOR-253210 IKBKG protein Q9Y6K9 UNIPROT IKBKB protein O14920 UNIPROT "up-regulates activity" binding 9606 SIGNOR-C14 SIGNOR-C14 12192055 t lperfetto "The n-terminal domain of ikkgamma is required both for the binding of ikkalfa and ikkbeta and their assembly into a high-molecular-weight complex essential for activation" SIGNOR-91705 RPL22 protein P35268 UNIPROT "60S cytosolic large ribosomal subunit" complex SIGNOR-C287 SIGNOR "form complex" binding -1 25901680 t lperfetto "Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins." SIGNOR-262499 MAP4K1 protein Q92918 UNIPROT LCP2 protein Q13094 UNIPROT up-regulates phosphorylation Ser376 SSFPQSAsLPPYFSQ 9606 BTO:0000782 17353368 t lperfetto "The serine/threonine kinase hpk-1 phosphorylates serine 376 of slp-76 and induces the interaction with 14-3-3 proteins" SIGNOR-153613 CAMK2A protein Q9UQM7 UNIPROT PEA15 protein Q15121 UNIPROT up-regulates phosphorylation Ser116 KDIIRQPsEEEIIKL 9606 15916534 t gcesareni "Pea-15 is a phosphoprotein containing a ser-104 phosphorylated by protein kinase c and a ser-116 phosphorylated by camkii (calcium/calmodulin-dependent protein kinase ii) or akt. Phosphorylation of ser-104 is implicated in the regulation of glucose metabolism, while phosphorylation at ser-116 is required for pea-15 recruitment to the disc (death-initiation signalling complex)" SIGNOR-137614 PPP2CB protein P62714 UNIPROT PRKCD protein Q05655 UNIPROT "down-regulates activity" dephosphorylation Ser645 LNEKARLsYSDKNLI 10090 BTO:0000944 11959144 t "PP2A(c) displayed the highest specific activity towards PKCdelta. The role of PP2A(c) in the dephosphorylation of PKCdelta in cells was supported by the demonstration that these proteins could be co-immunoprecipitated from NIH3T3 cells.|In conclusion, the evidence here indicates that PKCdelta de-phosphorylation and hence inactivation is effected by PP2A with which it forms a complex" SIGNOR-248595 USP5 protein P45974 UNIPROT UBC protein P0CG48 UNIPROT "up-regulates quantity" cleavage 9606 BTO:0000567 26235645 t miannu "Here we provide data suggesting that two of the four mammalian ubiquitin precursors, UBA52 and UBA80, are processed mostly post-translationally whereas the other two, UBB and UBC, probably undergo a combination of co- and post-translational processing. Using an unbiased biochemical approach we found that UCHL3, USP9X, USP7, USP5 and Otulin/Gumby/FAM105b are by far the most active DUBs acting on these precursors." SIGNOR-270822 GATA2 protein P23769 UNIPROT Adipogenesis phenotype SIGNOR-PH26 SIGNOR down-regulates 10090 11021798 f fspada "Constitutive gata-2 and gata-3 expression suppressed adipocyte differentiation and trapped cells at the preadipocyte stage." SIGNOR-78659 PTPN13 protein Q12923 UNIPROT PDCD10 protein Q9BUL8 UNIPROT down-regulates dephosphorylation 9606 17657516 t gcesareni "We also show that ccm3 directly binds to serine/threonine kinase 25 (stk25, ysk1, sok1) and the phosphatase domain of fas-associated phosphatase-1 (fap-1, ptpn13, ptp-bas, ptp-bl)." SIGNOR-157076 PRKCA protein P17252 UNIPROT AQP1 protein P29972 UNIPROT up-regulates phosphorylation Thr157 VLCVLATtDRRRRDL 9606 BTO:0000671 17522053 t llicata "Activation of protein kinase c (pkc) by 1-oleoyl-2-acetyl-sn-glycerol (oag) induced a marked increase of aqp1-dependent water permeability. This regulation was abolished in mutated aqp1 channels lacking both consensus pkc phosphorylation sites thr(157) and thr(239) (termed aqp1 deltapkc)." SIGNOR-155102 MMP7 protein P09237 UNIPROT DCN protein P07585 UNIPROT "down-regulates quantity by destabilization" cleavage Glu273 ANTPHLReLHLDNNK -1 9148753 t miannu "Degradation of decorin by matrix metalloproteinases. These data indicate proteolytic degradation of DCN by MMP-2, MMP-3 and MMP-7, and suggest the possibility that, under pathophysiological conditions, the digestion by the MMPs may induce tissue reactions mediated by TGF-beta1 released from DCN in the connective tissues." SIGNOR-256352 EPX protein P11678 UNIPROT EPX protein P11678 UNIPROT "up-regulates activity" "post translational modification" 9606 BTO:0000399 18694936 t miannu "Human eosinophils are bone marrow-derived, non-dividing granulocytes of the innate immune system, which store the highly cationic proteins eosinophil peroxidase (EPO), major basic protein (MBP), eosinophil-derived neurotoxin (EDN), and eosinophil cationic protein (ECP) in secondary granules. we demonstrated that Tyr nitration of the eosinophil granule proteins is exclusively mediated by EPO, in the presence of functional NADPH oxidase and minute amounts of NOx. EPO appears to nitrate itself via an autocatalytic mechanism." SIGNOR-261706 STAT5A protein P42229 UNIPROT SOCS3 protein O14543 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 12468433 t "We have also found SOCS2 and SOCS3 specifically induced in 32D/Flt3-ITD, both of which are STAT3/5 target genes and known negative regulators of receptor signaling" SIGNOR-261548 CAMK2D protein Q13557 UNIPROT TPD52 protein P55327 UNIPROT unknown phosphorylation Ser176 KNSPTFKsFEEKVEN 9606 20946871 t gcesareni "Here we demonstrate, using site-specific mutations, that ca(2+)-sensitive phosphorylation at serine 136 modulates the accumulation of d52 at the plasma membrane within 2 min of cell stimulation" SIGNOR-168550 AKT2 protein P31751 UNIPROT FOXO1 protein Q12778 UNIPROT "down-regulates activity" phosphorylation Thr24 LPRPRSCtWPLPRPE 9606 10377430 t lperfetto "Our results demonstrate that pkb/akt directly phosphorylates fkhr1, a member of the closely related fkhr subclass of the forkhead family of transcription factors, on at least two residues (threonine-24 and serine-253). These results indicate that phosphorylation by pkbyakt negatively regulates fkhr1 by promoting export from the nucleus." SIGNOR-68656 MIF protein P14174 UNIPROT HBB protein P68871 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 16636133 f "Regulation of expression" miannu "MIF inhibits cytodifferentiation and hemoglobin synthesis of MEL cells." SIGNOR-251831 GPS1 protein Q13098 UNIPROT "COP9 signalosome variant 2" complex SIGNOR-C487 SIGNOR "form complex" binding 9606 18850735 t miannu "The COP9 signalosome (CSN) is a multiprotein complex that plays a critical role in diverse cellular and developmental processes in various eukaryotic organisms. we have performed a comprehensive proteomic analysis of the human CSN complex using a new purification method and quantitative mass spectrometry. Purification of the human CSN complex from a stable 293 cell line expressing N-terminal HBTH-tagged CSN5 subunit was achieved by high-affinity streptavidin binding with TEV cleavage elution." SIGNOR-270765 MAP3K7 protein O43318 UNIPROT MAP3K7 protein O43318 UNIPROT "up-regulates activity" phosphorylation Thr178 LKICDFGtACDIQTH -1 20538596 t lperfetto "Analyses of phosphorylation site mutants of the activation segment indicate that autophosphorylation of Ser-192 precedes TAB1 phosphorylation and is followed by sequential phosphorylation of Thr-178, Thr-187, and finally Thr-184. Finally, we present a model for the chronological order of events governing TAB1-induced TAK1 autoactivation." SIGNOR-227536 DOK4 protein Q8TEW6 UNIPROT FYN protein P06241 UNIPROT up-regulates binding 9606 BTO:0000887;BTO:0001103;BTO:0000671 12730241 t gcesareni "Insulin receptor-phosphorylated irs5/dok4 associates with rasgap, crk, src, and fyn, but not phosphatidylinositol 3-kinase p85, grb2, shp-2, nck, or phospholipase cgamma src homology 2 domains, and activates mapk in cells." SIGNOR-100999 PRSS3 protein P35030 UNIPROT F2RL1 protein P55085 UNIPROT "up-regulates activity" cleavage Lys34 QGTNRSSkGRSLIGK -1 10978167 t lperfetto "PAR1E and PAR2E (10 microM) were incubated in the presence of the different proteases | The enzymes were used at the following concentrations: 0.5 unit/mL thrombin, 2.5 nM trypsin, 20 nM plasmin, 20 nM cathepsin G, 20 nM elastase, 20 nM proteinase 3, and 2 units/mL calpain I and II|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus.|Mass spectrometry studies of PAR2E predicted activation of PAR2 by trypsin through cleavage at the Arg36-Ser37 site, no effect of thrombin, and inactivation of the receptor by plasmin, calpain and leukocyte elastase, cathepsin G, and proteinase 3" SIGNOR-263607 Wnt proteinfamily SIGNOR-PF40 SIGNOR CTNNB1 protein P35222 UNIPROT "up-regulates quantity by stabilization" 17081971 f "The central player in the canonical Wnt cascade is β-catenin, a cytoplasmic protein whose stability is regulated by the destruction complex." SIGNOR-256240 PTPN22 protein Q9Y2R2 UNIPROT CD247 protein P20963 UNIPROT down-regulates dephosphorylation 9606 BTO:0000007 16461343 t amattioni "T cell signaling is negatively regulated by the activity of protein-tyrosine phosphatases. Native ptpn22 dephosphorylated tcrzeta in vitro and in cells." SIGNOR-144337 ULK1/Atg13/Fip200 complex SIGNOR-C100 SIGNOR AMBRA1 protein Q9C0C7 UNIPROT "up-regulates activity" phosphorylation 10090 20921139 t lperfetto "When autophagy is induced, ulk1 phosphorylates ambra1, releasing the autophagy core complex from dynein. Its subsequent relocalization to the endoplasmic reticulum enables autophagosome nucleation. Ambra1-dlc1 dissociates from the dynein complex upon ulk1-dependent ambra1 phosphorylation." SIGNOR-219388 PRKACA protein P17612 UNIPROT VASP protein P50552 UNIPROT unknown phosphorylation Ser157 EHIERRVsNAGGPPA 9606 16197368 t llicata "We show that, in human platelets, vasp is phosphorylated by pkc on ser157, but not ser239, in response to phorbol ester stimulation, in a manner blocked by the pkc inhibitor bim i (bisindolylmaleimide i)." SIGNOR-140841 2-[[5-methoxy-1-[4-(trifluoromethyl)phenyl]pentylidene]amino]oxyethanamine chemical CHEBI:93274 ChEBI SLC6A4 protein P31645 UNIPROT "down-regulates activity" "chemical inhibition" 9606 BTO:0000007 9537821 t miannu "Among the antidepressants that we tested, paroxetine, which is a serotonin selective re-uptake inhibitor based on animal data, was the most potent for the human serotonin transporter with a KD=0.13±0.01 nM. Some tricyclic antidepressants (clomipramine, imipramine and amitriptyline), as well as some other antidepressants (sertraline, fluoxetine, citalopram and fluvoxamine) and some of their metabolites (norfluoxetine, desmethylsertraline and desmethylcitalopram) were also very potent at the human serotonin transporter." SIGNOR-258880 PRKCA protein P17252 UNIPROT CLIP1 protein P30622 UNIPROT down-regulates phosphorylation Ser312 ASLKRSPsASSLSSM 9606 20519438 t lperfetto "Furthermore, by using phosphoproteomic analysis, we determined that s309 and s311 of clip-170 are phosphorylated in cells and mapped s311 as a protein kinase a (pka) phosphorylation site.phosphorylation of s311 may be critical for establishing the ?folded Back? Conformation of clip-170clip-170 open and folded back conformations represent active and inactive modes of the protein, respectively" SIGNOR-165857 MAPK14 protein Q16539 UNIPROT TP53 protein P04637 UNIPROT "up-regulates activity" phosphorylation Ser46 AMDDLMLsPDDIEQW 9606 BTO:0000093 10581258 t lperfetto "P38 regulates p53, but also in p53-defective tumor cells rewire their checkpoint response and become dependent in the p38/mk2 pathway in mcf-7 cells, p38 kinase activated p53 more effectively than other members of the ras pathway. p53 and p38 kinase exist in the same physical complex, and co-expression of p38 stabilized p53 protein. In vitro, p38 kinase phosphorylated p53 at ser33 and ser46, a newly identified site." SIGNOR-72703 SPAG5 protein Q96R06 UNIPROT CENPF protein P49454 UNIPROT "up-regulates activity" 9606 BTO:0000567 17664331 f lperfetto "Furthermore, although both the core kinetochore protein Hec1 and the spindle checkpoint kinase Bub1 were unaffected (Fig. 3 C), the kinetochore resident motor protein CENP-E (Yen et al., 1992) and its interaction partner CENP-F (Chan et al., 1998) were delocalized from the kinetochore in the absence of astrin. These cells remained cyclin B1 positive (unpublished data), confirming that they were still in mitosis. These data suggest that the presence of astrin is required for the kinetochore recruitment or maintenance of CENP-E and CENP-F." SIGNOR-252042 AMPK complex SIGNOR-C15 SIGNOR RPTOR protein Q8N122 UNIPROT down-regulates phosphorylation Ser722 PRLRSVSsYGNIRAV 10090 SIGNOR-C15 SIGNOR-C3 18439900 t lperfetto "These results suggest that AMPK activation can induce phosphorylation of both serine 722 and serine 792.|Raptor phosphorylation is required for inhibition of mTORC1 by AMPK" SIGNOR-263046 PRKACA protein P17612 UNIPROT PDE3A protein Q14432 UNIPROT unknown phosphorylation Ser312 SKSHRRTsLPCIPRE 9606 16153182 t llicata "Ser312 of pde3a was phosphorylated in an h-89-sensitive response to forskolin, indicative of phosphorylation by pka (camp-dependent protein kinase), but phosphorylation at this site did not stimulate 14-3-3 binding." SIGNOR-140289 Ub:E2 complex SIGNOR-C497 SIGNOR MGRN1 protein O60291 UNIPROT "up-regulates activity" ubiquitination 9606 34199813 t miannu "The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t" SIGNOR-271144 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR Fibrosis phenotype SIGNOR-PH90 SIGNOR up-regulates 9606 18483217 f "PDGF signaling has been implicated in several fibrotic conditions and is assumed to play a role in driving proliferation of cells with a myofibroblast phenotype." SIGNOR-254373 caesium(1+) chemical CHEBI:49547 ChEBI KCNJ13 protein O60928 UNIPROT "down-regulates activity" "chemical inhibition" 9606 BTO:0000007 9620703 t miannu "Figure 4 shows the response of Kir7.1 to increasing [Ba2+]o. The EC50 for Ba2+ block was 1 mM (Figure 4C), independent of the type of cell in which the channel was expressed. Other known inward rectifier K+ channels are sensitive to inhibition at much lower concentrations" SIGNOR-258926 MAF protein O75444 UNIPROT MMP13 protein P45452 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 20067416 f miannu "MMP-13 gene expression is regulated primarily at the transcriptional level. In this study, we investigated the role of c-maf in regulating MMP-13 transcription. Using transient transfection system with an c-maf construct, and MMP-13 promoter-luciferase constructs with specific mutations in transcription factor binding sites, we found that c-maf can significantly enhance MMP-13 promoter activity via the AP-1 sitecv" SIGNOR-254560 BRK1 protein Q8WUW1 UNIPROT Neurite_outgrowth phenotype SIGNOR-PH134 SIGNOR down-regulates 9606 23939472 f lperfetto "We found that NRF-1 positively regulates FAM134C and ENOX1, but negatively regulates C3orf10 in human neuroblastoma IMR-32 cells and primary rat cortical neurons. In IMR-32 cells, FAM134C positively regulates and C3orf10 negatively regulates neurite outgrowth, but ENOX1 plays no role in neurite outgrowth regulation. " SIGNOR-261491 motesanib chemical CHEBI:51098 ChEBI KDR protein P35968 UNIPROT "down-regulates activity" "chemical inhibition" -1 22037378 t Luana "Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here." SIGNOR-258253 LPAR5 protein Q9H1C0 UNIPROT GNAZ protein P19086 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257113 CSNK2A1 protein P68400 UNIPROT MAPK9 protein P45984 UNIPROT unknown phosphorylation Ser407 STEQTLAsDTDSSLD 9606 11062067 t lperfetto "The phosphorylation of thr-404 and ser-407 is not increased in response to other agonists that activate mkk7 and sapk1/jnk, suggesting that phosphorylation of these residues is catalysed by another protein kinase, such as ck2, which also phosphorylates thr-404 and ser-407 in vitro." SIGNOR-83711 VEZF1 protein Q14119 UNIPROT EDN1 protein P05305 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 BTO:0004294 11504723 t miannu "Vascular endothelial zinc finger 1 (Vezf1)/DB1 is a recently identified zinc finger-containing protein that is expressed specifically within endothelial cells during development. In this report, we demonstrate that Vezf1/DB1 is a nuclear localizing protein that potently and specifically activates transcription mediated by the human endothelin-1 promoter, in a Tax-independent manner, in transient transfection assays. Regulation of endothelin-1 promoter activity by Vezf1/DB1 provides a mechanism for endothelin-1 expression in the vascular endothelium during development and to maintain vascular tone" SIGNOR-266884 RPS6KB1 protein P23443 UNIPROT IRS1 protein P35568 UNIPROT "down-regulates activity" phosphorylation Ser636 SGDYMPMsPKSVSAP 10090 15306821 t lperfetto "Nevertheless, s6k1-deficient mice remain sensitive to insulin owing to the apparent loss of a negative feedback loop from s6k1 to insulin receptor substrate 1 (irs1), which blunts s307 and s636/s639 phosphorylation; thus under conditions of nutrient satiation s6k1 negatively regulatesinsulin." SIGNOR-127912 PRKCZ protein Q05513 UNIPROT PARD3 protein Q8TEW0 UNIPROT up-regulates phosphorylation Ser827 REGFGRQsMSEKRTK 9606 12390250 t gcesareni "These results imply that serine 827 in the apkc binding site of par-3 is a target of apkc and that the regulated interaction between a protein kinase, apkc, and its substrate, par-3, plays an essential role in the establishment of cell polarity" SIGNOR-94523 ATM protein Q13315 UNIPROT TP53BP1 protein Q12888 UNIPROT unknown phosphorylation Ser6 sQLDSDFS 9606 12697768 t llicata "To examine whether the respective sq sites become phosphorylated in vivo, we raised polyclonal antibodies against phosphorylated ser-6 (anti-s6p), phosphorylated ser-25 and ser-29 (anti-s25p/29p), and phosphorylated ser-784 (anti-s784p). All affinity-purified antisera recognized 53bp1" SIGNOR-100649 SLC16A4 protein O15374 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR down-regulates 9606 26384349 f lperfetto "Treatment with _-cyano-4-hydroxy cinnamate (CHC), a known inhibitor of MCT1, MCT2 and MCT4, dose-dependently induced cell death in MM cell lines and primary MM cells (Figure 1C). Thus, monocarboxylate transportation across membranes appears crucial for MM cell survival." SIGNOR-256582 IKZF2 protein Q9UKS7 UNIPROT LNPEP protein Q9UIQ6 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0003420 15894523 f miannu "Activator protein-2 (AP-2) and Ikaros transcription factors play significant roles in exerting high promoter activity of P-LAP/OTase in the trophoblastic cells. Moreover, P-LAP/OTase is transcriptionally regulated in a trophoblast-differentiation-dependent fashion via up-regulation of AP-2, putatively AP-2alpha." SIGNOR-255404 ABL2 protein P42684 UNIPROT CAT protein P04040 UNIPROT "up-regulates activity" phosphorylation Tyr386 YRARVANyQRDGPMC 9606 12777400 t Manara "These findings indicate that (i) ABL1 and Arg activate catalase by phosphorylation at both Tyr231 and Tyr386" SIGNOR-260772 RPS6KA3 protein P51812 UNIPROT KCNK3 protein O14649 UNIPROT "up-regulates activity" phosphorylation Ser393 GLMKRRSsV 9606 21357689 t gcesareni "The chaperone protein, 14-3-3, binds to a critical phosphorylated serine in the channel c termini of k2p3.1 and k2p9.1 (ser(393) and ser(373), respectively) and overcomes retention in the endoplasmic reticulum by ?COP. We sought to identify the kinase responsible for phosphorylation of the terminal serine in human and rat variants of k2p3.1 and k2p9.1. Adopting a bioinformatic approach, three candidate protein kinases were identified: camp-dependent protein kinase, ribosomal s6 kinase, and protein kinase c." SIGNOR-172470 SIRT3 protein Q9NTG7 UNIPROT CYP11A1 protein P05108 UNIPROT "up-regulates quantity by stabilization" deacetylation Lys149 KKSAAWKkDRVALNQ 9606 BTO:0002588 22585829 t lperfetto "Resveratrol stimulates cortisol biosynthesis by activating SIRT-dependent deacetylation of P450scc.|Stable overexpression of SIRT3 abrogates the cellular content of acetylated P450scc, concomitant with an increase in P450scc protein expression and cortisol secretion. Mutation of K148 and K149 to alanine stabilizes the expression of P450scc and results in a 1.5-fold increase in pregnenolone biosynthesis." SIGNOR-268718 "Translation release factor ERF1-ERF3" complex SIGNOR-C494 SIGNOR 80S_cytosolic_ribosome complex SIGNOR-C455 SIGNOR "down-regulates activity" binding 9606 28368393 t miannu "The essential ATP-binding cassette protein ABCE1 splits 80S ribosomes into 60S and 40S subunits after canonical termination or quality-control-based mRNA surveillance processes. Compared to the pre-splitting state, we observe repositioning of ABCE1's iron-sulfur cluster domain, which rotates 150° into a binding pocket on the 40S subunit. This repositioning explains a newly observed anti-association activity of ABCE1. Notably, the movement implies a collision with A-site factors, thus explaining the splitting mechanism." SIGNOR-270817 MAPK1 protein P28482 UNIPROT FOXO3 protein O43524 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser294 QLSKWPGsPTSRSSD 9606 18204439 t lperfetto "Here, we show that erk downregulates forkhead box o 3a (foxo3a) by directly interacting with and phosphorylating foxo3a at ser 294, ser 344 and ser 425, which consequently promotes cell proliferation and tumorigenesisMDM2 is required for ERk-mediated FOXO3a degradation." SIGNOR-160407 NAB2 protein Q15742 UNIPROT GFI1 protein Q99684 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 10090 16923394 f miannu "Impairing Egr-2 or Nab-2 induction resulted in sustained expression of Gfi-1, demonstrating that Egr-2 and Nab-2 negatively regulate Gfi-1 expression . Importantly, the Gfi-1 promoter was repressed via the Egr site by coexpression of Egr-2 and Nab-2. Thus, Egr-2 and Nab-2 directly repress the Gfi-1 gene." SIGNOR-256042 idarubicin chemical CHEBI:42068 ChEBI TOP2B protein Q02880 UNIPROT "down-regulates activity" "chemical inhibition" 9606 20824055 t miannu "Topoisomerase II (Top2) is a nuclear enzyme involved in several metabolic processes of DNA. Chemotherapy agents that poison Top2 are known to induce persistent protein-mediated DNA double strand breaks (DSB). In this report, by using knock down experiments, we demonstrated that Top2α was largely responsible for the induction of γH2AX and cytotoxicity by the Top2 poisons idarubicin and etoposide in normal human cells." SIGNOR-259328 nilotinib chemical CHEBI:52172 ChEBI KIT protein P10721 UNIPROT "down-regulates activity" "chemical inhibition" -1 22037378 t Luana "Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here." SIGNOR-258257 SLC36A2 protein Q495M3 UNIPROT alanine smallmolecule CHEBI:16449 ChEBI "up-regulates quantity" relocalization 9606 12748860 t lperfetto "Both PAT1 and PAT2 mediate 1:1 symport of protons and small neutral amino acids such as glycine, alanine, and proline.|The first member of the SLC36 family, present in both intracellular and plasma membranes, was identified independently as a lysosomal amino acid transporter (LYAAT1) responsible for the export of lysosomal proteolysis products into the cytosol and as a proton/amino acid transporter (PAT1) responsible for the absorption of amino acids in the gut." SIGNOR-264740 "Ub:E1 (UBA6 substrate)" complex SIGNOR-C496 SIGNOR UBE2E2 protein Q96LR5 UNIPROT "up-regulates activity" ubiquitination 9606 34199813 t miannu "The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t" SIGNOR-271351 "Ub:E1 (UBA6 substrate)" complex SIGNOR-C496 SIGNOR UBE2A protein P49459 UNIPROT "up-regulates activity" ubiquitination 9606 34199813 t miannu "The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t" SIGNOR-271361 PRKCA protein P17252 UNIPROT SHC1 protein P29353 UNIPROT "up-regulates activity" phosphorylation Ser139 EEWTRHGsFVNKPTR 10090 BTO:0000944 12052829 t lperfetto "Among them, Ser(29) in p52(Shc) (equivalent to Ser(138) in p66(Shc)) was phosphorylated only after TPA stimulation. Phosphorylation of this site together with the intact phosphotyrosine-binding domain was essential for ShcA binding to the protein-tyrosine phosphatase PTP-PEST. TPA-induced ShcA phosphorylation at this site (and hence, its association with PTP-PEST) was inhibited by a protein kinase C-specific inhibitor and was induced by overexpression of constitutively active mutants of protein kinase Calpha, -epsilon, and -delta isoforms." SIGNOR-263047 tRNA(Ile) smallmolecule CHEBI:29174 ChEBI Ile-tRNA(Ile) smallmolecule CHEBI:29160 ChEBI "up-regulates quantity" "precursor of" 9606 28271488 t miannu "Aminoacyl-tRNA synthetases (AARSs) are essential enzymes that specifically aminoacylate one tRNA molecule by the cognate amino acid. In mammals, nine synthetases, those specific for amino acids Arg, Asp, Gln, Glu, Ile, Leu, Lys, Met and Pro, associate into a multi-aminoacyl-tRNA synthetase complex, an association which is believed to play a key role in the cellular organization of translation, but also in the regulation of the translational and nontranslational functions of these enzymes." SIGNOR-270425 PTGER4 protein P35408 UNIPROT GNAI1 protein P63096 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257032 IRS1 protein P35568 UNIPROT GRB2 protein P62993 UNIPROT "up-regulates activity" binding 9606 BTO:0000156 11259577 t lperfetto "Association ofinsulinreceptor substrate 1 (irs-1) y895 with grb-2 mediates theinsulinsignaling involved in irs-1-deficient brown adipocyte mitogenesis." SIGNOR-236614 CDK5 protein Q00535 UNIPROT PIK3C3 protein Q8NEB9 UNIPROT "down-regulates activity" phosphorylation Thr668 ENLDLKLtPYKVLAT 9606 BTO:0000007 20513426 t miannu "Phosphorylation of Vps34 on Thr159 inhibits its interaction with Beclin 1. two additional amino acids in Vps34, Thr159 and Thr668, were found to be phosphorylated only after co-transfection with Cdk5/p25" SIGNOR-259811 PICK1 protein Q9NRD5 UNIPROT GRIA2 protein P42262 UNIPROT "up-regulates activity" binding 9534 BTO:0000298 25784538 t miannu "RAB39B directs GluA2 trafficking in neurons. GTP-bound RAB39B interacts with PICK1. In line with evidence that PICK1 can dimerize, the structural model suggests that dimerization of PICK1 is a prerequisite for simultaneous recognition of both RAB39B and GluA2 each by one of the PICK1 molecules in the PICK1 dimer (Fig. 6a–c). The existence of such complex is supported by our co-immunoprecipitation experiments shown above." SIGNOR-264046 TAF3 protein Q5VWG9 UNIPROT TFIID complex SIGNOR-C343 SIGNOR "form complex" binding 9606 27096372 t miannu "The general transcription factor IID (TFIID) plays a central role in the initiation of RNA polymerase II (Pol II)-dependent transcription by nucleating pre-initiation complex (PIC) assembly at the core promoter. TFIID comprises the TATA-binding protein (TBP) and 13 TBP-associated factors (TAF1-13), which specifically interact with a variety of core promoter DNA sequences." SIGNOR-263930 KPC complex SIGNOR-C523 SIGNOR CDKN1B protein P46527 UNIPROT "down-regulates quantity by destabilization" polyubiquitination 10090 BTO:0000944 15531880 t miannu " We now describe a previously unidentified E3 complex: KPC (Kip1 ubiquitination-promoting complex), consisting of KPC1 and KPC2. KPC1 contains a RING-finger domain, and KPC2 contains a ubiquitin-like domain and two ubiquitin-associated domains. KPC interacts with and ubiquitinates p27(Kip1) and is localized to the cytoplasm. Overexpression of KPC promoted the degradation of p27(Kip1), whereas a dominant-negative mutant of KPC1 delayed p27(Kip1) degradation.  Polyubiquitination activity of KPC was apparent with only Ubc4 or UbcH5A." SIGNOR-271513 RAB7A protein P51149 UNIPROT PIK3C3 protein Q8NEB9 UNIPROT "up-regulates activity" "guanine nucleotide exchange factor" BTO:0001131 14617358 t Sara "The p150 adapter protein is in a complex with rab7. The hVPS34/p150 complex colocalized with rab7 on late endosomes and hVPS34 activity was dependent on nucleotide cycling of rab7" SIGNOR-261302 NR0B2 protein Q15466 UNIPROT NR1H2 protein P55055 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0000195 12198243 f gcesareni "Here we show that shp can interact with the liver x receptors lxr? (nr1h3) and lxr? (nr1h2), as demonstrated by glutathione-s-transferase pull-down assays, mammalian two-hybrid, and coimmunoprecipitation experiments. In transfection assays, shp inhibits the expression of an artificial reporter driven by an lxr-response element and represses the transcriptional activation by lxr of the human atp-binding cassette transporter 1 (abca1) promoter. T" SIGNOR-91901 CDK9 protein P50750 UNIPROT POLR2A protein P24928 UNIPROT up-regulates phosphorylation Ser1948 SPTSPGYsPTSPTYS 9606 24385927 t lperfetto "Cyclin-dependent kinase 9 (cdk9) promotes elongation by rna polymerase ii (rnapii), mrna processing, and co-transcriptional histone modification. Cdk9 phosphorylates multiple targets, including the conserved rnapii elongation factor spt5 and rnapii itself" SIGNOR-203608 PRKACA protein P17612 UNIPROT GLI2 protein P10070 UNIPROT "down-regulates quantity by destabilization" phosphorylation 9606 19056373 t gcesareni "These results indicate that phosphorylation of Gli2 by PKA induces Gli2 processing and destabilization" SIGNOR-182573 clenbuterol chemical CHEBI:174690 ChEBI ADRB1 protein P08588 UNIPROT "up-regulates activity" "chemical activation" 10030 BTO:0000457 20590599 t Luana "Denopamine is the most selective ligand for β1-receptors, with regard to intrinsic activity and efficacy, and clenbuterol, procaterol, zinterol, AZ 40140d and salbutamol are more selective for the β2-adrenoceptor than the β1-adrenoceptor based on intrinsic activity and efficacy. " SIGNOR-257862 Ub:E2 complex SIGNOR-C497 SIGNOR AREL1 protein O15033 UNIPROT "up-regulates activity" ubiquitination 9606 34199813 t miannu "The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t" SIGNOR-271286 H2AC4 protein P04908 UNIPROT "Nucleosome_H3.1 variant" complex SIGNOR-C324 SIGNOR "form complex" binding -1 21812398 t miannu "The elemental repeating unit of chromatin is the nucleosome core particle (NCP), which consists of 146 base pairs of DNA wrapped in 1.65 left-handed superhelical turns around the histone octamer. The histone octamer comprises two each of the core histones, H2A, H2B, H3 and H4, which form two H2A/H2B dimers and an H3/H4 tetramer, respectively, in the NCP." SIGNOR-263719 VEGFD protein O43915 UNIPROT Angiogenesis phenotype SIGNOR-PH46 SIGNOR up-regulates 17326328 f lperfetto "More than a dozen different proteins have been identified as angiogenic activators, including vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), angiogenin, transforming growth factor (TGF)-α, TGF-β, tumor necrosis factor (TNF)-α, platelet-derived endothelial growth factor, granulocyte colony-stimulating factor, placental growth factor, interleukin-8, hepatocyte growth factor, and epidermal growth factor" SIGNOR-252278 SEPTIN12 protein Q8IYM1 UNIPROT SEPTIN6 protein Q14141 UNIPROT down-regulates binding 9606 BTO:0000567 18047794 t miannu "Sept12 interacts with sept6 and this interaction alters the filament structure of sept6 in hela cells." SIGNOR-159537 AKT proteinfamily SIGNOR-PF24 SIGNOR TBC1D4 protein O60343 UNIPROT unknown phosphorylation Ser588 RMRGRLGsVDSFERS 10090 BTO:0000011 11994271 t gcesareni "To determine directly whether AS160 was a substrate for Akt, we examined the phosphorylation of recombinant AS160, as well as mutant forms with Ser-588, Thr-642, or both converted to Ala, by recombinant Akt 1." SIGNOR-245268 TNFRSF1B protein P20333 UNIPROT TRAF2 protein Q12933 UNIPROT "up-regulates activity" binding 9606 8069916 t lperfetto "Our analysis indicates that traf1 and traf2 are associated with the cytoplasmic domain of tnf-r2 in a heterodimeric complex in which traf2 contacts the receptor directly." SIGNOR-34645 ATP6V1H protein Q9UI12 UNIPROT TGFBR1 protein P36897 UNIPROT "up-regulates activity" binding 10090 BTO:0004122 29782852 t miannu "ATP6V1H interacts with TGF-β receptor I and AP-2 complex to regulate the proliferation and differentiation of BMSCs." SIGNOR-266886 CDK7 protein P50613 UNIPROT RARG protein P13631 UNIPROT "up-regulates activity" phosphorylation Ser77 SEEMVPSsPSPPPPP 9534 10748061 t Luana "RARg Is Phosphorylated by cdk7 in Its B and F Regions | Mutation into alanine of Ser-77 and Ser-79 located in the A/B region reduced the transcriptional activity of hRARg1 (Fig. 9A), confirming that these phosphorylation sites are required for optimal transcription." SIGNOR-259853 PIK3C3 protein Q8NEB9 UNIPROT "Vps34 Complex I" complex SIGNOR-C242 SIGNOR "form complex" binding -1 30397185 t lperfetto "PtdIns3P recruits specific recognition modules that are common in protein-sorting pathways, such as autophagy and endocytic sorting. It is best characterized in two heterotetramers, complexes I and II. Complex I is composed of VPS34, VPS15, Beclin 1, and autophagy-related gene (ATG)14L, whereas complex II replaces ATG14L with UVRAG. |Complexes I and II are critical for early events in autophagy and endocytic sorting, respectively." SIGNOR-260316 EDA protein Q92838 UNIPROT EDA2R protein Q9HAV5 UNIPROT up-regulates binding 9606 BTO:0001253 12084975 t gcesareni "Identification of the major product of the eda gene (ectodysplasin a), a protein belonging to a group of tnf ligands, and molecular cloning of the cdna, encoding its receptor (edar), a member of the tnf receptor family, are presented. The role of an alternative eda receptor, localised on the x chromosome (xedar) in the developmental control of the differentiation of skin appendages, is discussed." SIGNOR-90040 HNF4A protein P41235 UNIPROT LDLR protein P01130 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000398 21123766 f miannu "Recent studies have demonstrated that PCSK9 mRNA expression was upregulated to a greater extent than that of the LDL receptor in human hepatocytes in primary culture. Our findings also support the role of SREBP-2 as a transcriptional regulator of both the LDL receptor and PCSK9 in human enterocytes." SIGNOR-254454 miR-146a mirna URS000075D8A0_9606 RNAcentral CXCR4 protein P61073 UNIPROT "up-regulates quantity by expression" "post transcriptional regulation" 9606 20516212 f Luisa "MiR-221 strongly upregulated GAX.ZEB2 is upregulated by serum and downregulates GAX, while the expression of miR-221 upregulates GAX and downregulates ZEB2." SIGNOR-268952 MELK protein Q14680 UNIPROT MELK protein Q14680 UNIPROT up-regulates phosphorylation Ser391 GAATPRTsQFTKYWT 9606 16216881 t lperfetto "We have mapped no less than 16 autophosphorylation sites including serines, threonines, and a tyrosine residue and show that the phosphorylation of thr167 and ser171 is required for the activation of melk.We have not yet explored the role of autophosphorylation of nine residues in the c-terminal, autoinhibitory domain (fig. 4c). An enticing hypothesis is that these autophosphorylations decrease the inhibitory potency of this domain and thereby contribute to the activation of the kinase." SIGNOR-141002 HES1 protein Q14469 UNIPROT NOC3L protein Q8WTT2 UNIPROT "down-regulates quantity" "transcriptional regulation" 9823 BTO:0003298 23611667 t "The expression level of FAD24 is inversely associated with that of HES1 in porcine MSCs after adipogenic induction. Enforced overexpression of HES1 in MSCs during the early stage of adipogenesis significantly repressed the transcription of FAD24 (P < 0.01) and the other pro-adipogenic genes" SIGNOR-253059 Ub:E2 complex SIGNOR-C497 SIGNOR IRF2BP2 protein Q7Z5L9 UNIPROT "up-regulates activity" ubiquitination 9606 34199813 t miannu "The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t" SIGNOR-271128 PRPF8 protein Q6P2Q9 UNIPROT "U4/U6.U5 snRNP complex" complex SIGNOR-C478 SIGNOR "form complex" binding 9606 30765414 t lperfetto "The major spliceosomal building blocks are the U1, U2, U4/U6, and U5 small nuclear ribonucleoproteins (snRNPs). Each consists of a small nuclear RNA (snRNA) (or two, in the case of U4/U6), seven Sm proteins that form a ring (or seven Lsm proteins in the case of U6), and a variable number of snRNP-specific proteins (Fig. 1F) (Will and Lührmann 2011). Under splicing conditions, the U4/U6 and U5 snRNPs form a 25S U4/U6.U5 tri-snRNP, in which the U4 and U6 snRNAs are base-paired, forming a three-way junction." SIGNOR-270641 PRKACA protein P17612 UNIPROT LASP1 protein Q14847 UNIPROT "down-regulates activity" phosphorylation Ser146 MEPERRDsQDGSSYR -1 12432067 t miannu "Lasp-1 binds to non-muscle filamentous (F) actin in vitro in a phosphorylation-dependent manner. Phosphorylation of recombinant lasp-1 with recombinant PKA increased the Kd and decreased the Bmax for lasp-1 binding to F-actin. PKA-dependent phosphorylation sites in rabbit lasp-1 to S99 and S146" SIGNOR-250074 EXOC3 protein O60645 UNIPROT "Exocyst_EXOC6B variant" complex SIGNOR-C491 SIGNOR "form complex" binding 9606 26240175 t miannu "The exocyst is an octameric protein complex that is implicated in the tethering of secretory vesicles to the plasma membrane prior to SNARE-mediated fusion." SIGNOR-270778 GPR174 protein Q9BXC1 UNIPROT GNAL protein P38405 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-256900 INCENP protein Q9NQS7 UNIPROT AURKB protein Q96GD4 UNIPROT up-regulates binding 9606 12925766 t gcesareni "Using recombinant proteins, we found that aurora b kinase activity was stimulated by incenp and that the c-terminal region of incenp was sufficient for activation." SIGNOR-86218 TWIST1 protein Q15672 UNIPROT NF1 protein P21359 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0004828 19051271 f miannu "we performed microarray analysis to compare the gene expression profiles in HGC-27 cells, with or without small interfering RNA (siRNA)-mediated depletion of TWIST. Our results showed that NF1, RAP1A, SRPX, RBL2, PFDN4, ILK, F2R, ERBB3, and MYB were up-regulated, whereas AKR1C2, FOS, GDF15, NR2F1, ATM, and CTPS were down-regulated after TWIST depletion" SIGNOR-255530 PDGFRB protein P09619 UNIPROT SHC1 protein P29353 UNIPROT up-regulates phosphorylation 9606 8195171 t gcesareni "In this study, we have characterized the interaction between the pdgf beta-receptor and shc. multiple autophosphorylation sites in the pdgf beta-receptor are responsible for the binding of shc." SIGNOR-36906 PPP1CA protein P62136 UNIPROT CAD protein P27708 UNIPROT "down-regulates activity" dephosphorylation Ser1406 CSGAGGRrLSSFVTK -1 4092695 t lperfetto "Cyclic AMP-dependent protein kinase phosphorylates two serine residues on the protein termed sites 1 and 2| Site 1: Arg-Leu-Ser(P)-Ser-Phe-Val-Thr-Lys Site 2: Ile-His-Arg-Ala-Ser(P)-Asp-Pro-Gly-Leu-Pro-Ala-Glu-Glu-Pro-Lys | Both phosphorylation and activation can be reversed using purified preparations of the catalytic subunits of protein phosphatases 1- and -2A, and inactivation also correlates better with dephosphorylation of site 1 rather than site 2." SIGNOR-263741 CSNK2A1 protein P68400 UNIPROT SNCA protein P37840 UNIPROT "down-regulates activity" phosphorylation Ser129 NEAYEMPsEEGYQDY 9606 10617630 t lperfetto "In vitro experiments and two-dimensional phosphopeptide mapping provided further evidence that serine 129 was phosphorylated by ck-1 and ck-2. Moreover, phosphorylation of serine 129 was reduced in vivo upon inhibition of ck-1 or ck-2.| together, these data may indicate that ck-1 and ck-2 are involved in the regulation of neuronal function and one may speculate that phosphorylation of alpha-synuclein could affect its binding to membranes." SIGNOR-73803 AKT2 protein P31751 UNIPROT MYO5A protein Q9Y4I1 UNIPROT "up-regulates activity" phosphorylation Thr1650 PTGLRKRtSSIADEG 10090 BTO:0000944 17515613 t miannu "Here we identify an Akt consensus phosphorylation motif in the actin-based motor protein myosin 5a and show that insulin stimulation leads to phosphorylation of myosin 5a at serine 1650. This Akt-mediated phosphorylation event enhances the ability of myosin 5a to interact with the actin cytoskeleton.Taken together, these data indicate that myosin 5a is a newly identified direct substrate of Akt2 and, upon insulin stimulation, phosphorylated myosin 5a facilitates anterograde movement of GLUT4 vesicles along actin to the cell surface." SIGNOR-262632 NR0B2 protein Q15466 UNIPROT THR proteinfamily SIGNOR-PF84 SIGNOR "down-regulates quantity by repression" "transcriptional regulation" 9606 11368516 f "inferred from family member" gcesareni "Shp (short heterodimer partner) is an orphan nuclear receptor lacking a dna binding domain that interacts with nuclear receptors (nr) including thyroid receptor (tr), retinoic acid receptors (rar and rxr), and estrogen receptors alpha and beta (eralpha and erbeta). Shp acts as a negative regulator of these receptors by inhibiting dna binding and transcriptional activation." SIGNOR-270298 linifanib chemical CHEBI:91435 ChEBI FLT3 protein P36888 UNIPROT "down-regulates activity" "chemical inhibition" -1 22037378 t Luana "Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here." SIGNOR-258242 TP53 protein P04637 UNIPROT GMPS protein P49915 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0000599;BTO:0003477;BTO:0001670 27939741 t miannu "Herein, we identified GMP synthetase (GMPS), a key enzyme of de novo purine biosynthesis, as an important p53 repression target using a large-scale proteomics approach. This p53-mediated repression of GMPS could be validated by immunoblotting in Sk-Hep1, HepG2, and HuH6 cells." SIGNOR-267342 HAT1 protein O14929 UNIPROT H4C1 protein P62805 UNIPROT "down-regulates activity" acetylation Lys13 KGGKGLGkGGAKRHR -1 28143904 t lperfetto "Histone acetyltransferase 1 is the founding member of the histone acetyltransferase superfamily and catalyzes lysine acetylation of newly synthesized histone H4|Lys12 for direct attack of the acetyl group of the cofactor.| It is postulated that histone acetylation, through charge neutralization of the cationic histone tails, weakens nucleosomal electrostatic interactions with anionic DNA, thus destabilizing internucleosomal contacts and nucleosomal structure and facilitating access to the promoter region for RNA polymerase and transcription factors." SIGNOR-264790 PTPN2 protein P17706 UNIPROT STAT6 protein P42226 UNIPROT "down-regulates activity" dephosphorylation 9606 17210636 t gcesareni "These results identify TCPTP as a physiological regulator of STAT6 phosphorylation and suggest that specific increases in TCPTP expression in ABC-like DLBCLs may contribute to the different biological characteristics of these tumors" SIGNOR-235192 CDK5 protein Q00535 UNIPROT DNM1 protein Q05193 UNIPROT "up-regulates activity" phosphorylation Ser778 GRRSPTSsPTPQRRA -1 12855954 t llicata "Here, we show that cyclin-dependent kinase 5 (Cdk5) phosphorylates dynamin I on Ser 774 and Ser 778 in vitro, which are identical to its endogenous phosphorylation sites in vivo. Cdk5 antagonists and expression of dominant-negative Cdk5 block phosphorylation of dynamin I, but not of amphiphysin or AP180, in nerve terminals and inhibit SVE. " SIGNOR-250662 diethylstilbestrol chemical CHEBI:41922 ChEBI ESR1 protein P03372 UNIPROT "up-regulates activity" "chemical activation" -1 9048584 t miannu "In total 37 substances were tested for both ER subtypes (Fig. 3 and Table 1). In Fig. 3 several examples of typical competitor curves obtained are shown. In all cases monophasic curves were obtained for compounds with significant affinity. . The present study is the first in which the ligand binding properties of both ER subtypes are measured separately, and caution is needed when comparing RBAs from this study with the previous studies involving mixtures of ER subtypes." SIGNOR-258598 AMPK complex SIGNOR-C15 SIGNOR SREBF1 protein P36956 UNIPROT down-regulates phosphorylation Ser396 TAVHKSKsLKDLVSA 9606 21459323 t lperfetto "Here we demonstrate that ampk interacts with and directly phosphorylates sterol regulatory element binding proteins (srebp-1c and -2). Ser372" SIGNOR-216533 DAPK3 protein O43293 UNIPROT MYL9 protein P24844 UNIPROT up-regulates phosphorylation Ser20 KRPQRATsNVFAMFD 9606 19851336 t lperfetto "More than a dozen kinases have been reported to phosphorylate the rlcs of nm ii (fig. 2), including myosin light chain kinase (mlck;also known as mylk), rho-associated, coiled coil-containing kinase (rock), citron kinase, leucine zipper interacting kinase (zipk;also known as dapk3) and myotonic dystrophy kinase-related cdc42-binding kinase (mrck;also known as cdc42bp)6,34,45,46. These kinases phosphorylate rlcs on ser19, thr18 or both, to relieve the inhibition imposed on the myosin molecule by unphosphorylated rlcs and the head_head interaction outlined above." SIGNOR-188789 MRGPRX1 protein Q96LB2 UNIPROT GNAZ protein P19086 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257326 SMAD1/5/8/SMAD4 complex SIGNOR-C215 SIGNOR DLX5 protein P56178 UNIPROT up-regulates "transcriptional regulation" 10090 BTO:0000165 12815054 f ggiuliani "Over-expression of Smad1 or Smad5, mediators of BMP-signaling, also induced Dlx5 expression even in the absence of BMP-2 treatment concomitant with positive ALP staining" SIGNOR-255837 TFAP2A protein P05549 UNIPROT LNPEP protein Q9UIQ6 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0003420 15894523 f miannu "Activator protein-2 (AP-2) and Ikaros transcription factors play significant roles in exerting high promoter activity of P-LAP/OTase in the trophoblastic cells. Moreover, P-LAP/OTase is transcriptionally regulated in a trophoblast-differentiation-dependent fashion via up-regulation of AP-2, putatively AP-2alpha." SIGNOR-255402 PRKACA protein P17612 UNIPROT POLD3 protein Q15054 UNIPROT down-regulates phosphorylation Ser458 GKANRQVsITGFFQR 9606 22148433 t llicata "In this study, we identified s458, located in the pcna-interacting protein (pip-box) motif of p68, as a phosphorylation site for pka. Phosphomimetic mutation of s458 resulted in a decrease in p68 affinity for pcna as well as the processivity of pol _." SIGNOR-195203 MAPKAPK2 protein P49137 UNIPROT TH protein P07101 UNIPROT "up-regulates activity" phosphorylation Ser19 KGFRRAVsELDAKQA -1 11359875 t miannu "MAPKAP-K2 phosphorylates both Ser19 and Ser40 of TH. Tyrosine hydroxylase (TH) has been reported to require binding of 14-3-3 proteins for optimal activation by phosphorylation." SIGNOR-250149 PTPRG protein P23470 UNIPROT SRC protein P12931 UNIPROT "down-regulates activity" dephosphorylation Tyr530 FTSTEPQyQPGENL -1 25624455 t miannu "PTPRG activation by the P1-WD peptide affected the tyrosine phosphorylation of several signaling molecules. Data analysis identified 31 molecules whose phosphorylation was modified in a statistically significant manner (Table I). inhibition of ABL1, BMX, BTK, DAB1, ITGB1, JAK2, KDR, KIT, LIMK1, MET, PDGFRB, SHC1, and VCL correlates with tyrosine dephosphorylation. In contrast, SRC inhibition correlates with hyperphosphorylation of the inhibitory Tyr530 residue and with dephosphorylation of the activatory Tyr419. Moreover, CDK2 and CTTN inhibition correlates with a hyperphosphorylation of the inhibitory Tyr15 and Tyr470, respectively. In contrast, a subgroup of 13 proteins, including BLNK, DOK2, ERBB2, GRIN2B, INSR, PDGFRA, PRKCD, PXN, STAT1, STAT2, STAT3, STAT5A, and ZAP70, appears to be activated by PTPRG activity." SIGNOR-254726 BMP2 protein P12643 UNIPROT ALPL protein P05186 UNIPROT up-regulates 9606 22298955 f gcesareni "FGF-2 null mice have impaired nuclear accumulation of Runx2 and hindered BMP-2 induced bone formation and ALP activity" SIGNOR-114589 RFC5 protein P40937 UNIPROT "RF-C complex" complex SIGNOR-C375 SIGNOR "form complex" binding 12930972 t lperfetto "RF‐C, a complex of five subunits, is conserved in all eukaryotes (reviewed in 5). In yeast, all subunits of RF‐C are essential for viability. The genes encoding all five subunits of mammalian RF‐C (145, 40, 38, 37 and 36 kDa) have been cloned" SIGNOR-265509 NDUFS6 protein O75380 UNIPROT "Mitochondrial respiratory chain complex I" complex SIGNOR-C277 SIGNOR "form complex" binding 30030361 t lperfetto "Thus, we now know the complete mammalian cI structure [22,23] and how the subunits are organized in six modules (N, Q, ND1, ND2, ND4 and ND5)The N-module, which is the tip of the hydrophilic arm and the last one to be incorporated [30,35], results from the assembly of NDUFV1, NDUFV2, NDUFS1 and NDUFA2 [34], to which NDUFA6, NDUFA7, NDUFA12, NDUFS4, NDUFS6 and NDUFV3 must be further associated with to complete the module [24]." SIGNOR-262180 DYRK1A protein Q13627 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR down-regulates phosphorylation 9606 19188143 t gcesareni "Additionally, ck1, dyrk1a, and cdk2 also phosphorylate foxos at various sites to inhibit foxos activity" SIGNOR-252905 FBXL12 protein Q9NXK8 UNIPROT ALDH3A1 protein P30838 UNIPROT "down-regulates quantity by destabilization" binding 10090 BTO:0001078 26124079 t miannu "We now show that SCFFBXL12 is an authentic E3 for the ALDH3 family of enzymes. We now show that the ubiquitin-dependent degradation of ALDH3 mediated by FBXL12 (F box and leucine-rich repeat protein 12) is essential for execution of the differentiation program of trophoblast stem cells (TSCs). FBXL12 is present only in eutherian mammals, and its expression is largely restricted to the placenta during mouse embryogenesis. FBXL12 was found to interact specifically with members of the ALDH3 family and to mediate their polyubiquitylation. Finally, coimmunoprecipitation analysis revealed that FBXL12 interacted efficiently only with members of the ALDH3 family (ALDH3A1, ALDH3A2, and ALDH3B1), showing little if any association with those of the ALDH1 family (ALDH1A1, ALDH1A2, and ALDH1A3) (Fig. 2H). Collectively, these results suggested that SCFFBXL12 is an authentic E3 specific for ALDH3 family members." SIGNOR-272813 LSM7 protein Q9UK45 UNIPROT "U4/U6.U5 snRNP complex" complex SIGNOR-C478 SIGNOR "form complex" binding 9606 30765414 t lperfetto "The major spliceosomal building blocks are the U1, U2, U4/U6, and U5 small nuclear ribonucleoproteins (snRNPs). Each consists of a small nuclear RNA (snRNA) (or two, in the case of U4/U6), seven Sm proteins that form a ring (or seven Lsm proteins in the case of U6), and a variable number of snRNP-specific proteins (Fig. 1F) (Will and Lührmann 2011). Under splicing conditions, the U4/U6 and U5 snRNPs form a 25S U4/U6.U5 tri-snRNP, in which the U4 and U6 snRNAs are base-paired, forming a three-way junction." SIGNOR-270647 NCOR1 protein O75376 UNIPROT PPARG protein P37231 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 22395773 t FFerrentino "In differentiated adipocyte cell lines, SIRT1 inhibits adipogenesis and enhances fat mobilization through lipolysis by suppressing the activity of PPARγ. SIRT1 achieves this by promoting the assembly of a corepressor complex, involving NCoR1 and SMRT, on the promoters of PPARγ target genes to repress their transcription." SIGNOR-253507 PAMPs stimulus SIGNOR-ST11 SIGNOR SLC11A1 protein P49279 UNIPROT up-regulates 9606 BTO:0000801 11909746 f "Functional studies in Nramp1 transfected macrophages have demonstrated that the Nramp1 protein plays a vital role in early macrophage activation [10,29,30]. Nramp1 is constitutively expressed in macrophage cell lines of the myeloid lineage (isolated peritoneal, splenic, and liver resident macrophages), and can be induced by treatment of macrophages with IFN-γ, or IFN-γ plus lipopolysaccharide (LPS)" SIGNOR-254039 "Golimumab (Simponi)" antibody DB06674 DRUGBANK TNF protein P01375 UNIPROT "down-regulates activity" binding 9606 33369527 t "Golimumab is a transgenic anti-TNF monoclonal antibody that acts primarily by targeting and neutralizing TNF, thus preventing inflammation." SIGNOR-272491 CHRM5 protein P08912 UNIPROT GNA15 protein P30679 UNIPROT "up-regulates activity" binding 9606 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257351 SHC1 protein P29353 UNIPROT MAPK3 protein P27361 UNIPROT "up-regulates activity" 10090 BTO:0000944 17673906 f lperfetto "We report that upon TGF__ stimulation, the activated TGF__ type I receptor (T_RI) recruits and directly phosphorylates ShcA proteins on tyrosine and serine. This dual phosphorylation results from an intrinsic T_RI tyrosine kinase activity that complements its well_defined serine_threonine kinase function. TGF___induced ShcA phosphorylation induces ShcA association with Grb2 and Sos, thereby initiating the well_characterised pathway linking receptor tyrosine kinases with Erk MAP kinases." SIGNOR-242625 MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR MAPK1 protein P28482 UNIPROT "up-regulates activity" phosphorylation 9606 BTO:0000443 12270934 t lperfetto "Mek1 as indicated by extensive phosphorylation of erk1 and erk2 during the initial 2 h of adipogenesis." SIGNOR-244795 SMARCB1 protein Q12824 UNIPROT CCNA1 protein P78396 UNIPROT down-regulates 9606 12226744 f miannu "We show that the ectopic expression of wild-type hsnf5/ini1, but not that of truncated versions, leads to a cell cycle arrest by inhibiting the entry into s phase of mrt cells. This g1 arrest is associated with down-regulation of a subset of e2f targets including cyclin a, e2f1 and cdc6." SIGNOR-92779 BCL2L1 protein Q07817 UNIPROT HIP1 protein O00291 UNIPROT down-regulates 9606 11007801 f miannu "Hip-1 activity was found to be independent of the ded-containing caspase 8 but was significantly inhibited by the antiapoptotic protein bcl-x(l), implicating the intrinsic pathway of apoptosis in hip-1-induced cell death." SIGNOR-82460 RAPH1 protein Q70E73 UNIPROT ENAH protein Q8N8S7 UNIPROT "up-regulates activity" binding 9606 20417104 t miannu "Here we show that Lpd is a substrate of Abl kinases and binds to the Abl SH2 domain. Phosphorylation of Lpd positively regulates the interaction between Lpd and Ena/VASP proteins." SIGNOR-268425 IKBKB protein O14920 UNIPROT TSC1 protein Q92574 UNIPROT down-regulates phosphorylation Ser487 AAISRELsEITTAEA 9606 BTO:0000150;BTO:0001130;BTO:0001271;BTO:0000527 19188143 t gcesareni "Here we show that ikkbeta, a major downstream kinase in the tnfalpha signaling pathway, physically interacts with and phosphorylates tsc1 at ser487 and ser511, resulting in suppression of tsc1phosphorylation of tsc2 (by akt and erk;refs. 28, 29) and tsc1(by ikkbeta;ref. 30) results in the disruption of the tsc1/2 complex, and thereby activates the oncogenic mtor signaling contributing to tumor progression." SIGNOR-183688 EPHA8 protein P29322 UNIPROT EPHA8 protein P29322 UNIPROT "up-regulates activity" phosphorylation Tyr839 LAYGERPyWNMTNRD 9606 BTO:0000007 10498895 t "Tyr-615 and Tyr-838 are major autophosphorylation sites of the EphA8 receptor. phosphorylation of Tyr-615 is critical for determining the association with Fyn whereas the integrity of Tyr-838 phosphorylation is required for efficient phosphorylation at Tyr-615 as well as other major sites." SIGNOR-251121 MEF2D protein Q14814 UNIPROT MYH1 protein P12882 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 BTO:0001103 15728583 t lperfetto "Myocyte enhancer factor-2 and serum response factor binding elements regulate fast Myosin heavy chain transcription in vivo. We show that the upstream promoter region of the gene most abundantly expressed in mouse skeletal muscles, IIb MyHC, retains binding activity and transcriptional activation for three positive transcription factors, the serum response factor, Oct-1, and myocyte enhancer factor-2, whereas the other two genes (IIa and IId/x) have nucleotide substitutions in these sites that reduce binding and transcriptional activation" SIGNOR-238751 AURKA protein O14965 UNIPROT AURKA protein O14965 UNIPROT up-regulates phosphorylation Thr288 APSSRRTtLCGTLDY 9606 24867643 t lperfetto "The upstream pak1 kinase can phosphorylate aurora a at t288, autophosphorylation appears to be the essential mode of activation. Our experiments suggest that phosphorylation of t288 is important for regulation of the aurora2 kinase both for its activity and its stability" SIGNOR-205106 PRKCE protein Q02156 UNIPROT TRPV1 protein Q8NER1 UNIPROT "up-regulates activity" phosphorylation Ser502 YFLQRRPsMKTLFVD 9606 BTO:0000007 11884385 t lperfetto "Direct phosphorylation of capsaicin receptor VR1 by protein kinase Cepsilon and identification of two target serine residues. | Patch clamp analysis of the point mutants where Ser or Thr residues were replaced with Ala in the total 16 putative phosphorylation sites showed that two Ser residues, Ser(502) and Ser(800) were involved in the potentiation of the capsaicin-evoked currents by either PMA or ATP." SIGNOR-249141 MAPK1 protein P28482 UNIPROT RPS6KA5 protein O75582 UNIPROT up-regulates phosphorylation Thr581 PDNQPLKtPCFTLHY 9606 BTO:0000887 11940578 t gcesareni "Together, our in vivo and in vitro studies indicate that the pkc/c-raf/mek/erk pathway plays a major role in the s6k1 activation in hypertrophic cardiac growth." SIGNOR-116489 TEAD1 protein P28347 UNIPROT MYF5 protein P13349 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 20153295 f lperfetto "We found that the expression of myf5 and cyclind1 remained significantly elevated upon induction of differentiation in cells that were overexpressing hyap1 s127a compared to cells transfected with wildtype hyap and empty vector;yap directly induced the transcription of ccnd1 and foxm1, in cooperation with tead transcription factor." SIGNOR-235599 SPI1 protein P17947 UNIPROT CD14 protein P08571 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 12393465 f apalma "In patients with t(8;21), expression of the cell surface markers CD11b, CD14, and CD64 was less in comparison to patients without t(8;21) (Figure 5B). CD14 and CD64 promoters have putative PU.1 binding sites but not AML1-, C/EBPα-, or MEF-binding sites suggesting that down-regulation of the function of PU.1 by AML1-ETO could possibly be an important step in progression toward leukemia." SIGNOR-255696 HERC2 protein O95714 UNIPROT USP20 protein Q9Y2K6 UNIPROT "down-regulates quantity by destabilization" polyubiquitination -1 25355518 t miannu "USP20 is regulated by HERC2 following DNA damage or replication stress.The HECT domain of WT HERC but not the catalytic inactive mutant (CA) ubiquitinated USP20 in vitro (Figure ​(Figure4G).4G). Taken together, these results suggested that HERC2 functions as an E3 ligase of USP20 and negatively regulates USP20 in unstressed cells." SIGNOR-272820 RET protein P07949 UNIPROT RET protein P07949 UNIPROT up-regulates phosphorylation Tyr806 PLLLIVEyAKYGSLR 9606 14711813 t llicata "Mass spectrometric analysis revealed that ret tyr(806), tyr(809), tyr(900), tyr(905), tyr(981), tyr(1062), tyr(1090), and tyr(1096) were autophosphorylation sites. these facts suggest that tyr806 and tyr809, located in this unique position, play a novel supplemental role for the activation loop upon phosphorylation." SIGNOR-121153 DLL1 protein O00548 UNIPROT NOTCH3 protein Q9UM47 UNIPROT up-regulates binding 9606 11006133 t gcesareni "These results suggest that delta1, jagged1, and jagged2 are ligands for notch1 and notch3 receptors." SIGNOR-82398 FBXO22 protein Q8NEZ5 UNIPROT BSG protein P35613 UNIPROT "down-regulates quantity by destabilization" binding 9606 BTO:0000007 28117675 t miannu "FBXO22 mediates poly-ubiquitination and degradation of CD147. Classically, F-box protein together with Skp1 and Cullin 1 constitute Skp-Cullin-F box ubiquitin E3 ligase (SCFs)" SIGNOR-272787 AKT1 protein P31749 UNIPROT ARFIP2 protein P53365 UNIPROT unknown phosphorylation Ser260 GTRGRLEsAQATFQA 9606 BTO:0000938 15809304 t llicata "Akt phosphorylated arfaptin 2 at ser(260). we have also demonstrated that arfaptin 2 phosphorylation restores proteasome activity that is inhibited by the presence of polyq-huntingtin in cells." SIGNOR-252476 CSNK2A1 protein P68400 UNIPROT DAXX protein Q9UER7 UNIPROT up-regulates phosphorylation Ser737 PEEIIVLsDSD 9606 21474068 t lperfetto "Daxx-sim is phosphorylated by ck2 kinase at residues s737 and s739. Phosphorylation promotes daxx-sim binding affinity toward sumo-1 over sumo-2/3, causing daxx preference for sumo-1 conjugation and interaction with sumo-1-modified factors." SIGNOR-173105 DNMT3A protein Q9Y6K1 UNIPROT CDKN2D protein P55273 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 26350239 f miannu "Quantitative real-time PCR (qPCR) was used to investigate the effect of DNMT3A on p18INK4C expression, along with the other INK4 members, including p15INK4B, p16INK4A and p19INK4D. The results showed that the depletion of DNMT3A increased the transcriptional levels of the four members of the INK4 family" SIGNOR-261510 MAPK8 protein P45983 UNIPROT APLP2 protein Q06481 UNIPROT up-regulates phosphorylation Thr736 VEVDPMLtPEERHLN 9606 14970211 t lperfetto "Phosphorylation at the thr(668) residue of app (with respect to the numbering conversion for the app 695 isoform) and the thr(736) residue of aplp2 (with respect to the numbering conversion for the aplp2 763 isoform) in their cytoplasmic domains acts as a molecular switch for their protein-protein interaction and is implicated in neural function(s) and/or alzheimer's disease pathogenesis. Here we demonstrate that both app and aplp2 can be phosphorylated by jnk at the thr(668) and thr(736) residues, respectively, in response to cellular stress." SIGNOR-122196 FASN protein P49327 UNIPROT NADPH(4-) smallmolecule CHEBI:57783 ChEBI "down-regulates quantity" "chemical modification" 9606 15507492 t "Human fatty acid synthase (FAS) is a complex homodimeric (552-kDa) enzyme that regulates the¬†de novo¬†biosynthesis of long-chain fatty acids. This cytosolic enzyme catalyzes the formation of 16 carbon (C16) palmitate, from acetyl-coenzyme A (acetyl-CoA) and malonyl-coenzyme A (malonyl-CoA) in the presence of NADPH.¬†" SIGNOR-267759 CDK2 protein P24941 UNIPROT NPM1 protein P06748 UNIPROT unknown phosphorylation Ser70 EAMNYEGsPIKVTLA 9606 BTO:0001271 19933706 t gcesareni "Simultaneous inactivation of two cdk phosphorylation sites at ser10 and ser70 (npm-aa) induced g(2)/m cell cycle arrest, phosphorylation of cdk1 at tyr15 (cdc2(tyr15)) and increased cytoplasmic accumulation of cdc25c." SIGNOR-161805 EIF2B4 protein Q9UI10 UNIPROT Ternary_GTP_eIF2_tRNA_complex complex SIGNOR-C452 SIGNOR "up-regulates activity" "guanine nucleotide exchange factor" 9606 15054402 t lperfetto "EIF2B converts the protein synthesis initiation factor 2 (eIF2) from an inactive GDP-bound form to an active eIF2-GTP complex owing to its guanine nucleotide exchange factor (GEF) activity." SIGNOR-269142 SGK3 protein Q96BR1 UNIPROT FOXO3 protein O43524 UNIPROT "down-regulates activity" phosphorylation Ser253 APRRRAVsMDNSNKY 9606 11154281 t lperfetto "Protein kinase SGK mediates survival signals by phosphorylating the forkhead transcription factor FKHRL1 (FOXO3a)|However, SGK and Akt display differences with respect to the efficacy with which they phosphorylate the three regulatory sites on FKHRL1. While both kinases can phosphorylate Thr-32, SGK displays a marked preference for Ser-315 whereas Akt favors Ser-253. These findings suggest that SGK and Akt may coordinately regulate the function of FKHRL1 by phosphorylating this transcription factor at distinct sites. The efficient phosphorylation of these three sites on FKHRL1 by SGK and Akt appears to be critical to the ability of growth factors to suppress FKHRL1-dependent transcription, thereby preventing FKHRL1 from inducing cell cycle arrest and apoptosis." SIGNOR-249135 YARS1 protein P54577 UNIPROT diphosphate(3-) smallmolecule CHEBI:33019 ChEBI "up-regulates quantity" "chemical modification" 9606 16429158 t miannu "YARS (also known as TyrRS) catalyzes the aminoacylation of tRNATyr with tyrosine by a two-step mechanism. Tyrosine is first activated by ATP to form tyrosyl-adenylate and is then transferred to tRNATyr" SIGNOR-270520 RPS6KB1 protein P23443 UNIPROT MXD1 protein Q05195 UNIPROT down-regulates phosphorylation Ser145 IERIRMDsIGSTVSS 9606 18451027 t llicata "Both rsk and s6k phosphorylate serine 145 of mad1 upon serum or insulin stimulation. Ser-145 phosphorylation of mad1 accelerates the ubiquitination and degradation of mad1 through the 26s proteasome pathway, which in turn promotes the transcriptional activity of myc." SIGNOR-178590 FBH1 protein Q8NFZ0 UNIPROT RAD51 protein Q06609 UNIPROT "up-regulates activity" binding -1 25585578 t miannu "The F-box DNA helicase 1 (FBH1) is a 3'-5' DNA helicase with a putative function as a negative regulator of HR. It is the only known DNA helicase to contain an F-box, suggesting that one of its functions is to act as a ubiquitin ligase as part of an SCF (SKP1, CUL1 and F-box) complex. Here we report that the central player in HR, RAD51, is ubiquitylated by the SCF(FBH1) complex. Expression of an ubiquitylation-resistant form of RAD51 in human cells leads to hyperrecombination, as well as several phenotypes indicative of an altered response to DNA replication stress. However, K58/64R RAD51 was ubiquitylated much less efficiently by FBH1 in vitro than was wild-type (WT) RAD51 (Fig. 1d), confirming that the primary sites of modification by FBH1 on RAD51 are K58 and K64." SIGNOR-272451 MAPKAPK2 protein P49137 UNIPROT UBE2J1 protein Q9Y385 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser184 KELARQIsFKAEVNS 9606 BTO:0000567 24020373 t miannu "Endoplasmic reticulum-associated ubiquitin-conjugating enzyme Ube2j1 is a novel substrate of MK2 (MAPKAP kinase-2) involved in MK2-mediated TNFα production. These findings strongly suggest that MK2 directly phosphorylates Ube2j1 at Ser(184) upon p38-activating stress in vivo." SIGNOR-263091 PTPRG protein P23470 UNIPROT ZAP70 protein P43403 UNIPROT "up-regulates activity" dephosphorylation Tyr319 TSVYESPySDPEELK -1 25624455 t miannu "PTPRG activation by the P1-WD peptide affected the tyrosine phosphorylation of several signaling molecules. Data analysis identified 31 molecules whose phosphorylation was modified in a statistically significant manner (Table I). inhibition of ABL1, BMX, BTK, DAB1, ITGB1, JAK2, KDR, KIT, LIMK1, MET, PDGFRB, SHC1, and VCL correlates with tyrosine dephosphorylation. In contrast, SRC inhibition correlates with hyperphosphorylation of the inhibitory Tyr530 residue and with dephosphorylation of the activatory Tyr419. Moreover, CDK2 and CTTN inhibition correlates with a hyperphosphorylation of the inhibitory Tyr15 and Tyr470, respectively. In contrast, a subgroup of 13 proteins, including BLNK, DOK2, ERBB2, GRIN2B, INSR, PDGFRA, PRKCD, PXN, STAT1, STAT2, STAT3, STAT5A, and ZAP70, appears to be activated by PTPRG activity." SIGNOR-254734 JUN protein P05412 UNIPROT Monocyte_differentiation phenotype SIGNOR-PH101 SIGNOR up-regulates 10090 BTO:0000725 17041602 f miannu "These results show that restoration of c-Jun expression rescues the myelomonocytic differentiation block in preleukemic PU.1-knockdown bone marrow cells, suggesting that c-Jun is a critical downstream target in PU.1-knockdown HSCs." SIGNOR-256066 NF1 protein P21359 UNIPROT ADCY3 protein O60266 UNIPROT up-regulates 9606 24431436 f miannu "Nf1encodes neurofibromin, a protein with multiple functions including ras inactivation (ras gtpase-activating protein or rasgap) and adenylyl cyclase (ac) activation" SIGNOR-204034 KIF19 protein Q2TAC6 UNIPROT "Plus-end directed sliding movement" phenotype SIGNOR-PH216 SIGNOR up-regulates 9606 19773780 f "In general, N-kinesins and C-kinesins drive microtubule plus end- and minus end-directed motilities, respectively, and M-kinesins depolymerize microtubules1,9 (Box 1).|Forty-five genes that encode kinesin superfamily proteins (also known as KIFs) have been discovered in the mouse and human genomes.|KIFs are molecular motors that directionally transport various cargos, including membranous organelles, protein complexes and mRNAs, along the microtubule system." SIGNOR-272532 miR-199a mirna URS0000759977_9606 RNAcentral RPS6 protein P62753 UNIPROT "up-regulates activity" 10090 21986534 t "This overexpression of miR-155 may suppress the expression of C/EBPβ and CREB by directly targeting their 3' untranslated regions (3' UTRs)" SIGNOR-255936 CDK11B protein P21127 UNIPROT EIF3F protein O00303 UNIPROT down-regulates phosphorylation Ser46 PAAAPASsSDPAAAA 9606 12446680 t lperfetto "The interaction between cdk11p46 and eif3 p47 occurs in vitro and in vivo. In addition, cdk11 protein kinase isolated from cells undergoing apoptosis can phosphorylate eif3 p47in vitro, and serine phosphorylation of eif3 p47 occurs in cells during apoptosis.Purified recombinant cdk11p46 inhibited translation of a reporter gene in vitro in a dose-dependent manner.These data suggest that the function of the caspase-processed cdk11p110 isoform may be to inhibit translation during apoptosis. However, whether or not this inhibition of protein translation occurs in an eif3 p47-dependent or -independent manner remains to be clarified." SIGNOR-95762 GDNF protein P39905 UNIPROT BIN1 protein O00499 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10116 15212950 f miannu "We characterize the network of 43 genes induced by GDNF overproduction of neuronal progenitor cells (ST14A), which mainly regulate migration and differentiation of neuronal progenitor cells.Laminin, Mpl3, Alcam, Bin1, Id1, Id2, Id3, neuregulin1, the ephrinB2-receptor, neuritin, focal adhesion kinase (FAK), Tc10, Pdpk1, clusterin, GTP-cyclooxygenase1, and follistatin are genes up-regulated by GDNF overexpression." SIGNOR-252178 TGFB1 protein P01137 UNIPROT HBB protein P68871 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 8142649 f Regulation miannu "Basic fibroblast growth factor (bFGF) and transforming growth factor-beta 1 (TGF-beta) have both been shown to act on hematopoietic progenitor cells. bFGF antagonized the TGF-beta-mediated induction of hemoglobin in a dose-dependent manner, with 0.1 ng/mL bFGF inhibiting hemoglobin induction by 40% and 10 ng/mL bFGF completely abrogating hemoglobin production." SIGNOR-251797 MAPK1 protein P28482 UNIPROT SMAD3 protein P84022 UNIPROT unknown phosphorylation Ser204 NHSMDAGsPNLSPNP 9606 19914168 t lpetrilli "In contrast, ERK2 phosphorylated all four Smad1 residues almost evenly, while showing a preference for S204 over S208 and S213 in Smad3" SIGNOR-161698 F2RL1 protein P55085 UNIPROT GNA14 protein O95837 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257359 CDK1 protein P06493 UNIPROT NUMA1 protein Q14980 UNIPROT down-regulates phosphorylation Thr2055 MAFSILNtPKKLGNS 9606 23921553 t llicata "Cdk1-mediated phosphorylation at t2055 negatively regulates numa cortical localization and that this phosphorylation is counteracted by ppp2ca phosphatase activity." SIGNOR-194825 PTPN2 protein P17706 UNIPROT JAK1 protein P23458 UNIPROT "down-regulates activity" dephosphorylation Tyr1034 AIETDKEyYTVKDDR 10090 11909529 t "The T cell protein tyrosine phosphatase is a negative regulator of janus family kinases 1 and 3|We have identified JAK1 and JAK3 as physiological substrates of TCPTP.| Using a site-specific antibody directed against the activation loop phosphotyrosines in JAK1 (pY1022/pY1023), we found that these sites were in fact dephosphorylated by TCPTP" SIGNOR-248395 VAC14 protein Q08AM6 UNIPROT "PAS complex" complex SIGNOR-C190 SIGNOR "form complex" binding 9606 BTO:0000007 17556371 t miannu "Here we have identified and characterized Sac3, a Sac domain phosphatase, as the Fig4 mammalian counterpart. Endogenous Sac3, a widespread 97-kDa protein, formed a stable ternary complex with ArPIKfyve and PIKfyve. Sac3 assembles with PIKfyve and ArPIKfyve in a stable ternary complex and controls PtdIns(3,5)P2 levels." SIGNOR-253530 APLNR protein P35414 UNIPROT GNAI3 protein P08754 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-256824 AMOT/MPP5/INADL/LIN7C complex SIGNOR-C27 SIGNOR WWTR1 protein Q9GZV5 UNIPROT down-regulates binding 10090 21145499 t milica "Because we found that multiple domains of taz/yap interacted with multiple components of the crumbs complex, which include pals1, lin7c, patj, and the crumbs regulator amot, we propose that this multifactoral interaction serves to ensure that assembly of the hippo pathway and efficient phosphorylation of taz/yap is coupled only by the assembly of the crumbs complex, rather than by any single component." SIGNOR-170361 "Cullin 3-RBX1-Skp1" complex SIGNOR-C526 SIGNOR DEK protein P35659 UNIPROT "down-regulates quantity by destabilization" ubiquitination Lys371 DFIKTTVkELIS 9606 BTO:0000007 25278611 t miannu "Here, we analyzed changes in the ubiquitin landscape induced by prostate cancer-associated mutations of SPOP, an E3 ubiquitin ligase substrate-binding protein. SPOP mutants impaired ubiquitylation of a subset of proteins in a dominant-negative fashion. Of these, DEK and TRIM24 emerged as effector substrates consistently up-regulated by SPOP mutants. Up-regulation of DEK, TRIM24 and NCOA3 is a feature of prostate cancer SPOP mutations. This result aligns well with the observation that multiple ubiquitylated DEK lysine residues were detected in the initial proteome analysis (fig. S2E)." SIGNOR-272835 MAPK3 protein P27361 UNIPROT PCBP2 protein Q15366 UNIPROT "up-regulates quantity by stabilization" phosphorylation Ser272 FSGIESSsPEVKGYW 9606 17475908 t miannu "We also identified 4 hnRNP-E2 MAPKERK1/2 phosphorylation sites and demonstrated that hnRNP-E2 is a bona fide MAPKERK1/2 substrate and that MAPKERK1/2-dependent phosphorylation of hnRNP-E2 at these amino acid residues is essential for increased hnRNP-E2 expression in BCR/ABL-expressing cells. Serine/threonine to alanine substitution abolishes hnRNP-E2 phosphorylation and markedly decreases its stability in BCR/ABL-expressing myeloid precursors. Consistent with the existence of a BCR/ABL-MAPK pathway that posttranslationally regulates hnRNP-E2 expression, sequence analysis of hnRNP-E2 revealed the presence of 4 consensus ERK phosphorylation sites (S/T-P)35,36 at amino acid residues 173, 189, 213, and 272 (Figure 2B)." SIGNOR-262916 (R)-2-hydroxyglutarate(2-) smallmolecule CHEBI:15801 ChEBI TET2 protein Q6N021 UNIPROT "down-regulates activity" "chemical inhibition" 9606 BTO:0001883 29090344 t miannu "Various studies have tried to investigate how the accumulation of R2-HG promotes leukemogenesis in cooperation with other frequently observed mutations in AML. An important role appears to be the ability of R2-HG to competitively inhibit multiple αKG-dependent dioxygenases. While TET2 normally catalyzes the conversion of 5-methylcytosine (5mC) into 5-hydroxymethylcytosine (5hmC), inhibition of TET2 by R2-HG has been found to result in a hypermethylated gene signature in HSPCs, which overlaps with the signatures of both IDH and TET2-mutated leukemic cells." SIGNOR-261829 POMC protein P01189 UNIPROT MC1R protein Q01726 UNIPROT "up-regulates activity" binding 9606 BTO:0000142 20371771 t lperfetto "The melanocortin (MC) receptor family consists of five Gs-coupled receptors that control various physiological functions in response to four distinct agonists, adrenocorticotropic hormone (ACTH, also known as corticotrophin) and alpha, beta, and gamma melanocyte-stimulating hormone (MSH), which are derived from the proopiomelanocortin precursor protein, and two inverse agonists, agouti and agouti-related proteins" SIGNOR-268700 HOXD10 protein P28358 UNIPROT MEIS1 protein O00470 UNIPROT "up-regulates activity" binding -1 9343407 t 2 miannu "We now show that the Hoxa-9 protein physically interacts with Meis1 proteins. Hox proteins from the other AbdB-like paralogs, Hoxa-10, Hoxa-11, Hoxd-12, and Hoxb-13, also form DNA binding complexes with Meis1b. DNA binding complexes formed by Meis1 with Hox proteins dissociate much more slowly than DNA complexes with Meis1 alone, suggesting that Hox proteins stabilize the interactions of Meis1 proteins with their DNA targets." SIGNOR-241226 NOXA1 protein Q86UR1 UNIPROT BCL2 protein P10415 UNIPROT "down-regulates activity" 9606 19879762 t lperfetto "BH3-only proteins containing only a single BH domain and including Puma, Noxa, Bid and Bad as well as other factors are particularly important for such neutralisation, binding and regulating the anti-apoptotic Bcl-2 proteins to promote apoptosis" SIGNOR-209684 ZDHHC2 protein Q9UIJ5 UNIPROT DLG4 protein P78352 UNIPROT "up-regulates activity" palmitoylation Cys3 cLCIVTTK 9606 23836932 t "Plasma membrane targeting of DHHC2 palmitoyltransferase rapidly recruited PSD-95 to the plasma membrane and proved essential for postsynaptic nanodomain formation." SIGNOR-262296 "phosphatidic acid" smallmolecule CHEBI:16337 ChEBI RAC1 protein P63000 UNIPROT up-regulates "chemical activation" 9606 18480413 t gcesareni "The c-terminal polybasic motif of rac1 is responsible for direct interaction with pa," SIGNOR-178632 HMGB1 protein P09429 UNIPROT HOXB1 protein P14653 UNIPROT "up-regulates activity" binding -1 8890171 t miannu "We show that HMG1 interacts with proteins encoded by the HOX gene family by establishing protein-protein contacts between the HMG box domains and the HOX homeodomain. The functional role of these interactions was studied using the transcriptional activity of the human HOXD9 protein as a model. HMG1 enhances, in a dose-dependent fashion, the sequence-specific DNA binding activity in vitro, and the transcriptional activation in a co-transfection assay in vivo, of the HOXD9 protein." SIGNOR-219853 tacedinaline chemical CHEBI:90195 ChEBI HDAC2 protein Q92769 UNIPROT "down-regulates activity" "chemical inhibition" -1 20139990 t Luana "Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1)." SIGNOR-258008 HIF1A protein Q16665 UNIPROT ALDOA protein P04075 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 8955077 f miannu "we characterize hypoxia response elements in the promoters of the ALDA, ENO1, and Ldha genes. Our data establish that functional hypoxia-response elements consist of a pair of contiguous transcription factor binding sites at least one of which contains the core sequence 5'-RCGTG-3' and is recognized by HIF-1. These results provide further evidence that the coordinate transcriptional activation of genes encoding glycolytic enzymes which occurs in hypoxic cells is mediated by HIF-1." SIGNOR-254422 AP3M2 protein P53677 UNIPROT "Neuronal AP-3" complex SIGNOR-C445 SIGNOR "form complex" binding 9606 BTO:0000938 19497727 t miannu "Mammals contain more than one AP-3 complex owing to the existence of pairs of genes encoding β3, μ3, and σ3 subunits (A and B isoforms). While both σ3A and σ3B are expressed ubiquitously and seem to be functionally equivalent, the B isoforms of β3 and μ3 display rather restricted expression patterns, mostly in cells of neuronal origin. This has led to the notion of the existence of two types of mammalian AP-3 complexes: a ubiquitous AP-3 comprising δ, β3A, μ3A, and σ3(A or B) subunits, and a brain-specific AP-3 complex containing δ, β3B, μ3B, and σ3(A or B)" SIGNOR-268520 LCK protein P06239 UNIPROT DEF6 protein Q9H4E7 UNIPROT "up-regulates activity" phosphorylation Tyr144 MVPDEVEyLLKKVLS 9606 BTO:0000661 18976935 t lperfetto "Here, we report that the T cell receptor (TCR)-induced translocation of SLAT to the immunological synapse required Lck-mediated phosphorylation of two tyrosine residues located in an immunoreceptor tyrosine-based activation motif-like sequence but was independent of the SLAT PH domain. This subcellular relocalization was coupled to, and necessary for, activation of the NFAT pathway|These results indicate that SLAT undergoes Lck-dependent phosphorylation on Tyr-144 and Tyr-133 upon TCR and CD28 stimulation." SIGNOR-253368 flumazenil chemical CHEBI:5103 ChEBI "GABA-A (a4-b1-g2) receptor" complex SIGNOR-C333 SIGNOR "up-regulates activity" "chemical activation" 9606 BTO:0000227 18790874 t brain lperfetto "Receptors containing the alpha4 or alpha6 subunits, together with beta and gamma2, do not bind the traditional BZ agonists, including zolpidem, but demonstrate high affinity for some ligands, notably the imidazobenzodiazepines such as flumazenil and Ro15-4513, or bretazenil" SIGNOR-263807 PRKDC protein P78527 UNIPROT RPA2 protein P15927 UNIPROT "down-regulates activity" phosphorylation Ser13 FESYGSSsYGGAGGY -1 9295339 t lperfetto "We showed previously that UV irradiation increases phosphorylation of the p34 subunit of human replication protein A (RPA) and that this hyperphosphorylation correlated with loss of activity of the DNA replication complex. | we detected phosphorylation of the RPA complex by DNA-PK on RPA-p34 sites Ser-23, Ser-29, and Ser-11, -12, or -13" SIGNOR-248982 FES protein P07332 UNIPROT FES protein P07332 UNIPROT up-regulates phosphorylation Tyr713 REEADGVyAASGGLR 9606 8663427 t llicata "Substitution of kinase domain tyrosine residues 713 or 811 with phenylalanine resulted in a loss of the 10- and 4-kda phosphopeptides, respectively, identifying these tyrosines as in vitro autophosphorylation sites. Cnbr cleavage analysis of fes isolated from 32po4-labeled 293t cells showed that tyr-713 and tyr-811 are also autophosphorylated in vivo. . Mutagenesis of tyr-713 reduced both autophosphorylation of tyr-811 and transphosphorylation of bcr, a recently identified fes substrate, supporting a major regulatory role for tyr-713." SIGNOR-42655 SRC protein P12931 UNIPROT CDH5 protein P33151 UNIPROT up-regulates phosphorylation Tyr685 LDARPSLyAQVQKPP 9606 BTO:0000975 16909109 t llicata "In vitro src assay, the ve-cadherin cytoplasmic domain is directly phosphorylated by purified src as well as the tyrosine residue 685 (tyr)685-containing peptide finally, we found that in a vegf-induced wound-healing assay, cadherin adhesive activity was impaired by src kinase inhibitors.RPSLY(685)aqvq." SIGNOR-148818 PTK2B protein Q14289 UNIPROT ASAP2 protein O43150 UNIPROT "up-regulates activity" phosphorylation 9606 BTO:0000007 10022920 t miannu "Tyrosine phosphorylation of Pap by Pyk2 or Src kinases. We have identified a new Pyk2 binding protein designated Pap. Pap is a multidomain protein composed of an N-terminal alpha-helical region with a coiled-coil motif, followed by a pleckstrin homology domain, an Arf-GAP domain, an ankyrin homology region, a proline-rich region, and a C-terminal SH3 domain. We demonstrate that Pap forms a stable complex with Pyk2 and that activation of Pyk2 leads to tyrosine phosphorylation of Pap in living cells." SIGNOR-269704 XRCC4 protein Q13426 UNIPROT DNA_repair phenotype SIGNOR-PH57 SIGNOR up-regulates 9606 10854421 f miannu "The DNA-dependent protein kinase (DNA-PK), consisting of Ku and the DNA-PK catalytic subunit (DNA-PKcs), and the DNA ligase IV-XRCC4 complex function together in the repair of DNA double-strand breaks by non-homologous end joining." SIGNOR-264530 DKK1 protein O94907 UNIPROT LRP6 protein O75581 UNIPROT down-regulates binding 9606 11448771 t gcesareni "We report that dkk-1 is a high-affinity ligand for lrp6 and inhibits wnt signaling by preventing fz-lrp6 complex formation induced by wnt. Dkk1 has been shown to inhibit wnt by binding to and antagonizing lrp5/6." SIGNOR-109247 PI3K complex SIGNOR-C156 SIGNOR AKT1 protein P31749 UNIPROT "up-regulates activity" 9606 BTO:0000586 16293724 f lperfetto "We show that PGE2 stimulates colon cancer cell growth through its heterotrimeric guanine nucleotide-binding protein;G protein)-coupled receptor, EP2, by a signaling route that involves the activation of phosphoinositide 3-kinase and the protein kinase Akt" SIGNOR-252711 PTPRK protein Q15262 UNIPROT EGFR protein P00533 UNIPROT unknown dephosphorylation Tyr1092 TFLPVPEyINQSVPK 10029 BTO:0000246 16263724 t "RPTP-kappa also reduced epidermal growth factor-dependent EGFR tyrosine phosphorylation in CHO cells. Purified RPTP-kappa preferentially dephosphorylated EGFR tyrosines 1068 and 1173 in vitro." SIGNOR-248722 INSR protein P06213 UNIPROT INSR protein P06213 UNIPROT "up-regulates activity" phosphorylation Tyr999 YASSNPEyLSASDVF -1 3166375 t lperfetto "This approach revealed that insulin stimulates autophosphorylation of the insulin-receptor beta-subunit in vitro on at least seven tyrosine residues distributed among three distinct domainsAt least two further tyrosine residues appeared to be phosphorylated after those in domains 2 and 3. These residues probably residue within a domain lying in close proximity to the inner face of the plasma membrane containing tyrosines 953, 960 and 972" SIGNOR-106526 IL17A protein Q16552 UNIPROT KRT17 protein Q04695 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000667 21796151 f miannu "IL-17A upregulates keratin 17 expression in keratinocytes through STAT1- and STAT3-dependent mechanisms." SIGNOR-255232 PHF2 protein O75151 UNIPROT H3-4 protein Q16695 UNIPROT "up-regulates activity" demethylation Lys5 kQTARKST 9606 21532585 t miannu "PHF2, a jmjC demethylase, is enzymatically inactive by itself, but becomes an active H3K9Me2 demethylase through PKA-mediated phosphorylation. This modification leads to targeting of the PHF2–ARID5B complex to its target promoters, where it removes the repressive H3K9Me2 mark." SIGNOR-264517 "3-phosphonato-D-glyceroyl phosphate(4-)" smallmolecule CHEBI:57604 ChEBI 3-phosphonato-D-glycerate(3-) smallmolecule CHEBI:58272 ChEBI "up-regulates quantity" "precursor of" 9606 16051738 t miannu "Phosphoglycerate kinase generates one molecule of ATP by catalyzing the reversible conversion of 1,3-bisphosphoglycerate to 3-phosphoglycerate. Two isozymes of PGK exist: PGK-1, ubiquitously expressed in all somatic cells, and PGK-2, expressed only in spermatozoa." SIGNOR-266499 DAB2IP protein Q5VWQ8 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR "down-regulates activity" binding 9606 27858941 t miannu "DAB2IP inhibits the PI3K–AKT axis by directly interacting with both proteins, reducing phosphorylation and activation of AKT. The GAP activity of DAB2IP can further enforce inhibition of the PI3K–AKT axis by reducing Ras-dependent activation of PI3K p110α subunit." SIGNOR-254751 RPS6KA1 protein Q15418 UNIPROT FLNA protein P21333 UNIPROT up-regulates phosphorylation Ser2152 TRRRRAPsVANVGSH 9606 BTO:0000848 15024089 t gcesareni "We show that the n-terminal kinase domain of rsk phosphorylates flna on ser(2152) in response to mitogens" SIGNOR-123458 GOLGA7 protein Q7Z5G4 UNIPROT ZDHHC9 protein Q9Y397 UNIPROT "up-regulates activity" binding 9606 BTO:0000007 16000296 t miannu "DHHC9 and GCP16 form a protein complex, and DHHC9 requires GCP16 for protein fatty acyltransferase activity and protein stability." SIGNOR-261353 FOXD2 protein O60548 UNIPROT PRKAR1A protein P10644 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000661 12621056 t Luana "Elevating the amounts of FOXD2 expression vector up to 12-fold relative to the RIα1b reporter construct demonstrated that maximal induction of the RIα1b promoter by FOXD2 was at least 5.8-fold" SIGNOR-261605 EXOSC6 protein Q5RKV6 UNIPROT Exosome_Complex complex SIGNOR-C255 SIGNOR "form complex" binding -1 24189234 t miannu "The RNA exosome is an evolutionarily conserved multi-protein complex involved in the 3' degradation of a variety of RNA transcripts. In the nucleus, the exosome participates in the maturation of structured RNAs, in the surveillance of pre-mRNAs and in the decay of a variety of noncoding transcripts. In the cytoplasm, the exosome degrades mRNAs in constitutive and regulated turnover pathways. The eukaryotic exosome, however, is composed of nine different subunits that are still somewhat related in sequence to the archaeal Rrp41-like subunits (Rrp41, Rrp46 and Mtr3), the archaeal Rrp42-like subunits (Rrp45, Rrp43 and Rrp42) and the cap proteins (Rrp4, Csl4 and Rrp40)." SIGNOR-261389 SRC protein P12931 UNIPROT PTK2 protein Q05397 UNIPROT up-regulates phosphorylation Tyr861 PIGNQHIyQPVGKPD 9606 15735019 t miannu "Surprisingly, we found that expression of SrcMF or Src251 resulted in increased tyrosine phosphorylation of FAK on Tyr(407), Tyr(576), Tyr(577), and Tyr(861), which are considered to be Src kinase substrates" SIGNOR-150492 PRKACA protein P17612 UNIPROT RHOA protein P61586 UNIPROT "down-regulates activity" phosphorylation Ser188 ARRGKKKsGCLVL 10090 12654918 t miannu "PKA phosphorylates RhoA on Ser188. the addition of a negative charge to Ser188 is sufficient to diminish both RhoA activation and activity within the context of a cell." SIGNOR-250047 TGFBI protein Q15582 UNIPROT "A6/b4 integrin" complex SIGNOR-C174 SIGNOR "up-regulates activity" binding 26387839 t lperfetto "BIGH3 binds molecules of the ECM, including fibronectin, laminin and different collagens ( Hashimoto et al., 1997 ; Hanssen et al., 2003) and serves as a ligand for several integrins|BIGH3 has been shown to interact with α3β1, αvβ3, αvβ5, α1β1, α6β4 and α7β1 integrin heterodimers" SIGNOR-253268 "MYOD1/SWI/SNF complex" complex SIGNOR-C93 SIGNOR MYL4 protein P12829 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000887 15870273 f miannu "Swi/snf enzymes are necessary for myod to activate muscle gene transcription / myod increased the expression of 94 genes and decreased that of 70 genes /these 94 genes (represented by 96 array features) were analyzed for their dependence on a functional brg1-based swi/snf complex. In the presence of dominant-negative brg1, 29 genes did not achieve full activation by myod, as determined by statistical criteria (q 0.05) and a twofold or more decrease in expression level (table 1; see also table s1 in the supplemental material)" SIGNOR-136697 thapsigargin chemical CHEBI:9516 ChEBI ATP2A2 protein P16615 UNIPROT "down-regulates activity" "chemical inhibition" 9534 30814986 t lperfetto "Treatment of Vero cells with SERCA-specific inhibitor (Thapsigargin) at a concentration that is nontoxic to the cells significantly reduced Peste des petits ruminants virus (PPRV) and Newcastle disease virus (NDV) replication. |Thapsigargin inhibits NDV-induced SERCA2 expression in Vero cells" SIGNOR-262021 EIF3_complex complex SIGNOR-C401 SIGNOR "40S cytosolic small ribosomal subunit" complex SIGNOR-C286 SIGNOR "up-regulates activity" binding 9606 16920360 t miannu "EIF3 binds 40S and inhibits the association of 60S. Structural analysis suggests that eIF3 performs this scaffolding function by binding to the 40S subunit on its solvent-exposed surface rather than on its interface with the 60S subunit, where the decoding sites exist. This location of eIF3 seems ideally suited for its other proposed regulatory functions, including reinitiating translation on polycistronic mRNAs and acting as a receptor for protein kinases that control protein synthesis." SIGNOR-266401 RPS6KA1 protein Q15418 UNIPROT IRS1 protein P35568 UNIPROT "down-regulates quantity by destabilization" phosphorylation 9606 BTO:0001103 21798082 t lperfetto "Negative feedback involves s6k, which inactivates irs by phosphorylation at multiple sites, thus inducing its degradation and altered cell localization." SIGNOR-175687 JMJD1C protein Q15652 UNIPROT H3-3A protein P84243 UNIPROT "down-regulates activity" demethylation Lys10 RTKQTARkSTGGKAP 9606 32034158 t miannu "We now determine that JMJD1C is recruited by USF-1 to various lipogenic genes for H3K9 demethylation to enhance chromatin accessibility in the fed state." SIGNOR-265169 Cytoplasmic_Dynein proteinfamily SIGNOR-PF67 SIGNOR Microtubule-based_movement phenotype SIGNOR-PH170 SIGNOR up-regulates 16440056 f lperfetto "Dyneins are large multi-subunit protein complexes that undertake a wide range of roles within the cell. They are adenosine triphosphate (ATP)–driven, microtubule minus-end-directed molecular motors that can be divided, based on function, into two classes: axonemal and cytoplasmic dyneins" SIGNOR-265019 "Cullin 3-RBX1-Skp1" complex SIGNOR-C526 SIGNOR INF2 protein Q27J81 UNIPROT "down-regulates quantity by destabilization" polyubiquitination Lys673 KFDVEVLkQLLKLLP 9606 BTO:0000007 28448495 t miannu "SPOP acts as an adaptor protein of the CUL3-RBX1 E3 ubiquitin ligase complex that generally recruits substrates for ubiquitination and subsequent degradation. Here, we revealed that SPOP recognizes a Ser/Thr (S/T)-rich motif in the C-terminal region of INF2 and triggers atypical polyubiquitination of INF2. These ubiquitination modifications do not lead to INF2 instability, but rather reduces INF2 localization in ER and mitochondrially associated DRP1 puncta formation, therefore abrogates its ability to facilitate mitochondrial fission. It revealed that INF2 was ubiquitinated at least at 7 lysine residues (Fig 2I). Interestingly, 5 of 7 ubiquitin attachment sites are localized in a short stretch of sequence (amino acids 612–682) within the FH2 domain of INF2 (Fig 2J)." SIGNOR-272804 CD19 protein P15391 UNIPROT LYN protein P07948 UNIPROT "up-regulates activity" binding 10090 BTO:0000776 25673924 t lperfetto "CD19 has an extracellular region containing two C2-type Ig-like domains and a cytoplasmic region of ~240 amino acids with 9 conserved tyrosine residues24. Lyn, a Src-family protein tyrosine kinase member, is the dominant kinase that phosphorylates CD19 upon stimulation. Once tyrosyl-phosphorylated, CD19 serves as a membrane-bound adaptor protein for Src homology 2-containing signaling molecules such as Lyn, Vav, and phosphatidylinositol 3-kinase, which further mediate downstream activation cascades." SIGNOR-242894 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR LIFR protein P42702 UNIPROT down-regulates phosphorylation 9606 7777512 t "inferred from 70% family members" gcesareni "Thus, our results identify the human lifr as a substrate for mapk and suggest a mechanism of heterologous receptor regulation of lifr signaling occurring at ser-1044." SIGNOR-270134 TRAF6 protein Q9Y4K3 UNIPROT LGMN protein Q99538 UNIPROT "up-regulates quantity by stabilization" polyubiquitination 9606 BTO:0000815 24610907 t miannu "We demonstrate that TRAF6 ubiquitinates the proform of AEP through K63-linked polyubiquitin, reversible by USP17, and forms a complex with HSP90α to subsequently promote pro-AEP intracellular stability as well as secretion. We now present evidence that AEP is a substrate for TRAF6 ubiquitination, resulting in AEP/TRAF6/HSP90α complex formation." SIGNOR-272853 SUN2 protein Q9UH99 UNIPROT "LINC complex" complex SIGNOR-C303 SIGNOR "form complex" binding 24481844 t lperfetto "LINC complex couples the nuclear lamina to the cytoskeleton. SUN domain proteins, SUN1 and SUN2, located at the inner nuclear membrane (INM) interact with the nuclear lamins, Lamin A/C, B1, and B2, that line the nucleoplasmic face of the INM. SUN domain proteins interact with Nesprins in the perinuclear space (PNS). Nesprins protrude from the outer nuclear membrane (ONM) and interact with the cytoskeleton, often through an intermediate binding partner. Nesprin 1 giant (g) and Nesprin 2g potentially link the NE directly to the Z-disc (Z), whereas Nesprin 1alpha and 2alpha may connect via an unknown intermediate protein. In addition, the shorter isoforms of Nesprin 1 and Nesprin 2 may localize to the INM." SIGNOR-263286 MYOD/E12E47 complex SIGNOR-C127 SIGNOR VEGFA protein P15692 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 BTO:0001103 18094043 t lperfetto "we further demonstrate that the myogenic transcription factor, MyoD, and its heterodimeric binding proteins E12 and E47, up-regulate the expression of endogenous VEGF through direct interaction with the VEGF promoter." SIGNOR-241545 SP1 protein P08047 UNIPROT THBD protein P07204 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 22406829 f miannu "In carcinomas the expression of thrombomodulin (TM) is inversely correlated with tumour progression and metastasis. The expression of TM is negatively regulated by NF-?B- and GSK3-?-dependent signalling pathways and positively regulated by retinoic acid and transcription factor Sp1 in PrEC, LNCaP and PC-3 cells, but not in DU-145 cells." SIGNOR-255216 DUSP6 protein Q16828 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR up-regulates dephosphorylation 9606 22521266 t gcesareni "Phosphorylated foxo1 is inactive and retained in the cytosol. Mkp-3 mediated dephosphorylation activates foxo1 and subsequentially promotes its nuclear translocation and binding to the promoters of gluconeogenic genes, such as phosphoenolpyruvate carboxykinase (pepck) and glucose-6-phosphatase (g6pase)." SIGNOR-252903 INTS4 protein Q96HW7 UNIPROT DYNC1H1 protein Q14204 UNIPROT "up-regulates quantity" 9606 BTO:0000567 23904267 f Monia "We propose a model in which nuclear localized Integrator complex, including ASUN, mediates 3′-end processing of snRNA, which in turn is required for normal processing of mRNA encoding a key regulator(s) of cytoplasmic dynein localization. When Integrator activity is compromised (e.g., by knockdown of an essential subunit), production of critical transcript(s) during interphase is impaired, leading to reduction of perinuclear dynein at G2/M." SIGNOR-261186 DYRK1B protein Q9Y463 UNIPROT CCND1 protein P24385 UNIPROT down-regulates phosphorylation Thr288 VDLACTPtDVRDVDI 9606 BTO:0000567 17046823 t lperfetto "Further, we found that not only gsk-3beta but also dyrk1b modulates cyclin d1 subcellular localization by the phosphorylation of thr(288). These results suggest that dif-3 induces degradation of cyclin d1 through the gsk-3beta- and dyrk1b-mediated threonine phosphorylation in hela cells" SIGNOR-150126 ATM protein Q13315 UNIPROT STK11 protein Q15831 UNIPROT unknown phosphorylation Thr363 IEDDIIYtQDFTVPG 9606 BTO:0000848 12234250 t llicata "We demonstrate that both dna-pk and atm efficiently phosphorylate lkb1 at thr-366 in vitro and provide evidence that atm mediates this phosphorylation in vivo. however, phosphorylation of lkb1 at thr-366 may have some role in enabling lkb1 to suppress cell growth" SIGNOR-92877 CAMK2B protein Q13554 UNIPROT STAT1 protein P42224 UNIPROT up-regulates phosphorylation Ser727 TDNLLPMsPEEFDEV 9606 17502367 t gcesareni "All stats are phosphorylated on at least one serine residue in their tad specifically, ser727 in stats 1 and 3 and ser721 in stat4. Stat serine kinases have been identified through the use of inhibitors, dominant-negative alleles, and in vitro kinase assays. They include mapk (p38mapk: stats 1, 3, 4;erk: stat3, 5;jnk: stat3), pkc_ (stat1, stat3), mtor (stat3), nlk (stat3 (42)), and camkii and ikk_ (stat1 (39, 40, 43)).STAT Serine phosphorylation regulates transcriptional activity (see below)." SIGNOR-154771 NF1 protein P21359 UNIPROT ADCY5 protein O95622 UNIPROT up-regulates 9606 BTO:0000938 24431436 f miannu "Nf1encodes neurofibromin, a protein with multiple functions including ras inactivation (ras gtpase-activating protein or rasgap) and adenylyl cyclase (ac) activation" SIGNOR-204140 GSK3B protein P49841 UNIPROT NOTCH2 protein Q04721 UNIPROT "down-regulates activity" phosphorylation Thr2074 VTPSPPGtVLTSALS 9606 BTO:0000007 12794074 t lperfetto "We show that gsk-3beta directly binds at c-terminal of the notch2 ankyrin repeats and phosphorylates thr-2068 and/or ser-2070, thr-2074, and thr-2093." SIGNOR-101574 MAPK3 protein P27361 UNIPROT POLR2A protein P24928 UNIPROT down-regulates phosphorylation Ser1619 SPSYSPTsPSYSPTS 9606 14662762 t lperfetto "Erk1/2 are major ser-5 kinases after h2o2 treatment. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination." SIGNOR-120172 FOXO1 protein Q12778 UNIPROT NPY protein P01303 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000614 28270795 f miannu "Foxo1 (when activated) stimulates the transcription of AgRP and NPY, but suppresses the transcription of POMC; thereby antagonizing the transcriptional action of STAT3 in these hypothalamic subpopulations." SIGNOR-263502 KAT5 protein Q92993 UNIPROT NOTCH1 protein P46531 UNIPROT down-regulates acetylation Lys2078 EGSYETAkVLLDHFA 9606 17636029 t gcesareni "This result implies that the residues k2019, k2039, k2044, and k2068 of notch1-ic are the major targets of the acetyltransferase activity of tip60." SIGNOR-156923 KEAP1 protein Q14145 UNIPROT "Cullin 3-RBX1-Skp1" complex SIGNOR-C526 SIGNOR "up-regulates activity" binding 9534 BTO:0001538 17046835 t miannu "Keap1-dependent ubiquitination of PGAM5 results in proteasome-dependent degradation of PGAM5. Keap1 is a Bric-a-Brac (BTB) 2 -Kelch protein that functions as a substrate adaptor protein for a Cul3-dependent E3 ubiquitin ligase complex." SIGNOR-272646 CSNK1G1 protein Q9HCP0 UNIPROT LRP6 protein O75581 UNIPROT up-regulates phosphorylation Thr1479 SSSSTKGtYFPAILN 9606 16341016 t gcesareni "Ck1gamma is associated with lrp6, which has multiple, modular ck1 phosphorylation sites. Wnt treatment induces the rapid ck1gamma-mediated phosphorylation of these sites within lrp6" SIGNOR-143029 BUB1 protein O43683 UNIPROT PLK1 protein P53350 UNIPROT up-regulates binding 9606 BTO:0000567 phosphorylation:Thr609 SAAQLAStPFHKLPV 16760428 t gcesareni "The plk1-bub1 interaction requires the polo-box domain (pbd) of plk1 and is enhanced by cyclin-dependent kinase 1 (cdk1)-mediated phosphorylation of bub1 at t609" SIGNOR-147061 ARID1A protein O14497 UNIPROT "SWI/SNF complex" complex SIGNOR-C92 SIGNOR "form complex" binding 9606 15627498 t miannu "We discuss recent insights in the functional differences between two evolutionary conserved subclasses of swi/snf-related chromatin remodeling factors. Onesubfamily comprises yeast swi/snf, fly bap and mammalian baf, whereas the other subfamily includes yeast rsc, fly pbap andmammalian pbaf. We review the subunit composition, conserved protein modules and biological functions of each of these subclasses ofswi/snf remodelers." SIGNOR-132919 U0126 chemical CHEBI:90693 ChEBI MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR down-regulates "chemical inhibition" 9606 9873633 t lperfetto "The mek1/2 inhibitors pd98059, sl327, and u0126 have been extensively used to implicate erk1/2 in neuroplasticity. u0126 was found to functionally antagonize ap-1 transcriptional activity via noncompetitive the dual specificity kinase mek with an ic50 of 0.07 microm for mek 1 and 0.06 microm for mek 2." SIGNOR-244958 GSK3B protein P49841 UNIPROT CDKN1A protein P38936 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser114 EEDHVDLsLSCTLVP 9606 BTO:0000093 17283049 t lperfetto "Glycogen synthase kinase 3beta phosphorylates p21waf1/cip1 for proteasomal degradation after uv irradiationhere, we show that ser-114 phosphorylation of p21 protein by glycogen synthase kinase 3beta (gsk-3beta) is required for its degradation in response to uv irradiation" SIGNOR-152941 RPS6KA5 protein O75582 UNIPROT EIF4EBP1 protein Q13541 UNIPROT "down-regulates activity" phosphorylation Thr46 GGTLFSTtPGGTRII 12213813 t lperfetto "In response to UV-B irradiation, the translation factor 4E-BP1 (eukaryotic initiation factor 4E [eIF4E]-binding protein 1) was phosphorylated at Thr36, Thr45, Ser64 and Thr69. Using either p38 MAPK inhibitors or the MSK inhibitor H89, UV-B-irradiation-induced phosphorylation was blocked [43]. 4E-BP1 binds to eIF4E in resting cells to prevent formation of a functional eIF4F complex, which is essential for cap-dependent initiation of translation. Phosphorylation of 4E-BP1 leads to dissociation from eIF4E" SIGNOR-262992 YWHAH protein Q04917 UNIPROT KCNK18 protein Q7Z418 UNIPROT "down-regulates activity" binding -1 18397886 t miannu "Phosphorylation of serine 264 in mouse TRESK was required for the binding of 14-3-3η. In the present study, we report that 14-3-3 proteins directly bind to the intracellular loop of TRESK and control the kinetics of the calcium-dependent regulation of the channel. Coexpression of 14-3-3η with TRESK blocked, whereas the coexpression of a dominant negative form of 14-3-3η accelerated the return of the K+ current to the resting state after the activation mediated by calcineurin in Xenopus oocytes." SIGNOR-263155 PRKCA protein P17252 UNIPROT TRPM4 protein Q8TD43 UNIPROT up-regulates phosphorylation Ser1145 RDKRESDsERLKRTS 9606 15590641 t gcesareni "Phorbol ester-induced activation of protein kinase c (pkc) increased the ca(2+) sensitivity of wild-type trpm4 but not of two mutants mutated at putative pkc phosphorylation sites." SIGNOR-132243 MN1 protein Q10571 UNIPROT Differentiation phenotype SIGNOR-PH37 SIGNOR down-regulates 10090 17494859 f irozzo "MN1 is a unique oncogene in hematopoiesis that both promotes proliferation/self-renewal and blocks differentiation, and may become useful as a predictive marker in AML treatment." SIGNOR-256016 CDK5 protein Q00535 UNIPROT NDEL1 protein Q9GZM8 UNIPROT "up-regulates activity" phosphorylation Ser231 GTENTFPsPKAIPNG 10090 12796778 t llicata "Three specific phosphorylation sites (Ser198, Thr219 and Ser231) and two weak phosphorylation sites (Ser242 and Thr245) for CDK5/p35 are located in this region of NUDEL | Each single or double mutant compromised,and the triple mutant completely eliminated, interaction with 14-3-3ε. | 14-3-3ε sustains NUDEL phosphorylation and protects it from phosphatase.e dynein motor function." SIGNOR-250676 CDK4 protein P11802 UNIPROT KAT2A protein Q92830 UNIPROT "up-regulates activity" phosphorylation Ser372 EEIYGANsPIWESGF 24870244 t lperfetto "Activated cyclin D1-Cdk4 kinase phosphorylates and activates GCN5|GCN5 T272A/S372A (AA) phosphorylation by cyclin D1-CDK4 kinase is diminished compared to GCN5 wild-type (WT)" SIGNOR-275494 STAT1 protein P42224 UNIPROT S100A10 protein P60903 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000567;BTO:0002923 12645529 f miannu "IFN-gamma induced a rapid tyrosine phosphorylation and nuclear translocation of STAT1 protein, which is involved in the binding to the GAS-2 site in the p11 promoter by EMSA analysis. These data suggest that IFN-gamma-induced p11 expression is mediated through the binding of STAT1 to GAS sites in the p11 promoter." SIGNOR-255237 PRKACA protein P17612 UNIPROT ARPP21 protein Q9UBL0 UNIPROT "up-regulates activity" phosphorylation Ser58 QERRKSKsGAGKGKL -1 10854908 t miannu "The specificity of antibody G534 was examined using recombinant full-length rat ARPP-21 phosphorylated by PKA. Radiolabeled ARPP-21 from a reaction containing [γ32P]ATP correlated with the detection of phospho-Ser55-ARPP-21 by immunoblotting (Fig. 1A, left and middle panels)." SIGNOR-263107 FGD2 protein Q7Z6J4 UNIPROT CDC42 protein P60953 UNIPROT "up-regulates activity" "guanine nucleotide exchange factor" 9606 BTO:0000007 32203420 t Luana "We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2)." SIGNOR-260552 GRM3 protein Q14832 UNIPROT calcium(2+) smallmolecule CHEBI:29108 ChEBI "up-regulates quantity" relocalization 9606 29953871 t miannu "Ca2+ is arguably the most important second messenger in the brain because of its pivotal roles in presynaptic neurotransmitter release, postsynaptic responses, and plasticity induction. iGluRs and mGluRs can generate intracellular Ca2+ signals, albeit by different mechanisms, whose crosstalk has not been thoroughly explored (Figure 2C). iGluRs allow the influx of extracellular Ca2+ upon pore opening." SIGNOR-264934 COMMD5 protein Q9GZQ3 UNIPROT RHOA protein P61586 UNIPROT "up-regulates activity" 9606 30021164 f miannu "We found that RhoA activity is decreased following COMMD5 depletion, suggesting that COMMD5 regulates cytoskeleton organization through RhoA signaling.We found that RhoA activity is decreased following COMMD5 depletion, suggesting that COMMD5 regulates cytoskeleton organization through RhoA signaling. However, the dynamics of Rho GTPase activities are highly complex and tightly regulated in order to achieve their specific subcellular localization (Marjoram et al., 2014); thus, the mechanism by which COMMD5 directly or indirectly regulates the activity of RhoA needs to be investigated further." SIGNOR-261690 ZEB1 protein P37275 UNIPROT EPCAM protein P16422 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0000150;BTO:0000584 23667256 f miannu "We found a similar ZEB1-dependent repression of EPCAM expression in human pancreatic and breast cancer cell lines, mediated through direct binding of ZEB1 to the EPCAM promoter." SIGNOR-255622 NR3C1 protein P04150 UNIPROT NR4A1 protein P22736 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 15591535 f gcesareni "Our data suggest a mechanism for transrepression between two nuclear receptors, gr and ngfi-b." SIGNOR-132251 PLK1 protein P53350 UNIPROT CENPQ protein Q7L2Z9 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser248 DLDILHNsSQMKSMS 9606 BTO:0000567 25670858 t lperfetto "Notably, although Plk1 did not alter the level of PBIP1 and CENP-Q ubiquitination, Plk1-dependent phosphorylation and delocalization of these proteins from kinetochores appeared to indirectly lead to their degradation in the cytosol. From these analyses, we identified nine CENP-Q residues (Thr-123, Thr-135, Ser-138, Ser-139, Ser-248, Ser-249, Ser-253, Ser-255, and Thr-256) that were phosphorylated in both in vitro and in vivo samples (Fig. 4B), suggesting that Plk1 phosphorylates these sites." SIGNOR-265227 PPP2CB protein P62714 UNIPROT RALA protein P11233 UNIPROT down-regulates dephosphorylation Ser194 NGKKKRKsLAKRIRE 9606 17540176 t miannu "Pp2a abeta-containing complexes dephosphorylate rala at ser183 and ser194, inactivating rala and abolishing its transforming function" SIGNOR-155353 CDC7 protein O00311 UNIPROT MCM2 protein P49736 UNIPROT up-regulates phosphorylation Ser41 RTDALTSsPGRDLPP 9606 16446360 t gcesareni "In the present study, we report the identification of cdc7/dbf4 phosphorylation sites on mcm2 and determine the functional role of cdc7/dbf4 phosphorylation of mcm2 in the initiation of dna replication in human cells." SIGNOR-143996 AKT3 protein Q9Y243 UNIPROT HSPB1 protein P04792 UNIPROT down-regulates phosphorylation Ser82 RALSRQLsSGVSEIR 9606 19593530 t "10383393: We demonstrate that both phosphorylated sHsps and the triple mutant Hsp27-S15D,S78D,S82D show significantly decreased abilities to act as molecular chaperones suppressing thermal denaturation and facilitating refolding of citrate synthase in vitro." lperfetto "First, the akt1, akt2, and akt3 isoforms can bind directly to hsp27 and can be found in a complex with p38 mapk, mk2, and hsp27 [98_100]. Second, rane and colleagues showed that akt could phosphorylate hsp27 at ser-82, but not ser-15 or ser-78, in vitro, while co-expression of an active akt mutant and hsp27 in hek cells resulted in hsp27 phosphorylation at the same residue." SIGNOR-186780 FGF2 protein P09038 UNIPROT MAPK14 protein Q16539 UNIPROT up-regulates 9606 11781339 f gcesareni "In these collagen gel cultures, p38 activation was induced more potently by fgf-2 treatment compared with that in proliferating cultures" SIGNOR-113649 PPP2CA protein P67775 UNIPROT PP2CA_R1A_R2A complex SIGNOR-C132 SIGNOR "form complex" binding 9606 23454242 t gcesareni "[PP2A] ... is multifarious as it is composed of catalytic, scaffold and regulatory subunits. The catalytic and scaffold subunits have two isoforms and the regulatory subunit has four different families containing different isoforms. The regulatory subunit is the most diverse with temporal and spatial specificity." SIGNOR-243424 RXRA protein P19793 UNIPROT RARA protein P10276 UNIPROT up-regulates binding 9606 1310351 t gcesareni "Here we report that the transcriptional activity of rar and rxr can be reciprocally modulated by direct interactions between the two proteins" SIGNOR-16665 DUSP6 protein Q16828 UNIPROT MAPK3 protein P27361 UNIPROT down-regulates dephosphorylation 9606 12840032 t gcesareni "P-erk1/2 proteins were efficiently dephosphorylated in vitro by protein phosphatases 1 and 2a (pp1/2a) and mapk phosphatase 3 (mkp3)." SIGNOR-103149 POT1 protein Q9NUX5 UNIPROT POT1/ACD complex SIGNOR-C64 SIGNOR "form complex" binding 9606 17237768 t miannu "We find that tpp1 and pot1 form a complex with telomeric dna that increases the activity and processivity of the human telomerase core enzyme." SIGNOR-152324 SRC protein P12931 UNIPROT BCAR1 protein P56945 UNIPROT "up-regulates activity" phosphorylation Tyr267 SQYGQEVyDTPPMAV 10090 12972425 t lperfetto "Cas is a member of the focal adhesion complex. Phosphorylation of Cas by Src is an important event leading to cell transformation. Using mass spectrometry, we have mapped 11 sites in Cas that are phosphorylated by Src. These sites are all located between residues 132 and 414 of CasBased on these data, 11 tyrosine residues (132, 169, 183, 196, 238, 253, 271, 291, 301, 391, and 414) were phosphorylated by Src|the biological activity of Cas depends on its phosphorylation by Src (16–18). After phosphorylation, Cas associates with a number of proteins, including Crk, Src, phosphatidylinositol 3-kinase, Nck, and phospholipase Cgamma, via SH2 binding motifs" SIGNOR-246401 ABCA1 protein O95477 UNIPROT HDL_assembly phenotype SIGNOR-PH61 SIGNOR up-regulates 9606 23077142 f miannu "Cholesterol efflux is the first step in the formation of HDL, which is initiated through the action of ATP binding cassette transporter (ABC) A1 on apolipoprotein (apo) A-I that produces nascent HDL (nHDL)." SIGNOR-252109 ABL1 protein P00519 UNIPROT WASF3 protein Q9UPY6 UNIPROT "up-regulates activity" phosphorylation Tyr151 KKDGLKFyTDPSYFF 9606 BTO:0000815 17623672 t "WAVE3-Abl interaction promotes the tyrosine phosphorylation of WAVE3 by Abl, and STI-571, a specific inhibitor of Abl kinase activity, abrogates the Abl-mediated phosphorylation of WAVE3." SIGNOR-262299 ATAT1 protein Q5SQI0 UNIPROT TUBA1A protein Q71U36 UNIPROT "up-regulates quantity by stabilization" acetylation Lys40 DGQMPSDkTIGGGDD -1 29703898 t lperfetto "Alpha-Tubulin acetyltransferase (alphaTAT1) is the major α-tubulin lysine-40 (K40) acetyltransferase in mammals, nematodes, and protozoa, and its activity plays a conserved role in several microtubule-based processes.|The tubulin subunits of microtubules are acetylated, and lysine-40 (K40) of the alpha-tubulin subunit has been identified as an important conserved site of microtubule acetylation (6–8). This modification is considered a hallmark of stable, long-lived microtubules" SIGNOR-272251 "N-[4-[(hydroxyamino)-oxomethyl]phenyl]carbamic acid [6-(diethylaminomethyl)-2-naphthalenyl]methyl ester" chemical CHEBI:94187 ChEBI HDAC3 protein O15379 UNIPROT "down-regulates activity" "chemical inhibition" -1 20139990 t Luana "Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1)." SIGNOR-257966 brimonidine chemical CHEBI:3175 ChEBI ADRA2A protein P08913 UNIPROT "up-regulates activity" "chemical activation" 9606 BTO:0000007 9605427 t miannu "AR agonists stimulated binding of [35S]GTPgS to HEK 293 cell membranes containing the human a2a, a2b, or a2c ARs (Fig. 6). EPI and NE were full agonists; clonidine and oxymetazoline were partial agonists, while antagonists (e.g. rauwolscine, 5 mM) did not stimulate [35S]GTPgS incorporation (Table 3). Although a few agonists showed a great deal of selectivity for a single receptor subtype, the rank order of agonist potency for selected compounds at the human receptors (Table 3) was: a2a: Dexmedetomidine . guanabenz . UK-14304 .clonidine . ST-91 . NE a2b: Dexmedetomidine . clonidine . guanabenz . NE .ST-91 . UK-14304 a2c: Dexmedetomidine . NE . UK-14304 . ST-91 $ clonidine .. guanabenz" SIGNOR-258902 PRKDC protein P78527 UNIPROT HSP90AA1 protein P07900 UNIPROT unknown phosphorylation Thr7 tQDQPMEE 9606 BTO:0000567 2507541 t lperfetto "Here we show that the dsDNA-activated protein kinase from human HeLa cells phosphorylates 2 threonine residues in the sequence PEETQTQDQPME at the amino terminus of human hsp90 alpha." SIGNOR-248888 acetyl-CoA(4-) smallmolecule CHEBI:57288 ChEBI "coenzyme A(4-)" smallmolecule CHEBI:57287 ChEBI "up-regulates quantity" "precursor of" 9606 19524112 t miannu "The biosynthetic enzyme, aspartate-N-acetyltransferase (Asp-NAT; EC 2.3.1.17) is a CNS specific enzyme that catalyzes the transfer of acetate from acetyl-CoA to L-aspartate forming NAA." SIGNOR-267520 TAB1 protein Q15750 UNIPROT ROR2 protein Q01974 UNIPROT down-regulates phosphorylation 9606 18762249 t gcesareni "Tak1 (tgf-beta activated kinase 1), a map3k, interacts with ror2 and phosphorylates its intracellular carboxyterminal serine/thronine/proline-rich (stp) domain" SIGNOR-180566 HES1 protein Q14469 UNIPROT Adipogenesis phenotype SIGNOR-PH26 SIGNOR down-regulates 10090 BTO:0000011 16282371 f "Notch signaling blocks differentiation of 3T3-L1 preadipocytes, and this can be mimicked by constitutive expression of the Notch target gene Hes-1" SIGNOR-253058 Ub:E2 complex SIGNOR-C497 SIGNOR NEURL1 protein O76050 UNIPROT "up-regulates activity" ubiquitination 9606 34199813 t miannu "The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t" SIGNOR-271043 GIT1 protein Q9Y2X7 UNIPROT ARHGEF6 protein Q15052 UNIPROT "up-regulates activity" binding 9606 BTO:0000132 26507661 t lperfetto "Screening for potential mediators of this effect resulted in the identification of the Rac1-specific GTPase-activating protein ARHGAP17 and the guanine nucleotide exchange factor ARHGEF6 as new PKA and PKG substrates in platelets. We mapped the PKA/PKG phosphorylation sites to serine 702 on ARHGAP17 using Phos-tag gels and to serine 684 on ARHGEF6. |we show that ARHGEF6 is constitutively linked to GIT1, a GAP of Arf family small G proteins, and that ARHGEF6 phosphorylation enables binding of the 14-3-3 adaptor protein to the ARHGEF6/GIT1 complex." SIGNOR-272165 GRM5 protein P41594 UNIPROT calcium(2+) smallmolecule CHEBI:29108 ChEBI "up-regulates quantity" relocalization 9606 29953871 t miannu "Ca2+ is arguably the most important second messenger in the brain because of its pivotal roles in presynaptic neurotransmitter release, postsynaptic responses, and plasticity induction. iGluRs and mGluRs can generate intracellular Ca2+ signals, albeit by different mechanisms, whose crosstalk has not been thoroughly explored (Figure 2C). iGluRs allow the influx of extracellular Ca2+ upon pore opening." SIGNOR-264936 PIAS1 protein O75925 UNIPROT SATB2 protein Q9UPW6 UNIPROT "down-regulates activity" sumoylation Lys233 YKKYKKIkVERVERE 9606 14701874 t gianni "We found that SATB2 differs from the closely related thymocyte-specific protein SATB1 by modifications of two lysines with the small ubiquitive related modifier (SUMO), which are augmented specifically by the SUMO E3 ligase PIAS1." SIGNOR-268932 PIN1 protein Q13526 UNIPROT IRF3 protein Q14653 UNIPROT "down-regulates quantity by destabilization" binding 9606 16699525 t lperfetto "Here we report that activation of IRF3 is negatively regulated by the peptidyl-prolyl isomerase Pin1. After stimulation by double-stranded RNA, induced phosphorylation of the Ser339–Pro340 motif of IRF3 led to its interaction with Pin1 and finally polyubiquitination and then proteasome-dependent degradation of IRF3. Suppression of Pin1 by RNA interference or genetic deletion resulted in enhanced IRF-3-dependent production of interferon-beta, with consequent reduction of virus replication." SIGNOR-252256 MAPK14 protein Q16539 UNIPROT CCND1 protein P24385 UNIPROT up-regulates phosphorylation 9606 20626350 t gcesareni "A large number of cytosolic proteins can be phosphorylated by p38 mapks, including phospholipase a2, the microtubule-associated protein tau, nhe-1, cyclin d1, cdk inhibitors, bcl2 family proteins, growth factor receptors or keratins" SIGNOR-166594 Platelet_alpha_granule_formation phenotype SIGNOR-PH136 SIGNOR VWF protein P04275 UNIPROT up-regulates 9606 NBK559062 f lperfetto "Exposed VWF bound to collagen from vascular injury and endothelial damage adheres to the GPIb receptor on platelets to initiate signaling pathways for platelet activation, the next step in primary hemostasis. VW|VWF released by Weibel-Palade bodies or alpha-granules can enter circulation or accumulate in the subendothelial matrix binding to collagen through its A3 domain. Once exposed under high shear stress conditions in the arterial circulation, VWF can bind to platelets via its A1 domain." SIGNOR-261863 P2RY1 protein P47900 UNIPROT GNAI1 protein P63096 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257072 FST protein P19883 UNIPROT GDF11 protein O95390 UNIPROT "down-regulates activity" binding 10090 24627466 t lperfetto "Follistatin (FST) is a member of the tissue growth factor β family and is a secreted glycoprotein that antagonizes many members of the family, including activin A, growth differentiation factor 11, and myostatin. |FST315-ΔHBS-Fc induced improvements in muscle repair after injury/atrophy by modulating the early inflammatory phase allowing for increased macrophage density, and Pax7-positive cells leading to an accelerated restoration of myofibers and muscle function." SIGNOR-251716 EEF1A1P5 protein Q5VTE0 UNIPROT Val-tRNA(Val) smallmolecule CHEBI:29164 ChEBI up-regulates relocalization 9606 23699257 t lperfetto "During protein synthesis, eEF1A binds to and delivers aminoacylated tRNAs (aa-tRNAs) to the elongating ribosome (Fig. 1). GTP bound to eEF1A is hydrolyzed upon codon-anticodon match between an aa-tRNA in the A site of the ribosome and mRNA bound to the ribosome." SIGNOR-269559 CASP3 protein P42574 UNIPROT Protein_degradation phenotype SIGNOR-PH96 SIGNOR up-regulates 10090 25787076 f miannu "The UPS by itself degrades actomyosin and myofibrillar proteins slowly, but when caspase-3 is activated, it cleaves actomyosin and the myofibrillar proteins to provide substrates for degradation in the UPS . Caspase-3 also can cleave specific subunits of the 19 S proteasome particle, which stimulates the proteolytic activity of the 26S proteasome[...] These results indicate that caspase-3 participates in the muscle proteolysis that is present in tumor-bearing mice." SIGNOR-255337 EGFR protein P00533 UNIPROT CBL protein P22681 UNIPROT up-regulates relocalization 9606 16829981 t "Cbl binds directly to Tyr1045 receptors" gcesareni "Likewise, cbl is recruited to erbb1 either directly (tyr1045), or indirectly, trough grb2" SIGNOR-147826 PTPRC protein P08575 UNIPROT LYN protein P07948 UNIPROT "down-regulates activity" dephosphorylation Tyr397 RVIEDNEyTAREGAK 10090 BTO:0000776 10415030 t "CD45 negatively regulates lyn activity by dephosphorylating both positive and negative regulatory tyrosine residues in immature B cells.| Phosphoamino acid analysis confirmed that Lyn is tyrosine phosphorylated with little serine or threonine phosphorylation. In CD45-negative cells, two bands at 8.2 and 4.1 kDa were phosphorylated in the absence of B cell Ag receptor (BCR) ligation. The 8.2-kDa band corresponded to a fragment containing the positive regulatory site (Tyr397), as assessed by its size and its phosphorylation in an in vitro kinase assay. The 4.1-kDa band was phosphorylated by COOH-terminal Src kinase, suggesting that it contains the COOH-terminal negative regulatory site (Tyr508)" SIGNOR-248353 Ub:E2 complex SIGNOR-C497 SIGNOR PDZRN4 protein Q6ZMN7 UNIPROT "up-regulates activity" ubiquitination 9606 34199813 t miannu "The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t" SIGNOR-271036 IFNGR1 protein P15260 UNIPROT JAK2 protein O60674 UNIPROT up-regulates binding 9606 17063185 t flangone "Interferon- (ifn;type ii ifn) induces reorganization of the ifn-receptor subunits, ifngr1 and ifngr2, activating the janus kinases jak1 and jak2, which are constitutively associated with each subunit, respectively" SIGNOR-150197 asparagine smallmolecule CHEBI:22653 ChEBI Asn-tRNA(Asn) smallmolecule CHEBI:29265 ChEBI "up-regulates quantity" "precursor of" 9606 32788587 t miannu "Asparaginyl-tRNA synthetase1 (NARS1) is a member of the ubiquitously expressed cytoplasmic Class IIa family of tRNA synthetases required for protein translation. Asparaginyl-tRNA synthetase1 (NARS1) belongs to the class IIa family, based upon a 7 beta-strand protein structure. There are two NARS genes: NARS1 functions in the cytoplasm while NARS2 functions in mitochondria, solely responsible for asparagine tRNA charging in these locations." SIGNOR-270460 WWTR1 protein Q9GZV5 UNIPROT TEAD3 protein Q99594 UNIPROT up-regulates binding 9606 23431053 t "YAP/TAZ mainly bind to the transcription factors TEAD1??4 to regulate genes involved in cell proliferation and cell death." gcesareni "When dephosphorylated, yap/taz enter nuclei and induce gene transcription by interacting with transcription factors tead14." SIGNOR-201415 RXRA protein P19793 UNIPROT THRB protein P10828 UNIPROT up-regulates binding 9606 10976919 t gcesareni "Like many receptors belonging to the superfamily of steroid/thyroid nuclear receptors, thyroid hormone receptors (trs) bind to specific th-dna responsive elements (tre) upstream of target gene in heterodimeric complex with the 9-cis retinoid acid receptor (rxr" SIGNOR-81449 NEUROG2 protein Q9H2A3 UNIPROT Neurogenesis phenotype SIGNOR-PH168 SIGNOR up-regulates 10090 BTO:0000938 BTO:0000142 18400164 f lperfetto "While the mechanisms by which Ngn2 promotes neurogenesis have been characterized, little is known about how Ngn2 confers neuronal cell-type identity during spinal cord development. Ngn1 and Ngn2, two mammalian orthologs of the Drosophila proneural bHLH gene atonal, are expressed in overlapping patterns throughout the developing nervous system and act as important regulators of developmental neurogenesis" SIGNOR-265173 ABL1 protein P00519 UNIPROT PTPN6 protein P29350 UNIPROT "up-regulates activity" phosphorylation Tyr564 SKHKEDVyENLHTKN 9606 8692915 t Manara "The results demonstrate that the SH3 domain of ABL1 interacts with a WPDHGVPSEP motif (residues 417-426) in the catalytic domain of SHPTP1 and that ABL1 phosphorylates C terminal Y536 and Y564 sites." SIGNOR-260821 DOCK4 protein Q8N1I0 UNIPROT RAC1 protein P63000 UNIPROT "up-regulates activity" "guanine nucleotide exchange factor" 10090 BTO:0001976 32009906 t miannu "DOCK4 (dedicator for cytokinesis 4), a guanine nucleotide exchange factor (GEF) for the small GTPase Rac1, is one of few genes that are associated with both ASD and dyslexia. " SIGNOR-266823 AMPK complex SIGNOR-C15 SIGNOR BAIAP2 protein Q9UQB8 UNIPROT down-regulates phosphorylation Ser366 KTLPRSSsMAAGLER 9606 19933840 t lperfetto "Using this approach for ppp1r12c, baiap2, and cdc27, we found that mutation of a single serine to alanine (s452, s366, and s379 respectively) resulted in almost a complete loss of ampk phosphorylation in these proteins. Termination of irsp53 function is suggested to occur following cdc42 dissociation, kinase phosphorylation of t340 and t360, and subsequent 14-3-3 binding, which competes for sh3 partners, thus allowing filopodial retraction" SIGNOR-216572 "1D-myo-inositol 1,4,5-trisphosphate" smallmolecule CHEBI:16595 ChEBI ITPR1 protein Q14643 UNIPROT "up-regulates activity" "chemical activation" 9606 24646566 t miannu "The key event in activation of fluid secretion is an increase in intracellular [ca2+] ([ca2+]i) triggered by ip3-induced release of ca2+ from er via the ip3r. ip3rs determine the site of initiation and the pattern of [ca2+]i signal in the cell." SIGNOR-256239 EIF4H protein Q15056 UNIPROT EIF4A1 protein P60842 UNIPROT "up-regulates activity" binding -1 11418588 t "Either eIF4B or eIF4H stimulated the initial rate and amplitude of eIF4A-dependent duplex unwinding, and the magnitude of stimulation is dependent on duplex stability" SIGNOR-261294 Microtubule_polimerization phenotype SIGNOR-PH106 SIGNOR Neurite_outgrowth phenotype SIGNOR-PH134 SIGNOR up-regulates 9606 28347630 f miannu "Microtubules are essential for the generation, migration and differentiation of neurons. Within dendrites microtubules have also been implicated in the formation and plasticity of spines. For instance, the treatment of hippocampal neurons with low doses of the microtubule destabilizing drug Nocodazole impairs BDNF induced dendritic spine formation" SIGNOR-266830 PIM1 protein P11309 UNIPROT CDKN1A protein P38936 UNIPROT "up-regulates quantity by stabilization" phosphorylation Thr145 QGRKRRQtSMTDFYH 9606 20307683 t lperfetto "Pim-2 phosphorylation of p21(cip1/waf1) enhances its stability and inhibits cell proliferation in hct116 cellshere we demonstrate that like pim-1, pim-2 also phosphorylates the cell cycle inhibitor p21(cip1/waf1) (p21) on thr145 in vitro and in vivo" SIGNOR-164642 RPS6KA1 protein Q15418 UNIPROT EIF4B protein P23588 UNIPROT up-regulates phosphorylation Ser422 RERSRTGsESSQTGT 9606 15071500 t gcesareni "S6k1/s6k2 specifically phosphorylate ser422 in vitro. Substitution of ser422 with ala results in a loss of activity in an in vivo translation assay, indicating that phosphorylation of this site plays an important role in eif4b function." SIGNOR-123993 N-(4-methoxyphenyl)sulfonyl-N-[2-[2-(1-oxido-4-pyridin-1-iumyl)ethenyl]phenyl]acetamide chemical CHEBI:91440 ChEBI PLK1 protein P53350 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-193309 TOB2 protein Q14106 UNIPROT "CCR4-NOT complex" complex SIGNOR-C439 SIGNOR "down-regulates activity" binding 9606 BTO:0000567 18377426 t miannu "We found that Tob associates with the CCR4-NOT complex. The carboxyl-terminal half of Tob interacted with Cnot1, a core protein of the CCR4-NOT complex. We further showed that the deadenylase activity associated with the complex was suppressed in vitro by Tob. " SIGNOR-273615 S1PR3 protein Q99500 UNIPROT GNA14 protein O95837 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257437 PCDHA12 protein Q9UN75 UNIPROT ITGB1 protein P05556 UNIPROT "up-regulates activity" binding 9606 BTO:0000227 16697637 t miannu "The clustered protocadherins comprise the largest subfamily of the cadherin superfamily and are predominantly expressed in the nervous system. Pcdh-alpha proteins interact with beta1-integrin to promote cell adhesion." SIGNOR-265673 MAPK3 protein P27361 UNIPROT POLR2A protein P24928 UNIPROT down-regulates phosphorylation Ser1944 GSTYSPTsPGYSPTS 9606 14662762 t lperfetto "Erk1/2 are major ser-5 kinases after h2o2 treatment. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination." SIGNOR-120256 GAPDH protein P04406 UNIPROT "D-glyceraldehyde 3-phosphate(2-)" smallmolecule CHEBI:59776 ChEBI "down-regulates quantity" "chemical modification" 9606 11724794 t miannu "GAPDH is commonly known as a key enzyme in glycolysis (GAPDH catalyzes the NAD-mediated oxidative phosphorylation of glyceraldehyde 3-phosphate to 1,3-diphosphoglycerate), a number of intriguing intracellular roles have been reported including modulation of the cytoskeleton, kinase activity, and the promotion of vesicle fusion" SIGNOR-266495 GP5 protein P40197 UNIPROT "GPIb-IX-V complex" complex SIGNOR-C270 SIGNOR "form complex" binding 9606 BTO:0000132 16293600 t lperfetto "The GPIb-V-IX receptor consists of 4 transmembrane subunits: GPIbα, disulfide-linked to GPIbβ, and the noncovalently associated GPIX and GPV components, in ratios of 2:2:2:1." SIGNOR-261849 ATM protein Q13315 UNIPROT BRCA1 protein P38398 UNIPROT up-regulates phosphorylation 9606 BTO:0000150 10550055 t gcesareni "Results from this study indicate that the checkpoint protein kinase atm (mutated in ataxia telangiectasia) was required for phosphorylation of brca1 in response to ionizing radiation. Brca1 is phosphorylated at tyrosine residues in an atm-dependent, radiation-dependent manner." SIGNOR-72075 PRKCD protein Q05655 UNIPROT PRKCD protein Q05655 UNIPROT up-regulates phosphorylation Ser299 NQVTQRAsRRSDSAS 9606 17603046 t gcesareni "Here, we demonstrate that pkcdelta undergoes in vitro autophosphorylation at three sites within its v3 region (s299, s302, s304), each of which is unique to this pkc isoform and evolutionarily conserved" SIGNOR-156523 PTGER3 protein P43115 UNIPROT GNAZ protein P19086 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257111 MAPK1 protein P28482 UNIPROT ERF protein P50548 UNIPROT down-regulates phosphorylation Thr526 GEAGGPLtPRRVSSD 9606 7588608 t lperfetto "Consistent with the in vivo phosphorylation and inactivation by ras, erf is efficiently phosphorylated in vitro by erk2 and cdc2/cyclin b kinases, at sites similar to those detected in vivo. Furthermore, a single mutation at position 526 results in the loss of a specific phosphopeptide both in in vivo and in vitro (by erk2) labeling. Substitution of thr526 for glutamic acid also decreases the repression ability of erf" SIGNOR-29505 enzalutamide chemical CHEBI:68534 ChEBI AR protein P10275 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-194325 MICU1 protein Q9BPX6 UNIPROT MCU_MICU2_variant complex SIGNOR-C502 SIGNOR "form complex" binding 9606 32315830 t miannu "MCU is a Ca2+-selective channel that mediates mitochondrial Ca2+ influx. The human channel contains tetrameric pore-forming MCU, regulatory subunits MICU1/2, and EMRE that is required both for channel function and MICU1/2-mediated Ca2+ regulation." SIGNOR-270876 FGFR1 protein P11362 UNIPROT FRS2 protein Q8WU20 UNIPROT "up-regulates activity" phosphorylation 10116 BTO:0002809 9182757 t fspada "In this report, we demonstrate that FGF stimulation induces tyrosine phosphorylation of a novel lipid anchored docking protein, termed FRS2, that forms a complex with Grb2/Sos, thus linking FGF-receptor activation to the Ras/MAPK signaling pathway." SIGNOR-236944 RUVBL1 protein Q9Y265 UNIPROT "R2SP co-chaperone" complex SIGNOR-C517 SIGNOR "form complex" binding 9606 29844425 t miannu "Systematic interaction analyses show that one RPAP3-like protein, SPAG1, binds PIH1D2 and RUVBL1/2 to form an R2TP-like complex termed R2SP.  This co-chaperone is enriched in testis and among 68 of the potential clients identified, some are expressed in testis and others are ubiquitous. One substrate is liprin-α2, which organizes large signaling complexes." SIGNOR-270939 NOTCH proteinfamily SIGNOR-PF30 SIGNOR JAG1 protein P78504 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 20953350 f gcesareni "Contact with skip is required for biological activity of notchic. A mutation in the fourth ankyrin repeat that abolished notch signal transduction did not affect interaction with cbf1 but abolished interaction with skip." SIGNOR-254348 TFDP1 protein Q14186 UNIPROT E2F1 protein Q01094 UNIPROT "up-regulates activity" binding 9606 14618416 t miannu "DP-1 is a heterodimerization partner for members of the E2F family of transcription factors; E2F/DP-1 regulates the expression of various cellular promoters, particularly gene products that are involved in the cell cycle." SIGNOR-253865 TP53 protein P04637 UNIPROT G6PD protein P11413 UNIPROT "down-regulates activity" binding 9606 BTO:0001938;BTO:0001109 21336310 t miannu "The p53 protein binds to glucose-6-phosphate dehydrogenase (G6PD), the first and rate-limiting enzyme of the PPP, and prevents the formation of the active dimer." SIGNOR-267468 "cyclosporin A" chemical CHEBI:4031 ChEBI Calcineurin complex SIGNOR-C155 SIGNOR down-regulates "chemical inhibition" 9606 15276472 t gcesareni "Calcineurin catalytic activity is inhibited by the immunosuppressive drugs cyclosporine and fk506 through complexes with immunophilin proteins." SIGNOR-252307 NHLRC1 protein Q6VVB1 UNIPROT EPM2A protein O95278 UNIPROT "down-regulates quantity by destabilization" polyubiquitination 9606 BTO:0000007 15930137 t miannu "Here, we demonstrate that malin is a single subunit E3 ubiquitin (Ub) ligase and that its RING domain is necessary and sufficient to mediate ubiquitination. Additionally, malin interacts with and polyubiquitinates laforin, leading to its degradation. " SIGNOR-271547 SMARCE1 protein Q969G3 UNIPROT "SWI/SNF complex" complex SIGNOR-C92 SIGNOR "form complex" binding 9606 15627498 t miannu "We discuss recent insights in the functional differences between two evolutionary conserved subclasses of swi/snf-related chromatin remodeling factors. Onesubfamily comprises yeast swi/snf, fly bap and mammalian baf, whereas the other subfamily includes yeast rsc, fly pbap andmammalian pbaf. We review the subunit composition, conserved protein modules and biological functions of each of these subclasses ofswi/snf remodelers." SIGNOR-132942 SYK protein P43405 UNIPROT SNCA protein P37840 UNIPROT down-regulates phosphorylation Tyr125 VDPDNEAyEMPSEEG 9606 BTO:0000975;BTO:0000142 11744621 t llicata "Here, we show that alpha-synuclein (alpha-syn) is an outstanding substrate for the protein tyrosine kinase p72syk (syk), which phosphorylates three tyrosyl residues in its c-terminal domain (y-125, y-133, and y-136), here, we show that _-syn is an outstanding substrate for syk and that once it is tyrosine phosphorylated, it loses the ability to form oligomers." SIGNOR-113061 MAPK1 protein P28482 UNIPROT RAF1 protein P04049 UNIPROT down-regulates phosphorylation 9606 9922370 t gcesareni "Mapkerk1/2 is also able to phopshorylate the egf receptor, the ras exchange factor sos, mkkkraf1, and mkkmek1. The phosphorylation of each of these proteins by mapkerk1/2 is believed to reduce their catalytic activity" SIGNOR-64169 CDKN2A protein Q8N726 UNIPROT ATR protein Q13535 UNIPROT "up-regulates activity" phosphorylation 9606 15775976 t gcesareni "Regulation of NF-kappaB and p53 through activation of ATR and Chk1 by the ARF tumour suppressorInduction of ATR activity in Hs68 E2F1ER cells by endogenous ARF." SIGNOR-134781 SPOP protein O43791 UNIPROT NCOA3 protein Q9Y6Q9 UNIPROT "down-regulates quantity by destabilization" binding 9606 24239470 t miannu "Mutations in SPOP represent the most common point mutations in primary prostate cancer,with recurrent mutations in SPOP in 6% to 15% of multiple independent cohorts. Wild-type SPOP will bind and promote the degradation of SRC-3,whereas prostate cancer–derived SPOP mutants lose this ability,leading to increased androgen signaling in certain model systems." SIGNOR-251529 STAT6 protein P42226 UNIPROT PPARG protein P37231 UNIPROT "down-regulates activity" 10090 24948596 f "IL-4 was shown to inhibit lipid accumulation in adipose tissue by a mechanism that includes activation of Stat6, which suppresses PPARα transcriptional activity" SIGNOR-254682 CDKN2A protein Q8N726 UNIPROT NPM1 protein P06748 UNIPROT "down-regulates quantity by destabilization" binding 9606 14636574 t gcesareni "The Arf-NPM interaction seems to be critical in regulating the stability of both proteins. Arf, in fact, induces polyubiquitination and degradation of NPM and inhibits its effects on ribogenesis (18). NPM, instead, protects Arf from degradation and, surprisingly, antagonizes its ability to inhibit cell division" SIGNOR-245077 GSK3B protein P49841 UNIPROT ACLY protein P53396 UNIPROT "up-regulates activity" phosphorylation Ser451 STSTPAPsRTASFSE 10653665 t "Thr 446 and Ser 450, which are phosphorylated by glycogen synthase kinase-3 (GSK-3)" SIGNOR-251218 imatinib chemical CHEBI:45783 ChEBI KIT protein P10721 UNIPROT "down-regulates activity" "chemical inhibition" -1 22037378 t Luana "Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here." SIGNOR-258225 PDE4DIP protein Q5VU43 UNIPROT MYBPC3 protein Q14896 UNIPROT up-regulates binding 9606 21569246 t miannu "This study ascribes a novel function to mmgl isoform 4: it meets all criteria for classification as an akap, and we show that is involved in the phosphorylation of cmybpc as well as ctni, hence mmgl is an important regulator of cardiac contractility." SIGNOR-173766 KDM5B protein Q9UGL1 UNIPROT H3C1 protein P68431 UNIPROT "up-regulates activity" demethylation Lys5 kQTARKST 9606 30246379 t miannu "KDM5 subfamily is capable of removing tri‐ and di‐ methyl marks from lysine 4 on histone H3 (H3K4). Depending on the methylation site, its effect on transcription can be either activating or repressing." SIGNOR-264302 SMARCC2 protein Q8TAQ2 UNIPROT "SWI/SNF ACTL6A-ARID1A-SMARCA2 variant" complex SIGNOR-C470 SIGNOR "form complex" binding 9606 30397315 t miannu "Mammalian SWI/SNF (mSWI/SNF) complexes are ATP-dependent chromatin remodelers that modulate genomic architecture and DNA accessibility, enabling timely and appropriate control of gene expression. They are combinatorially assembled from the products of 29 total genes into three final-form complexes: canonical BAF, PBAF (polybromo-associated BAF complexes), and a newly-defined non-canonical BAF (ncBAF), with specific subunits specifying distinct complexes, such as PBRM1, ARID2, and BRD7 in PBAF complexes, ARID1A/ARID1B and DPF2 in canonical BAF (cBAF) complexes, and GLTSCR1/GLTSCR1L and BRD9 in ncBAF complexes" SIGNOR-269823 ZNF304 protein Q9HCX3 UNIPROT CDKN2A protein Q8N726 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0000391 24623306 t Luana "Finally, we show that ZNF304 also directs transcriptional silencing of INK4-ARF in human embryonic stem cells." SIGNOR-266098 CSNK2A1 protein P68400 UNIPROT IRS1 protein P35568 UNIPROT unknown phosphorylation Ser24 GYLRKPKsMHKRFFV -1 8349691 t llicata "These data suggest that casein kinase II mediates a portion of the insulin-stimulated serine/threonine phosphorylation of overexpressed IRS-1 in vivo. | Thr-502 was identified as the major casein kinase II-catalyzed phosphorylation site in rat IRS-1." SIGNOR-250907 ICAM1 protein P05362 UNIPROT ITGAX protein P20702 UNIPROT up-regulates binding 9606 7679388 t gcesareni "Using assays to quantify cd11c-mediated cell adhesion, we demonstrate that cd11c recognizes icam-2 and vcam-1. The cd11c-binding site on vcam-1 appears to be different from that used by the integrin alpha4." SIGNOR-31388 17beta-estradiol smallmolecule CHEBI:16469 ChEBI "17beta-estradiol 3-sulfate(1-)" smallmolecule CHEBI:136582 ChEBI "up-regulates quantity" "precursor of" -1 7779757 t Luana "HEST-1 maximally sulfates β-estradiol and estrone at concentrations of 20 nM." SIGNOR-269750 RBPJ protein Q06330 UNIPROT DUSP1 protein P28562 UNIPROT up-regulates binding 10090 17158101 t gcesareni "Notch induction of mkp-1 depends on an rbp-j-dependent mechanism." SIGNOR-236851 SULT1E1 protein P49888 UNIPROT "17beta-estradiol 3-sulfate(1-)" smallmolecule CHEBI:136582 ChEBI "up-regulates quantity" "chemical modification" -1 7779757 t Luana "HEST-1 maximally sulfates β-estradiol and estrone at concentrations of 20 nM." SIGNOR-269751 ABCC4 protein O15439 UNIPROT BLOC-1 complex SIGNOR-C381 SIGNOR "up-regulates activity" binding 9606 BTO:0000132 23805129 t lperfetto "The multidrug transporter MRP4, a multidrug resistance protein, is found on platelet dense granules and is proposed to transport adenine nucleotides into these granules (Jedlitschky et al., 2004). Uptake of serotonin from platelet cytosol into dense granules is mediated by vesicular monoamine transporter 2 (VMAT2). " SIGNOR-265996 CSNK2A2 protein P19784 UNIPROT SAT1 protein P21673 UNIPROT unknown phosphorylation -1 8954982 t llicata "Casein kinase 2 phosphorylates recombinant human spermidine/spermine N1-acetyltransferase on both serine and threonine residues. | suggesting that the Ser-phosphorylated residues are located in the C-terminus of the protein, probably Ser 146 and 149." SIGNOR-251036 PAK3 protein O75914 UNIPROT RAF1 protein P04049 UNIPROT up-regulates phosphorylation Ser338 RPRGQRDsSYYWEIE 9606 9823899 t llicata "The protein kinase pak3 positively regulates raf-1 activity through phosphorylation of serine 338." SIGNOR-62043 MRTFA protein Q969V6 UNIPROT SRF protein P11831 UNIPROT up-regulates binding 9606 BTO:0000887;BTO:0001260 21673106 t gcesareni "Similarly, the myocd-related transcription factor (mrtf) family of proteins, mrtf-a and mrtf-b, are also involved in the transcriptional regulation of contractile gene markers as coactivators of srf." SIGNOR-174264 PPM1A protein P35813 UNIPROT PAK1 protein Q13153 UNIPROT "down-regulates activity" dephosphorylation Ser57 KKDRFYRsILPGDKT 10116 18586681 t "Both sites were dephosphorylated with the same kinetics; the anti-Ser(P)198 antibody was subsequently used as it exhibited lower background staining. Direct comparison of PP2Cα with purified PP1 and PP2A lead us to conclude that at the same molar ratio PP2Cα was the most efficient in dephosphorylating PAK1 (Fig. 1D). In this case we monitored two autophosphorylation sites in the Pak1 N-terminal regulatory region (Ser57 and Ser198/203) using phosphospecific antibodies: both sites showed the same kinetics of inactivation." SIGNOR-248493 PPP1R14B protein Q96C90 UNIPROT PPP1CB protein P62140 UNIPROT "down-regulates activity" binding -1 12144526 t lperfetto "We conclude that ILK may activate smooth-muscle contraction both directly, via phosphorylation of myosin, and indirectly, via phosphorylation and activation of CPI-17 and PHI-1, leading to inhibition of MLCP.|CPI-17 and PHI-1 thiophosphorylated by ILK at Thr(38) or Thr(57) respectively inhibited myosin light-chain phosphatase (MLCP) activity bound to myosin" SIGNOR-265743 GABPB2 protein Q8TAK5 UNIPROT HCFC1 protein P51610 UNIPROT "down-regulates activity" binding 9606 BTO:0000567 10675337 t miannu "The C1 factor interacts with the GABP_ transactivation domain.The domain of the C1 factor required for C1–GABP interaction can inhibit GABP_dependent transcriptional activation" SIGNOR-221318 PRKAA1 protein Q13131 UNIPROT PFKFB2 protein O60825 UNIPROT "up-regulates activity" phosphorylation Ser466 PVRMRRNsFTPLSSS 9606 BTO:0000562 SIGNOR-C15 11069105 t gcesareni "Heart 6-phosphofructo-2-kinase activation by insulin results from ser-466 and ser-483 phosphorylation and requires 3-phosphoinositide-dependent kinase-1, but not protein kinase b." SIGNOR-84061 STK4 protein Q13043 UNIPROT LATS2 protein Q9NRM7 UNIPROT up-regulates phosphorylation Ser872 HQRCLAHsLVGTPNY 9606 23431053 t milica "MST1/2 directly phosphorylate Lats1/2 at the hydrophobic motif (Lats1 T1079 and Lats2 T1041), and this phosphorylation is required for Lats1/2 activation" SIGNOR-201298 SIRT1 protein Q96EB6 UNIPROT SMAD7 protein O15105 UNIPROT down-regulates deacetylation Lys70 GKAVRGAkGHHHPHP 9606 17098745 t gcesareni "Sirt1 reversed acetyl-transferase (p300)-mediated acetylation of two lysine residues (lys-64 and -70) on smad7. sirt1-mediated deacetylation of smad7 enhanced smad ubiquitination regulatory factor 1 (smurf1)-mediated ubiquitin proteasome degradation, which contributed to the low expression of smad7 in sirt1-overexpressing mesangial cells." SIGNOR-150599 MAP4K1 protein Q92918 UNIPROT MAP3K1 protein Q13233 UNIPROT up-regulates phosphorylation 9606 8824585 t gcesareni "Hpk1 binds and phosphorylates mekk1 directly," SIGNOR-43996 SOX8 protein P57073 UNIPROT FOXK2 protein Q01167 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000410 32550913 t miannu "We showed for the first time that Aurora-A interacts directly with SOX8 and phosphorylates the protein at Ser327 to further regulate the SOX8/FOXK1 axis, which modulates cell senescence and glycolysis, ultimately leading to cisplatin resistance.. Our results showed that SOX8 targets FOXK1, thereby regulating its transcription, which has significant impacts on senescence, glycolysis and chemoresistance in ovarian cancer." SIGNOR-273613 tertatolol chemical CHEBI:135244 ChEBI HTR1A protein P08908 UNIPROT "down-regulates activity" "chemical inhibition" 10029 9760039 t miannu "Marked differences were observed between the actions of ‘antagonists’ (Table 2; Fig. 2D ). methiothepin and butaclamol, as well asspiperone, exhibited negative efficacy by concentration-dependently inhibiting S GTPgS binding below basal levels, indicating that they act as inverse agonists in this system.WAY 100,135, yUH 301 and the 5-HTreceptor1A and b-adrenergic receptor antagonist ,ytertatolol, acted as ‘neutral’ antagonists, exhibiting antagonist activity without any detectable agonist or inverse agonist effects." SIGNOR-258862 ARHGAP8 protein P85298 UNIPROT RHOA protein P61586 UNIPROT "down-regulates activity" "gtpase-activating protein" 9606 BTO:0000007 32203420 t Luana "We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2)." SIGNOR-260463 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR SOX2 protein P48431 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 BTO:0000596 24942200 t flangone "During neural fate specification, nuclear translocation of ERK1/2 is critical for its activation of Sox2 transcription. More-over, melatonin-induced Sox2 expression, through ERK1/ 2 activation, could locate between base pairs2719 and 1708 in the mouse Sox2 gene." SIGNOR-241977 SCF-betaTRCP complex SIGNOR-C5 SIGNOR NFKB1 protein P19838 UNIPROT "up-regulates activity" ubiquitination 9534 BTO:0004055 11295495 t lperfetto "The scf-betatrcp complex is responsible for the ubiquitination of p100 and p105 following their phosphorylation by ikk." SIGNOR-217190 Ub:E2 complex SIGNOR-C497 SIGNOR RNF121 protein Q9H920 UNIPROT "up-regulates activity" ubiquitination 9606 34199813 t miannu "The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t" SIGNOR-271226 CDK2 protein P24941 UNIPROT GRK2 protein P25098 UNIPROT down-regulates phosphorylation Ser670 KMKNKPRsPVVELSK 9606 20080565 t gcesareni "We report that grk2 protein levels are transiently down-regulated during the g2/m transition by a mechanism involving cdk2-mediated phosphorylation of grk2 at serine670, which triggers binding to the prolyl-isomerase pin1 and subsequent degradation." SIGNOR-163279 AKT1 protein P31749 UNIPROT BAD protein Q92934 UNIPROT "down-regulates activity" phosphorylation Ser99 PFRGRSRsAPPNLWA 9606 BTO:0000938 9346240 t lperfetto "Experiments in this study reveal that akt phosphorylates bad both in vitro and in vivo and that akt-mediated phosphorylation of bad effectively blocks bad induced cell death.[...] In addition, these findings implicate a particular phosphorylation site on bad, serine 136, in the suppression of bad-mediated death by akt.[...]The Phosphorylation of bad may lead to the prevention of cell death via a mechanism that involves the selective association of the phosphorylated forms of bad with 14-3-3 protein isoforms. Akt phosphorylates bad in vitro and in vivo we show that growth factor activation of the pi3'k/akt signaling pathway culminates in the phosphorylation of the bcl-2 family member bad, thereby suppressing apoptosis and promoting cell survival. Akt phosphorylates bad in vitro and in vivo erbb-mediated phosphorylation of bad by akt promotes survival by blocking the interaction of this pro-apoptotic molecule with bcl-2 and bcl-x proteins" SIGNOR-52863 PRKCA protein P17252 UNIPROT DLX3 protein O60479 UNIPROT "down-regulates activity" phosphorylation Ser138 KPRTIYSsYQLAALQ -1 11343707 t lperfetto "Dlx3 is primarily phosphorylated by PKC alpha. By deletion and mutational analysis, we show that the serine residue S(138), located in the homeodomain of Dlx3 protein, was specifically phosphorylated by PKC. The phosphorylation of purified Dlx3 proteins by PKC partially inhibited formation of complexes between Dlx3 protein and DNA. These results suggest that Dlx3 protein can be directly phosphorylated by PKC and this affects the DNA binding activity of Dlx3." SIGNOR-249096 MRE11 protein P49959 UNIPROT ATM protein Q13315 UNIPROT up-regulates binding 9606 18854157 t gcesareni "One of the earliest events is recruitment and activation of the atm at the damaged dna sites through the mre11rad50nbs1 (mrn) sensor complex. the mre11/rad50/nbs1 (mrn) complex maintains genomic stability by bridging dna ends and initiating dna damage signaling through activation of the atm kinase." SIGNOR-181628 CDK1 protein P06493 UNIPROT CDC25C protein P30307 UNIPROT down-regulates phosphorylation Ser168 SEMKYLGsPITTVPK 9606 8119945 t gcesareni "Phosphorylation at thr-48, thr-67, ser-122, thr-130, ser-168 and ser-214 occurs at g2 and g2-m transition and is catalyzed by cdk1. Ser-168 phosphorylation levels are lower than those at the other 5 cdk1 sites. Phosphorylation by cdk1 leads to increased activity." SIGNOR-36279 CEBPD protein P49716 UNIPROT IL23A protein Q9NPF7 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 BTO:0000801 23028973 f "CEBPD activated in macrophages played a functional role in promoting the tube formation of endothelial cells and the migration and proliferation of synoviocytes. In vivo DNA binding assays and reporter assays showed that CEBPD up-regulated CCL20, CXCL1, IL23A and TNFAIP6 transcripts through direct binding to their promoter regions." SIGNOR-254061 5-carboxamidotryptamine chemical CHEBI:48292 ChEBI HTR1A protein P08908 UNIPROT "up-regulates activity" "chemical activation" 10029 BTO:0000246 9550290 t miannu "Together, these data show that (i) [3H]-S 15535 is a highly selective 5-HT1A receptor ligand which labels both G-protein-coupled and uncoupled 5-HT1A receptors, (ii) antagonists, such as WAY 100,635, which yield monophasic isotherms in competition with both [3H]-agonists and [3H]-antagonists, are not sensitive to the G-protein coupling state of the receptor, but (iii) spiperone and methiothepin behaved as inverse agonists, their competition isotherms with [3H]-S 15535 being modulated in an opposite manner to those of agonists." SIGNOR-258888 AMPK complex SIGNOR-C15 SIGNOR FOXO proteinfamily SIGNOR-PF27 SIGNOR "up-regulates activity" phosphorylation Ser413 GLMQRSSsFPYTTKG 9606 BTO:0000007 17711846 t gcesareni "Phosphorylation by AMPK leads to the activtion of FOXO3 transcriptional activity without affecting FOXO3 subcellular localization." SIGNOR-252881 UNC13B protein O14795 UNIPROT SNARE_complex complex SIGNOR-C346 SIGNOR "up-regulates activity" "transcriptional regulation" 9606 BTO:0000938 30267828 t miannu "In neuronal exocytosis, Munc18-1 (aSM-protein) and Munc13-1/2 (similar to CATCHRs) arethe relevant proteins responsible for SNARE-complex formation. Munc18-1 associates with syntaxin-1 in its‘closed’ conformation, i.e. with the regulatory Habc-domain folded against the SNARE (H3-)-domain. Opening-up of syntaxin is catalyzed by the Mun-domainwithin Munc13-1/2 and allows assembly with the partnerSNARE SNAP-25 and possibly VAMP2." SIGNOR-263972 SCN8A protein Q9UQD0 UNIPROT sodium(1+) chemical CHEBI:29101 ChEBI "up-regulates quantity" relocalization 9606 27262167 t miannu "Voltage-gated Na1 channels (NaV channels) drive the rapid upstroke of action potentials in cardiac and skeletal muscle and in most neurons, thereby serving as initiators of electrical activity in excitable tissue. Nine genes encode a family of homologous of NaV channel pore-forming a subunits. While channels are open, Na1 ions flux through the central pore down an electrochemical gradient, further depolarizing the membrane and triggering an action potential." SIGNOR-253406 "Cullin 3-RBX1-Skp1" complex SIGNOR-C526 SIGNOR SEC31B protein Q9NQW1 UNIPROT "up-regulates activity" monoubiquitination lys641 9606 BTO:0000567 22358839 t miannu "By analyzing mouse embryonic stem cell (mESC) division, we have identified Cul3Klhl12 as a regulator of COPII coat formation. Cul3Klhl12 monoubiquitinates Sec31 and drives assembly of large COPII-coats. As a result, ubiquitination by Cul3Klhl12 is essential for collagen export, a step that is required for integrin-dependent mESC division." SIGNOR-272015 TRIM27 protein P14373 UNIPROT STK38L protein Q9Y2H1 UNIPROT "up-regulates activity" ubiquitination Lys119 TGHIYAMkILRKSDM 10090 35670107 t "K11 corresponds to the 11th Lysine, which is in position 119 in the full length sequence" lperfetto "TRIM27 catalyzes non-degradative K6- and K11-linked ubiquitination of the serine/threonine kinase 38-like (STK38L) kinase. In turn, STK38L ubiquitination promotes its activation and phosphorylation of ULK1 at Ser495, rendering ULK1 in a permissive state for TRIM27-mediated hyper-ubiquitination of ULK1" SIGNOR-270347 MAD2L1BP protein Q15013 UNIPROT MCC complex SIGNOR-C382 SIGNOR "down-regulates quantity by destabilization" binding 9606 BTO:0000567 25092294 t miannu "We have indeed showed that TRIP13 action to disassemble the Cdc20–Mad2 complex requires the presence of p31comet (Fig. 3A). We furthermore found that the joint action of TRIP13 and p31comet is also required for the release of Mad2 from MCC, for the complete disassembly of MCC and for relieving APC/C from checkpoint inhibition (Figs. 3 and ​and4).4)." SIGNOR-265979 HDAC1 protein Q13547 UNIPROT EGR1 protein P18146 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 21983014 f "In conclusion we demonstrated that treatment of HeLa cells with DMC leads to an enhanced formation of a complex consisting of NF-κB and HDAC1 that binds to the EGR1 promoter resulting in downregulation of EGR1 expression which plays a major role for transcriptional inhibition of mGPES-1 expression." SIGNOR-254257 PAX7 protein P23759 UNIPROT MYOD1 protein P15172 UNIPROT "down-regulates quantity by destabilization" 10090 17548510 f "Simone Vumbaca" "Previously, we showed that Pax7 overexpression in adult primary myoblasts down-regulates MyoD and prevents myogenin induction, inhibiting myogenesis. We show that Pax7 prevents muscle differentiation independently of its transcriptional activity, affecting MyoD function. [...] Pax7 expression affects MyoD protein stability" SIGNOR-255637 RIMBP3B protein A6NNM3 UNIPROT RIMS3 protein Q9UJD0 UNIPROT "down-regulates activity" binding 10116 BTO:0001009 11988172 t miannu "SH3 domains of RBPs interact with RIMs. The enhancement of depolarization-induced secretion in PC12 cells by fusion proteins that suppress the associations of RBPs with RIMs and α1 suggests that RBPs may repress RIMs, either directly or through associated proteins." SIGNOR-264374 TKT protein P29401 UNIPROT "sedoheptulose 7-phosphate" smallmolecule CHEBI:15721 ChEBI "up-regulates quantity" "chemical modification" 9606 24929114 t miannu "Transketolase (TK, EC 2.2.1.1) is the key rate-limiting enzyme of the non-oxidative branch of the pentose phosphate pathway of carbohydrate transformation. TKs (with the exception of the enzymes of mammalian origin) are characterized by broad substrate specificity. Xylulose 5-phosphate (X5P), fructose 6-phosphate (F6P), erythrulose 4-phosphate, and sedoheptulose 7-phosphate are typical donor substrates of TK; ribose 5-phosphate (R5P), glyceraldehyde 3-phosphate (G3P), and erythrose 4-phosphate are typical acceptor substrates." SIGNOR-267087 BMP2 protein P12643 UNIPROT BMPR1A/1B/2 complex SIGNOR-C29 SIGNOR up-regulates binding 10090 BTO:0001957 11714695 t lperfetto "For this, bmp-2 binds first to the high affinity receptor bri and then recruits brii into the signaling complex." SIGNOR-237000 MAPK3 protein P27361 UNIPROT CTTN protein Q14247 UNIPROT up-regulates phosphorylation Ser405 KTQTPPVsPAPQPTE 9606 BTO:0000938 21079800 t gcesareni "Cortactin is regulated by multiple phosphorylation events, including phosphorylation of s405 and s418 by extracellular regulated kinases (erk)1/2. Erk1/2 phosphorylation of cortactin has emerged as an important positive regulatory modification, enabling cortactin to bind and activate the arp2/3 regulator neuronal wiskott-aldrich syndrome protein (n-wasp), promoting actin polymerization and enhancing tumor cell movement." SIGNOR-169682 HBB protein P68871 UNIPROT EDN1 protein P05305 UNIPROT "down-regulates activity" 9606 8573884 f "Regulation of localization" miannu "Hb inhibitory activity toward ET-1 production might be related to Hb mediated endothelial oxidative injury." SIGNOR-251766 SRC protein P12931 UNIPROT RAF1 protein P04049 UNIPROT up-regulates phosphorylation Tyr340 RGQRDSSyYWEIEAS 9606 7692235 t gcesareni "We also show that phosphorylation of raf-1 on serine 338 by pak1 and tyrosines 340 and 341 by src relieves autoinhibition and that this occurs through a specific decrease in the binding of the raf-1 regulatory domain to its catalytic domain." SIGNOR-32081 S1PR2 protein O95136 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates binding 9606 10488065 t gcesareni "Edg-3 and edg-5 couple not only to gibut also to gqand g13." SIGNOR-70664 CLU protein P10909 UNIPROT SCF-betaTRCP complex SIGNOR-C5 SIGNOR "up-regulates activity" binding 9606 BTO:0001321 20068069 t miannu "CLU-2 is a ubiquitin binding protein (UBP) that enhances proteasome activity. sCLU promotes degradation of COMMD1. sCLU interacts with the SCF-βTrCP E3 ligase complex, serving as a scaffolding chaperone to form a multimeric protein complex that facilitates COMMD1 and I-κB ubiquitination and proteasomal degradation." SIGNOR-271429 ARVCF protein O00192 UNIPROT CDH1 protein P12830 UNIPROT "up-regulates quantity by stabilization" binding 9606 BTO:0001109 14610055 t miannu "To clarify the role of p120 in mammalian cells, we have knocked down p120 with siRNA in cells expressing epithelial (E-), placental (P-), neuronal (N-), and vascular endothelial (VE-) cadherins. We report that each of these cadherins, as well as α- and β-catenins, were rapidly degraded in the absence of p120, resulting in loss of cell–cell adhesion. The effect was clearly dose dependent, indicating that p120 expression levels may directly determine cadherin levels. Degradation of p120-uncoupled cadherin occurred after its arrival at the surface, indicating that p120 regulates cadherin turnover at the level of internalization or recycling. p120 homologues ARVCF and δ-catenin could substitute for p120, so at least one family member is likely required to maintain adhesion. Thus, cadherin complexes are rapidly turned over and degraded in mammalian cells in the absence of direct interaction with p120 or a p120 family member." SIGNOR-252133 EPAS1 protein Q99814 UNIPROT KDM1A protein O60341 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 32938217 t SaraGualdi "To this end, we confirm that KDM3A, KDM4B, KDM4C, KDM5B, KDM5C, and KDM62 are direct targets of HIF-1a while extent the list of known targets to KDM2A, KDM2B, KDM4D, KDM5A, and KDM6A. The results demonstrated that majority of the KDMs were similarly induced (KDM2A, KDM2B, KDM3A, KDM4B, KDM4C, KDM4D, KDM5A, KDM5B, KDM5C, KDM6B, and KDM7A) or repressed (KDM NO66 and KDM1A) by both HIF-1a and HIF-2a." SIGNOR-271588 TSHB protein P01222 UNIPROT TSH complex SIGNOR-C412 SIGNOR "form complex" binding 9606 BTO:0001379 8196184 t scontino "TSH is a heterodimer composed of common alpha subunit and unique beta subunit encoded by genes located on different chromosomes. It is known that the expression of these subunit genes is regulated in different mechanism by several extracellular factors." SIGNOR-267047 CDK2 protein P24941 UNIPROT RAD54L protein Q92698 UNIPROT "down-regulates activity" phosphorylation Ser49 QIQECFLsPFRKPLS -1 29295984 t miannu "Effect of CDK2 phosphorylation on the RAD54 activities. We find that the RAD54 N-terminal domain (NTD) is responsible for initiation of BM through two coupled, but distinct steps; specific binding to Holliday junctions and RAD54 oligomerization. Furthermore, we find that the RAD54 oligomeric state can be controlled by NTD phosphorylation at S49, a CDK2 consensus site, which inhibits RAD54 oligomerization and, consequently, BM." SIGNOR-273599 MAPK8 protein P45983 UNIPROT AP1 complex SIGNOR-C154 SIGNOR "up-regulates activity" phosphorylation Ser73 VGLLKLAsPELERLI 9534 BTO:0000298 8137421 t miannu "JNK1 binds to the c-Jun transactivation domain and phosphorylates it on Ser-63 and Ser-73. The effect on AP-1 transcriptional activity results, in part, from enhanced phosphorylation of the c-Jun NH2-terminal activation domain." SIGNOR-252355 ammonium smallmolecule CHEBI:28938 ChEBI "L-glutamine zwitterion" smallmolecule CHEBI:58359 ChEBI "up-regulates quantity" "precursor of" 9606 30158707 t miannu "Glutamine synthetase, encoded by the gene GLUL, is an enzyme that converts glutamate and ammonia to glutamine. certain cell types express glutamine synthetase (GS; also called glutamate-ammonia ligase; GLUL), the enzyme capable of de novo glutamine production from glutamate and ammonia in an ATP and Mg2+/Mn2+ requiring reaction." SIGNOR-267823 PRKCD protein Q05655 UNIPROT RPS6KB2 protein Q9UBS0 UNIPROT unknown phosphorylation Ser473 PPSGTKKsKRGRGRP 9606 12529391 t gcesareni "Pkc-mediated phosphorylation at s486 does not affect s6k activity but eliminates the function of its nuclear localization signal and causes retention of an activated form of the kinase in the cytoplasm." SIGNOR-97287 AMPK complex SIGNOR-C15 SIGNOR INSR protein P06213 UNIPROT up-regulates phosphorylation 9606 BTO:0000887 22207502 t lperfetto "Ampk phosphorylates and activates theinsulinreceptor, providing a direct link between ampk and theinsulin pathway." SIGNOR-216619 ARNTL protein O00327 UNIPROT PPARA protein Q07869 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 BTO:0000759 16556735 t miannu "We demonstrate that PPARalpha plays a specific role in the peripheral circadian control because it is required to maintain the circadian rhythm of the master clock gene brain and muscle Arnt-like protein 1 (bmal1) in vivo. This regulation occurs via a direct binding of PPARalpha on a potential PPARalpha response element located in the bmal1 promoter. Reversely, BMAL1 is an upstream regulator of PPARalpha gene expression." SIGNOR-268025 PRKG1 protein Q13976 UNIPROT GABRR1 protein P24046 UNIPROT unknown phosphorylation Ser443 PQRKSQRsSYVSMRI -1 12175859 t miannu "Here, we have identified phosphorylation sites on the human ρ1 GABA receptor for six protein kinases widely expressed in the brain: protein kinase C (PKC); cAMP‐dependent protein kinase (PKA); calmodulin‐dependent kinase (CaMKII); casein kinase (CKII); mitogen‐activated protein kinase (MAPK); and cGMP‐dependent protein kinase (PKG). The 1 IC-loop does not have consensus sequences for PKG, but we found that this enzyme phosphorylated the same sites as PKA: S422, S423 (Fig. 5A).An extensive functional analysis comparing wild type 1 receptors and receptors with select or multiple phosphorylation sites removed as well as pharmacological manipulation of five kinase pathways failed to reveal any functional effects of phosphorylation" SIGNOR-262756 CDK5/CDK5R1 complex SIGNOR-C144 SIGNOR MAPT protein P10636 UNIPROT "down-regulates activity" phosphorylation Ser713 GAEIVYKsPVVSGDT 9606 BTO:0000590 12387894 t lperfetto "We found that cdk5 phosphorylated tau(441) at Thr-181, Ser-199, Ser-202, Thr-205, Thr-212, Ser-214, Thr-217, Thr-231, Ser-235, Ser-396, and Ser-404, but not at Ser-262, Ser-400, Thr-403, Ser-409, Ser-413, or Ser-422. GSK-3beta phosphorylated all the cdk5-catalyzed sites above except Ser-235." SIGNOR-251591 AKT1 protein P31749 UNIPROT mTORC1 complex SIGNOR-C3 SIGNOR "up-regulates activity" phosphorylation 9606 17130464 t "Translocation from Cytoplasm to Nucleus" lperfetto "Phosphorylation of pras40-thr246 by pkb/akt, and pras40-ser183 and pras40-ser221 by mtorc1 results in dissociation from mtorc1, and its binding to 14-3-3 proteins." SIGNOR-252540 F2RL3 protein Q96RI0 UNIPROT GNA14 protein O95837 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257419 HIF1A protein Q16665 UNIPROT PDK1 protein Q15118 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0003291 16517405 t miannu "Activation of glycolytic genes by HIF-1 is considered critical for metabolic adaptation to hypoxia through increased conversion of glucose to pyruvate and subsequently to lactate. We found that HIF-1 also actively suppresses metabolism through the tricarboxylic acid cycle (TCA) by directly trans-activating the gene encoding pyruvate dehydrogenase kinase 1 (PDK1). PDK1 inactivates the TCA cycle enzyme, pyruvate dehydrogenase (PDH), which converts pyruvate to acetyl-CoA." SIGNOR-267444 1,2-diacyl-sn-glycerol smallmolecule CHEBI:17815 ChEBI PRKCA protein P17252 UNIPROT up-regulates binding 9606 14967450 t "PKCs (PRKCA, PRKCB and PRKCG) are activated by calcium and diacylglycerol (DAG) in the presence of phosphatidylserine." gcesareni "The molecular requirements for diacylglycerol (dag) and calcium (ca2+) to promote pkc membrane translocation, the hallmark of pkc activation, have been clarified." SIGNOR-121956 MMP2 protein P08253 UNIPROT HAPLN1 protein P10915 UNIPROT "down-regulates quantity by destabilization" cleavage Leu40 QAENGPHlLVEAEQA -1 7694569 t miannu "Matrix metalloproteinases cleave at two distinct sites on human cartilage link protein. Sequencing studies of modified link protein components revealed that stromelysins-1 and -2, gelatinases A and B and collagenase cleaved specifically between His16 and Ile17, and matrilysin, stromelysin-2 and gelatinase A cleaved between Leu25 and Leu26. Based on previously determined in situ cleavage sites it is evident that matrix metalloproteinases are not solely responsible for the accumulation of link protein degradation products in adult human cartilage, indicating that additional proteolytic agents are involved in the normal catabolism of human cartilage matrix." SIGNOR-256333 MAPK1 protein P28482 UNIPROT STK11 protein Q15831 UNIPROT "down-regulates activity" phosphorylation Ser428 SSKIRRLsACKQQ 9606 25846811 t lperfetto "Directly and/or through the activation of p90RSK, ERK phosphorylates LKB-1 at Ser325 and Ser428. The phosphorylation of LKB-1 causes the dissociation of LKB-1 from AMPK, resulting in the impaired activation of AMPK." SIGNOR-209876 Ub:E2 complex SIGNOR-C497 SIGNOR RNF165 protein Q6ZSG1 UNIPROT "up-regulates activity" ubiquitination 9606 34199813 t miannu "The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t" SIGNOR-271176 HNF4A protein P41235 UNIPROT ABCG5 protein Q9H222 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0000398 21123766 f miannu "these results indicate that HMG-CoAR inhibition with atorvastatin stimulates intestinal expression of NPC1L1 and PCSK9, increases cholesterol absorption, and reduces ABCG5/8 expression; these effects are mediated most likely by stimulation of the transcription factors SREBP-2 and HNF-4α." SIGNOR-254457 MAPK1 protein P28482 UNIPROT SMAD1 protein Q15797 UNIPROT down-regulates phosphorylation Ser214 PTSSDPGsPFQMPAD 9606 9335504 t llicata "In contrast to the bmp-stimulated phosphorylation of smad1, which affects carboxy-terminal serines and induces nuclear accumulation of smad1, erk-mediated phosphorylation specifically inhibits the nuclear accumulation of smad1. phosphorylation occurs at specific serines within the region linking the inhibitory and effector domains of smad1" SIGNOR-52691 AR protein P10275 UNIPROT SEPTIN7 protein Q16181 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0001321 16281084 f "After AR antagonist flutamide treatment, three hundred and twenty-six genes (3.93%) expressed differentially, 97 down-regulated and 219 up-regulated. Among them, eight up-regulated genes might be cell cycle-related, namely CDC10, NRAS, BTG1, Wee1, CLK3, DKFZP564A122, CDKN1A and BTG2. The CDKN1A and BTG1 gene mRNA expression was confirmed to be higher in the experimental group by RT-PCR, while p53 mRNA expression had no significant changes." SIGNOR-253677 SIRT1 protein Q96EB6 UNIPROT RELA protein Q04206 UNIPROT "down-regulates activity" deacetylation Lys310 KRTYETFkSIMKKSP 9606 BTO:0002207 15152190 t gcesareni "SIRT1 physically interacts with the RelA/p65 subunit of NF-kappaB and inhibits transcription by deacetylating RelA/p65 at lysine 310." SIGNOR-238817 PDE4DIP protein Q5VU43 UNIPROT PRKAR2A protein P13861 UNIPROT up-regulates binding 9606 21569246 t miannu "Mmgl acts as a dual-specific akap by anchoring pka regulatory isoforms r1a and r2a." SIGNOR-173831 CSNK2A1 protein P68400 UNIPROT HDAC3 protein O15379 UNIPROT "up-regulates activity" phosphorylation Ser424 DHDNDKEsDVEI 9606 15805470 t llicata "A protein kinase CK2 phosphoacceptor site in the HDAC3 protein was identified at position Ser424, which is a nonconserved residue among the class I HDACs. Mutation of this residue was found to reduce deacetylase activity." SIGNOR-250889 AKT proteinfamily SIGNOR-PF24 SIGNOR PFKFB2 protein O60825 UNIPROT unknown phosphorylation Ser466 PVRMRRNsFTPLSSS 9606 BTO:0000567 12853467 t "14-3-3s bind directly to cardiac PFK-2 phosphorylated by PKB. PFK-2 was phosphorylated on both Ser466 and Ser483 by PKB. the precise mechanism of fru-2,6-P2 regulation by 14-3-3s is still puzzling." SIGNOR-251484 [4-[2-(1H-indazol-3-yl)ethenyl]phenyl]-(1-piperazinyl)methanone chemical CHEBI:91441 ChEBI FLT3 protein P36888 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-193615 "lysophosphatidic acids" smallmolecule CHEBI:32957 ChEBI LATS1 protein O95835 UNIPROT down-regulates 10090 22863277 f milica "Serum-borne lysophosphatidic acid (lpa) and sphingosine 1-phosphophate (s1p) act through g12/13-coupled receptors to inhibit the hippo pathway kinases lats1/2, thereby activating yap and taz transcription coactivators, which are oncoproteins repressed by lats1/2." SIGNOR-198517 SMO protein Q99835 UNIPROT FYN protein P06241 UNIPROT up-regulates phosphorylation 9606 23074268 t gcesareni "Instead, shh rapidly and locally stimulated phosphorylation of the src family kinase (sfk) members src and fyn in a smo-dependent fashion." SIGNOR-199156 Ub:E2 complex SIGNOR-C497 SIGNOR TRIM11 protein Q96F44 UNIPROT "up-regulates activity" ubiquitination 9606 34199813 t miannu "The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t" SIGNOR-271083 PTK6 protein Q13882 UNIPROT AKT1 protein P31749 UNIPROT up-regulates phosphorylation Tyr315 TFCGTPEyLAPEVLE 9606 15994200 t gcesareni "These observations suggest that RET/PTC is able to phosphorylate the Y315 residue of PKB, an event that results in maximal activation of PKB for RET/PTC-induced thyroid tumorigenesis." SIGNOR-252617 SDHA protein P31040 UNIPROT SDH complex SIGNOR-C400 SIGNOR "form complex" binding 9606 16143825 t miannu "Mitochondrial succinate dehydrogenase (SDH) consists merely of four nuclearly encoded subunits. It participates in the electron transfer in the respiratory chain and in succinate catabolism in the Krebs cycle. The SDH enzyme, also known as respiratory chain complex II, faces the mitochondrial matrix and is bound to the inner membrane. Four nuclear genes encode the four subunits, SDHA (15 exons), SDHB (8 exons), SDHC (6 exons) and SDHD (4 exons), mapping on to chromosomes 5p15, 1p35-p36.1, 1q21 and 11q23, respectively." SIGNOR-266271 GABRA2 protein P47869 UNIPROT "GABA-A (a2-b1-g2) receptor" complex SIGNOR-C331 SIGNOR "form complex" binding 9606 BTO:0000227 18790874 t "brain, See table 3 for identified complexes" lperfetto "The assembly of GABAA-R as heteropentamers produces complex subtype heterogeneity in structure, which is the major determinant of their pharmacological profile.|Evidence is greatly in favor of a pentameric receptor and most GABAA-R subtypes are formed from two copies of a single alpha, two copies of a single beta, and one copy of another subunit, such as gamma, delta, or epsilon." SIGNOR-263753 SMARCD1 protein Q96GM5 UNIPROT "Muscle cell-specific SWI/SNF ARID1A variant" complex SIGNOR-C481 SIGNOR "form complex" binding 9606 BTO:0000887 11073988 t miannu "The SWI/SNF family of chromatin-remodeling complexes facilitates gene activation by assisting transcription machinery to gain access to targets in chromatin. Our data suggest that BAF250 confers specificity to the human BAF complex and may recruit the complex to its targets through either protein-DNA or protein-protein interactions." SIGNOR-270694 PPP1CA protein P62136 UNIPROT RAF1 protein P04049 UNIPROT "up-regulates activity" dephosphorylation Ser259 SQRQRSTsTPNVHMV 9606 16630891 t "We have identified a complex comprised of Shoc2/Sur-8 and the catalytic subunit of protein phosphatase 1 (PP1c) as a highly specific M-Ras effector. M-Ras targets Shoc2-PP1c to stimulate Raf activity by dephosphorylating the S259 inhibitory site of Raf proteins" SIGNOR-251649 TLK1 protein Q9UKI8 UNIPROT RAD9A protein Q99638 UNIPROT unknown phosphorylation Thr355 EPSTVPGtPPPKKFR 9606 24376897 t "The effect has been demonstrated using Q9UKI8-2" llicata "Here we show that rad9 is phosphorylated in a tlk-dependent manner in vitro and in vivo, and that t355 within the c-terminal tail is the primary targeted residue." SIGNOR-203503 NCOA2 protein Q15596 UNIPROT NR3C1 protein P04150 UNIPROT "up-regulates activity" binding 10090 BTO:0000801 29170386 t "Here we report that GRIP1 loss in macrophages attenuates glucocorticoid induction of several anti-inflammatory targets, and that GC treatment of quiescent macrophages globally directs GRIP1 toward GR binding sites dominated by palindromic GC response elements (GRE), suggesting a non-redundant GRIP1 function as a GR coactivator." SIGNOR-256095 PTPN22 protein Q9Y2R2 UNIPROT ZAP70 protein P43403 UNIPROT down-regulates dephosphorylation Tyr493 LGADDSYyTARSAGK 9606 BTO:0000007 16461343 t miannu "Native ptpn22 dephosphorylated lck and zap70 at their activating tyrosine residues tyr-394 and tyr-493, respectively, but not at the regulatory tyrosines tyr-505 (lck) or tyr-319 (zap70)." SIGNOR-144345 sorafenib chemical CHEBI:50924 ChEBI KDR protein P35968 UNIPROT "down-regulates activity" "chemical inhibition" -1 22037378 t Luana "Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here." SIGNOR-258285 PRKCB protein P05771 UNIPROT NCF1 protein P14598 UNIPROT up-regulates phosphorylation Ser304 GAPPRRSsIRNAHSI 9606 BTO:0000130 12056906 t lperfetto "Phosphopeptide mapping of p47(phox) showed that, as opposed to pkc zeta, pkc alpha, beta ii, and delta are able to phosphorylate all the major pkc sites. The use of p47(phox) mutants identified serines 303, 304, 315, 320, 328, 359, 370, and 379 as targets of pkc alpha, beta ii, and delta.Taken together, these results suggest that pkc alpha, beta ii, delta, and zeta expressed in human neutrophils can individually phosphorylate p47(phox) and induce both its translocation and nadph oxidase activation." SIGNOR-89186 TAB2 protein Q9NYJ8 UNIPROT MAP3K7 protein O43318 UNIPROT "up-regulates activity" binding 9606 8638164 t lperfetto "The yeast two-hybrid system has now revealed two human proteins, termed tab1 and tab2 (for tak1 binding protein), that interact with tak1. Overproduction of tab1 enhanced activity of the plasminogen activator inhibitor 1 gene promoter, which is regulated by tgf-beta, and increased the kinase activity of tak1. . These results define tab2 as an adaptor linking tak1 and traf6 and as a mediator of tak1 activation in the il-1 signaling pathway . taken together, these results indicate that polyubiquitination of rip1 mediates the independent recruitment of tab2 and nemo, which in turn recruits tak1 and ikk, respectively, to tnf-r1." SIGNOR-105860 ROCK2 protein O75116 UNIPROT IRF4 protein Q15306 UNIPROT up-regulates phosphorylation Ser447 YHRSIRHsSIQE 9606 BTO:0000782 20697158 t miannu "Carock2 phosphorylated irf4 at either of 2 distinct phosphorylation sites, s446 and s447 / rock2-mediated phosphorylation of irf4 regulated the synthesis of il-17 and il-21 and the differentiation of th17 cells." SIGNOR-167467 "N-[4-[(hydroxyamino)-oxomethyl]phenyl]carbamic acid [6-(diethylaminomethyl)-2-naphthalenyl]methyl ester" chemical CHEBI:94187 ChEBI HDAC2 protein Q92769 UNIPROT "down-regulates activity" "chemical inhibition" -1 20139990 t Luana "Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1)." SIGNOR-257965 MAPKAPK2 protein P49137 UNIPROT TH protein P07101 UNIPROT "up-regulates activity" phosphorylation Ser40 GQGAPGPsLTGSPWP -1 11359875 t miannu "MAPKAP-K2 phosphorylates both Ser19 and Ser40 of TH. Tyrosine hydroxylase (TH) has been reported to require binding of 14-3-3 proteins for optimal activation by phosphorylation." SIGNOR-250150 ADRM1 protein Q16186 UNIPROT "26S Proteasome" complex SIGNOR-C307 SIGNOR "form complex" binding 9606 BTO:0000007 29636472 t lperfetto "Here, we report near-atomic resolution cryo-EM structures of the activated human proteasome|The proteasome is composed of a 28-subunit barrel-shaped core particle (CP) and two 19- subunit regulatory particles (RP)5–8 capped at both sides of the CP|Human proteasomes were purified through affinity chromatography on a large scale from a stable HEK293 cell line" SIGNOR-263342 FGA protein P02671 UNIPROT Fibrinogen complex SIGNOR-C311 SIGNOR "form complex" binding -1 25427968 t lperfetto "Fibrinogen is a plasma glycoprotein mainly synthesised by hepatocytes and circulating as a 340-kDa hexamer consisting of two sets of three different polypeptide chains (Aalpha, Bbeta, and gamma, encoded by the FGA, FGB, and FGG gene, respectively)." SIGNOR-263392 CTNND2 protein Q9UQB3 UNIPROT CDH3 protein P22223 UNIPROT "up-regulates quantity by stabilization" binding 9606 BTO:0001109 14610055 t miannu "To clarify the role of p120 in mammalian cells, we have knocked down p120 with siRNA in cells expressing epithelial (E-), placental (P-), neuronal (N-), and vascular endothelial (VE-) cadherins. We report that each of these cadherins, as well as α- and β-catenins, were rapidly degraded in the absence of p120, resulting in loss of cell–cell adhesion. The effect was clearly dose dependent, indicating that p120 expression levels may directly determine cadherin levels. Degradation of p120-uncoupled cadherin occurred after its arrival at the surface, indicating that p120 regulates cadherin turnover at the level of internalization or recycling. p120 homologues ARVCF and δ-catenin could substitute for p120, so at least one family member is likely required to maintain adhesion. Thus, cadherin complexes are rapidly turned over and degraded in mammalian cells in the absence of direct interaction with p120 or a p120 family member." SIGNOR-252130 AKT1 protein P31749 UNIPROT FOXO3 protein O43524 UNIPROT "down-regulates quantity by destabilization" phosphorylation Thr32 QSRPRSCtWPLQRPE 19951971 t lperfetto "AKT phosphorylates FOXO3a at three conserved sites (Thr32, Ser253 and Ser315), therefore creating binding sites for the 14-3-3 chaperone proteins and leading to the active export of FOXO3a to the cytoplasm where it is targeted for proteasomal degradation." SIGNOR-249625 F10 protein P00742 UNIPROT APOH protein P02749 UNIPROT "down-regulates activity" cleavage Lys336 HSSLAFWKTDASDVK -1 9596664 t lperfetto "In the previous study, we found that factor Xa can produce the nicked form by cleaving Lys 317-Thr 318, using recombinant human domain V (r-Domain V). |The cleavage was completely inhibited by plasmin inhibitor (alpha2PI). The nicked form was demonstrated to show reduced affinity for CL with a dissociation constant of one order of magnitude larger than that of the intact beta2GPI." SIGNOR-266997 MYOCD protein Q8IZQ8 UNIPROT KLF4 protein O43474 UNIPROT down-regulates 9606 21673106 f "miR-143 and miR-145 target KLF4" gcesareni "These results further confirm that bmp4 requires mrtf-a, whereas tgf-_ requires myocd for the induction of pri-mir-143/145 and down-regulation of klf4." SIGNOR-174319 PRKACA protein P17612 UNIPROT SREBF1 protein P36956 UNIPROT down-regulates phosphorylation Ser338 IEKRYRSsINDKIIE 9606 16381800 t llicata "Sterol regulatory element-binding protein 1 is negatively modulated by pka phosphorylation. ser338 of srebp-1a and ser314 of srebp-1c are pka phosphorylation sites." SIGNOR-143392 F11 protein P03951 UNIPROT F9 protein P00740 UNIPROT "up-regulates activity" cleavage 9606 BTO:0000131 20110423 t lperfetto "Factor XI (FXI) is the zymogen of an enzyme (FXIa) that contributes to hemostasis by activating factor IX.|The characterization of the apple disk structure, and its relationship to the catalytic domain, have provided new insight into the mechanism of FXI activation, the interaction of FXIa with the substrate factor IX, and the binding of FXI to platelets." SIGNOR-263537 MCF2L protein O15068 UNIPROT RHOA protein P61586 UNIPROT "up-regulates activity" "guanine nucleotide exchange factor" 9606 BTO:0000007 32203420 t Luana "We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2)." SIGNOR-260559 CTDSP1 protein Q9GZU7 UNIPROT POLR2A protein P24928 UNIPROT "up-regulates activity" dephosphorylation Ser1647 SPSYSPTsPSYSPTS -1 22137580 t "Phosphorylation and dephosphorylation of the C-terminal domain (CTD) of RNA polymerase II (Pol II) represent a critical regulatory checkpoint for transcription. Transcription initiation requires Fcp1/Scp1-mediated dephosphorylation of phospho-CTD. | This combined structure-function analysis discloses the residues in Scp1 involved in CTD binding and its preferential dephosphorylation of P.Ser5 of the CTD heptad repeat." SIGNOR-248770 PRKAA1 protein Q13131 UNIPROT GLI1 protein P08151 UNIPROT "down-regulates activity" phosphorylation Ser408 GPLPRAPsISTVEPK 9606 26190112 t Luana "AMPK phosphorylates GLI1 at serines 102 and 408 and threonine 1074. Mutation of these three sites into alanine prevents phosphorylation by AMPK. This in turn leads to increased GLI1 protein stability, transcriptional activity, and oncogenic potency." SIGNOR-259863 AKT2 protein P31751 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR "down-regulates activity" phosphorylation Ser315 DFRSRTNsNASTVSG 9606 BTO:0000150;BTO:0001130;BTO:0001271;BTO:0000527 19188143 t lperfetto "Akt-dependent phosphorylation of foxo3a (thr32, ser253, and ser315 for human foxo3) enhances foxo3a/14-3-3 Interaction and promotes foxo3a nuclear export to the cytoplasm, resulting in the repression of foxo3a transcriptional function akt phosphorylates members of the foxo factors (forkhead family of transcription factors), leading to binding of 14-3-3 proteins and cytoplasmic localisation. In particular, akt phosphorylates foxo1 on thr24, ser256 and ser319. Foxo 3alfa and foxo4 are phosphorylated on equivalent sites." SIGNOR-252868 afatinib chemical CHEBI:61390 ChEBI ERBB2 protein P04626 UNIPROT "down-regulates activity" "chemical inhibition" -1 22037378 t Luana "Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here." SIGNOR-258066 PABPC1 protein P11940 UNIPROT "messenger RNA" smallmolecule CHEBI:33699 ChEBI "up-regulates quantity by stabilization" binding 9606 25480299 t lperfetto "As poly(A)+ mRNAs are associated with poly(A) binding protein (PABP) in cells|his result suggests that PABPC1 binds preferentially to long poly(A) tails and protects them from TUT4/7 and thereby enhances the selectivity of uridylation according to poly(A) tail length." SIGNOR-268318 PTH protein P01270 UNIPROT MMP13 protein P45452 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 17656568 f miannu "Parathyroid hormone (PTH) functions as an essential regulator of calcium homeostasis and as a mediator of bone remodeling. We have already shown that PTH stimulates the expression of matrix metalloproteinase-13 (MMP-13), which is responsible for degrading components of extracellular matrix." SIGNOR-254234 LMNA protein P02545 UNIPROT Adipogenesis phenotype SIGNOR-PH26 SIGNOR down-regulates 10090 BTO:0000944 16415042 f "Cleaved by CASP6" amattioni "Nuclear lamin A inhibits adipocyte differentiation: implications for Dunnigan-type familial partial lipodystrophy.|We conclude that A-type lamins act as inhibitors of adipocyte differentiation, possibly by affecting PPARgamma2 and insulin signaling." SIGNOR-45455 STK4 protein Q13043 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR up-regulates phosphorylation Ser212 SSAGWKNsIRHNLSL 9606 18394876 t gcesareni "Bonni and coworkers demonstrated that mst1 can phosphorylate foxo3 (and subsequently, foxo1) principally ser207 (ser212 in foxo1), a conserved site in the forkhead domain. This phosphorylation interdicts 14-3-3 binding, promotes foxo nuclear residence and transcriptional activity. The other major signaling modules that directly regulate the activity of the foxo factors include the stress-activated jun-n-terminal kinase (jnk), the mammalian ortholog of the ste20-like protein kinase (mst1), and the deacetylase sirt1." SIGNOR-252999 RALGDS protein Q12967 UNIPROT RIT1 protein Q92963 UNIPROT "up-regulates activity" binding 9606 10545207 t miannu "Rit and Rin were found to interact with the known Ras binding proteins RalGDS, Rlf, and AF-6/Canoe. These interactions were GTP and effector domain dependent and suggest that RalGDS, Rlf, and AF-6 are Rit and Rin effectors." SIGNOR-220859 PRKACA protein P17612 UNIPROT TNNI3 protein P19429 UNIPROT "up-regulates activity" phosphorylation Ser23 PAPIRRRsSNYRAYA 9606 15769444 t lperfetto "Phosphorylation at ser 23/24 (e.g., by pka or pkg) results in reduction in myofilament ca2+ sensitivity and an increase in crossbridge cycling rate, leading to acceleration of relaxation and an increase in power output but a reduced economy of contraction. Conversely, phosphorylation at ser 43/45 (by pkc) is associated with reduced maximum ca2+-activated force and decreased crossbridge cycling rates, which are likely to reduce power output and delay relaxation, with an increased economy of contraction." SIGNOR-134605 ITPR1 protein Q14643 UNIPROT calcium(2+) smallmolecule CHEBI:29108 ChEBI "up-regulates quantity" "chemical modification" 9606 24646566 t miannu "The key event in activation of fluid secretion is an increase in intracellular [ca2+] ([ca2+]i) triggered by ip3-induced release of ca2+ from er via the ip3r. ip3rs determine the site of initiation and the pattern of [ca2+]i signal in the cell." SIGNOR-256238 MTOR protein P42345 UNIPROT MAF1 protein Q9H063 UNIPROT down-regulates phosphorylation Ser68 PPQTSGLsPSRLSKS 9606 SIGNOR-C3 20516213 t fstefani "The protein is phosphorylated mainly on residues s60, s68, and s75, and this inhibits its pol iii repression function. The responsible kinase is mtorc1, which phosphorylates maf1 directly." SIGNOR-165795 CNOT9 protein Q92600 UNIPROT GIGYF1 protein O75420 UNIPROT "up-regulates activity" binding 9606 BTO:0000007 20878056 t miannu "Through interaction analysis of RQCD1 with full-length or partial proteins of GIGYF1 and GIGYF2, segments corresponding to 620-665th and 667-712th amino acids were identified as potential interacting regions on GIGYF1 and GIGYF2, respectively, with RQCD1. we found that RQCD1 was required for enhancement of the interaction of Grb10 with GIGYF1 and GIGYF2" SIGNOR-260059 "RFX complex" complex SIGNOR-C104 SIGNOR HLA-DPA1 protein P20036 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" -1 11258423 f "The RFX complex is comprised of three proteins – RFX5, RFXB, and RFXAP – all of which are required for expression of MHCII genes|In our current studies, we have utilized electrophoretic mobility shift assays to characterize the DNA binding of the RFX5(1–330)2•RFXAP•RFXB complex to the proximal regulatory region from the HLA-DRα gene to gain insight into the DNA binding properties of the RFX complex" SIGNOR-253995 DLL3 protein Q9NYJ7 UNIPROT NOTCH proteinfamily SIGNOR-PF30 SIGNOR "up-regulates activity" binding 9606 BTO:0000776 16140393 t lperfetto "Notch signaling is a highly conserved pathway involved in cell fate choice during development with Delta and Jagged constituting the two evolutionary conserved families of Notch ligands. These ligands are transmembrane proteins with conserved biochemical structure that share their receptors and signal through a common mechanism. Upon ligand binding Notch receptors are proteoliticaly cleaved, the intracellular domain of Notch (NICD) is released and translocated to the nucleus, where it activates target genes. In mammals, four receptors and five ligands have been described. Delta-1, Delta-3 and Delta-4 are homologues to Drosophila Delta and Jagged-1 and Jagged-2 to Drosophila Serrate." SIGNOR-254316 N(6)-(1,2-dicarboxylatoethyl)-AMP(4-) smallmolecule CHEBI:57567 ChEBI AMP smallmolecule CHEBI:456215 ChEBI "up-regulates quantity" "precursor of" 9606 22812634 t miannu "ADSL carries out two non-sequential steps of de novo AMP synthesis, the conversion of succinylaminoimidazolecarboxamide ribonucleotide (SAICAR) and succinyladenosine monophosphate (SAMP) into aminoimidazolecarboxamide ribotide (AICAR) and adenosine monophosphate (AMP), respectively, with the concomitant release of fumarate in each case" SIGNOR-268067 MAPK1 protein P28482 UNIPROT GORASP1 protein Q9BQQ3 UNIPROT "down-regulates activity" phosphorylation Ser274 DPLPGPGsPSHSAPD 10116 BTO:0000951 15834132 t miannu "Here we show that GRASP65 is phosphorylated on serine 277 in interphase cells, and this is strongly enhanced in response to the addition of serum or epidermal growth factor. This is directly mediated by ERK suggesting that GRASP65 has some role in growth factor signal transduction. These results argue against Ser-277 phosphorylation alone causing the dissolution of GRASP65 oligomers and cisternal unstacking, although it may make a significant contribution to these events." SIGNOR-262841 Ub:E2 complex SIGNOR-C497 SIGNOR SMURF2 protein Q9HAU4 UNIPROT "up-regulates activity" ubiquitination 9606 34199813 t miannu "The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t" SIGNOR-271298 Ub:E2 complex SIGNOR-C497 SIGNOR BIRC3 protein Q13489 UNIPROT "up-regulates activity" ubiquitination 9606 34199813 t miannu "The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t" SIGNOR-271049 PPP2R5C protein Q13362 UNIPROT TP53 protein P04637 UNIPROT "up-regulates quantity by stabilization" dephosphorylation Thr55 DDIEQWFtEDPGPDE 9606 BTO:0001938 17245430 t "Ablation of the B56gamma protein by RNAi, which abolishes the Thr55 dephosphorylation in response to DNA damage, reduces p53 stabilization, Bax expression and cell apoptosis. To investigate the molecular mechanisms, we have shown that the endogenous B56gamma protein level and association with p53 increase after DNA damage. Finally, we demonstrate that Thr55 dephosphorylation is required for B56gamma3-mediated inhibition of cell proliferation and cell transformation." SIGNOR-268154 AMPK complex SIGNOR-C15 SIGNOR mTORC1 complex SIGNOR-C3 SIGNOR "down-regulates activity" phosphorylation 9606 BTO:0000007 18439900 t lperfetto "The phosphorylation of raptor by ampk is required for the inhibition of mtorc1 and cell-cycle arrest induced by energy stress." SIGNOR-216430 EYA3 protein Q99504 UNIPROT H2AX protein P16104 UNIPROT down-regulates dephosphorylation Tyr143 ATQASQEy 9606 20965415 t gcesareni "Tyr142 is dephosphorylated by the tyr phosphatases eya1 and eya3." SIGNOR-168927 belinostat chemical CHEBI:61076 ChEBI HDAC3 protein O15379 UNIPROT "down-regulates activity" "chemical inhibition" -1 20139990 t Luana "Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1)." SIGNOR-257953 BCL2L11 protein O43521 UNIPROT BCL2 protein P10415 UNIPROT "down-regulates activity" binding 9606 BTO:0000007 18498746 t lperfetto "We show that mutation of the phosphorylation site Thr-112 causes decreased binding of Bim to the antiapoptotic protein Bcl2 and can increase cell survival." SIGNOR-178676 RPS6K proteinfamily SIGNOR-PF26 SIGNOR CREB1 protein P16220 UNIPROT "up-regulates activity" phosphorylation Ser119 EILSRRPsYRKILND 9606 BTO:0000938 10558990 t lperfetto "The rsks phosphorylate the trascription factor creb at serine 133 to promote cell survival." SIGNOR-252782 TFPI protein P10646 UNIPROT VLDLR protein P98155 UNIPROT up-regulates binding 9606 11278667 t gcesareni "Binding studies revealed that full-length tfpi, but not the truncated tfpi molecule, is recognized by the very low density lipoprotein receptor (vldl receptor) indicating that this receptor is a novel high affinity endothelial cell receptor for tfpi" SIGNOR-106353 ESR2 protein Q92731 UNIPROT CRH protein P06850 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000614 8408641 t lperfetto "Evidence of direct estrogenic regulation of human corticotropin-releasing hormone gene expression. Potential implications for the sexual dimophism of the stress response and immune/inflammatory reaction.|Gel retardation and immunoprecipitation demonstrated specific association between the perfect half-palindromic EREs of hCRH gene and the DNA binding domain of hER in vitro." SIGNOR-268722 JAZF1 protein Q86VZ6 UNIPROT NR2C2 protein P49116 UNIPROT down-regulates binding 9606 15302918 t miannu "Tip27 interacts specifically with tak1 / tip27 functions as a tak1-selective repressor" SIGNOR-127900 JAK3 protein P52333 UNIPROT JAK1 protein P23458 UNIPROT "up-regulates activity" phosphorylation Tyr1034 AIETDKEyYTVKDDR -1 12559972 t "Phosphorylation by recombinant JAK3 of a peptide substrate corresponding to the JAK1 activation loop (KAIETDKEYYTVKD)" SIGNOR-251363 HTR6 protein P50406 UNIPROT GNAI1 protein P63096 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257073 Dihydromorphine chemical CHEBI:4575 ChEBI OPRM1 protein P35372 UNIPROT "up-regulates activity" "chemical activation" 10029 BTO:0000246 9686407 t miannu "Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors." SIGNOR-258787 FOSL2 protein P15408 UNIPROT FOSL1 protein P15407 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0004603 13679379 t Luana "Members of the AP1 family distinctly regulated the fra-1 promoter. In particular, coexpression of c-Jun, Jun-D, and Fra-2 up-regulated fra-1 transcription. " SIGNOR-261602 fumarate(2-) smallmolecule CHEBI:29806 ChEBI (S)-malate(2-) smallmolecule CHEBI:15589 ChEBI "up-regulates quantity" "precursor of" 9606 30761759 t miannu "Fumarate hydratases (FHs, fumarases) catalyze the reversible conversion of fumarate into l-malate. FHs are distributed over all organisms and play important roles in energy production, DNA repair and as tumor suppressors." SIGNOR-266278 iloprost chemical CHEBI:63916 ChEBI PTGIR protein P43119 UNIPROT "up-regulates activity" "chemical activation" 9606 BTO:0002524 31160049 t "Ligand-GPCR dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257574 DIO proteinfamily SIGNOR-PF83 SIGNOR 3,3'-diiodothyronine smallmolecule CHEBI:35430 ChEBI "up-regulates quantity" "small molecule catalysis" 9606 BTO:0004055 12746313 t "inferred from family member" scontino "Human type III iodothyronine deiodinase (D3) catalyzes the conversion of T(4) to rT(3) and of T(3) to 3, 3'-diiodothyronine (T2) by inner-ring deiodination. Like types I and II iodothyronine deiodinases, D3 protein contains selenocysteine (SeC) in the highly conserved core catalytic center at amino acid position 144." SIGNOR-270307 MAPK14 protein Q16539 UNIPROT JDP2 protein Q8WYK2 UNIPROT unknown phosphorylation Thr148 VRTDSVKtPESEGNP -1 12225289 t miannu "Wild-type JDP2 exhibited efficient phosphorylation by the p38 kinase, the mutant JDP2 T%)A did not incorporate labelled Figure 5 JDP2 C-terminal domain is necessary but not sufficient for p38 phosphorylation (A) p38 phosphorylated JDP2 at Thr-148. Bacterially purified His-JDP2 (Wt) or His-JDP2 T148A (Ala) were incubated with bacterially purified activated p38 F327S [21] in the presence of [γ- 32P]ATP for 30 min. Proteins were resolved by SDS/PAGE (12 % gel), dried and exposed to autoradiography. (B) The JDP2 C-terminal domain is necessary but not sufficient for phosphorylation by p38 kinase. Bacterially purified GST fusion proteins with full-length JDP2 (Wt) C-terminally truncated JDP2 (∆C) and JDP2 C-terminal fragment (Dock) were used in an in vitro kinase assay as described in (A). A representative experiment is presented. (C) In vitro kinase assay using GST-JDP2 (JDP2wt), JDP2 ∆C and JDP2-Dock as substrates with either activated p38 or HA-JNK2 kinases. Protein mixtures were resolved by SDS/PAGE, fixed, dried and analysed by PhosphorImaging. The results represent meansS.E.M. from three independent experiments. phosphate in the presence of activated p38 kinase. This indicates that both p38 and JNK kinases are able to integrate stress signals to JDP2 Thr-148" SIGNOR-250100 TRIM58 protein Q8NG06 UNIPROT DYNC1I2 protein Q13409 UNIPROT "down-regulates quantity by destabilization" polyubiquitination -1 25241935 t miannu "Trim58 ubiquitinates dynein and promotes its proteasomal degradation. Trim58 binds DIC directly, polyubiquitinates it in vitro, and induces proteasomal degradation of the dynein holocomplex in vivo." SIGNOR-272841 LCK protein P06239 UNIPROT ZAP70 protein P43403 UNIPROT "up-regulates activity" phosphorylation Tyr319 TSVYESPySDPEELK 10090 BTO:0000782 10037717 t "the protein tyrosine kinase (PTK) ZAP-70 is rapidly phosphorylated on several tyrosine residues, presumably by two mechanisms: an autophosphorylation and a trans-phosphorylation by the Src-family PTK Lck. we demonstrate that phosphorylation of Tyr319 is required for the positive regulation of ZAP-70 function" SIGNOR-251393 "Ub:E1 (UBA6 substrate)" complex SIGNOR-C496 SIGNOR UBE2J1 protein Q9Y385 UNIPROT "up-regulates activity" ubiquitination 9606 34199813 t miannu "The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t" SIGNOR-271342 "NMDA receptor_2B" complex SIGNOR-C348 SIGNOR DLG4 protein P78352 UNIPROT "up-regulates activity" binding 9606 BTO:0000938 11052931 t miannu "Another central component of the NMDA receptor signaling complex is the scaffold protein PSD-95 (also referred to as SAP-90). The first and second PDZ domains bind tightly to the tails of the NR2 subunits of the NMDA receptor" SIGNOR-264223 TAB3 protein Q8N5C8 UNIPROT JNK proteinfamily SIGNOR-PF15 SIGNOR up-regulates binding 9606 25290089 t lperfetto "The irak1/traf6 complex can also activate jnk and p38 signalling through assembly of a catalytically active tab2-tab3-tak1 complex." SIGNOR-205449 Gbeta proteinfamily SIGNOR-PF4 SIGNOR RAF1 protein P04049 UNIPROT down-regulates phosphorylation 9606 16407412 t "inferred from 70% family members" gcesareni "Using mass spectrometry, we identified raf-1 phosphorylation on three sp motif sites: s289/s296/s301. These sites were phosphorylated by extracellular signal-regulated kinase (erk)-1 in vitro, and their phosphorylation in vivo was dependent on endogenous erk activity. Functionally, erk-1 expression sustains raf-1 activation in a manner dependent on raf-1 phosphorylation on the identified sites, and s289/296/301a substitution markedly decreases the in vivo activity of raf-1 s259a." SIGNOR-270010 EIF2AK1 protein Q9BQI3 UNIPROT EIF2S1 protein P05198 UNIPROT down-regulates phosphorylation Ser52 MILLSELsRRRIRSI 9606 3352609 t lperfetto "The wild-type and ser-48 mutant proteins became extensively phosphorylated by eif-2 kinases . The ser-51 mutant showed little covalent modification by the endogenous enzymes. Phosphorylation of the serine 51 residue in the alpha-subunit of translational initiation factor 2 in eukaryotes (eif2 alpha) impairs protein synthesis presumably by sequestering eif2b, a rate-limiting pentameric guanine nucleotide exchange protein which catalyzes the exchange of gtp for gdp in the eif2-gdp binary complex" SIGNOR-24543 TDGF1 protein P13385 UNIPROT Skeletal_muscle_differentiation phenotype SIGNOR-PH1 SIGNOR up-regulates 9606 BTO:0002314 BTO:0000887;BTO:0001103 23129614 f miannu "Cripto, a regulator of early embryogenesis, is a novel regulator of muscle regeneration and satellite cell progression toward the myogenic lineage." SIGNOR-192439 MAPK1 protein P28482 UNIPROT POLR2A protein P24928 UNIPROT down-regulates phosphorylation Ser1787 SPNYSPTsPSYSPTS 9606 14662762 t lperfetto "Erk1/2 are major ser-5 kinases after h2o2 treatment. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination." SIGNOR-120124 CHUK protein O15111 UNIPROT NCOA3 protein Q9Y6Q9 UNIPROT up-regulates phosphorylation Ser857 PPYNRAVsLDSPVSV 9606 BTO:0000551 22505454 t gcesareni "Herein, we report the successful identification of six functional in vivo src-3 phosphorylation sites." SIGNOR-196953 "Cullin 3-RBX1-Skp1" complex SIGNOR-C526 SIGNOR DEK protein P35659 UNIPROT "down-regulates quantity by destabilization" ubiquitination Lys284 VKSANVKkADSSTTK 9606 25278611 t miannu "Here, we analyzed changes in the ubiquitin landscape induced by prostate cancer-associated mutations of SPOP, an E3 ubiquitin ligase substrate-binding protein. SPOP mutants impaired ubiquitylation of a subset of proteins in a dominant-negative fashion. Of these, DEK and TRIM24 emerged as effector substrates consistently up-regulated by SPOP mutants. Up-regulation of DEK, TRIM24 and NCOA3 is a feature of prostate cancer SPOP mutations. This result aligns well with the observation that multiple ubiquitylated DEK lysine residues were detected in the initial proteome analysis (fig. S2E)." SIGNOR-272830 FCGR2B protein P31994 UNIPROT TLR4 protein O00206 UNIPROT "down-regulates activity" 9606 24445665 f lperfetto "Triggering of FcgammaRIIB also subverted the normal activation of DCs by the TLR4 agonist lipopolysaccharide. In addition, triggering of FcgammaRIIB by immune complexes might affect the differentiation of moDCs. When moDCs develop from monocytes invitro in the presence of immune complexes, their differentiation is hampered and they no longer produce IL-12 in response to TLR4 agonists." SIGNOR-249525 "2-cyclopentyl-4-(5-phenyl-1H-pyrrolo[2,3-b]pyridin-3-yl)benzoic acid" chemical CHEBI:95066 ChEBI SGK3 protein Q96BR1 UNIPROT "down-regulates activity" "chemical inhibition" 9606 BTO:0003136 25458846 t lperfetto "A catalytic small molecule pan-SGK inhibitor, GSK650394 (Sherk et al., 2008) also significantly blocks MCF7, ZR-75-1, and T47D cell migration (Figure 5C, Figures S4B–C). Finally, ectopic expression of SGK3 also promotes invasive migration through Matrigel (Figure 5D). Therefore, SGK3 protein kinase activity promotes migration of breast cancer cells that display elevated levels of INPP4B." SIGNOR-262019 IRX1 protein P78414 UNIPROT ERMAP protein Q96PL5 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0002392 20440264 f Luana "We identified a number of target genes by global microarray analysis after IRX1 transfection combined with real-time PCR and chromatin immunoprecipitation assay.| Upregulation of PTGS2, ANPEP, KDR, UGT8, INHBA, ERMAP, RALGPS1 and SPON1 was confirmed." SIGNOR-261667 TRIP11 protein Q15643 UNIPROT THR proteinfamily SIGNOR-PF84 SIGNOR up-regulates binding 9606 9256431 t "inferred from family member" miannu "Trip230 binds to rb independently of thyroid hormone while it forms a complex with tr in a thyroid hormone-dependent manner. Ectopic expression of the protein trip230 in cells, but not a mutant form that does not bind to tr, enhances specifically tr-dependent transcriptional activity." SIGNOR-270295 SPI1 protein P17947 UNIPROT FCGR1A protein P12314 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 12393465 f apalma "In patients with t(8;21), expression of the cell surface markers CD11b, CD14, and CD64 was less in comparison to patients without t(8;21) (Figure 5B). CD14 and CD64 promoters have putative PU.1 binding sites but not AML1-, C/EBPŒ±-, or MEF-binding sites suggesting that down-regulation of the function of PU.1 by AML1-ETO could possibly be an important step in progression toward leukemia." SIGNOR-255697 PURA protein Q00577 UNIPROT MYH6 protein P13533 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 12933792 f miannu "In functional assays, PURalpha and PURbeta repressed alpha-myosin heavy chain (alpha-MHC) gene expression in the presence of upstream regulatory sequences of the gene." SIGNOR-253902 Enolase proteinfamily SIGNOR-PF74 SIGNOR 2-phosphonato-D-glycerate(3-) smallmolecule CHEBI:58289 ChEBI "down-regulates quantity" "chemical modification" 9606 29767008 t miannu "Alpha-enolase (ENO1), also known as 2-phospho-D-glycerate hydrolase, is a metalloenzyme that catalyzes the conversion of 2-phosphoglyceric acid to phosphoenolpyruvic acid in the glycolytic pathway. Subsequent studies have shown that three types of enolase isoenzymes exist in mammals: Œ±-enolase (ENO1) is present in almost all mature tissues; Œ≤-enolase (ENO3) exists primarily in muscle tissues; and Œ≥-enolase (ENO2) occurs mainly in nervous and neuroendocrine tissues. All enolases are composed of two identical subunits." SIGNOR-266531 INSR protein P06213 UNIPROT IRS1 protein P35568 UNIPROT "up-regulates activity" phosphorylation Tyr632 GRKGSGDyMPMSPKS 10116 11416002 t lperfetto "All known IRS proteins contain multiple YXXM motifs that upon phosphorylation by activated insulin re- ceptors Tyr(612) and Tyr(632) in human insulin receptor substrate-1 are important for full activation of insulin-stimulated phosphatidylinositol 3-kinase activity and translocation of GLUT4 in adipose cells" SIGNOR-236709 MPHOSPH10 protein O00566 UNIPROT IMP3 protein Q9NV31 UNIPROT "up-regulates activity" binding -1 28813493 t miannu "Mpp10 represents a platform for the interaction of multiple factors within the 90S pre-ribosome. In eukaryotes, ribosome assembly is a highly complex process that involves more than 200 assembly factors that ensure the folding, modification and processing of the different rRNA species as well as the timely association of ribosomal proteins. One of these factors, Mpp10 associates with Imp3 and Imp4 to form a complex that is essential for the normal production of the 18S rRNA." SIGNOR-261173 AMPK complex SIGNOR-C15 SIGNOR KPNA2 protein P52292 UNIPROT up-regulates phosphorylation Ser105 QAARKLLsREKQPPI 9606 15342649 t lperfetto "Ampk phosphorylated importin alpha1 on ser(105). Accordingly, expression of importin alpha1 proteins bearing k22r or s105a mutations failed to mediate the nuclear import of hur in intact cells. Our results point to importin alpha1 as a critical downstream target of ampk and key mediator of ampk-triggered hur nuclear import." SIGNOR-216449 ADRA2B protein P18089 UNIPROT GNAI1 protein P63096 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-256714 Ub:E2 complex SIGNOR-C497 SIGNOR RC3H2 protein Q9HBD1 UNIPROT "up-regulates activity" ubiquitination 9606 34199813 t miannu "The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t" SIGNOR-271006 CSNK2A2 protein P19784 UNIPROT SPIB protein Q01892 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser144 DSPALEVsDSESDEA 9606 BTO:0000567 10618498 t llicata "Phosphorylation of the Spi-B transcription factor reduces its intrinsic stability. | Serine residues 37 in the transactivation domain and 129, 144 and 146 in the PEST domain of Spi-B are phosphorylated by CKII in vitro | The CKII phosphorylation sites mapped in vitro are phosphorylated in vivo" SIGNOR-251040 GOLPH3 protein Q9H4A6 UNIPROT mTORC2 complex SIGNOR-C2 SIGNOR "up-regulates activity" 9606 BTO:0000018;BTO:0005011 19553991 f "Mechanistically, GOLPH3 regulates cell size, enhances growth factor-induced mTOR signaling in human cancer cells and alters response to mTOR inhibitor in vivo." SIGNOR-253556 AURKB protein Q96GD4 UNIPROT HASPIN protein Q8TF76 UNIPROT "up-regulates activity" phosphorylation Ser93 RVPKDRPsLTVTPKR 9606 BTO:0000567 21658950 t miannu "Phosphorylation by Aurora B is required for full Haspin activity toward H3T3 in mitosis" SIGNOR-262657 KLHL12 protein Q53G59 UNIPROT SEC31A protein O94979 UNIPROT "up-regulates activity" binding 9606 BTO:0000567 22358839 t miannu "By analyzing mouse embryonic stem cell (mESC) division, we have identified Cul3Klhl12 as a regulator of COPII coat formation. Cul3Klhl12 monoubiquitinates Sec31 and drives assembly of large COPII-coats. As a result, ubiquitination by Cul3Klhl12 is essential for collagen export, a step that is required for integrin-dependent mESC division." SIGNOR-272010 PTPRB protein P23467 UNIPROT ALK protein Q9UM73 UNIPROT down-regulates dephosphorylation 9606 BTO:0000785 17681947 t gcesareni "Rptpbeta/zeta dephosphorylates alk at the site(s) in alk that is undergoing autophosphorylation through autoactivation." SIGNOR-157175 TGFb proteinfamily SIGNOR-PF5 SIGNOR SMAD3/SMAD4 complex SIGNOR-C9 SIGNOR "up-regulates quantity by expression" "transcriptional regulation" 9606 30017632 f miannu "Transforming growth factor-β1 (TGF-β1) is considered as a crucial mediator in tissue fibrosis and causes tissue scarring largely by activating its downstream small mother against decapentaplegic (Smad) signaling. Different TGF-β signalings play different roles in fibrogenesis. TGF-β1 directly activates Smad signaling which triggers pro-fibrotic gene overexpression. Excessive studies have demonstrated that dysregulation of TGF-β1/Smad pathway was an important pathogenic mechanism in tissue fibrosis. Smad2 and Smad3 are the two major downstream regulator that promote TGF-β1-mediated tissue fibrosis, while Smad7 serves as a negative feedback regulator of TGF-β1/Smad pathway thereby protects against TGF-β1-mediated fibrosis." SIGNOR-260428 CTDSP1 protein Q9GZU7 UNIPROT SMAD2 protein Q15796 UNIPROT "down-regulates activity" dephosphorylation Ser255 ELSPTTLsPVNHSLD 9606 BTO:0000007 17035229 t "SCP1 Dephosphorylates Smad2/3 in the Linkers|MAPK-mediated linker phosphorylation appears to have a dual role in Smad2/3 regulation. Mitogens and hyperactive Ras result in extracellular signal-regulated kinase (ERK)-mediated phosphorylation of Smad3 at Ser-204, Ser-208, and Thr-179 and of Smad2 at Ser-245/250/255 and Thr-220. Mutation of these sites increases the ability of Smad3 to activate target genes, suggesting that MAPK phosphorylation of Smad3 is inhibitory (11, 12). However, in contrast, ERK-dependent phosphorylation of Smad2 at Thr-8 enhances its transcriptional activity" SIGNOR-248797 MFNG protein O00587 UNIPROT NOTCH1 protein P46531 UNIPROT up-regulates binding 9606 10935626 t Fucosylation gcesareni "Manic fringe elongates the o-linked fucose saccharides on full-length notch1 and notch1 egf repeats 1923." SIGNOR-80555 NCSTN protein Q92542 UNIPROT APH1A protein Q96BI3 UNIPROT up-regulates binding 9606 BTO:0000142 12857757 t gcesareni "We show that mammalian aph-1 (maph-1), a conserved multipass membrane protein, physically associates with nicastrin and the heterodimers of the presenilin amino- and carboxyl-terminal fragments in human cell lines and in rat brain. Similar to the loss of presenilin or nicastrin, the inactivation of endogenous maph-1 using small interfering rnas results in the decrease of presenilin levels, accumulation of gamma-secretase substrates (app carboxyl-terminal fragments), and reduction of gamma-secretase products (amyloid-beta peptides and the intracellular domains of app and notch)." SIGNOR-103611 EGFR protein P00533 UNIPROT CRK protein P46108 UNIPROT "down-regulates activity" phosphorylation Tyr221 GGPEPGPyAQPSVNT 9606 BTO:0000007 9642287 t llicata "To address these questions, we have developed an antibody that specifically recognizes the CrkII protein phosphorylated on Tyr221, and we found that the EGF receptor directly phosphorylates CrkII on Tyr221. Furthermore, we observed that the phosphorylation of Tyr221 of CrkII correlated with its dissociation from the EGF receptor, implicating the phosphorylation of Tyr221 in the negative feedback of binding to the EGF receptor." SIGNOR-251091 ANAPC1 protein Q9H1A4 UNIPROT APC-c complex SIGNOR-C150 SIGNOR "form complex" binding 16896351 t lperfetto "The anaphase promoting complex/cyclosome (APC/C) is a ubiquitin ligase that has essential functions in and outside the eukaryotic cell cycle. It is the most complex molecular machine that is known to catalyse ubiquitylation reactions, and it contains more than a dozen subunits that assemble into a large 1.5-MDa complex." SIGNOR-252001 HOXD12 protein P35452 UNIPROT MAFG protein O15525 UNIPROT "down-regulates activity" binding -1 11036080 t miannu "Hoxd12 and MHox, that interact with v-/c-Maf, using the phage display method. The Hox proteins also could associate with the other Maf protein family members, MafB, MafK, MafF, and MafG, but not with Jun and Fos. The Hox proteins negatively regulated the DNA binding, transactivation and cell-transforming abilities of Maf." SIGNOR-221958 JAK2 protein O60674 UNIPROT JAK2 protein O60674 UNIPROT "up-regulates activity" phosphorylation Tyr221 IRAKIQDyHILTRKR 9606 BTO:0000007 15143187 t "JAK2 is autophosphorylated on tyrosines 221 and 1007. tyrosines 221 and 570 in JAK2 may serve as regulatory sites in JAK2, with phosphorylation of tyrosine 221 increasing kinase activity and phosphorylation of tyrosine 570 decreasing kinase activity" SIGNOR-251356 DCAF12 protein Q5T6F0 UNIPROT MAGEA3 protein P43357 UNIPROT "down-regulates quantity by destabilization" binding 9606 BTO:0002806 31267705 t miannu " The CRL4‐DCAF12 E3 ubiquitin ligase degrades MAGE‐A3/6" SIGNOR-272254 SETDB1 protein Q15047 UNIPROT SETDB1/NLK/CHD7 complex SIGNOR-C189 SIGNOR "form complex" binding 10090 21952300 t FFerrentino "The non-canonical WNT ligand WNT5A activates the histone methyltransferase SET domain bifurcated 1 (SETDB1)42. SETDB1 forms a complex with chromodomain helicase DNA-binding 7 (CHD7) and NEMO-like kinase (NLK) to inhibit the ability of PPARγ to transcriptionally activate its downstream metabolic target genes in the MSC cell line ST2 and in 3T3‑L1 cells42,43." SIGNOR-253522 CSNK2A1 protein P68400 UNIPROT GTF2A1 protein P52655 UNIPROT "up-regulates activity" phosphorylation Ser280 VDGTGDTsSEEDEDE -1 11278496 t llicata "We now show that human TFIIA is phosphorylated in vivo on serine residues that are partially conserved between yeast and human TFIIA large subunits. Alanine substitution mutation of serine residues 316 and 321 in TFIIA alphabeta reduced TFIIA phosphorylation significantly in vivo. Additional alanine substitutions at serines 280 and 281 reduced phosphorylation to undetectable levels. Mutation of all four serine residues reduced the ability of TFIIA to stimulate transcription in transient transfection assays with various activators and promoters, indicating that TFIIA phosphorylation is required globally for optimal function." SIGNOR-250874 SYN1 protein P17600 UNIPROT ACTB protein P60709 UNIPROT "up-regulates activity" binding 9606 BTO:0000938 15265865 t miannu "Synapsins, a family of neuron-specific phosphoproteins, have been demonstrated to regulate the availability of synaptic vesicles for exocytosis by binding to both synaptic vesicles and the actin cytoskeleton in a phosphorylation-dependent manner." SIGNOR-269184 CHUK protein O15111 UNIPROT COPS5 protein Q92905 UNIPROT "down-regulates activity" phosphorylation Thr205 EGPSEYQtIPLNKIE -1 31950832 t lperfetto "Overexpression of IKKalpha or IKKbeta leads to enhanced phosphorylation of CSN5, the catalytic subunit for CSN deneddylase activity. Mutational analyses have revealed that phosphorylation at serine 201 and threonine 205 of CSN5 impairs CSN-mediated deneddylation activity in vitro." SIGNOR-275508 MRAP2 protein Q96G30 UNIPROT MC4R protein P32245 UNIPROT "down-regulates activity" binding 10029 BTO:0000246 19329486 t miannu "We report that MRAP and MRAP2 can interact with all 5 MCRs. This interaction results in MC2R surface expression and signaling. In contrast, MRAP and MRAP2 can reduce MC1R, MC3R, MC4R, and MC5R responsiveness to [Nle4,D-Phe7]alpha-melanocyte-stimulating hormone (NDP-MSH). MRAP and MRAP2 can reduce the surface expression of MC4R and also the signaling of this receptor. we observed a significant decrease in the cell-surface expression of MC4R and MC5R in the presence of MRAP and MRAP2. It is interesting that MRAP and MRAP2 have opposite effects in the modulation of different MCR family members." SIGNOR-252363 MMP14 protein P50281 UNIPROT FGA protein P02671 UNIPROT "down-regulates quantity by destabilization" cleavage Phe117 MEILRGDfSSANNRD -1 10930399 t lperfetto "Matrix metalloproteinases collagenase-2, macrophage elastase, collagenase-3, and membrane type 1-matrix metalloproteinase impair clotting by degradation of fibrinogen and factor XII| We have now investigated the role of collagenase-2 (MMP-8), macrophage elastase (MMP-12), collagenase-3 (MMP-13), and membrane type 1-matrix metalloproteinase (MT1-MMP, MMP-14) in the degradation of fibrinogen and Factor XII of the plasma clotting system.|MMP-14 27YVATRDN g-chain| 105XDAATLKSR g-chain | 92LTYNPDES g-chain |105LTTNIXEXL a-chain|433LVTSKGDKE a-chain| 117FXSANNRD a-chain" SIGNOR-263621 PRKCD protein Q05655 UNIPROT YWHAZ protein P63104 UNIPROT "down-regulates activity" phosphorylation Ser58 VVGARRSsWRVVSSI 9606 12861023 t lperfetto "We confirmed that MAPKAPK2 interacted with and phosphorylated 14-3-3zeta in vitro and in HEK293 cells. | Experimentally, S58D mutation significantly impaired both 14-3-3zeta dimerization and binding to Raf-1." SIGNOR-249222 ADCY2 protein Q08462 UNIPROT "3',5'-cyclic AMP" smallmolecule CHEBI:17489 ChEBI "up-regulates quantity" "chemical modification" 9606 15385642 t miannu "Adenylyl cyclases (AC), a family of enzymes that catalyze the synthesis of cyclic AMP, are critical regulators of cellular functions." SIGNOR-265004 SRC protein P12931 UNIPROT CAV2 protein P51636 UNIPROT down-regulates phosphorylation Tyr19 LFMDDDSySHHSGLE 9606 12091389 t lperfetto "We show that caveolin-2 undergoes src-induced phosphorylation on tyrosine 19. we conclude that the tyrosine phosphorylation of caveolin-2 (tyr(p)(19)) may function as a signal that is recognized by the cellular machinery to induce the dissociation of caveolin-2 from caveolin-1 oligomers" SIGNOR-90225 MAST1 protein Q9Y2H9 UNIPROT PTEN protein P60484 UNIPROT down-regulates phosphorylation 9606 15951562 t gcesareni "Mast1 was found to associate to pten." SIGNOR-138003 ATM protein Q13315 UNIPROT TP53 protein P04637 UNIPROT "up-regulates quantity by stabilization" phosphorylation Ser15 PSVEPPLsQETFSDL 9606 11875057 t gcesareni "In response to ionizing radiation (ir), atm, the gene product mutated in ataxia telangiectasia, stabilizes and activates p53 through phosphorylation of ser15 and (indirectly) ser20. Here we show that phosphorylation of p53 on ser46, a residue important for p53 apoptotic activity, as well as on ser9, in response to ir also is dependent on the atm protein kinase. one pathway involves the phosphorylation of p53 and its negative regulator mdm2 by ataxia telangiectasia mutated (atm) and chk2 causing p53 activation and stabilization." SIGNOR-115340 GATAD2A protein Q86YP4 UNIPROT "MBD3/NuRD complex" complex SIGNOR-C338 SIGNOR "form complex" binding 9606 27098840 t miannu "The NuRD complex is a multi-protein transcriptional corepressor that couples histone deacetylase and ATP-dependent chromatin remodelling activities.In humans, an assembly of proteins called the NuRD complex makes chromatin more compact by removing acetyl groups from nucleosomes." SIGNOR-263858 pertuzumab antibody DB06366 DRUGBANK ERBB2 protein P04626 UNIPROT "down-regulates activity" binding 9606 BTO:0000176 15093539 t miannu "Pertuzumab binds to ErbB2 near the center of domain II, sterically blocking a binding pocket necessary for receptor dimerization and signaling." SIGNOR-259900 ATM protein Q13315 UNIPROT PNKP protein Q96T60 UNIPROT up-regulates phosphorylation Ser126 PPGTPLVsQDEKRDA 9606 21824916 t lperfetto "We demonstrate that pnkp is phosphorylated by the dna-dependent protein kinase (dna-pk) and ataxia-telangiectasia mutated (atm) in vitro. The major phosphorylation site for both kinases was serine 114, with serine 126 being a minor site. Purified pnkp protein with mutation of serines 114 and 126 had decreased dna kinase and dna phosphatase activities and reduced affinity for dna in vitro." SIGNOR-176012 SOD2 protein P04179 UNIPROT superoxide smallmolecule CHEBI:18421 ChEBI "down-regulates quantity" "chemical modification" 9606 29301787 t lperfetto "Oxidative stress contributes to diabetes mellitus (DM)–induced endothelial dysfunction, which is one of the most common causes of cardiovascular morbidity and mortality.1,2 The major cellular defense against superoxide (O2•−) is SODs (superoxide dismutases), which consists of the SOD1 (cytoplasmic copper zinc SOD [Cu/ZnSOD]), the SOD2 (mitochondrial MnSOD), and the SOD3 (extracellular Cu/ZnSOD)." SIGNOR-272281 "MIS12 complex" complex SIGNOR-C362 SIGNOR "KMN network" complex SIGNOR-C366 SIGNOR "form complex" binding 18007590 t lperfetto "The 10-subunit KMN assembly (comprising KNL1, MIS12, and NDC80 complexes, designated KNL1C, MIS12C, and NDC80C) binds microtubules and regulates mitotic checkpoint function through NDC80C and KNL1C," SIGNOR-265216 PITX1 protein P78337 UNIPROT GNRH1 protein P01148 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 10090 19106114 f miannu "Knockdown of PITX1 or PITX2 isoforms impaired GNRH1 induction, and endogenous PITX1 bound to the candidate PITX binding site on the LHB promoter." SIGNOR-254921 LYPLA2 protein O95372 UNIPROT GAP43 protein P17677 UNIPROT "down-regulates quantity by destabilization" deacetylation Cys3 cCMRRTKQ 9606 BTO:0000567 21152083 t miannu "Acyl-protein thioesterase 2 catalyzes the deacylation of peripheral membrane-associated GAP-43. In this work, we investigated the deacylation of growth-associated protein-43 (GAP-43), a dually acylated protein at cysteine residues 3 and 4. Thus, the results demonstrate that APT-2 is the protein thioesterase involved in the acylation/deacylation cycle operating in GAP-43 subcellular distribution.we demonstrated that the reduction in the protein level was abrogated when cells were also treated with proteasome inhibitors (chloroquine, MG132 and lactacystin) which strongly suggest that GAP-43 deacylation is an early and necessary step for its later ubiquitination and degradation by the proteasome. In addition, it also suggests that acyl-protein thioesterase levels not only regulate palmitate turnover but also global protein turnover of GAP-43." SIGNOR-266767 MIB1 protein Q86YT6 UNIPROT RYK protein P34925 UNIPROT down-regulates ubiquitination 9606 21875946 t gcesareni "We discovered that ryk both physically and functionally interacts with the e3 ubiquitin ligase mind bomb 1 (mib1).We Found that overexpressed ryk and mib1 colocalized and that the overexpression of mib1 leads to the loss of surface ryk expression. In addition, biochemical studies revealed that mib1 promotes the ubiquitination and degradation of ryk. Endogenous ryk and mib1 were required for the wnt-dependent activation of wnt/ctnnb1 signaling" SIGNOR-176282 NUP210 protein Q8TEM1 UNIPROT NPC complex SIGNOR-C263 SIGNOR "form complex" binding 27016207 t lperfetto "The protein inventory of the NPC has been studied for a very diverse set of eukaryotes, including trypanosomes, fungi, plants, animals, and humans [4], [5], [6], [7], [8], [9]. In all cases, about 30 different Nups were found (Fig. 2)." SIGNOR-262072 TTL protein Q8NG68 UNIPROT TUBA1B protein P68363 UNIPROT down-regulates tyrosination 9606 22020298 t miannu "Tubulin tyrosine ligase (ttl) adds a c-terminal tyr to __tubulin as part of a tyrosination/detyrosination cycle present in most eukaryotic cells. / ttl inhibits spontaneous tubulin polymerization" SIGNOR-176915 tandutinib chemical CHEBI:90237 ChEBI PDGFRB protein P09619 UNIPROT "down-regulates activity" "chemical inhibition" -1 22037378 t Luana "Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here." SIGNOR-258299 RNF19A protein Q9NV58 UNIPROT SNCAIP protein Q9Y6H5 UNIPROT "up-regulates quantity" ubiquitination 9606 BTO:0000007 12750386 t miannu "Ubiquitylation of synphilin-1 by Dorfin. A, synphilin-1 is ubiquitylated in HEK293 cells. Several lines of evidence have suggested that derangements in the ubiquitin-proteasome protein degradation pathway may have a prominent role in the pathogenesis of PD (5). Our present study shows that Dorfin, an E3 ubiquityl ligase, is colocalized with ubiquitin in LBs of PD and physically binds to ubiquitylate synphilin-1, which is known to be a major component of LBs" SIGNOR-271455 AKT1 protein P31749 UNIPROT BLVRA protein P53004 UNIPROT "up-regulates activity" phosphorylation Ser230 LKRNRYLsFHFKSGS 15870194 t lperfetto "Site-directed mutagenesis, mass spectrometry, and kinetic analyses identified S(230) in hBVR (225)RNRYLSF sequence as the Akt1 target." SIGNOR-275517 SRC protein P12931 UNIPROT FLT4 protein P35916 UNIPROT up-regulates phosphorylation Tyr830 PLEEQCEyLSYDASQ 9606 20431062 t lperfetto "Vegfr-3 is a direct c-src target and mass spectrometry analysis identified the sites phosphorylated by c-src as tyrosine 830, 833, 853, 1063, 1333, and 1337 vegfr-3 phosphorylation activates the recruitment to the receptor of the adaptor proteins crki/ii and shc inducing activation of jnk." SIGNOR-165047 ACTB protein P60709 UNIPROT "NuA4 complex" complex SIGNOR-C459 SIGNOR "form complex" binding 9606 14966270 t miannu "NuA4 (for nucleosome acetyltransferase of H4) is a 12-subunit HAT complex responsible for acetylation of histone H4 and H2A N-terminal tails." SIGNOR-269293 BCL2L11 protein O43521 UNIPROT BCL2L1 protein Q07817 UNIPROT down-regulates binding 9606 15694340 t gcesareni "Bim can induce apoptosis by interacting with anti-apoptotic members of the bcl2 family, including bcl2, bcl-xl and mcl-1.Bim binds bcl-2, bcl2l1, bcl2l2, mcl1 and a1 tightly." SIGNOR-133829 RBX1 protein P62877 UNIPROT "Cullin 7-RBX1-Skp1" complex SIGNOR-C528 SIGNOR "form complex" binding 9606 BTO:0001109 phosphorylation:Thr286 17205132 t miannu "FBXW8 associates with CUL1 or CUL7 and forms a complex with SKP1 and RBX1 " SIGNOR-271626 MDM2 protein Q00987 UNIPROT HIF1A protein Q16665 UNIPROT "down-regulates quantity by destabilization" ubiquitination 9606 BTO:0001109 10640274 t miannu "We find that p53 promotes Mdm2-mediated ubiquitination and proteasomal degradation of the HIF-1alpha subunit of hypoxia-inducible factor 1 (HIF-1), a heterodimeric transcription factor that regulates cellular energy metabolism and angiogenesis in response to oxygen deprivation." SIGNOR-271385 MAPK14 protein Q16539 UNIPROT MEF2A protein Q02078 UNIPROT "up-regulates activity" phosphorylation Thr312 QATQPLAtPVVSVTT 9606 9858528 t lperfetto "We show that mef2a, but not mef2b or mef2d, is a substrate for p38. Threonines 312 and 319 are the key regulatory phosphorylation sites by p38 in mef2a. Phosphorylation at these sites enhances transcriptional activity of mef2a" SIGNOR-62780 CSNK2A1 protein P68400 UNIPROT CTNNA1 protein P35221 UNIPROT down-regulates phosphorylation Ser641 TPEELDDsDFETEDF 9606 BTO:0000527 19941816 t gcesareni "We demonstrate here that egfr activation results in disruption of the complex of beta-catenin and alpha-catenin, thereby abrogating the inhibitory effect of alpha-catenin on beta-catenin transactivation via ck2alpha-dependent phosphorylation of alpha-catenin at s641." SIGNOR-161847 "trichostatin A" chemical CHEBI:46024 ChEBI HDAC2 protein Q92769 UNIPROT "down-regulates activity" "chemical inhibition" -1 17868033 t Luana "Our findings suggest that hydroxamic acid-derived compounds such as TSA, NVP-LAQ824, panobinostat, ITF2357, vorinostat and belinostat act as potent pan-HDAC isoform inhibitors. A notable observation was the similarity between belinostat and vorinostat in the biochemical isoform assays; both compounds exhibit similar EC50 values in all but the HDAC8 assay." SIGNOR-257942 AKT proteinfamily SIGNOR-PF24 SIGNOR RAF1 protein P04049 UNIPROT down-regulates phosphorylation Ser259 SQRQRSTsTPNVHMV 9606 BTO:0000222 BTO:0000887;BTO:0001760 10576741 t gcesareni "The stage-specific inhibitory action of Akt correlated with its stage-specific ability to form a complex with Raf, suggesting the existence of differentially expressed mediators of an inhibitory Akt-Raf complex." SIGNOR-72669 NPC complex SIGNOR-C263 SIGNOR mRNA-nucleus_export phenotype SIGNOR-PH127 SIGNOR up-regulates 9606 28831067 f lperfetto "The NXF1:NXT1 complex and NUP153 interact with the amino terminus of SUN1 |In analogy to a proposal made by Chang et al.4, Nesprins could help anchoring SUN1 near the NPC to enable it to fulfill its task in mRNA export." SIGNOR-263295 PML-RARalpha "fusion protein" SIGNOR-FP2 SIGNOR SP1 protein P08047 UNIPROT "up-regulates activity" binding -1 18025157 t "We show that PML-RARα physically interacts with Sp1 in the absence of DNA. In this report, we show that PML-RARα interacts with Sp1 and may interfere with the expression of genes that are not normally regulated by retinoic acid receptors." SIGNOR-255729 TFAP4 protein Q01664 UNIPROT NFIA protein Q12857 UNIPROT "up-regulates activity" binding 9606 BTO:0001109 19505873 t miannu "We also observed moderately increased recruitment of CTCF, HDAC1, and SP1 by the full-length AP-4 onto the WT DNA beads." SIGNOR-226586 LEF1 protein Q9UJU2 UNIPROT MYC protein P01106 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 19653274 f gcesareni "Expression of Lef-1 FL, but not the newly identified Lef-1 Deltaexon VI, induced the expression of the cell cycle regulating proteins c-myc and cyclin D1 in cooperation with beta-catenin and it enhanced cell proliferation" SIGNOR-245351 PRKG1 protein Q13976 UNIPROT ITPR1 protein Q14643 UNIPROT unknown phosphorylation Ser1764 RPSGRREsLTSFGNG 10116 BTO:0004578 8132598 t lperfetto "Phosphorylation of the inositol 1,4,5-trisphosphate receptor by cyclic GMP-dependent protein kinase. | The synthetic peptide corresponding to serine 1755 (GRRESLTSFG) was phosphorylated with aKm in the range of 30-40 microM by both kinases. The kinetic analysis revealed that this peptide substrate is the best substrate described for cGMP kinase to date. Vascular smooth muscle cells prelabeled with [32P]orthophosphate and treated with atrial natriuretic peptide or sodium nitroprusside to elevate cGMP also resulted in increased labeling of the IP3 receptor. Phosphorylation of IP3 receptor by cGMP kinase may regulate the function of IP3 receptor in vascular smooth muscle cells and contribute to the effect of cGMP to regulate intracellular calcium levels." SIGNOR-248916 MAPK1 protein P28482 UNIPROT STIM1 protein Q13586 UNIPROT up-regulates phosphorylation Ser575 LVEKLPDsPALAKKA 9606 BTO:0000222 22298426 t gcesareni "The netrin-2-mediated nfatc3 activation was coincident with robust interactions between cdo and stim1 in myoblasts and the erk-mediated stim1 phosphorylation at serine 575" SIGNOR-192788 FOXO3 protein O43524 UNIPROT IDH1 protein O75874 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 25648147 t miannu "We identify FOXOs as transcriptional activators of IDH1. FOXOs promote IDH1 expression and thereby maintain the cytosolic levels of α-ketoglutarate and NADPH." SIGNOR-260089 CD3E protein P07766 UNIPROT NCK1 protein P16333 UNIPROT "up-regulates activity" relocalization 9606 BTO:0000661 12110186 t "We present strong evidence that ligand engagement of TCR-CD3 induces a conformational change that exposes a proline-rich sequence in CD3ϵ and results in recruitment of the adaptor protein Nck." SIGNOR-259934 3-isobutyl-1-methylxanthine chemical CHEBI:48518 ChEBI PPARG protein P37231 UNIPROT up-regulates 9606 11279134 f fspada "The differentiation of 3t3-l1 preadipocytes is regulated in part by a cascade of transcriptional events involving activation of the ccaat/enhancer-binding proteins (c/ebps) and peroxisome proliferator-activated receptor gamma (ppargamma) by dexamethasone (dex), 3-isobutyl-1-methylxanthine (mix), and insulin" SIGNOR-106484 EFNB1 protein P98172 UNIPROT EPHB1 protein P54762 UNIPROT up-regulates binding 9606 11713248 t tpavlidou "We show here that despite its lack of kinase activity, ephb6 undergoes inducible tyrosine phosphorylation upon stimulation with the eph-b receptor subfamily ligand ephrin-b1. Overexpression of a catalytically active member of the eph-b subfamily, ephb1, resulted in increased ephb6 phosphorylation. Ephb1-induced ephb6 phosphorylation was ligand-dependent and required the functional catalytic activity of ephb1." SIGNOR-111851 CBL protein P22681 UNIPROT ABL1 protein P00519 UNIPROT "down-regulates quantity by destabilization" ubiquitination 9606 BTO:0001271 20675402 t lperfetto "We found that while c-cbl e3 ligase induced ubiquitin-dependent degradation of mature and phosphorylated bcr-abl proteins" SIGNOR-167194 NR3C1 protein P04150 UNIPROT KLF5 protein Q13887 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 BTO:0000746 27777311 t "We show that in addition, DEX-bound GR directly promotes the expression of adipogenic TFs, including C/EBPβ, Klf5, Klf9, and C/EBPα" SIGNOR-256118 HDAC2 protein Q92769 UNIPROT SNAI2 protein O43623 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 23836662 f miannu "We further demonstrated that PER2 served as a transcriptional corepressor, which recruited polycomb proteins EZH2 and SUZ12 as well as HDAC2 to octamer transcription factor 1 (OCT1) (POU2F1) binding sites of the TWIST1 and SLUG promoters to repress expression of these EMT genes." SIGNOR-254156 FYN protein P06241 UNIPROT SLAMF1 protein Q13291 UNIPROT "up-regulates activity" phosphorylation Tyr307 QDPCTTIyVAATEPV 9534 BTO:0000298 11806999 t "All 3 tyrosines of CD150 (Tyr281, Tyr307, Tyr327) are phosphorylated by the src kinase Fyn. CD150 is unique among its homologues in the immunoglobulin superfamily in that it is able to bind SAP, a floating SH2 domain, in the absence of tyrosine phosphorylation. In this study, using a detailed mutagenesis mapping approach we have shown that SAP binding to CD150 is in fact bimodal. Prior to tyrosine phosphorylation, SAP binds the membrane-proximal motif surrounding Tyr281. Following tyrosine phosphorylation by tyrosine kinases such as Fyn, SAP binds additionally to the distal motif surrounding Tyr327." SIGNOR-251182 Ub:E2 complex SIGNOR-C497 SIGNOR UBR5 protein O95071 UNIPROT "up-regulates activity" ubiquitination 9606 34199813 t miannu "The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t" SIGNOR-271299 UBR2 protein Q8IWV8 UNIPROT RECQL4 protein O94761 UNIPROT up-regulates binding 9606 BTO:0000567 15317757 t miannu "The isolated recql4, assayed as a complex with ubr1 and ubr2, exhibited dna-stimulated atpase activity but was inactive as either dna helicase or dna translocase / the discovery, in the present work, that these ub ligases, ubr1 and ubr2, interact with the putative helicase recql4 (fig. 2), and that recql4 is a long-lived, non-ubiquitylated protein in hela cells" SIGNOR-128214 RUNX1 protein Q01196 UNIPROT HHEX protein Q03014 UNIPROT "up-regulates quantity" "transcriptional regulation" 9606 28213513 t "We identified Hhex as a direct target of RUNX1 and FLT3-ITD stimulation and confirmed high HHEX expression in FLT3-ITD AMLs. HHEX could replace RUNX1 in cooperating with FLT3-ITD to induce AML." SIGNOR-256305 MAPK14 protein Q16539 UNIPROT ATF2 protein P15336 UNIPROT "up-regulates activity" phosphorylation 9606 BTO:0000007 10085140 t lperfetto "On the other hand, sapks such as jnks and p38 phosphorylate atf-2 at thr-69, thr-71, and ser-90 which lie close to the n-terminal transcriptional activation domain and stimulate itstrans-activating capacity our results indicate that atf-2 not only directly binds to smad3/4 hetero-oligomers but also that atf-2 is phosphorylated by tgf- signaling via tak1 and p38." SIGNOR-65593 ZDHHC5 protein Q9C0B5 UNIPROT S1PR1 protein P21453 UNIPROT "up-regulates activity" palmitoylation 9606 BTO:0000793 29185452 t "We propose that DHHC5-mediated palmitoylation of S1P1R determines Gi coupling and its signalling in a spatio/temporal manner." SIGNOR-261140 NUP58 protein Q9BVL2 UNIPROT NPC complex SIGNOR-C263 SIGNOR "form complex" binding 27016207 t lperfetto "The protein inventory of the NPC has been studied for a very diverse set of eukaryotes, including trypanosomes, fungi, plants, animals, and humans [4], [5], [6], [7], [8], [9]. In all cases, about 30 different Nups were found (Fig. 2)." SIGNOR-262077 "GABA-B receptor" complex SIGNOR-C336 SIGNOR Excitatory_synaptic_transmission phenotype SIGNOR-PH133 SIGNOR down-regulates 9606 BTO:0000227 9872316 f brain lperfetto "GABA (gamma-aminobutyric acid) is the main inhibitory neurotransmitter in the mammalian central nervous system, where it exerts its effects through ionotropic (GABA(A/C)) receptors to produce fast synaptic inhibition and metabotropic (GABA(B)) receptors to produce slow, prolonged inhibitory signals." SIGNOR-263794 MAPK8 protein P45983 UNIPROT BCL2 protein P10415 UNIPROT down-regulates phosphorylation Thr69 SRDPVARtSPLQTPA 9606 18570871 t gcesareni "Together, our findings demonstrate that jnk1-mediated multisite phosphorylation of bcl-2 stimulates starvation-induced autophagy by disrupting the bcl-2/beclin 1 complex." SIGNOR-179096 ZMIZ1 protein Q9ULJ6 UNIPROT Chromatine_condensation phenotype SIGNOR-PH21 SIGNOR up-regulates 10090 BTO:0001825 26522984 f miannu "Our data suggest that Zmiz1 and Notch1 cooperatively recruit each other to chromatin through direct interaction via the TPR resulting in a slight increase in activating histone marks and decrease of repressive histone marks." SIGNOR-263938 WNT5A protein P41221 UNIPROT GSK3B/Axin/APC complex SIGNOR-C110 SIGNOR down-regulates 9606 21078818 f lperfetto "We demonstrate here that prototype canonical wnt3a and noncanonical wnt5a ligands specifically trigger completely unrelated endogenous coreceptors-lrp5/6 and ror1/2, respectively-through a common mechanism that involves their wnt-dependent coupling to the frizzled (fzd) coreceptor and recruitment of shared components, including dishevelled (dvl), axin, and glycogen synthase kinase 3 (gsk3)." SIGNOR-227958 PRKACA protein P17612 UNIPROT NDE1 protein Q9NXR1 UNIPROT up-regulates phosphorylation Thr131 LERAKRAtIMSLEDF 9606 BTO:0000142 21677187 t lperfetto "Here, we demonstrate that disc1 and pde4 modulate nde1 phosphorylation by camp-dependent protein kinase a (pka) and identify a novel pka substrate site on nde1 at threonine-131 (t131).Since phosphorylated t131 is detectable at multiple subcellular locations (centrosome, nucleus, postsynaptic density, proximal axon), there is potential for disc1/pde4 to influence several important brain processes that critically depend on the nde1/ndel1/lis1 comple" SIGNOR-174410 "Ub:E1 (UBA1 substrate)" complex SIGNOR-C495 SIGNOR UBE2T protein Q9NPD8 UNIPROT "up-regulates activity" ubiquitination 9606 34199813 t miannu "The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t" SIGNOR-271316 CDK1 protein P06493 UNIPROT EPN1 protein Q9Y6I3 UNIPROT "down-regulates activity" phosphorylation Ser382 FSDPWGGsPAKPSTN 10029 BTO:0000246 10764745 t miannu "Phosphorylation of POB1 and Epsin by p34cdc2 kinase. Their phosphorylation sites (Ser411 of POB1 and Ser357 of Epsin) were determined. Phosphorylated Epsin and EpsinS357D formed a complex with α-adaptin less efficiently than wild type Epsin." SIGNOR-262723 17beta-estradiol smallmolecule CHEBI:16469 ChEBI estrone smallmolecule CHEBI:17263 ChEBI "up-regulates quantity" "precursor of" -1 8099587 t Luana "17 beta-HSD type 2 was capable of catalyzing the interconversion of testosterone and androstenedione as well as estradiol and estrone. " SIGNOR-269761 AIP protein O00170 UNIPROT GREB1 protein Q4ZG55 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0000093 21984905 f miannu "We show that XAP2 is recruited to the promoter of ERα regulated genes like the breast cancer marker gene pS2 or GREB1 and negatively regulate the expression of these genes in MCF-7 cells." SIGNOR-253735 AURKB protein Q96GD4 UNIPROT NINL protein Q9Y2I6 UNIPROT up-regulates phosphorylation Ser585 RLPKNRHsPSWSPDG 9606 20864540 t lperfetto "Importantly, nlp is characterized as a novel substrate of aurora b and can be phosphorylated by aurora b. The specific phosphorylation sites are mapped at ser-185, ser-448, and ser-585. The phosphorylation at ser-448 and ser-585 is likely required for nlp association with aurora b and localization at midbody. Meanwhile, the phosphorylation at ser-185 is vital to nlp protein stability. Disruptions of these phosphorylation sites abolish cytokinesis and lead to chromosomal instability." SIGNOR-168053 PRKAR1B protein P31321 UNIPROT PRKACB protein P22694 UNIPROT "down-regulates activity" binding 9606 26687711 t "Inactive PKA exists as a holoenzyme, comprised of two regulatory (R) subunits and two catalytic subunits . In the presence of cAMP, the holoenzyme becomes active by binding two cAMP molecules cooperatively to each R subunit, resulting in a conformational change in the R subunits, thus releasing the two C subunits to phosphorylate downstream targets" SIGNOR-258756 IKBKB protein O14920 UNIPROT BAD protein Q92934 UNIPROT down-regulates phosphorylation 9606 SIGNOR-C14 23332762 t gcesareni "Ikk phosphorylates bad at serine-26 (ser26) and primes it for inactivation." SIGNOR-192614 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR PAPOLA protein P51003 UNIPROT "up-regulates activity" phosphorylation Ser558 GSSQGRNsPAPAVTA 10090 BTO:0000964 34048556 t lperfetto "Once an oocyte resumes meiosis, activated CDK1 and ERK1/2 cooperatively mediate the phosphorylation of three serine residues of PAPalpha, 537, 545 and 558, thereby leading to increased activity." SIGNOR-268343 PASK protein Q96RG2 UNIPROT GYS1 protein P13807 UNIPROT "down-regulates activity" phosphorylation -1 16275910 t gcesareni "Recombinant human PASK (hPASK) phosphorylates purified muscle glycogen synthase, causing robust inactivation. Furthermore, hPASK interacts directly with glycogen synthase when expressed in cultured cells and this interaction and the phosphorylation of glycogen synthase by human PASK (hPASK) are inhibited by glycogen." SIGNOR-245866 BUD13 protein Q9BRD0 UNIPROT "U2 snRNP complex" complex SIGNOR-C479 SIGNOR "form complex" binding 9606 30765414 t lperfetto "The major spliceosomal building blocks are the U1, U2, U4/U6, and U5 small nuclear ribonucleoproteins (snRNPs). Each consists of a small nuclear RNA (snRNA) (or two, in the case of U4/U6), seven Sm proteins that form a ring (or seven Lsm proteins in the case of U6), and a variable number of snRNP-specific proteins (Fig. 1F) (Will and Lührmann 2011). Under splicing conditions, the U4/U6 and U5 snRNPs form a 25S U4/U6.U5 tri-snRNP, in which the U4 and U6 snRNAs are base-paired, forming a three-way junction." SIGNOR-270672 MMP2 protein P08253 UNIPROT LRP2 protein P98164 UNIPROT "up-regulates quantity" binding 10116 28659595 t miannu "We show that megalin/LRP-2 acts as an endocytic receptor for proMMP-2:TIMP-2 complex. We found that RAP, an antagonist of the LDL receptor family18, competed with binding of proMMP-2:TIMP-2 complex onto rat BN16 epithelial cells." SIGNOR-265255 IRAK4 protein Q9NWZ3 UNIPROT IRAK4 protein Q9NWZ3 UNIPROT "up-regulates activity" phosphorylation Thr342 ASEKFAQtVMTSRIV 9606 BTO:0000007 17141195 t lperfetto "The present data indicate that the kinase activity of irak-4 is dependent on the autophosphorylations at t342" SIGNOR-151006 PDGFRA protein P16234 UNIPROT CRK protein P46108 UNIPROT up-regulates binding 9606 19426560 t amattioni "Crk can interact directly with tyrosine kinase receptors (for example pdgfr?) And can transmit signals downstream" SIGNOR-185664 FYN protein P06241 UNIPROT LAT protein O43561 UNIPROT up-regulates phosphorylation Tyr200 SMESIDDyVNVPESG 9606 BTO:0000782 16938345 t gcesareni "Both lck and syk, phosphorylate the itam-like motifs on lat at y171y191, which is essential for induction of the interaction of lat with downstream signaling molecules such as grb2, plc-gamma1 and c-cbl, and for activation of mapk-erk." SIGNOR-149174 "CPSF complex" complex SIGNOR-C53 SIGNOR PAPOLA protein P51003 UNIPROT "up-regulates activity" relocalization 9606 14749727 t lperfetto "Recombinant hfip1 is sufficient to stimulate the in vitro polyadenylation activity of pap in a u-rich element-dependent manner. hfip1, cpsf160 and pap form a ternary complex in vitro, suggesting that hfip1 and cpsf160 act together in poly(a) site recognition and in cooperative recruitment of pap to the rna." SIGNOR-268323 "lysophosphatidic acids" smallmolecule CHEBI:32957 ChEBI LPAR3 protein Q9UBY5 UNIPROT up-regulates "chemical activation" 9606 22863277 t gcesareni "Lpa binds to a family of gpcrs known as lpa receptors (lpa1-6) to initiate intracellular signaling. Lpa1 was highly expressed and lpa3 was detectable in hek293a cells compared to other lpa receptors." SIGNOR-198526 MAP3K7 protein O43318 UNIPROT NFKBIB protein Q15653 UNIPROT down-regulates phosphorylation 9606 9480845 t gcesareni "Overexpression oftak1together with its activator protein,tak1binding protein 1 (tab1), induced thenucleartranslocation of nf-kappa b p50/p65 heterodimer accompanied by the degradation of i kappa b alpha and i kappa b beta, and the expression of kappa b-dependent reporter gene." SIGNOR-55719 MMP19 protein Q99542 UNIPROT ECM stimulus SIGNOR-ST20 SIGNOR down-regulates 17318226 f lperfetto "Historically, MMPs were thought to function mainly as enzymes that degrade structural components of the ECM." SIGNOR-272386 "orotidine 5'-phosphate(3-)" smallmolecule CHEBI:57538 ChEBI UMP smallmolecule CHEBI:16695 ChEBI "up-regulates quantity" "precursor of" 9606 2912371 t miannu "Uridine 5'-phosphate (UMP) synthase contains two sequential catalytic activities for the synthesis of orotidine 5'-phosphate (OMP) from orotate (EC 2.4.2.10, orotate phosphoribosyltransferase) and the decarboxylation of OMP to form UMP (EC 4.1.1.23, OMP decarboxylase)." SIGNOR-267439 AMFR protein Q9UKV5 UNIPROT CD3D protein P04234 UNIPROT "down-regulates quantity by destabilization" polyubiquitination 9606 BTO:0000007 11724934 t miannu "Gp78 specifically recruits MmUBC7, a ubiquitin-conjugating enzyme (E2) implicated in ER-associated degradation (ERAD), through a region distinct from the RING finger. gp78 can target itself for proteasomal degradation in a RING finger- and MmUBC7-dependent manner. Importantly, gp78 can also mediate degradation of CD3-delta, a well-characterized ERAD substrate. " SIGNOR-272670 PBK protein Q96KB5 UNIPROT "Histone H3" proteinfamily SIGNOR-PF69 SIGNOR unknown phosphorylation 9606 16982762 t gcesareni "Pbk/topk could phosphorylate histone h3 at ser10 in vitro and in vivo, and mediated its growth-promoting effect through histone h3 modification." SIGNOR-265364 GPKOW protein Q92917 UNIPROT DHX16 protein O60231 UNIPROT "up-regulates quantity" binding 25296192 t miannu "In this report, we showed that GPKOW interacted directly with the DHX16/hPRP2 and with RNA. Immuno-depletion of GPKOW from HeLa nuclear extracts resulted in an inactive spliceosome that still bound DHX16." SIGNOR-266300 FKBP1A protein P62942 UNIPROT TGFBR1 protein P36897 UNIPROT "down-regulates activity" binding 9606 BTO:0005493 8756725 t lperfetto "Blocking fkbp12/type i receptor interaction with fk506 nonfunctional derivatives enhances the ligand activity, indicating that fkbp12 binding is inhibitory to the signaling pathways of the tgf beta family ligands" SIGNOR-236142 MAPK1 protein P28482 UNIPROT SOS1 protein Q07889 UNIPROT "down-regulates activity" phosphorylation 9606 10197981 t lperfetto "These results suggest that oncogenic ras, acting through mek1 and erk kinases, induces the phosphorylation of smad2 and smad3" SIGNOR-236242 IKBKB protein O14920 UNIPROT IKBKB protein O14920 UNIPROT "down-regulates activity" phosphorylation Ser697 QPSTASNsLPEPAKK 9606 10195894 t "Once activated, IKKbeta autophosphorylated at a carboxyl-terminal serine cluster. Such phosphorylation decreased IKK activity and may prevent prolonged activation of the inflammatory response." SIGNOR-251282 LEF1 protein Q9UJU2 UNIPROT OCA2 protein Q04671 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 22234890 f miannu "the SNP rs12913832 has strong statistical association with human pigmentation. It is located within an intron of the nonpigment gene HERC2, 21 kb upstream of the pigment gene OCA2, and the region surrounding rs12913832 is highly conserved among animal species.In darkly pigmented human melanocytes carrying the rs12913832 T-allele, we detected binding of the transcription factors HLTF, LEF1, and MITF to the HERC2 rs12913832 enhancer, and a long-range chromatin loop between this enhancer and the OCA2 promoter that leads to elevated OCA2 expression." SIGNOR-254555 EP300 protein Q09472 UNIPROT MAML1 protein Q92585 UNIPROT up-regulates acetylation 9606 17300219 t gcesareni "The n-terminal domain of maml1 directly interacts with both p300 and histones, and the p300-maml1 complex specifically acetylates histone h3 and h4 tails in chromatin. Furthermore, p300 acetylates maml1 and evolutionarily conserved lysine residues in the maml1 n-terminus are direct substrates for p300-mediated acetylation." SIGNOR-153035 MTOR protein P42345 UNIPROT SGK1 protein O00141 UNIPROT up-regulates phosphorylation Ser422 AEAFLGFsYAPPTDS 9606 SIGNOR-C2 18925875 t gcesareni "Mtorc2 immunoprecipitated from wild-type, but not from mlst8- or rictor-knockout cells, phosphorylated sgk1 at ser(422)" SIGNOR-181531 4-[2-(2-chloro-4-fluoroanilino)-5-methyl-4-pyrimidinyl]-N-[(1S)-1-(3-chlorophenyl)-2-hydroxyethyl]-1H-pyrrole-2-carboxamide chemical CHEBI:95049 ChEBI MAPK1 protein P28482 UNIPROT "down-regulates activity" "chemical inhibition" 9606 BTO:0001271 31482470 t miannu "In the present study, we have shown that ERK2 inhibitor VX-11e demonstrates a potent synergy with voreloxin in leukemia cell lines and that this effect is associated with the inhibition of proliferation, cell cycle arrest and induction of apoptosis." SIGNOR-262244 POLE2 protein P56282 UNIPROT "DNA polymerase epsilon" complex SIGNOR-C377 SIGNOR "form complex" binding 9606 BTO:0000567 10801849 t lperfetto "Identification and cloning of two histone fold motif-containing subunits of HeLa DNA polymerase epsilon." SIGNOR-265519 SRC protein P12931 UNIPROT CELF2 protein O95319 UNIPROT "up-regulates activity" phosphorylation Tyr63 LKELFEPyGAVYQIN -1 17855367 t miannu "Site-directed mutagenesis of putative tyrosine phosphorylation sites in CUGBP2 identified tyrosine 39 as a c-Src target, and a CUGBP2 with a mutated tyrosine 39 displayed an attenuated ability to bind COX-2 mRNA." SIGNOR-263195 LRRK2 protein Q5S007 UNIPROT LRRK2 protein Q5S007 UNIPROT up-regulates phosphorylation Thr2035 GIKTSEGtPGFRAPE 9606 BTO:0000938 20595391 t lperfetto "Three putative autophosphorylation sites (thr-2031, ser-2032, and thr-2035) have been identified within the activation segment of the lrrk2 kinase domain based on sequence homology to mixed-lineage kinases. Phosphorylation at one or more of these sites is critical for the kinase activity of lrrk2." SIGNOR-166474 dabrafenib chemical CHEBI:75045 ChEBI CDK16 protein Q00536 UNIPROT "down-regulates activity" "chemical inhibition" 9606 29112787 t Monia "We have identified dabrafenib as a potent inhibitor of NEK9 and CDK16, and our studies suggest that inhibition of these kinases may have activity against cancers that do not harbor BRAF mutations. We confirmed NEK9 to be a potent target of dabrafenib by in vitro kinase assays, with inhibition of NEK9 observed in the single-digit nanomolar range." SIGNOR-261073 GSK3B protein P49841 UNIPROT SREBF1 protein P36956 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser430 DTLTPPPsDAGSPFQ 9606 BTO:0000007 19126544 t lperfetto "Importantly, we demonstrate that the mature form of endogenous SREBP1 is phosphorylated on Ser-434. Glycogen synthase kinase-3 phosphorylates Ser-434, and the phosphorylation of this residue is attenuated in response to insulin signaling. Interestingly, phosphorylation of Ser-434 promotes the glycogen synthase kinase-3-dependent phosphorylation of Thr-426 and Ser-430 and destabilizes SREBP1." SIGNOR-236030 INPPL1 protein O15357 UNIPROT CBLC protein Q9ULV8 UNIPROT down-regulates binding 9606 BTO:0000567 15668240 t gcesareni "This association between ship2 and cbl could sequester cbl from the egfr, thereby regulating the kinetics of egfr-cbl association and subsequent internalization and degradation of the receptor." SIGNOR-133388 hydrosulfide smallmolecule CHEBI:29919 ChEBI Vasodilation phenotype SIGNOR-PH223 SIGNOR up-regulates 26539823 f lperfetto "We have recently shown, that in arterial (HAEC) end venular (HUVEC) endothelial cells, GPBAR1 agonism increases the expression/ activity of cystathione-γ-liase (CSE, CTH, EC 4.4.1), a key enzyme in the “trans-sulfuration pathway” that generates hydrogen sulfide (H2S), a vasodilatory agent" SIGNOR-275831 PRKACA protein P17612 UNIPROT TH protein P07101 UNIPROT "up-regulates activity" phosphorylation Ser40 GQGAPGPsLTGSPWP -1 11359875 t miannu "HTH1 was phosphorylated at Ser40 by PKA. Tyrosine hydroxylase (TH) has been reported to require binding of 14-3-3 proteins for optimal activation by phosphorylation. phosphorylationof hTH1‚4 at Ser40, to a stoichiometry of up to 1.0 molphosphate per mol TH subunit, dramatically increases their binding to 14-3-3 proteins." SIGNOR-250061 PRKCA protein P17252 UNIPROT NCF1 protein P14598 UNIPROT up-regulates phosphorylation Ser315 AHSIHQRsRKRLSQD 9606 BTO:0000130 12056906 t lperfetto "Phosphopeptide mapping of p47(phox) showed that, as opposed to pkc zeta, pkc alpha, beta ii, and delta are able to phosphorylate all the major pkc sites. The use of p47(phox) mutants identified serines 303, 304, 315, 320, 328, 359, 370, and 379 as targets of pkc alpha, beta ii, and delta.Taken together, these results suggest that pkc alpha, beta ii, delta, and zeta expressed in human neutrophils can individually phosphorylate p47(phox) and induce both its translocation and nadph oxidase activation." SIGNOR-89158 MAPK1 protein P28482 UNIPROT CTTN protein Q14247 UNIPROT up-regulates phosphorylation Ser418 TEERLPSsPVYEDAA 9606 BTO:0000938 21079800 t gcesareni "Cortactin is regulated by multiple phosphorylation events, including phosphorylation of s405 and s418 by extracellular regulated kinases (erk)1/2. Erk1/2 phosphorylation of cortactin has emerged as an important positive regulatory modification, enabling cortactin to bind and activate the arp2/3 regulator neuronal wiskott-aldrich syndrome protein (n-wasp), promoting actin polymerization and enhancing tumor cell movement." SIGNOR-169678 WIPI2 protein Q9Y4P8 UNIPROT ATG16L1 protein Q676U5 UNIPROT "up-regulates quantity" binding 9606 BTO:0001938 28561066 t miannu "WIPI1 assists WIPI2 in recruiting ATG16L for LC3 lipidation. WIPI1-WIPI2 heterodimer may function more efficiently in ATG16L complex recruitment." SIGNOR-268478 TNFRSF1A protein P19438 UNIPROT TRADD protein Q15628 UNIPROT "up-regulates activity" binding 9606 BTO:0000007 7758105 t lperfetto "We have identified a novel 34 kda protein, designated tradd, that specifically interacts with an intracellular domain of tnfr1 tradd interacts with the death domain of tnfrsf1a to initiate distinct signaling cascades for two of the most important biological activities of tnf, nf-kb activation and programmed cell death tradd, a novel protein that specifically interacts with the death domain of tnfr1 and activates signaling pathways for both of these activities when overexpressed." SIGNOR-32739 3,3',5'-triiodothyronine smallmolecule CHEBI:28774 ChEBI THRB protein P10828 UNIPROT "up-regulates activity" binding 9606 BTO:0001073 29407449 t scontino "T3 binds its receptor (TR) in the nucleus. TRs are ligand-dependent transcription factors belonging to the type II group of NHRs. TRs are encoded by two genes, Thra and Thrb." SIGNOR-267254 zotepine chemical CHEBI:32316 ChEBI HTR1D protein P28221 UNIPROT "down-regulates activity" "chemical inhibition" 10116 BTO:0000529 8935801 t miannu "Risperidone and its active metabolite 9-OH-risperidone were compared to reference antipsychotic drugs (haloperidol, pipamperone, fluspirilene, clozapine, zotepine) and compounds under development (olanzapine, seroquel, sertindole, ORG-5222, ziprasidone) for in vitro binding to neurotransmitter receptors in brain tissue and on membranes of recombinant cells expressing cloned human receptors and for in vivo occupancy of neurotransmitter receptors in rat and guinea-pig brain following acute treatment (2 h., s.c.). The binding affinities of the compounds for various neurotransmitter receptors were measured using membrane preparations of animal brain regions and of recombinant cells expressing cloned, mostly human receptors. Receptors, tissues and cells are indicated in Table I; results are shown in Table 4A-B." SIGNOR-258550 MARK1 protein Q9P0L2 UNIPROT MAP2 protein P11137 UNIPROT "down-regulates activity" phosphorylation Ser1799 RRLSNVSsSGSINLL -1 8631898 t miannu "Here we show that p110mark phosphorylates analogous KXGS sites in the microtubule binding domains of the neuronal MAP2 and the ubiquitous MAP4. Phosphorylation in vitro leads to the dissociation of MAP2 and MAP4 from microtubules and to a pronounced increase in dynamic instability." SIGNOR-250167 BHLHE40 protein O14503 UNIPROT BHLHE40 protein O14503 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 10090 BTO:0000944 14672706 f lperfetto "We show here an autofeedback loop of Dec1 encoding a basic helix–loop–helix transcription factor: CLOCK/BMAL increased the promoter activity of Dec1, and DEC1 and DEC2 as well as PERs and CRYs suppressed the induced expression." SIGNOR-253715 PKN1 protein Q16512 UNIPROT MEFV protein O15553 UNIPROT "down-regulates activity" phosphorylation Ser208 VRLRRNAsSAGRLQG 10090 BTO:0004732 27270401 t no miannu "PKNs bind to human pyrin and phosphorylate S208 and S242. Pyrin forms an inflammasome when mutant or in response to bacterial modification of the GTPase RhoA. We found that RhoA activated the serine-threonine kinases PKN1 and PKN2 that bind and phosphorylate pyrin. Phosphorylated pyrin bound to 14-3-3 proteins, regulatory proteins that in turn blocked the pyrin inflammasome." SIGNOR-275462 PKN2 protein Q16513 UNIPROT MEFV protein O15553 UNIPROT "down-regulates activity" phosphorylation Ser242 SGKMRPRsLEVTIST 10090 BTO:0004732 27270401 t no miannu "PKNs bind to human pyrin and phosphorylate S208 and S242. Pyrin forms an inflammasome when mutant or in response to bacterial modification of the GTPase RhoA. We found that RhoA activated the serine-threonine kinases PKN1 and PKN2 that bind and phosphorylate pyrin. Phosphorylated pyrin bound to 14-3-3 proteins, regulatory proteins that in turn blocked the pyrin inflammasome." SIGNOR-275463 PKN2 protein Q16513 UNIPROT MEFV protein O15553 UNIPROT "down-regulates activity" phosphorylation Ser208 VRLRRNAsSAGRLQG 10090 BTO:0004732 27270401 t no miannu "PKNs bind to human pyrin and phosphorylate S208 and S242. Pyrin forms an inflammasome when mutant or in response to bacterial modification of the GTPase RhoA. We found that RhoA activated the serine-threonine kinases PKN1 and PKN2 that bind and phosphorylate pyrin. Phosphorylated pyrin bound to 14-3-3 proteins, regulatory proteins that in turn blocked the pyrin inflammasome." SIGNOR-275464 RHOA protein P61586 UNIPROT PKN1 protein Q16512 UNIPROT "up-regulates activity" binding 10090 BTO:0004732 27270401 t no miannu "PKNs bind to human pyrin and phosphorylate S208 and S242. Pyrin forms an inflammasome when mutant or in response to bacterial modification of the GTPase RhoA. We found that RhoA activated the serine-threonine kinases PKN1 and PKN2 that bind and phosphorylate pyrin. Phosphorylated pyrin bound to 14-3-3 proteins, regulatory proteins that in turn blocked the pyrin inflammasome." SIGNOR-275465 RHOA protein P61586 UNIPROT PKN2 protein Q16513 UNIPROT "up-regulates activity" binding 10090 BTO:0004732 27270401 t no miannu "PKNs bind to human pyrin and phosphorylate S208 and S242. Pyrin forms an inflammasome when mutant or in response to bacterial modification of the GTPase RhoA. We found that RhoA activated the serine-threonine kinases PKN1 and PKN2 that bind and phosphorylate pyrin. Phosphorylated pyrin bound to 14-3-3 proteins, regulatory proteins that in turn blocked the pyrin inflammasome." SIGNOR-275466 PRKCI protein P41743 UNIPROT ECT2 protein Q9H8V3 UNIPROT up-regulates phosphorylation Thr359 YLYEKANtPELKKSV 9606 BTO:0000551 21189248 t gcesareni "Our data support a model in which pkc?-Mediated phosphorylation regulates ect2 binding to the oncogenic pkc?-Par6 complex thereby activating rac1 activity and driving transformed growth and invasion." SIGNOR-170790 CDK1 protein P06493 UNIPROT KHDRBS1 protein Q07666 UNIPROT unknown phosphorylation Thr317 RGALVRGtPVRGAIT 9606 9315091 t lperfetto "Phosphorylation of sam68 by purified cdc2." SIGNOR-51275 LATS1 protein O95835 UNIPROT CDC26 protein Q8NHZ8 UNIPROT "up-regulates activity" phosphorylation Thr7 tRLELKLD 25723520 t lperfetto "LATS1 and LATS2 phosphorylate CDC26 to modulate assembly of the tetratricopeptide repeat subcomplex of APC/C|Overall, these results suggest that LATS1/2 are novel kinases involved in APC/C phosphorylation and indicate a direct regulatory link between LATS1/2 and APC/C|Here, we demonstrate that LATS1 phosphorylates the Thr7 (T7) residue of the APC/C component CDC26 directly" SIGNOR-275472 LATS1 protein O95835 UNIPROT MTF1 protein Q14872 UNIPROT "down-regulates activity" phosphorylation Ser152 EGCPRTYsTAGNLRT 35027733 t lperfetto "The Hippo pathway kinases LATS1 and LATS2 attenuate cellular responses to heavy metals through phosphorylating MTF1|the Hippo pathway kinase LATS phosphorylates and inhibits MTF1|LATS phosphorylates MTF1 at S152 and disrupts its association with the promoters of heavy metal response genes, resulting in the loss of heavy metal response gene expression" SIGNOR-275473 LATS2 protein Q9NRM7 UNIPROT CDC26 protein Q8NHZ8 UNIPROT "up-regulates activity" phosphorylation Thr7 tRLELKLD 25723520 t lperfetto "LATS1 and LATS2 phosphorylate CDC26 to modulate assembly of the tetratricopeptide repeat subcomplex of APC/C|Overall, these results suggest that LATS1/2 are novel kinases involved in APC/C phosphorylation and indicate a direct regulatory link between LATS1/2 and APC/C" SIGNOR-275474 LATS2 protein Q9NRM7 UNIPROT MTF1 protein Q14872 UNIPROT "down-regulates activity" phosphorylation Ser152 EGCPRTYsTAGNLRT 35027733 t lperfetto "The Hippo pathway kinases LATS1 and LATS2 attenuate cellular responses to heavy metals through phosphorylating MTF1|the Hippo pathway kinase LATS phosphorylates and inhibits MTF1|LATS phosphorylates MTF1 at S152 and disrupts its association with the promoters of heavy metal response genes, resulting in the loss of heavy metal response gene expression" SIGNOR-275475 APC-c complex SIGNOR-C150 SIGNOR FBXW5 protein Q969U6 UNIPROT "down-regulates quantity by destabilization" ubiquitination 21725316 t lperfetto "We show that FBXW5 levels are controlled by the anaphase-promoting (APC/C) complex, which targets FBXW5 for degradation during mitosis and G1, thereby helping to reset the centrosome duplication machinery." SIGNOR-275477 LRRK2 protein Q5S007 UNIPROT AKT1 protein P31749 UNIPROT up-regulates phosphorylation Ser473 RPHFPQFsYSASGTA 9606 BTO:0000938 21658387 t lperfetto "A knockdown experiment using intact cells also demonstrated LRRK2-mediated phosphorylation of Akt1 (Ser473), suggesting that Akt1 is a convincing candidate for the physiological substrate of LRRK2." SIGNOR-174044 PRKCZ protein Q05513 UNIPROT NCF1 protein P14598 UNIPROT up-regulates phosphorylation Ser359 EERQTQRsKPQPAVP 9606 BTO:0000130 12056906 t lperfetto "Phosphopeptide mapping of p47(phox) showed that, as opposed to pkc zeta, pkc alpha, beta ii, and delta are able to phosphorylate all the major pkc sites. The use of p47(phox) mutants identified serines 303, 304, 315, 320, 328, 359, 370, and 379 as targets of pkc alpha, beta ii, and delta.Taken together, these results suggest that pkc alpha, beta ii, delta, and zeta expressed in human neutrophils can individually phosphorylate p47(phox) and induce both its translocation and nadph oxidase activation." SIGNOR-89280 EGR1 protein P18146 UNIPROT HYAL1 protein Q12794 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0004796 18718911 f miannu "In 253J-Lung and HT1376 bladder cancer cell lines, which show high HYAL-1 expression, transcription factors Egr-1, AP-2, and NFκB bind the HYAL-1 promoter. Because both SP1 and Egr-1 have two overlapping binding sites within the promoter (Fig. 5), it appears that although SP1 binding to the methylated HYAL-1 promoter turns off transcription, binding of Erg-1 (and also AP-2) to the unmethylated promoter turns on transcription." SIGNOR-253878 CDK1 protein P06493 UNIPROT EEF2K protein O00418 UNIPROT down-regulates phosphorylation Ser359 GTEEKCGsPQVRTLS 9606 18337751 t gcesareni "Phosphorylation at ser359 inhibits eef2k activity even at high calcium concentrations. we demonstrate that cdc2 contributes to controlling eef2 phosphorylation in cells. inactivation of eef2k by cdc2 may serve to keep eef2 active during mitosis" SIGNOR-177982 PTPRG protein P23470 UNIPROT DOK2 protein O60496 UNIPROT "up-regulates activity" dephosphorylation Tyr139 CMEENELySSAVTVG -1 25624455 t miannu "PTPRG activation by the P1-WD peptide affected the tyrosine phosphorylation of several signaling molecules. Data analysis identified 31 molecules whose phosphorylation was modified in a statistically significant manner (Table I). inhibition of ABL1, BMX, BTK, DAB1, ITGB1, JAK2, KDR, KIT, LIMK1, MET, PDGFRB, SHC1, and VCL correlates with tyrosine dephosphorylation. In contrast, SRC inhibition correlates with hyperphosphorylation of the inhibitory Tyr530 residue and with dephosphorylation of the activatory Tyr419. Moreover, CDK2 and CTTN inhibition correlates with a hyperphosphorylation of the inhibitory Tyr15 and Tyr470, respectively. In contrast, a subgroup of 13 proteins, including BLNK, DOK2, ERBB2, GRIN2B, INSR, PDGFRA, PRKCD, PXN, STAT1, STAT2, STAT3, STAT5A, and ZAP70, appears to be activated by PTPRG activity." SIGNOR-254698 GOLGA3 protein Q08378 UNIPROT GOPC protein Q9HD26 UNIPROT "up-regulates activity" binding 9606 BTO:0000567 15951434 t miannu "Golgin-160 belongs to the golgin family of Golgi-localized proteins, which have been implicated in Golgi structure and function. PIST (also known as GOPC, CAL, and FIG) has been implicated in the trafficking of a subset of plasma membrane proteins, supporting a role of golgin-160 in vesicular trafficking. binding of golgin-160, TC10, and syntaxin-6 to PIST may coordinate membrane trafficking of some plasma membrane proteins in cell types where these proteins are expressed." SIGNOR-261234 CTSG protein P08311 UNIPROT C3 protein P01024 UNIPROT "up-regulates activity" cleavage Leu751 LGLARSNlDEDIIAE 9606 BTO:0001412 1861080 t miannu "Plasma membrane elastase and cathepsin G from U937 cells cleave C3 into C3a- and C3b-like fragments; further incubation leads to C3c- and C3dg-like fragments, as judged from SDS-PAGE analysis of the digests. Sequencing of the C3b-like fragment purified by reverse phase chromatography indicates that initial cleavage of C3 by purified cathepsin G occurs at two positions in the amino-terminal part of the alpha-chain, at a Arg-Ser bond located between residues 748 and 749 and at a Leu-Asp bond between residues 751 and 752." SIGNOR-256348 PDCD1 protein Q15116 UNIPROT DNM1L protein O00429 UNIPROT "down-regulates activity" 9606 BTO:0000782 34535949 f Barakat "Mechanistically, we provided evidence that PD1 signaling downregulates Drp1 activating phosphorylation on Ser616 (and consequently mitochondrial fragmentation) via the inhibition of ERK1/2 and mTOR kinases." SIGNOR-275406 FBXW5 protein Q969U6 UNIPROT SASS6 protein Q6UVJ0 UNIPROT "down-regulates quantity by destabilization" ubiquitination 21725316 t lperfetto "We identify the centriolar protein HsSAS-6 (refs 4,5) as a critical substrate of the SCF-FBXW5 complex. FBXW5 binds HsSAS-6 and promotes its ubiquitylation in vivo. |expression of the wild-type form of FBXW5 accelerated the degradation of HsSAS-6 to a half-life of less than two hours" SIGNOR-275478 HIPK2 protein Q9H2X6 UNIPROT PPM1D protein O15297 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser54 QPLPPRPsPAALPGG 23871434 t lperfetto "WIP1, a homeostatic regulator of the DNA damage response, is targeted by HIPK2 for phosphorylation and degradation|Analysis of the phosphoamino acids of WIP1 revealed that both Ser85 and Ser54 are phosphorylation sites, confirming that HIPK2 is a protein kinase for WIP1 phosphorylation at Ser54 as well as Ser85" SIGNOR-275480 HIPK2 protein Q9H2X6 UNIPROT PPM1D protein O15297 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser85 PLPDAGAsPAPSRCC 23871434 t lperfetto "WIP1, a homeostatic regulator of the DNA damage response, is targeted by HIPK2 for phosphorylation and degradation|Analysis of the phosphoamino acids of WIP1 revealed that both Ser85 and Ser54 are phosphorylation sites, confirming that HIPK2 is a protein kinase for WIP1 phosphorylation at Ser54 as well as Ser85" SIGNOR-275481 AMPK complex SIGNOR-C15 SIGNOR HIPK2 protein Q9H2X6 UNIPROT "down-regulates activity" phosphorylation Thr1116 AALGSTGtVAHLVAS 23871434 t "Phosphosite positions are derived from Figure S5" lperfetto "AMPKalpha2-mediated inhibition of WIP1 phosphorylation by HIPK2|Site-directed mutagenesis of Thr112 and Ser114 in the N terminus, and Thr1107 in the C terminus markedly reduced HIPK2 phosphorylation by AMPKalpha2 in vitro" SIGNOR-275484 "diarsenic trioxide" chemical CHEBI:30621 ChEBI PIN1 protein Q13526 UNIPROT "down-regulates activity" "chemical inhibition" 9606 30093655 t "Here we show that ATO targets Pin1 and cooperates with ATRA to exert potent anticancer activity. ATO inhibits and degrades Pin1, and suppresses its oncogenic function by noncovalent binding to Pin1’s active site" SIGNOR-259923 PLK4 protein O00444 UNIPROT TUBGCP6 protein Q96RT7 UNIPROT "up-regulates activity" phosphorylation Ser1465 PVDPQVQsAADETAV -1 22302995 t miannu "Plk4 interacts with and phosphorylates GCP6. we show that GCP6 is an integral component of the centriole and required for centriole duplication. Moreover, we find that GCP6 interacts in vitro and in vivo with Plk4. We show that phosphorylation of GCP6 by Plk4 is required for Plk4-induced centriole overduplication." SIGNOR-262908 AKT proteinfamily SIGNOR-PF24 SIGNOR STK3 protein Q13188 UNIPROT down-regulates phosphorylation Thr117 IIRLRNKtLIEDEIA 9606 BTO:0000150 20231902 t gcesareni "Akt phosphorylates mst2 at thr117 in vitro and in vivo, which leads to mst2 cleavage and kinase activity as well as nuclear translocation." SIGNOR-164298 PRKCD protein Q05655 UNIPROT CAT protein P04040 UNIPROT "up-regulates activity" phosphorylation Ser167 LFPSFIHsQKRNPQT 9935 24211614 t Manara "Endothelin-1 stimulates catalase activity through the PKCδ-mediated phosphorylation of serine 167." SIGNOR-260904 ATM protein Q13315 UNIPROT DCLRE1C protein Q96SD1 UNIPROT up-regulates phosphorylation Ser503 NDEITDEsLENFPSS 9606 16874298 t lperfetto "The artemis nuclease is defective in radiosensitive severe combined immunodeficiency patients and is required for the repair of a subset of ionising radiation induced dna double-strand breaks (dsbs) in an atm and dna-pk dependent process. Here, we show that artemis phosphorylation by atm and dna-pk in vitro is primarily attributable to s503, s516 and s645 and demonstrate atm dependent phosphorylation at serine 645 in vivo" SIGNOR-148315 AMPK complex SIGNOR-C15 SIGNOR HIPK2 protein Q9H2X6 UNIPROT "down-regulates activity" phosphorylation Ser121 LMRRSTVsLLDTYQK 23871434 t "Phosphosite positions are derived from Figure S5" lperfetto "AMPKalpha2-mediated inhibition of WIP1 phosphorylation by HIPK2|Site-directed mutagenesis of Thr112 and Ser114 in the N terminus, and Thr1107 in the C terminus markedly reduced HIPK2 phosphorylation by AMPKalpha2 in vitro" SIGNOR-275483 PRKAA2 protein P54646 UNIPROT HIPK2 protein Q9H2X6 UNIPROT "down-regulates activity" phosphorylation Thr119 HNLMRRStVSLLDTY 23871434 t "Phosphosite positions are derived from Figure S5" lperfetto "AMPKalpha2-mediated inhibition of WIP1 phosphorylation by HIPK2|Site-directed mutagenesis of Thr112 and Ser114 in the N terminus, and Thr1107 in the C terminus markedly reduced HIPK2 phosphorylation by AMPKalpha2 in vitro" SIGNOR-275485 NKX2-5 protein P52952 UNIPROT ANKRD1 protein Q15327 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10116 BTO:0003265 9043061 f "Finally, a carp promoter-lacZ transgene, which displays cardiac-specific expression in wild-type and Nkx2-5(+/-) background, was also significantly reduced in Nkx2-5(-/-) embryos, indicating that Nkx2-5 either directly or indirectly regulates carp promoter activity during in vivo cardiogenesis as well as in cultured cardiac myocytes" SIGNOR-253646 Ub:E2 complex SIGNOR-C497 SIGNOR PRKN protein O60260 UNIPROT "up-regulates activity" ubiquitination 9606 34199813 t miannu "The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t" SIGNOR-271041 glycine smallmolecule CHEBI:15428 ChEBI N(1)-(5-phospho-beta-D-ribosyl)glycinamide(1-) smallmolecule CHEBI:143788 ChEBI "up-regulates quantity" "precursor of" 9606 34283828 t miannu "In humans, GART [phosphoribosylglycinamide formyltransferase (EC 2.1.2.2) / phosphoribosylglycinamide synthetase (EC 6.3.4.13) / phosphoribosylaminoimidazole synthetase (EC 6.3.3.1)] is a trifunctional protein which catalyzes the second, third, and fifth reactions of the ten step de novo purine synthesis (DNPS) pathway. The second step of DNPS is conversion of phosphoribosylamine (5-PRA) to glycineamide ribonucleotide (GAR)." SIGNOR-267297 "Brivanib alaninate" chemical CID:11154925 PUBCHEM FLT4 protein P35916 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-190729 G3BP2 protein Q9UN86 UNIPROT Stress_granules phenotype SIGNOR-PH124 SIGNOR up-regulates 9606 BTO:0000007 23279204 f miannu "Ras-GTPase-activating protein SH3 domain-binding protein 1 (G3BP1) is a component of SGs that initiates the assembly of SGs by forming a multimer. In this study, we examined the role of G3BP2, a close relative of G3BP1, in SG formation. Although single knockdown of either G3BP1 or G3BP2 in 293T cells partially reduced the number of SG-positive cells induced by arsenite, the knockdowns of both genes significantly reduced the number. G3BP2 formed a homo-multimer and a hetero-multimer with G3BP1. Moreover, like G3BP1, the overexpression of G3BP2 induced SGs even without stress stimuli." SIGNOR-260864 PIK3CB protein P42338 UNIPROT PIP3 smallmolecule CHEBI:16618 ChEBI "up-regulates quantity" "chemical modification" 9606 21779497 t lperfetto "The activation of pi3k results in the generation of the second messenger, phosphatidylinositol 3,4,5-triphosphate (pip3) from phosphatidylinositol 4,5-bisphosphate (pip2). In vivo, class i pi3ks primarily generate phosphatidylinositol-3,4,5-trisphosphate (pip3) from phosphatidylinositol- 4,5-bisphosphate (pi-4,5-p2)" SIGNOR-175241 miR-155 mirna URS000062749E_9606 RNAcentral GFI1 protein Q99684 UNIPROT "down-regulates quantity by repression" "post transcriptional regulation" 9606 24708856 t miannu "We found overexpression of miR-155 led to increase in cJUN, FOS and TRIB2, and decrease in MEIS1, GFI1, cMYC and JARID2." SIGNOR-255762 NPFFR2 protein Q9Y5X5 UNIPROT GNAI1 protein P63096 UNIPROT "up-regulates activity" binding 9606 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-256709 MMP10 protein P09238 UNIPROT ECM stimulus SIGNOR-ST20 SIGNOR down-regulates 17318226 f lperfetto "Historically, MMPs were thought to function mainly as enzymes that degrade structural components of the ECM." SIGNOR-272378 CDK7 protein P50613 UNIPROT TP53 protein P04637 UNIPROT unknown phosphorylation Ser33 LPENNVLsPLPSQAM 9606 9372954 t llicata "We have mapped a major site of phosphorylation by cak to ser-33 of p53 and have demonstrated as well that p53 is phosphorylated at this site in vivo." SIGNOR-53311 ARHGAP23 protein Q9P227 UNIPROT RAC1 protein P63000 UNIPROT "down-regulates activity" "gtpase-activating protein" 9606 BTO:0000007 32203420 t Luana "We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2)." SIGNOR-260480 RNF43 protein Q68DV7 UNIPROT FZD2 protein Q14332 UNIPROT up-regulates relocalization 9606 23151663 t gcesareni "Frizzled receptors are regu__lated by cycles of ubiquitylation and deubiquitylation61 (see above), and znrf3 and rnf43 act as frizzled ubiquitin ligases, removing frizzled and possibly lrp6 from the plasma membrane" SIGNOR-199585 NAMPT protein P43490 UNIPROT CLOCK/BMAL1 complex SIGNOR-C195 SIGNOR down-regulates 19299583 f lperfetto "Using Per2:luciferase transcriptional reporter assays in HEK293 cells (Fig. 2C-E; S2), we show that inhibition of NAMPT by FK866 led to a significant increase in the CLOCK:BMAL1-driven transcription of the Per2:luciferase reporter (Fig. 2C), indicating that reduced NAMPT-mediated NAD+ biosynthesis released CLOCK:BMAL1 from the SIRT1-dependent suppression." SIGNOR-253721 SMO protein Q99835 UNIPROT GNG3 protein P63215 UNIPROT up-regulates binding 9606 23074268 t gcesareni "Consistent with its predicted topology, smo couples to a specific family of inhibitory g protein (gis) to regulate hh signaling." SIGNOR-199186 Telatinib chemical CID:9808844 PUBCHEM KDR protein P35968 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-207224 ADAM17 protein P78536 UNIPROT NOTCH proteinfamily SIGNOR-PF30 SIGNOR up-regulates cleavage 10090 23729744 t apalma "Receptor–ligand engagement triggers a second NECD cleavage (S2 cleavage) by a metalloproteinase ADAM (known as Kuzbanian in Drosophila melanogaster)" SIGNOR-255371 NKRF protein O15226 UNIPROT IFNB1 protein P01574 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 10090 BTO:0005065 10562553 t Luana "Constitutive silencing of IFN-beta promoter is mediated by NRF (NF-kappaB-repressing factor), a nuclear inhibitor of NF-kappaB" SIGNOR-266227 VWF protein P04275 UNIPROT F8 protein P00451 UNIPROT "up-regulates activity" binding 9606 23020315 t miannu "Binding of FVIII to VWF is needed to maintain appropriate plasma levels, as FVIII plasma levels and half-life are remarkably reduced in the absence of VWF" SIGNOR-251967 CDX2 protein Q99626 UNIPROT LCT protein P09848 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9148757 t "By electrophoretic mobility-shift assay it was shown that the factor Cdx-2 (a homoeodomain-protein related to caudal) binds to a TTTAC sequence in the CE-LPH1. Furthermore it was demonstrated that Cdx-2 is able to activate reporter gene transcription by binding to CE-LPH1." SIGNOR-253964 PIM1 protein P11309 UNIPROT MDM2 protein Q00987 UNIPROT up-regulates phosphorylation Ser186 RQRKRHKsDSISLSF 9606 BTO:0000785 18467333 t gcesareni "Additionally, the pim kinases phosphorylate mdm2 in vitro and in cultured cells at ser166 and ser186, two previously identified targets of other signaling pathways, including akt." SIGNOR-178619 ROCK1 protein Q13464 UNIPROT DES protein P17661 UNIPROT unknown phosphorylation Thr17 RVSSYRRtFGGAPGF 9606 BTO:0000971 10574968 t lperfetto "We developed antibodies specifically recognizing the kinase-dependent phosphorylation of desmin at Thr-16, Thr-75, and Thr-76. With these antibodies, phosphorylation of desmin was observed specifically at the cleavage furrow in late mitotic Saos-2 cells. We then found that treatment of the interphase cells with calyculin A revealed phosphorylation at all the three sites of desmin" SIGNOR-249032 PDGFB protein P01127 UNIPROT PDGFRA protein P16234 UNIPROT "up-regulates activity" binding 9606 11331882 t miannu "Pdgf-b activates both pdgfr-alpha and pdgfr-beta" SIGNOR-107397 IKBKB protein O14920 UNIPROT NFKBIA protein P25963 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser32 LLDDRHDsGLDSMKD 11815618 t lperfetto "Nuclear factor-kappaB activation depends on phosphorylation and degradation of its inhibitor protein, IkapapB. The phosphorylation of I_Balpha on Ser32 and Ser36 is initiated by an IkapapB kinase (IKK) complex that includes a catalytic heterodimer composed of I_B kinase 1 (IKK-1) and IkapapB kinase 2 (IKK-2) as well as a regulatory adaptor subunit, NF-kappaB essential modulator." SIGNOR-249365 CDK2 protein P24941 UNIPROT TP63 protein Q9H3D4 UNIPROT down-regulates phosphorylation Ser560 LARLGCSsCLDYFTT 9606 18769144 t lperfetto "Atm kinase is a master switch for the delta np63 alpha phosphorylation/degradation in human head and neck squamous cell carcinoma cells upon dna damage. We previously found that the pro-apoptotic dna damaging agent, cisplatin, mediated the proteasome-dependent degradation of delta np63 alpha associated with its increased phosphorylated status. We found that delta np63 alpha is phosphorylated in the time-dependent fashion at the following positions: s385, t397 and s466, which were surrounded by recognition motifs for atm, cdk2 and p70s6k kinases, respectively" SIGNOR-180763 AURKB protein Q96GD4 UNIPROT MAPRE3 protein Q9UPY8 UNIPROT up-regulates phosphorylation Ser176 MQTSGRLsNVAPPCI 9606 23712260 t lperfetto "Phosphorylation of eb3 at s176 by aurora b ensures successful cytokinesis completion by promoting midbody mt stability and midbody stabilization." SIGNOR-202130 ATM protein Q13315 UNIPROT PRKAA2 protein P54646 UNIPROT "up-regulates activity" phosphorylation Thr172 SDGEFLRtSCGSPNY 23871434 t lperfetto "ATM phosphorylates AMPKalpha2 to induce inhibitory phosphorylation of HIPK2|" SIGNOR-275488 CDK1 protein P06493 UNIPROT PPM1D protein O15297 UNIPROT "down-regulates quantity by destabilization" dephosphorylation Ser40 PTAEEKPsPRRSLSQ 33309518 t lperfetto "Phosphorylation of multiple residues in the catalytic domain of PPM1D during mitosis, including Ser40 by Cyclin-dependent kinase 1 (CDK1), leads to ubiquitination of PPM1D and subsequent proteasomal degradation by Adenomatous polyposis coli (APC) and cell-division cycle protein 20 (CDC20)" SIGNOR-275489 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR PPM1D protein O15297 UNIPROT "down-regulates quantity by destabilization" dephosphorylation Ser40 PTAEEKPsPRRSLSQ 33309518 t lperfetto "Phosphorylation of multiple residues in the catalytic domain of PPM1D during mitosis, including Ser40 by Cyclin-dependent kinase 1 (CDK1), leads to ubiquitination of PPM1D and subsequent proteasomal degradation by Adenomatous polyposis coli (APC) and cell-division cycle protein 20 (CDC20)" SIGNOR-275490 PPM1D protein O15297 UNIPROT MDM4 protein O15151 UNIPROT "up-regulates quantity by stabilization" dephosphorylation Ser403 DLAHSSEsQETISSM 33309518 t lperfetto "PPM1D also inhibits p53 activity by dephosphorylating Ser395 and stabilizing MDM2 and by dephosphorylating Ser403 on MDMX" SIGNOR-275491 PTTG1 protein O95997 UNIPROT ESPL1 protein Q14674 UNIPROT "down-regulates activity" binding 9606 15737063 t lperfetto "Prior to anaphase, separase is kept inactive by its inhibitor securin" SIGNOR-275538 CAMK2A protein Q9UQM7 UNIPROT DAGLA protein Q9Y4D2 UNIPROT "down-regulates activity" phosphorylation Ser782 APLATMEsLSDTESL 23502535 t lperfetto "Activated CaMKII interacted with the C-terminal domain of DGLalpha, phosphorylated two serine residues and inhibited DGLalpha activity. |CaMKIIalpha phosphorylates DGLalpha at Ser808 and Ser782" SIGNOR-275539 RAD21 protein O60216 UNIPROT ERG protein P11308 UNIPROT "down-regulates activity" relocalization 9606 BTO:0001545 26607380 t miannu "Large-scale AML genome re-sequencing efforts have identified novel recurrently mutated genes, including the members of the cohesin complex (RAD21, SMC3, SMC1A, and STAG2), implicated in the pathogenesis of this disease.Using ATAC-seq, we determined that mutant cohesin lead to a state of elevated chromatin accessibility and higher predicted binding at transcription factor binding sites for ERG, GATA2, and RUNX1. Moreover, using ChIP-Seq, we formally demonstrated increased binding of GATA2 and RUNX1 to these sites. Finally, we demonstrated that knockdown of these three TFs in human HSPC can revert the differentiation block induced by mutant cohesin. These results support a model in which mutant cohesin impairs hematopoietic differentiation and enforces stem cell programs through the modulation of ERG, GATA2, and RUNX1 chromatin accessibility, expression, and activity." SIGNOR-261515 "(4S)-2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid O5-[3-(4,4-diphenyl-1-piperidinyl)propyl] ester O3-methyl ester" chemical CHEBI:103931 ChEBI ADRA1A protein P35348 UNIPROT "down-regulates activity" "chemical inhibition" 10029 BTO:0000246 7651358 t miannu "Membrane preparations from CHO cells stably transfected with the cloned human a1-AR genes showed saturable binding of [‘251]HEAT; Bm,,ı values were 1.3 ± 0.2, 5.5 ± 0.1, and 1.1 ± 0.1 pmol/mg of protein, with Kd values of 110 ± 21, 60 ± 1, and 300 ± 26 ıM (three experiments each), for the ala-, alb-, and ald-ARS, respectively. The potencies of a1-AR agonists and antagonists at the cloned human a1-ARs are shown in Table 1." SIGNOR-258463 DLGAP4 protein Q9Y2H0 UNIPROT SHANK3 protein Q9BYB0 UNIPROT "up-regulates activity" relocalization 9606 BTO:0000938 28179641 t miannu "SHANK proteins are ‘master’ scaffolding proteins that tether and organize intermediate scaffolding proteins. They are located at excitatory synapses, where they are crucial for proper synaptic development and function. SAPAP proteins subsequently bind to the PDZ domain of members of the SHANK protein family. SHANK proteins then bind to the actin cytoskeleton and to Homer protein, which in turn interacts with mGluRs. Through these extended links, PSD95, SAPAP, SHANK and Homer proteins form a quaternary complex that brings together mGluR and NMDAR complexes in the PSD (FIG. 3)." SIGNOR-264597 CSNK2A1 protein P68400 UNIPROT MYH9 protein P35579 UNIPROT up-regulates phosphorylation Ser1943 RKGAGDGsDEEVDGK 9606 22123909 t gcesareni "In egf-stimulated cells, the myosin-iia heavy chain is phosphorylated on the casein kinase 2 site (s1943)" SIGNOR-177818 PRKCD protein Q05655 UNIPROT CXCR4 protein P61073 UNIPROT "down-regulates activity" phosphorylation Ser338 KGKRGGHsSVSTESE 9606 10521508 t Manara "Therefore, internalization of CXCR4 in response to PMA appears to be mediated by activation of protein kinase C | However, mutation of the dileucine motif or the serines at positions 324, 325, 338, and 339 profoundly decreased internalization." SIGNOR-260900 NTRK1 protein P04629 UNIPROT PLCG1 protein P19174 UNIPROT up-regulates phosphorylation 9606 8384556 t gcesareni "The nerve growth factor (ngf) receptor/trk associated with and phosphorylated phospholipase c gamma (plc gamma)" SIGNOR-38538 DAB2IP protein Q5VWQ8 UNIPROT PIK3R1 protein P27986 UNIPROT "down-regulates activity" binding 9606 27858941 t miannu "DAB2IP binds the p85 subunit of PI3K through its PR domain and prevents PI3K-p85 relocation from the cytoplasm to the membrane, a necessary step for PI3K activation and signaling to AKT. Notably, DAB2IP reinforces this inhibitory effect by directly binding AKT.2" SIGNOR-254757 Gbeta proteinfamily SIGNOR-PF4 SIGNOR SOS1 protein Q07889 UNIPROT down-regulates phosphorylation 9606 8816480 t "inferred from 70% family members" gcesareni "In this report, we describe the identification of five map kinase sites (s-1137, s-1167, s-1178, s-1193, and s-1197) on hsos1" SIGNOR-270112 "Erythrocytic spectrin" complex SIGNOR-C384 SIGNOR Cell_shape phenotype SIGNOR-PH182 SIGNOR up-regulates 9606 24302288 f lperfetto "Spectrin is multifunctional, and spectrin-based networks are important for maintaining the shape and mechanical properties of erythrocytes." SIGNOR-266032 PRKCA protein P17252 UNIPROT THOC5 protein Q13769 UNIPROT up-regulates phosphorylation Ser5 sSKKRKPK 9606 BTO:0000801;BTO:0000876 15221008 t llicata "We conclude m-csf-mediated activation of pkcalpha can potentiate fmip action to initiate survival/differentiation signaling." SIGNOR-126568 GAB1 protein Q13480 UNIPROT PIK3CA protein P42336 UNIPROT up-regulates binding 9606 11043767 t lperfetto "We have shown that gab1 colocalizes pi3k with sh2 domain-containing inositol phosphatase (ship) and shp2, two enzymes that regulate pi3k-dependent signaling. The src homology 2 (sh2) domain of the phosphatidylinositol 3-kinase (pi3k) regulatory subunit binds gab1 in a phosphorylation-independent manner. Moreover, the regulatory subunit of pi3k can mediate the association of gab1 and receptor protein-tyrosine kinases including the insulin, egf, and ngf receptors, all of which phosphorylate gab1." SIGNOR-83343 "Ub:E1 (UBA1 substrate)" complex SIGNOR-C495 SIGNOR UBE2Z protein Q9H832 UNIPROT "up-regulates activity" ubiquitination 9606 34199813 t miannu "The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t" SIGNOR-271313 Avasimibe chemical CID:166558 PUBCHEM SOAT1 protein P35610 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-190119 BAZ2B protein Q9UIF8 UNIPROT H3-5 protein Q6NXT2 UNIPROT "down-regulates activity" binding 9606 acetylation:Lys15 ARKSTGGkAPRKQLA 31999386 t miannu "The BAZ2B bromodomain has been shown to bind to acetylated H3K14 (H3K14ac), whose presence at promoter regions is generally associated with gene activation. This suggests a potential role for BAZ2B in transcriptional activation." SIGNOR-266621 DDHD2 protein O94830 UNIPROT "1-acyl-sn-glycerol 3-phosphate" smallmolecule CHEBI:16975 ChEBI "up-regulates quantity" "chemical modification" 9606 22922100 t miannu "Members of the intracellular phospholipase A1 family of proteins have been implicated in organelle biogenesis and membrane trafficking. The mammalian family comprises three members: phosphatidic acid-preferring phospholipase A1 (PA-PIA1)/DDHD1, p125/Sec23ip and KIAA0725p/DDHD2, all of which have a DDHD domain." SIGNOR-269655 pralatrexate chemical CHEBI:71223 ChEBI DHFR protein P00374 UNIPROT "down-regulates activity" "chemical inhibition" 9606 23409799 t miannu "Pralatrexate is a small molecule with a chemical formula C23H23N7O5 and a molecular weight of 477.48 g/mol (Box 1). It competitively inhibits dihydrofolate reductase (DHFR) and thymidylate synthase." SIGNOR-259353 CCR3 protein P51677 UNIPROT p38 proteinfamily SIGNOR-PF16 SIGNOR up-regulates 9606 11591790 f "We and others have recently found that eotaxin activates extracellular signal-regulated kinase (ERK)-1/2 and p38 mitogen-activated protein (MAP) kinases in eosinophils, and that these kinases are indispensable for eosinophil chemotaxis and degranulation" SIGNOR-254358 CTNNB1 protein P35222 UNIPROT CCND1 protein P24385 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000782 15735151 f gcesareni "Activated dvl binds and inhibits the phosphorylation of beta catenin by gsk3beta/alfa, blocking beta catenin degradation (fig 2?2),), so that beta catenin accumulates and translocates to the nucleus, where it interacts with the t cell specific factor (tcf)/lymphoid enhancer binding factor 1 (lef-1) transcription factor and induces the transcription of target genes such as c-jun, c-myc, and cyclin d1" SIGNOR-134216 IL7 protein P13232 UNIPROT IL2RG protein P31785 UNIPROT up-regulates binding 9606 11418623 t gcesareni "The common gamma-chain (gamma(c)) is an indispensable subunit of the functional receptor complexes for il-4, il-7, il-9, il-15, il-2, il21" SIGNOR-108864 MAP2K6 protein P52564 UNIPROT HSF4 protein Q9ULV5 UNIPROT "up-regulates activity" phosphorylation Thr471 LGLPGALtIYSTPES 24361130 t lperfetto "Regulation of Hsf4b nuclear translocation and transcription activity by phosphorylation at threonine 472| At the upstream, MEK6 was found to interact with Hsf4b and enhance Hsf4b's nuclear translocation and transcription activity, probably by phosphorylation at sites such as T472. Taken together, our results suggest that phosphotylation of Hsf4b at T472 by protein kinases such as MEI" SIGNOR-275493 MTOR protein P42345 UNIPROT DEPTOR protein Q8TB45 UNIPROT down-regulates phosphorylation Ser293 SSGYFSSsPTLSSSP 9606 22017875 t llicata "Our data reveal critical roles for mtor itself as well as cki in generating a degron in deptor that is recognized by _-trcp, and promotes deptor turnover by the proteasome." SIGNOR-176849 TRIB2 protein Q92519 UNIPROT PKM protein P14618 UNIPROT "up-regulates activity" phosphorylation Ser37 MCRLDIDsPPITARN 9606 BTO:0000018 35790734 t miannu " This study demonstrated that TRIB2, not a ""pseudokinase"", has the kinase activity to directly phosphorylate PKM2 at serine 37 in cancer cells. " SIGNOR-275431 VPS4A protein Q9UN37 UNIPROT CHMP3 protein Q9Y3E7 UNIPROT "up-regulates activity" cleavage -1 30989108 t Giorgia "Here, we show, using high-speed atomic force microscopy and electron microscopy, that the AAA-type adenosine triphosphatase VPS4 constricts and cleaves ESCRT-III CHMP2A-CHMP3 helical filaments in vitro. Our results demonstrate that VPS4 actively constricts ESCRT-III filaments and cleaves them before their complete disassembly. We propose that the formation of ESCRT-III dome-like end caps by VPS4 within a membrane neck structure constricts the membrane to set the stage for membrane fission." SIGNOR-260847 ANK2 protein Q01484 UNIPROT DMD protein P11532 UNIPROT "up-regulates quantity" relocalization 10090 BTO:0001103 19109891 t miannu "We present evidence for an ankyrin-based mechanism for sarcolemmal localization of dystrophin and beta-DG. Ankyrin-B thus is an adaptor required for sarcolemmal localization of dystrophin, as well as dynactin-4." SIGNOR-266712 ROCK1 protein Q13464 UNIPROT FHOD1 protein Q9Y613 UNIPROT up-regulates phosphorylation Ser1137 RSRGNRKsLRRTLKS 9606 18239683 t lperfetto "Rock phosphorylates the c-terminal residues ser1131, ser1137, and thr1141 of formin homology domain protein 1 (fhod1). Phosphorylation of fhod1 at the three residues fully disrupts the autoinhibitory interaction, which culminates in formation of stress fibres." SIGNOR-160548 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR RANGAP1 protein P46060 UNIPROT up-regulates phosphorylation Ser428 EPAPVLSsPPPADVS 9606 15037602 t lperfetto "Here, we show that rangap1 is phosphorylated on residues t409, s428, and s442. Phosphorylation occurs before nuclear envelope breakdown and is maintained throughout mitosis . Alternatively, phosphorylated rangap1 may recruit specific sumo target proteins to ranbp2's catalytic domain." SIGNOR-216781 NME1 protein P15531 UNIPROT NME1 protein P15531 UNIPROT unknown phosphorylation Ser120 GRNIIHGsDSVESAE -1 8810265 t miannu "For autophosphorylated rNm23-H1, phosphorylation was observed at serine 44 and on a fragment containing serines 120, 122, and 125.The biochemical function of Nm23 serine phosphorylation is unknown." SIGNOR-250300 isoleucine smallmolecule CHEBI:24898 ChEBI Ile-tRNA(Ile) smallmolecule CHEBI:29160 ChEBI "up-regulates quantity" "precursor of" 9606 28271488 t miannu "Aminoacyl-tRNA synthetases (AARSs) are essential enzymes that specifically aminoacylate one tRNA molecule by the cognate amino acid. In mammals, nine synthetases, those specific for amino acids Arg, Asp, Gln, Glu, Ile, Leu, Lys, Met and Pro, associate into a multi-aminoacyl-tRNA synthetase complex, an association which is believed to play a key role in the cellular organization of translation, but also in the regulation of the translational and nontranslational functions of these enzymes." SIGNOR-270426 TTK protein P33981 UNIPROT CDCA8 protein Q53HL2 UNIPROT up-regulates phosphorylation 9606 18243099 t amattioni "Direct phosphorylation of the aurora b regulator borealin by mps1 enhances aurora b activity and is essential for chromosome alignment" SIGNOR-160604 CSF2 protein P04141 UNIPROT CSF2RA protein P15509 UNIPROT "up-regulates activity" binding 9606 BTO:0000801 18551128 t lperfetto "The GM-CSF receptor (CSF2R) is a heterodimer composed of a specific ligand-binding subunit (CSF2Ralpha) and a common signal-transduction subunit (CSF2Rbeta)" SIGNOR-249501 STRN4 protein Q9NRL3 UNIPROT PPP2CB protein P62714 UNIPROT "up-regulates activity" binding 10090 BTO:0000938 29802198 t miannu "The striatin family proteins interact with the structural (A) and catalytic (C) subunits of the protein phosphatase, PP2A, and are also termed the B‴ family of PP2A subunits (4). Within heterotrimeric PP2A complexes, striatins function as one of many regulatory B subunits thought to be responsible for substrate selection and localization of PP2A isoforms" SIGNOR-261699 PRKAA1 protein Q13131 UNIPROT RBBP7 protein Q16576 UNIPROT "up-regulates activity" phosphorylation Ser314 LKLHTFEsHKDEIFQ -1 28143904 t lperfetto "AMPK increased HAT1 activity through phosphorylation of HAT1-Ser190 and RBBP7-Ser314| interaction between RBBP7 and HAT1 is required for acetyltransferase activity" SIGNOR-264784 CDK4 protein P11802 UNIPROT KAT2A protein Q92830 UNIPROT "up-regulates activity" phosphorylation Thr272 LNYWKLEtPAQFRQR 24870244 t lperfetto "Activated cyclin D1-Cdk4 kinase phosphorylates and activates GCN5|GCN5 T272A/S372A (AA) phosphorylation by cyclin D1-CDK4 kinase is diminished compared to GCN5 wild-type (WT)" SIGNOR-275495 CyclinD/CDK4 complex SIGNOR-C18 SIGNOR KAT2A protein Q92830 UNIPROT "up-regulates activity" phosphorylation Ser372 EEIYGANsPIWESGF 24870244 t lperfetto "Activated cyclin D1-Cdk4 kinase phosphorylates and activates GCN5|GCN5 T272A/S372A (AA) phosphorylation by cyclin D1-CDK4 kinase is diminished compared to GCN5 wild-type (WT)" SIGNOR-275496 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR WWC1 protein Q8IX03 UNIPROT unknown phosphorylation 9606 BTO:0000149 24269383 t "inferred from 70% family members" llicata "We demonstrated that erk1/2 phosphorylate kibra at ser(548) in cells as well as in vitro." SIGNOR-270208 ELANE protein P08246 UNIPROT F2RL1 protein P55085 UNIPROT "down-regulates activity" cleavage Val53 SHVTGKGvTVETVFS -1 10978167 t lperfetto "PAR1E and PAR2E (10 microM) were incubated in the presence of the different proteases | The enzymes were used at the following concentrations: 0.5 unit/mL thrombin, 2.5 nM trypsin, 20 nM plasmin, 20 nM cathepsin G, 20 nM elastase, 20 nM proteinase 3, and 2 units/mL calpain I and II|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus.|Mass spectrometry studies of PAR2E predicted activation of PAR2 by trypsin through cleavage at the Arg36-Ser37 site, no effect of thrombin, and inactivation of the receptor by plasmin, calpain and leukocyte elastase, cathepsin G, and proteinase 3" SIGNOR-263590 CSNK2B protein P67870 UNIPROT BRCA1 protein P38398 UNIPROT unknown phosphorylation Ser1572 ESGISLFsDDPESDP -1 10403822 t llicata "Subsequent studies showed that BRCA1 was phosphorylated in vitro by CK2. An analysis by site directed mutagenesis of BRCA1 showed that in vitro phosphorylation by CK2 required a serine at aa1572. These data implicate CK2 as a potential mediator of BRCA1 activity." SIGNOR-251055 NMBR protein P28336 UNIPROT GNAL protein P38405 UNIPROT "up-regulates activity" binding 9606 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-256918 CTSG protein P08311 UNIPROT F2R protein P25116 UNIPROT "down-regulates activity" cleavage Phe43 ATLDPRSfLLRNPND -1 10978167 t lperfetto "PAR1E and PAR2E (10 microM) were incubated in the presence of the different proteases | The enzymes were used at the following concentrations: 0.5 unit/mL thrombin, 2.5 nM trypsin, 20 nM plasmin, 20 nM cathepsin G, 20 nM elastase, 20 nM proteinase 3, and 2 units/mL calpain I and II|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus.|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus.|Plasmin, calpain and leukocyte elastase, cathepsin G, and proteinase 3 cleaved at multiple sites and would be expected to disable PAR1 by cleaving COOH-terminal to the activation site." SIGNOR-263562 CDK2 protein P24941 UNIPROT MYBL2 protein P10244 UNIPROT unknown phosphorylation Thr440 LDSCNSLtPKSTPVK BTO:0000007 10095772 t llicata "In summary, our work has identified several phosphorylation sites for cyclin A/Cdk2 in B-Myb and shown that mutation of at least one of these sites has a strong effect on the inducibility of the B-Myb transactivation potential by cyclin A/Cdk2." SIGNOR-250738 tolazoline chemical CHEBI:28502 ChEBI ADRA2A protein P08913 UNIPROT "down-regulates activity" "chemical inhibition" 9606 9605427 t miannu "AR agonists stimulated binding of [35S]GTPgS to HEK 293 cell membranes containing the human a2a, a2b, or a2c ARs (Fig. 6). EPI and NE were full agonists; clonidine and oxymetazoline were partial agonists, while antagonists (e.g. rauwolscine, 5 mM) did not stimulate [35S]GTPgS incorporation (Table 3). Although a few agonists showed a great deal of selectivity for a single receptor subtype, the rank order of agonist potency for selected compounds at the human receptors (Table 3) was: a2a: Dexmedetomidine . guanabenz . UK-14304 .clonidine . ST-91 . NE a2b: Dexmedetomidine . clonidine . guanabenz . NE .ST-91 . UK-14304 a2c: Dexmedetomidine . NE . UK-14304 . ST-91 $ clonidine .. guanabenz" SIGNOR-258912 NKX2-3 protein Q8TAU0 UNIPROT MADCAM1 protein Q13477 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 10790368 t Luana "We provide evidence that NKX2.3 can activate MAdCAM-1 transcription directly" SIGNOR-266219 EED protein O75530 UNIPROT "Polycomb repressive complex 2" complex SIGNOR-C130 SIGNOR "form complex" binding 9606 23110252 t lperfetto "The PRC2 core, conserved from Drosophila to humans, is composed of four proteins that add up to about 230 kDa (Figure 1A) (see Margueron and Reinberg, 2010 for a recent review): EED (present in different isoforms), either one of the two methyltranferases Ezh1 or Ezh2 (Ezh1/2), Suz12, and either RbAp46 or RbAp48 (RbAp46/48)." SIGNOR-241897 Gbeta proteinfamily SIGNOR-PF4 SIGNOR FOS protein P01100 UNIPROT up-regulates phosphorylation 9606 7816602 t "inferred from 70% family members" lperfetto "Phosphorylation of the c-fos and c-jun hob1 motif stimulates its activation capacity here we show that the hob1-containing activation domain of c-fos is stimulated by ha-ras in vivo and phosphorylated by a map kinase family member in vitro and that mutating t232 to ala abolishes both functions." SIGNOR-270105 CENPA protein P49450 UNIPROT "CENP-A nucleosome" complex SIGNOR-C321 SIGNOR "form complex" binding -1 23324462 t miannu "In vitro assembly of both yeast and human CENP-A nucleosomes yields standard octameric structures containing two copies each of CENP-A, H2A, H2B and H4 histones. Human CENP-A also produces rigidified homotypic CENP-A/H4 tetramers in vitro." SIGNOR-263702 MDM2 protein Q00987 UNIPROT MDM4 protein O15151 UNIPROT down-regulates ubiquitination 9606 16511560 t lperfetto "The mdm2 homolog mdmx is an important regulator of p53 during mouse embryonic development. Dna damage promotes mdmx phosphorylation, nuclear translocation, and degradation by mdm2." SIGNOR-144970 CyclinD/CDK4 complex SIGNOR-C18 SIGNOR KAT2A protein Q92830 UNIPROT "up-regulates activity" phosphorylation Thr272 LNYWKLEtPAQFRQR 24870244 t lperfetto "Activated cyclin D1-Cdk4 kinase phosphorylates and activates GCN5|GCN5 T272A/S372A (AA) phosphorylation by cyclin D1-CDK4 kinase is diminished compared to GCN5 wild-type (WT)" SIGNOR-275497 TP53 protein P04637 UNIPROT AIFM1 protein O95831 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 23506862 t miannu "P53 regulates basal expression of AIF and SCO2 and facilitates oxidative phosphorylation. The expression of GLUT1, GLUT4, and HK2 is negatively regulated by p53, whereas TIGAR expression is induced by p53. The net result of p53-mediated regulation of these glycolytic enzymes is the suppression of glycolysis. In addition, p53 directly binds and inhibits G6PD activity and downregulates the pentose phosphate pathway." SIGNOR-267462 FGF2 protein P09038 UNIPROT FGFR3 protein P22607 UNIPROT up-regulates binding 9606 22298955 t gcesareni "Fgf-2 and fgf-9 increased expression of other osteogenic factors bmp-2 and tgf-beta1, and endogenous fgf/fgfr signaling is a positive upstream regulator of the bmp-2 gene in calvarial osteoblasts." SIGNOR-195588 SOCS3 protein O14543 UNIPROT IL6ST protein P40189 UNIPROT "down-regulates activity" binding 9606 BTO:0000887;BTO:0001103 19620279 t miannu "We now show that SOCS1, SOCS3, and PIAS1 promote myogenic differentiation by specifically inhibiting the LIF-induced JAK1/STAT1/STAT3 pathway via distinct targets; whereas SOCS1 and SOCS3 selectively bind and inhibit JAK1 and gp130, respectively, PIAS1 targets mainly the activated STAT1 and prevents its binding to DNA." SIGNOR-202045 HNF1B protein P35680 UNIPROT AKR1C4 protein P17516 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0003846 2044952 f 2 miannu "Hepatocyte nuclear factor (HNF)-4_/_, HNF-1_, and vHNF-1 regulate the cell-specific expression of the human dihydrodiol dehydrogenase (DD)4/AKR1C4 gene.HNF-1_ binds to the target element in the rat DBP gene in the liver, while vHNF-1 recognizes a target element in extrahepatic tissues. The ability of vHNF-1-A to activate the rat DBP gene is much higher than that of vHNF-1-C." SIGNOR-239960 FOXC1 protein Q12948 UNIPROT RBPJ protein Q06330 UNIPROT up-regulates binding 9606 21871448 t gcesareni "We demonstrate that physical interactions occur between wt1, foxc1/2 and rbpj, suggestive of the formation of multimeric transcriptional complexes." SIGNOR-176183 RIPK3 protein Q9Y572 UNIPROT PDH complex SIGNOR-C402 SIGNOR "up-regulates activity" phosphorylation -1 29358703 t miannu "Here, we show that RIP3 activates the pyruvate dehydrogenase complex (PDC, also known as PDH), the rate-limiting enzyme linking glycolysis to aerobic respiration, by directly phosphorylating the PDC E3 subunit (PDC-E3) on T135." SIGNOR-268065 CSNK2A1 protein P68400 UNIPROT CFTR protein P13569 UNIPROT down-regulates phosphorylation Thr1471 IAALKEEtEEEVQDT 9606 21930781 t lperfetto "Cftr possesses two ck2 phosphorylation sites (s422 and t1471) the t1471 residue, previously described as a site for cftr phosphorylation by ck2 (25), seems to be critical for cftr turnover and processing." SIGNOR-176627 FBXO11 protein Q86XK2 UNIPROT DTL protein Q9NZJ0 UNIPROT down-regulates binding 9606 23478441 t miannu "We determined that the f-box protein fbxo11 interacts with cdt2,a dcaf protein that controls cell-cycle progression, and recruits cdt2 to the scf(fbxo11)complex to promote its proteasomal degradation." SIGNOR-192325 CSNK2A2 protein P19784 UNIPROT TCF7L2 protein Q9NQB0 UNIPROT "up-regulates activity" phosphorylation Ser59 SETNQNSsSDSEAER -1 11711551 t llicata "We show here that Tcf-4 can be phosphorylated in vitro by protein kinase CK2 stoichiometrically in amino acids Ser-58-Ser-59-Ser-60. Phosphorylation of these residues does not modify the interaction of Tcf-4 with beta-catenin but reduces its association to plakoglobin. | Experiments performed using a Tcf-4 mutant with decreased interaction to plakoglobin demonstrated that binding to this protein negatively affected the transcriptional activity of Tcf-4." SIGNOR-251045 ECT2 protein Q9H8V3 UNIPROT RHOA protein P61586 UNIPROT "up-regulates activity" "guanine nucleotide exchange factor" 9606 BTO:0000007 32203420 t Luana "We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2)." SIGNOR-260550 FYN protein P06241 UNIPROT FYN protein P06241 UNIPROT up-regulates phosphorylation Tyr420 RLIEDNEyTARQGAK 9606 22080863 t lperfetto "Previously, we reported that sfks can serve as bona fide substrates for tcptp and that tcptp dephosphorylates the y418 activation loop autophosphorylation site (corresponding to y394 in lck and y417 in fyn) to inactivate sfks" SIGNOR-177109 ATOH7 protein Q8N100 UNIPROT POU4F2 protein Q12837 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0002181 11172005 t Luana "Thus, these data suggest that the expression of Brn3b can be activated directly by Math5 and that it is also subject to positive feedback regulation by Brn3 proteins." SIGNOR-261567 EGFR protein P00533 UNIPROT LRRK1 protein Q38SD2 UNIPROT "down-regulates activity" phosphorylation Tyr971 TQQTEEQyFQFLAKF 9534 BTO:0000298 22337768 t miannu "In this study, we demonstrate that EGFR regulates the kinase activity of LRRK1 via tyrosine phosphorylation and that this is required for proper endosomal trafficking of EGFR. Phosphorylation of LRRK1 at Tyr-944 results in reduced LRRK1 kinase activity." SIGNOR-262856 EIF2B3 protein Q9NR50 UNIPROT EIF2S2 protein P20042 UNIPROT "up-regulates activity" "guanine nucleotide exchange factor" 9606 15054402 t lperfetto "EIF2B converts the protein synthesis initiation factor 2 (eIF2) from an inactive GDP-bound form to an active eIF2-GTP complex owing to its guanine nucleotide exchange factor (GEF) activity." SIGNOR-269131 PIM2 protein Q9P1W9 UNIPROT PK proteinfamily SIGNOR-PF80 SIGNOR "down-regulates activity" phosphorylation 9606 BTO:0000007 24142698 t "Here, we identified the protein-serine/threonine kinase PIM2, a known oncogene, as a novel binding partner of PKM2. The interaction between PIM2 and PKM2 was confirmed by multiple biochemical approaches in vitro and in cultured cells. Importantly, we found that PIM2 could directly phosphorylate PKM2 on the Thr-454 residue, resulting in an increase of PKM2 protein levels. Compared with wild type, PKM2 with the phosphorylation-defective mutation displayed a reduced effect on glycolysis" SIGNOR-268148 NFIX protein Q14938 UNIPROT GAS6 protein Q14393 UNIPROT "down-regulates quantity" "transcriptional regulation" 10090 31838646 t Gianni "By integrating transcriptomic profiling (RNA-seq) of Nfia- and Nfix-deficient GNPs with epigenomic profiling (ChIP-seq against NFIA, NFIB and NFIX, and DNase I hypersensitivity assays), we reveal that these transcription factors share a large set of potential transcriptional targets, suggestive of complementary roles for these NFI family members in promoting neural development" SIGNOR-268888 YAP1 protein P46937 UNIPROT Cell_death phenotype SIGNOR-PH109 SIGNOR down-regulates 9606 23075495 f gcesareni "Yap and taz are two main downstream effectors of the hippo pathway, and they function as transcription co-activators to promote cell proliferation and inhibit apoptosis." SIGNOR-256669 GAK protein O14976 UNIPROT CLTC protein Q00610 UNIPROT "up-regulates activity" phosphorylation Thr606 ILGNQMFtHYDRAHI 10090 31272276 t miannu "Clathrin heavy chain (CHC) was phosphorylated at T606 by its association partner cyclin G-associated kinase (GAK). This phosphorylation was required for proper cell proliferation and tumor growth of cells implanted into nude mice. " SIGNOR-275448 KAT2A protein Q92830 UNIPROT PLCG1 protein P19174 UNIPROT "down-regulates activity" acetylation 24870244 t lperfetto "The histone acetyltransferase GCN5 (general control non-repressed protein 5) acetylates PGC-1alpha and suppresses its transcriptional activity, whereas sirtuin 1 deacetylates and activates PGC-1alpha." SIGNOR-275498 SIRT1 protein Q96EB6 UNIPROT PLCG1 protein P19174 UNIPROT "up-regulates activity" deacetylation 24870244 t lperfetto "The histone acetyltransferase GCN5 (general control non-repressed protein 5) acetylates PGC-1alpha and suppresses its transcriptional activity, whereas sirtuin 1 deacetylates and activates PGC-1alpha." SIGNOR-275499 SUN5 protein Q8TC36 UNIPROT "LINC complex" complex SIGNOR-C303 SIGNOR "form complex" binding 24481844 t lperfetto "LINC complex couples the nuclear lamina to the cytoskeleton. SUN domain proteins, SUN1 and SUN2, located at the inner nuclear membrane (INM) interact with the nuclear lamins, Lamin A/C, B1, and B2, that line the nucleoplasmic face of the INM. SUN domain proteins interact with Nesprins in the perinuclear space (PNS). Nesprins protrude from the outer nuclear membrane (ONM) and interact with the cytoskeleton, often through an intermediate binding partner. Nesprin 1 giant (g) and Nesprin 2g potentially link the NE directly to the Z-disc (Z), whereas Nesprin 1alpha and 2alpha may connect via an unknown intermediate protein. In addition, the shorter isoforms of Nesprin 1 and Nesprin 2 may localize to the INM." SIGNOR-263289 AMFR protein Q9UKV5 UNIPROT MFN1 protein Q8IWA4 UNIPROT "down-regulates quantity by destabilization" polyubiquitination 9534 BTO:0000298 23427266 t miannu "Gp78 induces ubiquitylation and proteasomal degradation of Mfn1 and Mfn2." SIGNOR-272886 CSNK1G1 protein Q9HCP0 UNIPROT FOXO1 protein Q12778 UNIPROT "down-regulates activity" phosphorylation Ser325 SSNASTIsGRLSPIM -1 11980723 t llicata "Phosphorylation of Ser319 forms a consensus sequence for phosphorylation by CK1, allowing it to phosphorylate Ser322, which in turn primes the CK1-catalysed phosphorylation of Ser325 | Multisite phosphorylation of the region containing Ser319, Ser322, Ser325 and Ser329 provides a signal for the nuclear exclusion of FKHR" SIGNOR-250821 "PAR-1 (Protease-Activated Receptor) Selective Activating Peptide" smallmolecule CID:71312048 PUBCHEM F2R protein P25116 UNIPROT "up-regulates activity" "chemical activation" 9606 BTO:0002524 31160049 t "Ligand-GPCR dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257484 pipamperone chemical CHEBI:78549 ChEBI HTR1D protein P28221 UNIPROT "down-regulates activity" "chemical inhibition" 10116 BTO:0000529 8935801 t miannu "Risperidone and its active metabolite 9-OH-risperidone were compared to reference antipsychotic drugs (haloperidol, pipamperone, fluspirilene, clozapine, zotepine) and compounds under development (olanzapine, seroquel, sertindole, ORG-5222, ziprasidone) for in vitro binding to neurotransmitter receptors in brain tissue and on membranes of recombinant cells expressing cloned human receptors and for in vivo occupancy of neurotransmitter receptors in rat and guinea-pig brain following acute treatment (2 h., s.c.). The binding affinities of the compounds for various neurotransmitter receptors were measured using membrane preparations of animal brain regions and of recombinant cells expressing cloned, mostly human receptors. Receptors, tissues and cells are indicated in Table I; results are shown in Table 4A-B." SIGNOR-258574 RABGEF1 protein Q9UJ41 UNIPROT RAB5A protein P20339 UNIPROT "up-regulates activity" "guanine nucleotide exchange factor" 10090 27411398 t lperfetto "AP-1/sigma1A-ArfGAP1-Rabex-5 complex formation leads to more endosomal Rabex-5 and enhanced, Rab5GTP-stimulated Vps34 PI3-kinase activity, which is essential for multivesicular body endosome formation." SIGNOR-260707 NFE2L2 protein Q16236 UNIPROT HMOX1 protein P09601 UNIPROT "up-regulates quantity" "transcriptional regulation" 9606 31257023 f "Nrf2 accumulation in lung cancers causes the stabilization of Bach1 by inducing Ho1, the enzyme catabolizing heme." SIGNOR-259334 cinolazepam chemical CHEBI:59514 ChEBI "GABA-A (a1-b1-g2) receptor" complex SIGNOR-C330 SIGNOR "up-regulates activity" "chemical activation" 9606 BTO:0000227 18790874 t brain lperfetto "The BZ-sensitive GABAA-Rs can be further subdivided, in that receptors containing the alpha1 subunit have a higher sensitivity to a subpopulation of BZ site ligands, the benzodiazepines quazepam and cinolazepam (Sieghart, 1989) or nonbenzodiazepines such as zolpidem (an imidazopyridine) and a few others, including CL218-872 (triazolopyridazine), zaleplon, and indiplon, and abecarnil (β-carboline), (Olsen and Gordey, 2000; Korpi et al., 2002; Sieghart and Ernst, 2005)." SIGNOR-263801 PRKD1 protein Q15139 UNIPROT ATP7B protein P35670 UNIPROT "up-regulates activity" phosphorylation Ser1453 DDDGDKWsLLLNGRD 9606 BTO:0000599 21189263 t lperfetto "ATP7B trafficking was markedly reduced by the Ser-478/481/1121/1453 to Ala mutation. We conclude that PKD plays a key role in copper-dependent serine phosphorylation, permitting high levels of ATP7B protein expression and trafficking." SIGNOR-272294 phosphatidylethanolamine chemical CHEBI:16038 ChEBI Outer_mitochondrial_membrane complex SIGNOR-C410 SIGNOR "form complex" binding 9606 25627476 t lperfetto "The OMM is comprised of a phospholipid bilayer that houses vital components such as metabolic enzymes and transport proteins|he OMM contains a variety of lipids. The major components of this bilayer include phosphatidylcholine (PC), phosphatidylethanolamine (PE) and phosphatidylinositol (PI) |It has been reported that in the mammalian OMM, the most prominent of these lipids are PC (~54 % of total), PE (~29 %) and PI (~14 %) (Daum and Vance 1997). The remaining lipids comprise approximately 3 % of the total OMM composition." SIGNOR-266999 CDC26 protein Q8NHZ8 UNIPROT APC-c complex SIGNOR-C150 SIGNOR "form complex" binding 16896351 t lperfetto "The anaphase promoting complex/cyclosome (APC/C) is a ubiquitin ligase that has essential functions in and outside the eukaryotic cell cycle. It is the most complex molecular machine that is known to catalyse ubiquitylation reactions, and it contains more than a dozen subunits that assemble into a large 1.5-MDa complex." SIGNOR-252011 Kindlin proteinfamily SIGNOR-PF48 SIGNOR "Av/b8 integrin" complex SIGNOR-C185 SIGNOR "up-regulates activity" binding 9606 29544897 t miannu "Kindlins bind with β-integrin cytoplasmic tails and execute broad biological functions including directed cell migration, proliferation, differentiation and survival." SIGNOR-259013 GRK2 protein P25098 UNIPROT SLC9A5 protein Q14940 UNIPROT "down-regulates activity" phosphorylation Thr714 EESDSSEtEKEDDEG 21296876 t lperfetto "Simultaneous mutation of five Ser/Thr residues within 702-714 to Ala ((702)ST/AA(714)) abolished phosphorylation and binding of beta-arrestin2. In transfected cells, the CK2 catalytic alpha subunit formed a complex with NHE5 and decreased wild-type but not (702)ST/AA(714) NHE5 activity, further supporting a regulatory role for this kinase. The rate of internalization of (702)ST/AA(714) was also diminished and relatively insensitive to overexpression of beta-arrestin2." SIGNOR-275502 GRK2 protein P25098 UNIPROT SLC9A5 protein Q14940 UNIPROT "down-regulates activity" phosphorylation Ser702 AVILTVEsEEEEEES 21296876 t lperfetto "Simultaneous mutation of five Ser/Thr residues within 702-714 to Ala ((702)ST/AA(714)) abolished phosphorylation and binding of beta-arrestin2. In transfected cells, the CK2 catalytic alpha subunit formed a complex with NHE5 and decreased wild-type but not (702)ST/AA(714) NHE5 activity, further supporting a regulatory role for this kinase. The rate of internalization of (702)ST/AA(714) was also diminished and relatively insensitive to overexpression of beta-arrestin2." SIGNOR-275503 MAPK14 protein Q16539 UNIPROT NFATC4 protein Q14934 UNIPROT "down-regulates activity" phosphorylation Ser168 QGGGAFFsPSPGSSS 10029 BTO:0001131 11997522 t miannu "P38 MAP kinase phosphorylates Ser168 and Ser170 of NFATc4. Mutational replacement of Ser168,170 with Ala promotes NFATc4 nuclear localization and increases NFATc4-mediated transcription activity." SIGNOR-250107 GRK2 protein P25098 UNIPROT SLC9A5 protein Q14940 UNIPROT "down-regulates activity" phosphorylation Ser709 SEEEEEEsDSSETEK 21296876 t lperfetto "Simultaneous mutation of five Ser/Thr residues within 702-714 to Ala ((702)ST/AA(714)) abolished phosphorylation and binding of beta-arrestin2. In transfected cells, the CK2 catalytic alpha subunit formed a complex with NHE5 and decreased wild-type but not (702)ST/AA(714) NHE5 activity, further supporting a regulatory role for this kinase. The rate of internalization of (702)ST/AA(714) was also diminished and relatively insensitive to overexpression of beta-arrestin2." SIGNOR-275504 ARRB2 protein P32121 UNIPROT SLC9A5 protein Q14940 UNIPROT "down-regulates activity" relocalization 21296876 t lperfetto "Internalization of the Na(+)/H(+) exchanger NHE5 into recycling endosomes is enhanced by the endocytic adaptor proteins beta-arrestin1 and -2, best known for their preferential recognition of ligand-activated G protein-coupled receptors (GPCRs)" SIGNOR-275506 CHUK protein O15111 UNIPROT COPS5 protein Q92905 UNIPROT "down-regulates activity" phosphorylation Ser201 KPPDEGPsEYQTIPL -1 31950832 t lperfetto "Overexpression of IKKalpha or IKKbeta leads to enhanced phosphorylation of CSN5, the catalytic subunit for CSN deneddylase activity. Mutational analyses have revealed that phosphorylation at serine 201 and threonine 205 of CSN5 impairs CSN-mediated deneddylation activity in vitro." SIGNOR-275507 SMAD3/SMAD4 complex SIGNOR-C9 SIGNOR Fibrosis phenotype SIGNOR-PH90 SIGNOR up-regulates 9606 30017632 f miannu "Smad4 interacted withSmad2/3 and participated in the transcription of downstream pro-fi-brotic target genes" SIGNOR-260441 CDK7 protein P50613 UNIPROT CDK12 protein Q9NYV4 UNIPROT "up-regulates activity" phosphorylation Thr893 SEESRPYtNKVITLW 24662513 t lperfetto "Although Cdk12/CycK kinase complex lacking T-loop phosphorylation showed some basal activity towards a CTD substrate prephosphorylated at position Ser7, its activity was significantly increased upon coexpression with the CAK from S. cerevisiae (Supplementary Fig. 9a). Mutation of T893 to E to mimic phosphorylation showed no effect on basal kinase activity. Quantitative phosphorylation of a single residue occurred upon coexpression with Cak1, as determined by ESI mass spectrometry (Supplementary Fig. 9b)." SIGNOR-275509 "CAK complex" complex SIGNOR-C456 SIGNOR CDK12 protein Q9NYV4 UNIPROT "up-regulates activity" phosphorylation Thr893 SEESRPYtNKVITLW 24662513 t lperfetto "Although Cdk12/CycK kinase complex lacking T-loop phosphorylation showed some basal activity towards a CTD substrate prephosphorylated at position Ser7, its activity was significantly increased upon coexpression with the CAK from S. cerevisiae (Supplementary Fig. 9a). Mutation of T893 to E to mimic phosphorylation showed no effect on basal kinase activity. Quantitative phosphorylation of a single residue occurred upon coexpression with Cak1, as determined by ESI mass spectrometry (Supplementary Fig. 9b)." SIGNOR-275510 AURKA protein O14965 UNIPROT NSD2 protein O96028 UNIPROT "up-regulates quantity by stabilization" phosphorylation Ser56 SKAQLSSsLQEGVMQ 35389552 t lperfetto "Mechanistically, Aurora A phosphorylated NSD2 at S56 residue to protect the protein from cleavage and degradation, thus methylation of Aurora A and phosphorylation of NSD2 bilaterally formed a positive regulating loop." SIGNOR-275512 PRKCZ protein Q05513 UNIPROT PIAS4 protein Q8N2W9 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser18 MVMSFRVsDLQMLLG 27162139 t lperfetto "In this study, we discovered a new protein isoform encoded by KIAA0317, termed fibrosis-inducing E3 ligase 1 (FIEL1), which potently stimulates the TGFbeta signaling pathway through the site-specific ubiquitination of PIAS4.FIEL1 targets PIAS4 using a double locking mechanism that is facilitated by the kinases PKCzeta and GSK3beta. Specifically, PKCzeta phosphorylation of PIAS4 and GSK3beta phosphorylation of FIEL1 are both essential for the degradation of PIAS4.|These experiments suggested that PKCzeta is an authentic regulator of PIAS4 protein stability; Q21 and phosphorylated S18 of PIAS4 are both required for FIEL1 interaction." SIGNOR-275513 INSR protein P06213 UNIPROT BLVRA protein P53004 UNIPROT "up-regulates activity" phosphorylation Tyr198 EERKEDQyMKMTVCL 15870194 t lperfetto "Human BVR (hBVR) also reduces the hemeoxygenase activity product biliverdin to bilirubin and is directly activated by insulin receptor kinase (IRK).|in addition to Y198 in the YMKM motif, 2 other tyrosines, Y228 in the YLSF motif and Y291 in the C-terminus of the protein, are directly phosphorylated by IRK" SIGNOR-275514 PRKACA protein P17612 UNIPROT TAL1 protein P17542 UNIPROT down-regulates phosphorylation Ser122 DGRMVQLsPPALAAP 9606 22310283 t gcesareni "Thus, our data revealed a novel interplay between pka phosphorylation and tal1-mediated epigenetic regulation that regulates hematopoietic transcription and differentiation programs during hematopoiesis and leukemogenesis." SIGNOR-195987 INSR protein P06213 UNIPROT BLVRA protein P53004 UNIPROT "up-regulates activity" phosphorylation Tyr228 PGLKRNRyLSFHFKS 15870194 t lperfetto "Human BVR (hBVR) also reduces the hemeoxygenase activity product biliverdin to bilirubin and is directly activated by insulin receptor kinase (IRK).|in addition to Y198 in the YMKM motif, 2 other tyrosines, Y228 in the YLSF motif and Y291 in the C-terminus of the protein, are directly phosphorylated by IRK" SIGNOR-275515 INSR protein P06213 UNIPROT BLVRA protein P53004 UNIPROT "up-regulates activity" phosphorylation Tyr291 LAEEIQKyCCSRK 15870194 t lperfetto "Human BVR (hBVR) also reduces the hemeoxygenase activity product biliverdin to bilirubin and is directly activated by insulin receptor kinase (IRK).|in addition to Y198 in the YMKM motif, 2 other tyrosines, Y228 in the YLSF motif and Y291 in the C-terminus of the protein, are directly phosphorylated by IRK" SIGNOR-275516 IKBKB protein O14920 UNIPROT COPS5 protein Q92905 UNIPROT "down-regulates activity" phosphorylation Ser201 KPPDEGPsEYQTIPL -1 31950832 t lperfetto "Overexpression of IKKalpha or IKKbeta leads to enhanced phosphorylation of CSN5, the catalytic subunit for CSN deneddylase activity. Mutational analyses have revealed that phosphorylation at serine 201 and threonine 205 of CSN5 impairs CSN-mediated deneddylation activity in vitro." SIGNOR-275518 IKBKB protein O14920 UNIPROT COPS5 protein Q92905 UNIPROT "down-regulates activity" phosphorylation Thr205 EGPSEYQtIPLNKIE -1 31950832 t lperfetto "Overexpression of IKKalpha or IKKbeta leads to enhanced phosphorylation of CSN5, the catalytic subunit for CSN deneddylase activity. Mutational analyses have revealed that phosphorylation at serine 201 and threonine 205 of CSN5 impairs CSN-mediated deneddylation activity in vitro." SIGNOR-275519 CDK5 protein Q00535 UNIPROT CAMKK2 protein Q96RR4 UNIPROT down-regulates phosphorylation Ser133 LPYSPVSsPQSSPRL 9606 22778263 t lperfetto "Cdk5 and gsk3 phosphorylate ser-129, ser-133, and ser-137. Mutation of ser-129, ser-133, and ser-137 increases autonomous activity with little change in ca2 /cam-dependent activity." SIGNOR-198115 BLVRA protein P53004 UNIPROT bilirubin(2-) smallmolecule CHEBI:57977 ChEBI "down-regulates quantity" "chemical modification" 9606 BTO:0000759 7929092 t lperfetto "This report describes for the first time the identification of four forms of biliverdin reductase including two biliverdin-IX beta reductases and two biliverdin-IX alpha reductases, designated isozymes I and II and isozymes III and IV, respectively, in human liver cytosolic fractions." SIGNOR-275520 BLVRA protein P53004 UNIPROT biliverdin(2-) smallmolecule CHEBI:57991 ChEBI "up-regulates quantity" "chemical modification" 9606 BTO:0000759 7929092 t lperfetto "This report describes for the first time the identification of four forms of biliverdin reductase including two biliverdin-IX beta reductases and two biliverdin-IX alpha reductases, designated isozymes I and II and isozymes III and IV, respectively, in human liver cytosolic fractions." SIGNOR-275521 RNF10 protein Q8N5U6 UNIPROT MEOX2 protein P50222 UNIPROT "up-regulates activity" binding 10090 BTO:0000944 16335786 t miannu "RFN10 co-immunoprecipitates with MEOX2. RNF10 potentiates MEOX2 transcriptional activation" SIGNOR-236968 bilirubin(2-) smallmolecule CHEBI:57977 ChEBI biliverdin(2-) smallmolecule CHEBI:57991 ChEBI "up-regulates quantity" "precursor of" 9606 BTO:0000759 7929092 t lperfetto "This report describes for the first time the identification of four forms of biliverdin reductase including two biliverdin-IX beta reductases and two biliverdin-IX alpha reductases, designated isozymes I and II and isozymes III and IV, respectively, in human liver cytosolic fractions." SIGNOR-275522 BLVRB protein P30043 UNIPROT bilirubin(2-) smallmolecule CHEBI:57977 ChEBI "down-regulates quantity" "chemical modification" 9606 BTO:0000759 7929092 t lperfetto "This report describes for the first time the identification of four forms of biliverdin reductase including two biliverdin-IX beta reductases and two biliverdin-IX alpha reductases, designated isozymes I and II and isozymes III and IV, respectively, in human liver cytosolic fractions." SIGNOR-275523 BLVRB protein P30043 UNIPROT biliverdin(2-) smallmolecule CHEBI:57991 ChEBI "up-regulates quantity" "chemical modification" 9606 BTO:0000759 7929092 t lperfetto "This report describes for the first time the identification of four forms of biliverdin reductase including two biliverdin-IX beta reductases and two biliverdin-IX alpha reductases, designated isozymes I and II and isozymes III and IV, respectively, in human liver cytosolic fractions." SIGNOR-275524 PRKCD protein Q05655 UNIPROT BLVRA protein P53004 UNIPROT "up-regulates activity" phosphorylation Ser21 VGVGRAGsVRMRDLR 22584576 t lperfetto "LC-MS/MS analysis of PKCdelta-activated intact hBVR identified phosphorylated serine positions 21, 33, 230, and 237, corresponding to the hBVR Src homology-2 domain motif (Ser(230) and Ser(237)), flanking the ATP-binding motif (Ser(21)) and in PHPS sequence (Ser(33)) as targets of PKCdelta. |PKCdelta potentiated hBVR reductase activity and accelerated the rate of bilirubin formation." SIGNOR-275525 PRKCD protein Q05655 UNIPROT BLVRA protein P53004 UNIPROT "up-regulates activity" phosphorylation Ser237 SFHFKSGsLENVPNV 22584576 t lperfetto "LC-MS/MS analysis of PKCdelta-activated intact hBVR identified phosphorylated serine positions 21, 33, 230, and 237, corresponding to the hBVR Src homology-2 domain motif (Ser(230) and Ser(237)), flanking the ATP-binding motif (Ser(21)) and in PHPS sequence (Ser(33)) as targets of PKCdelta. |PKCdelta potentiated hBVR reductase activity and accelerated the rate of bilirubin formation." SIGNOR-275526 TAF1A protein Q15573 UNIPROT "SL1 complex" complex SIGNOR-C464 SIGNOR "form complex" binding 9606 30693017 t lperfetto "SL1 comprises TBP, TAF1A (also known as TAFI48), TAF1B (also known as TAFI63), TAF1C (also known as TAFI110), and TAF1D (also known as TAFI41) and recruits the RNAP1 complex to induce PIC formation." SIGNOR-269566 PRKCD protein Q05655 UNIPROT BLVRA protein P53004 UNIPROT "up-regulates activity" phosphorylation Ser33 DLRNPHPsSAFLNLI 22584576 t lperfetto "LC-MS/MS analysis of PKCdelta-activated intact hBVR identified phosphorylated serine positions 21, 33, 230, and 237, corresponding to the hBVR Src homology-2 domain motif (Ser(230) and Ser(237)), flanking the ATP-binding motif (Ser(21)) and in PHPS sequence (Ser(33)) as targets of PKCdelta. |PKCdelta potentiated hBVR reductase activity and accelerated the rate of bilirubin formation." SIGNOR-275527 GSK3B protein P49841 UNIPROT AREL1 protein O15033 UNIPROT "down-regulates quantity by destabilization" phosphorylation Thr783 IAAPTHStLPTAHTC 27162139 t lperfetto "These experiments suggested that GSK3beta phosphorylation of FIEL1 is required for PIAS4 targeting, and FIEL1 residues P779 and phosphorylated T783 are both required for PIAS4 interaction |FIEL1 T783A mutant overexpression completely failed to decrease PIAS4 protein level." SIGNOR-275528 AURKB protein Q96GD4 UNIPROT SSU72 protein Q9NP77 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser19 CSSNQNRsMEAHNIL 24149858 t lperfetto "Here we report that Aurora B kinase directly interacts with and phosphorylates Ssu72, a new cohesin-binding phosphatase, at Ser 19 in vitro and in vivo. The Aurora B-mediated phosphorylation of Ssu72 causes the structural modification of Ssu72 protein, downregulates phosphatase activity and triggers the ubiquitin-dependent degradation of Ssu72." SIGNOR-275529 AURKB protein Q96GD4 UNIPROT SSU72 protein Q9NP77 UNIPROT "down-regulates activity" phosphorylation Ser19 CSSNQNRsMEAHNIL 24149858 t lperfetto "Here we report that Aurora B kinase directly interacts with and phosphorylates Ssu72, a new cohesin-binding phosphatase, at Ser 19 in vitro and in vivo. The Aurora B-mediated phosphorylation of Ssu72 causes the structural modification of Ssu72 protein, downregulates phosphatase activity and triggers the ubiquitin-dependent degradation of Ssu72." SIGNOR-275530 SSU72 protein Q9NP77 UNIPROT STAG2 protein Q8N3U4 UNIPROT "up-regulates activity" dephosphorylation Ser1224 PASIMDEsVLGVSMF 20818333 t lperfetto "Additional experiments revealed that Ssu72 directly interacts with Rad21 and SA2 in vitro and in vivo, and associates with sister chromatids in human cells. Interestingly, depletion or mutational inactivation of Ssu72 phosphatase activity caused the premature resolution of sister chromatid arm cohesion, whereas the overexpression of Ssu72 yielded high resistance to this resolution.|anti‐phospho SA2 serine 1224" SIGNOR-275531 PLK1 protein P53350 UNIPROT STAG2 protein Q8N3U4 UNIPROT "down-regulates activity" dephosphorylation Ser1224 PASIMDEsVLGVSMF 9606 BTO:0000567 15737063 t lperfetto "Two phosphorylation sites in Scc1 (Thr144 and Thr312) match the consensus proposed by Nakajima et al. [24]. These two sites, in addition to one in Scc1 (Ser454) and three in SA2 (Thr1109, Ser1137, and Ser1224) conform with the consensus proposed by Barr et al. [25]. These findings are consistent with the possibility that at least some of the sites in Scc1 and SA2 are directly phosphorylated by Plk1.|Phosphorylation of SA2 Is Essential for the Dissociation of Cohesin from Chromosomes during Prophase and Prometaphase" SIGNOR-275532 PLK1 protein P53350 UNIPROT STAG2 protein Q8N3U4 UNIPROT "down-regulates activity" dephosphorylation Thr1109 MWLSREQtLHTPVMM 9606 BTO:0000567 15737063 t lperfetto "Two phosphorylation sites in Scc1 (Thr144 and Thr312) match the consensus proposed by Nakajima et al. [24]. These two sites, in addition to one in Scc1 (Ser454) and three in SA2 (Thr1109, Ser1137, and Ser1224) conform with the consensus proposed by Barr et al. [25]. These findings are consistent with the possibility that at least some of the sites in Scc1 and SA2 are directly phosphorylated by Plk1.|Phosphorylation of SA2 Is Essential for the Dissociation of Cohesin from Chromosomes during Prophase and Prometaphase" SIGNOR-275533 BBC3 protein Q9BXH1 UNIPROT BAX protein Q07812 UNIPROT up-regulates relocalization 9606 BTO:0000551 19439449 t gcesareni "Puma promotes bax translocation by both by directly interacting with bax and by competitive binding to bcl-x(l) in uv-induced apoptosis." SIGNOR-185671 PLK1 protein P53350 UNIPROT STAG2 protein Q8N3U4 UNIPROT "down-regulates activity" dephosphorylation Ser1137 KRLRPEDsFMSVYPM 9606 BTO:0000567 15737063 t lperfetto "Two phosphorylation sites in Scc1 (Thr144 and Thr312) match the consensus proposed by Nakajima et al. [24]. These two sites, in addition to one in Scc1 (Ser454) and three in SA2 (Thr1109, Ser1137, and Ser1224) conform with the consensus proposed by Barr et al. [25]. These findings are consistent with the possibility that at least some of the sites in Scc1 and SA2 are directly phosphorylated by Plk1.|Phosphorylation of SA2 Is Essential for the Dissociation of Cohesin from Chromosomes during Prophase and Prometaphase" SIGNOR-275534 PLK1 protein P53350 UNIPROT RAD21 protein O60216 UNIPROT "down-regulates quantity by destabilization" dephosphorylation Ser175 REIMREGsAFEDDDM 9606 BTO:0000567 15737063 t lperfetto "We suspected that the observed enhancement of Scc1's cleavability in the presence of Plk1 might be due to phosphorylation at two sites that are directly adjacent to the cleavage sites, Ser175 and Ser454, which we had found to be phosphorylated in mitosis in vivo (Table 1). We therefore mutated these two residues to alanine, thereby creating mutant Scc1-S175A/S454A (see Figure 1C), and tested the cleavability of this mutant in the absence or presence of Plk1 in vitro. |Scc1 phosphorylation is dispensable for cohesin dissociation from chromosomes in early mitosis but enhances the cleavability of Scc1 by separase." SIGNOR-275535 PLK1 protein P53350 UNIPROT RAD21 protein O60216 UNIPROT "down-regulates quantity by destabilization" dephosphorylation Ser454 EPSRLQEsVMEASRT 9606 BTO:0000567 15737063 t lperfetto "We suspected that the observed enhancement of Scc1's cleavability in the presence of Plk1 might be due to phosphorylation at two sites that are directly adjacent to the cleavage sites, Ser175 and Ser454, which we had found to be phosphorylated in mitosis in vivo (Table 1). We therefore mutated these two residues to alanine, thereby creating mutant Scc1-S175A/S454A (see Figure 1C), and tested the cleavability of this mutant in the absence or presence of Plk1 in vitro. |Scc1 phosphorylation is dispensable for cohesin dissociation from chromosomes in early mitosis but enhances the cleavability of Scc1 by separase." SIGNOR-275536 ESPL1 protein Q14674 UNIPROT RAD21 protein O60216 UNIPROT "down-regulates quantity by destabilization" cleavage 9606 15737063 t lperfetto "In order to segregate sister chromatids to opposite poles in anaphase, cohesin has to be removed from chromosomes. In budding yeast, the prevalent mode of cohesin removal is by proteolytic cleavage of the Scc1 subunit at the onset of anaphase by the endopeptidase separase" SIGNOR-275537 CAMK2A protein Q9UQM7 UNIPROT DAGLA protein Q9Y4D2 UNIPROT "down-regulates activity" phosphorylation Ser808 RSIRGSPsLHAVLER 23502535 t lperfetto "Activated CaMKII interacted with the C-terminal domain of DGLalpha, phosphorylated two serine residues and inhibited DGLalpha activity. |CaMKIIalpha phosphorylates DGLalpha at Ser808 and Ser782" SIGNOR-275540 MTOR protein P42345 UNIPROT ELP1 protein O95163 UNIPROT "up-regulates activity" phosphorylation Ser1174 SETSSVVsGSEMSGK 29925953 t lperfetto "Human ELP1 S1174 phosphorylation was triggered by insulin treatment, as shown by the specific phosphorylated (p)ELP1 (S1174) antibody, and addition of a phosphorylation-mutant variant of the ELP1 protein (ELP1(S1174A)) to ELP1-depleted BRAFV600E melanoma cells failed to rescue cell survival |In line with these findings, mTORC2 activity, but not mTORC1, was required for the insulin-induced phosphorylation of Elp1 S1174" SIGNOR-275541 CHUK protein O15111 UNIPROT NFKBIA protein P25963 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser36 RHDSGLDsMKDEEYE 9606 BTO:0000567 SIGNOR-C14 9346241 t lperfetto "We described the purification of a 900 kda protein kinase complex, the ikb kinase (ikk), that phosphorylates ikbalfa and ikbbeta at the sites that mediate their ubiquitination and degradation" SIGNOR-52879 mTORC2 complex SIGNOR-C2 SIGNOR ELP1 protein O95163 UNIPROT "up-regulates activity" phosphorylation Ser1174 SETSSVVsGSEMSGK 29925953 t lperfetto "Human ELP1 S1174 phosphorylation was triggered by insulin treatment, as shown by the specific phosphorylated (p)ELP1 (S1174) antibody, and addition of a phosphorylation-mutant variant of the ELP1 protein (ELP1(S1174A)) to ELP1-depleted BRAFV600E melanoma cells failed to rescue cell survival |In line with these findings, mTORC2 activity, but not mTORC1, was required for the insulin-induced phosphorylation of Elp1 S1174" SIGNOR-275542 Ub:E2 complex SIGNOR-C497 SIGNOR NEDD4 protein P46934 UNIPROT "up-regulates activity" ubiquitination 9606 34199813 t miannu "The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t" SIGNOR-271300 FYN protein P06241 UNIPROT PTPRT protein O14522 UNIPROT "down-regulates activity" phosphorylation Tyr915 Y-->K 19816407 t lperfetto "Synapse formation by PTPRT was inhibited by phosphorylation of tyrosine 912 within the membrane-proximal catalytic domain of PTPRT by Fyn. This tyrosine phosphorylation reduced phosphatase activity of PTPRT" SIGNOR-275543 CDK5 protein Q00535 UNIPROT VRK3 protein Q8IV63 UNIPROT "up-regulates activity" phosphorylation Ser108 RPPTPKSsPQKTRKS 27346674 t lperfetto "Vaccinia-related kinase 3 (VRK3), a member of the VRK family, is widely expressed in human tissues and increases VHR phosphatase activity through a direct binding|Here we report that oxidative stress-induced cyclin-dependent kinase 5 (CDK5) activation stimulates neuroprotective signaling via phosphorylation of vaccinia-related kinase 3 (VRK3) at Ser 108. The binding of vaccinia H1-related (VHR) phosphatase to phosphorylated VRK3 increased its affinity for phospho-ERK and subsequently downregulated ERK activation|" SIGNOR-275544 CDK5/CDK5R1 complex SIGNOR-C144 SIGNOR VRK3 protein Q8IV63 UNIPROT "up-regulates activity" phosphorylation Ser108 RPPTPKSsPQKTRKS 27346674 t lperfetto "Vaccinia-related kinase 3 (VRK3), a member of the VRK family, is widely expressed in human tissues and increases VHR phosphatase activity through a direct binding|Here we report that oxidative stress-induced cyclin-dependent kinase 5 (CDK5) activation stimulates neuroprotective signaling via phosphorylation of vaccinia-related kinase 3 (VRK3) at Ser 108. The binding of vaccinia H1-related (VHR) phosphatase to phosphorylated VRK3 increased its affinity for phospho-ERK and subsequently downregulated ERK activation|" SIGNOR-275545 VRK3 protein Q8IV63 UNIPROT DUSP3 protein P51452 UNIPROT "up-regulates activity" binding 27346674 t lperfetto "Vaccinia-related kinase 3 (VRK3), a member of the VRK family, is widely expressed in human tissues and increases VHR phosphatase activity through a direct binding" SIGNOR-275546 PRKAA1 protein Q13131 UNIPROT MCU protein Q8NE86 UNIPROT "up-regulates activity" phosphorylation Ser57 TVHQRIAsWQNLGAV -1 30858581 t lperfetto "Cellular ATP levels drop during early mitosis, and the mitochondrial Ca2+ transients boost mitochondrial respiration to restore energy homeostasis. This is achieved through mitosis-specific MCU phosphorylation and activation by the mitochondrial translocation of energy sensor AMP-activated protein kinase (AMPK). |In vitro kinase assays showed that AMPK immunoprecipitated from cells as well as recombinant AMPK phosphorylated MCU at Ser57" SIGNOR-275547 AMPK complex SIGNOR-C15 SIGNOR MCU protein Q8NE86 UNIPROT "up-regulates activity" phosphorylation Ser57 TVHQRIAsWQNLGAV -1 30858581 t lperfetto "Cellular ATP levels drop during early mitosis, and the mitochondrial Ca2+ transients boost mitochondrial respiration to restore energy homeostasis. This is achieved through mitosis-specific MCU phosphorylation and activation by the mitochondrial translocation of energy sensor AMP-activated protein kinase (AMPK). |In vitro kinase assays showed that AMPK immunoprecipitated from cells as well as recombinant AMPK phosphorylated MCU at Ser57" SIGNOR-275548 EGFR protein P00533 UNIPROT KCND3 protein Q9UK17 UNIPROT "up-regulates activity" phosphorylation Tyr136 GDCCYEEyKDRKREN 22198508 t lperfetto "Our results demonstrate that human atrial I(to) and cloned hKv4.3 channels are modulated by EGFR kinase via phosphorylation of the Y136 residue and by Src-family kinases via phosphorylation of the Y108 residue|We found that human atrial I(to) was inhibited by the broad-spectrum PTK inhibitor genistein, the selective epidermal growth factor receptor (EGFR) kinase inhibitor AG556, and the Src-family kinases inhibitor PP2." SIGNOR-275549 MAPK8 protein P45983 UNIPROT ARHGAP8 protein P85298 UNIPROT "up-regulates activity" phosphorylation Ser455 TKPTLPPsPLMAARR 28092672 t lperfetto "Furthermore, we identify that BPGAP1 (a BCH domain-containing, Cdc42GAP-like Rho GTPase-activating protein) promotes MEK partner 1 (MP1)-induced ERK activation on late endosome through scaffolding MP1/MEK1 complex. This regulatory function requires phosphorylation of BPGAP1 by JNK at its C terminal tail (Ser424) to unlock its autoinhibitory conformation." SIGNOR-275550 ARHGAP8 protein P85298 UNIPROT LAMTOR3 protein Q9UHA4 UNIPROT "up-regulates activity" binding 28092672 t lperfetto "Furthermore, we identify that BPGAP1 (a BCH domain-containing, Cdc42GAP-like Rho GTPase-activating protein) promotes MEK partner 1 (MP1)-induced ERK activation on late endosome through scaffolding MP1/MEK1 complex. This regulatory function requires phosphorylation of BPGAP1 by JNK at its C terminal tail (Ser424) to unlock its autoinhibitory conformation." SIGNOR-275551 MAPK8 protein P45983 UNIPROT NFE2 protein Q16621 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser157 LNYSDAEsLELEGTE 19966288 t lperfetto "Through use of different approaches including nano-scale proteomics, we show that activated-JNK, or Phospho-JNK (P-JNK), physically interacts with p45/NF-E2 and phosphorylates its Ser157 residue. This reaction leads to the poly-ubiquitination of p45/NF-E2 at one or more of six Lys residues, one of which being also a sumoylation site, and its degradation through the proteasome pathway." SIGNOR-275552 ITCH protein Q96J02 UNIPROT NFE2 protein Q16621 UNIPROT "down-regulates activity" ubiquitination 9606 BTO:0000007 18718448 t lperfetto "Itch regulates p45/NF-E2 in vivo by Lys63-linked ubiquitination| Interestingly, Itch suppressed the transactivation activity of p45/NF-E2 by adding a Lys63-linked polyubiquitin chain. Confocal microscopy revealed that ubiquitinated p45/NF-E2 became localized in the cytoplasm when Itch was over-expressed. Thus, Itch-mediated ubiquitination of p45/NF-E2 does not target the protein for proteasomal degradation, but instead retains p45/NF-E2 in the cytoplasm, where it cannot function as a transactivator." SIGNOR-275553 MAPK8 protein P45983 UNIPROT SARM1 protein Q6SZW1 UNIPROT "down-regulates activity" phosphorylation Ser548 AAREMLHsPLPCTGG 30333228 t lperfetto "C-Jun N-terminal kinase (JNK)-mediated phosphorylation of SARM1 regulates NAD+ cleavage activity to inhibit mitochondrial respiration|Here, we report that NAD+ cleavage activity of SARM1 is regulated by its own phosphorylation at serine 548. The phosphorylation of SARM1 was mediated by c-jun N-terminal kinase (JNK) under oxidative stress conditions, resulting in inhibition of mitochondrial respiration concomitant with enhanced activity of NAD+ cleavage. Nonphosphorylatable mutation of Ser-548 or treatment with a JNK inhibitor decreased SARM1 activity." SIGNOR-275554 PLK1 protein P53350 UNIPROT SUZ12 protein Q15022 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser539 RPKRTKAsMSEFLES 25855382 t lperfetto "PLK1 and HOTAIR Accelerate Proteasomal Degradation of SUZ12 and ZNF198 during Hepatitis B Virus-Induced Liver Carcinogenesis|In SUZ12, residues 539, 541 and 546 phosphorylated by Plk1 in vitro" SIGNOR-275557 PLK1 protein P53350 UNIPROT ZMYM2 protein Q9UBW7 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser305 QPGVDSLsPVASLPK 25855382 t lperfetto "PLK1 and HOTAIR Accelerate Proteasomal Degradation of SUZ12 and ZNF198 during Hepatitis B Virus-Induced Liver Carcinogenesis|Similar analyses with ZNF198 identified two clusters of putative Plk1 phosphorylation sites in vitro. A cluster of serine residues at the N-terminus of ZNF198, S303, S305, and S309, and a cluster at the C-terminus, S1056 and S1064. The triple Ser to Ala mutant, S303A/S305A/S309A, consistently exhibited the lowest level of phosphorylation in vitro, in comparison to the double S1056A/S1064A mutant" SIGNOR-275558 PLK1 protein P53350 UNIPROT ZMYM2 protein Q9UBW7 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser303 QKQPGVDsLSPVASL 25855382 t lperfetto "PLK1 and HOTAIR Accelerate Proteasomal Degradation of SUZ12 and ZNF198 during Hepatitis B Virus-Induced Liver Carcinogenesis|Similar analyses with ZNF198 identified two clusters of putative Plk1 phosphorylation sites in vitro. A cluster of serine residues at the N-terminus of ZNF198, S303, S305, and S309, and a cluster at the C-terminus, S1056 and S1064. The triple Ser to Ala mutant, S303A/S305A/S309A, consistently exhibited the lowest level of phosphorylation in vitro, in comparison to the double S1056A/S1064A mutant" SIGNOR-275559 ixabepilone chemical CHEBI:63605 ChEBI TUBB3 protein Q13509 UNIPROT "down-regulates activity" "chemical inhibition" 9606 18945860 t miannu "Ixabepilone, the first drug in a new class of microtubule-stabilizing agents called epothilones, offers a new treatment option for patients with metastatic or locally advanced breast cancer who are refractory to standard chemotherapy." SIGNOR-259349 PLK1 protein P53350 UNIPROT ZMYM2 protein Q9UBW7 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser309 DSLSPVAsLPKQIFQ 25855382 t lperfetto "PLK1 and HOTAIR Accelerate Proteasomal Degradation of SUZ12 and ZNF198 during Hepatitis B Virus-Induced Liver Carcinogenesis|Similar analyses with ZNF198 identified two clusters of putative Plk1 phosphorylation sites in vitro. A cluster of serine residues at the N-terminus of ZNF198, S303, S305, and S309, and a cluster at the C-terminus, S1056 and S1064. The triple Ser to Ala mutant, S303A/S305A/S309A, consistently exhibited the lowest level of phosphorylation in vitro, in comparison to the double S1056A/S1064A mutant" SIGNOR-275560 FOXO3 protein O43524 UNIPROT CITED2 protein Q99967 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000150 18158893 f gcesareni "Foxo3a induces expression of cited2" SIGNOR-160127 DLX5 protein P56178 UNIPROT RUNX2 protein Q13950 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 22298955 f gcesareni "Dlx5 can drive runx2 expression and osteogenic differentiation in developing cranial suture mesenchyme , indicat-ing that dlx5 can work as an upstream gene of runx2." SIGNOR-195576 PRKCD protein Q05655 UNIPROT FBXO25 protein Q8TCJ0 UNIPROT "up-regulates activity" phosphorylation Ser178 DLLQDLSsTLCILIR 10090 BTO:0002572 25419709 t lperfetto "FBXO25 encodes an orphan F-box protein that determines the substrate specificity of the SCF (SKP1-CUL1-F-box)(FBXO25) ubiquitin ligase complex. An unbiased screen uncovered the prosurvival protein HCLS1-associated protein X-1 (HAX-1) as the bona fide substrate of FBXO25 that is targeted after apoptotic stresses. Protein kinase Cdelta (PRKCD) initiates this process by phosphorylating FBXO25 and HAX-1, thereby spatially directing nuclear FBXO25 to mitochondrial HAX-1.|Accordingly, PRKCD-induced phosphorylation of Hax-1 at Ser210 and Fbxo25 at Ser178 was associated with decreased expression of Hax-1 in control cells," SIGNOR-275561 PRKCD protein Q05655 UNIPROT HAX1 protein O00165 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser210 QPKSYFKsISVTKIT 10090 BTO:0002572 25419709 t lperfetto "FBXO25 encodes an orphan F-box protein that determines the substrate specificity of the SCF (SKP1-CUL1-F-box)(FBXO25) ubiquitin ligase complex. An unbiased screen uncovered the prosurvival protein HCLS1-associated protein X-1 (HAX-1) as the bona fide substrate of FBXO25 that is targeted after apoptotic stresses. Protein kinase Cdelta (PRKCD) initiates this process by phosphorylating FBXO25 and HAX-1, thereby spatially directing nuclear FBXO25 to mitochondrial HAX-1.|Accordingly, PRKCD-induced phosphorylation of Hax-1 at Ser210 and Fbxo25 at Ser178 was associated with decreased expression of Hax-1 in control cells," SIGNOR-275562 RB1 protein P06400 UNIPROT MYOD1 protein P15172 UNIPROT up-regulates binding 9606 21902831 t gcesareni "Cycline/cdk2 blocks myod-induced gene expression through the phosphorylation of rb, preventing rb from binding and transactivating myod, and triggering s phase entry instead of differentiation." SIGNOR-176563 MYCT1 protein Q8N699 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR up-regulates 9606 BTO:0000670;BTO:0000738 30283340 f miannu "Overexpression of MYCT1 Inhibits Proliferation and Induces Apoptosis in Human Acute Myeloid Leukemia HL-60 and KG-1a Cells in vitro and in vivo" SIGNOR-261729 FBXO25 protein Q8TCJ0 UNIPROT HAX1 protein O00165 UNIPROT "down-regulates quantity by destabilization" ubiquitination 10090 BTO:0002572 25419709 t lperfetto "FBXO25 encodes an orphan F-box protein that determines the substrate specificity of the SCF (SKP1-CUL1-F-box)(FBXO25) ubiquitin ligase complex. An unbiased screen uncovered the prosurvival protein HCLS1-associated protein X-1 (HAX-1) as the bona fide substrate of FBXO25 that is targeted after apoptotic stresses. Protein kinase Cdelta (PRKCD) initiates this process by phosphorylating FBXO25 and HAX-1, thereby spatially directing nuclear FBXO25 to mitochondrial HAX-1." SIGNOR-275563 PRKCD protein Q05655 UNIPROT SHOC2 protein Q9UQ13 UNIPROT "down-regulates quantity by destabilization" phosphorylation Thr71 VAFSVDNtIKRPNPA 29383184 t lperfetto "PKCalpha/delta phosphorylate Sur8 at Thr-71 and Ser-297, respectively. This phosphorylation is essential for polyubiquitin-dependent degradation of Sur8." SIGNOR-275564 PRKCD protein Q05655 UNIPROT SHOC2 protein Q9UQ13 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser297 GLRYNRLsAIPRSLA 29383184 t lperfetto "PKCalpha/delta phosphorylate Sur8 at Thr-71 and Ser-297, respectively. This phosphorylation is essential for polyubiquitin-dependent degradation of Sur8." SIGNOR-275565 SRC_kinase_family proteinfamily SIGNOR-PF32 SIGNOR KCND3 protein Q9UK17 UNIPROT "up-regulates activity" phosphorylation Tyr108 GKLHYPRyECISAYD 22198508 t lperfetto "Our results demonstrate that human atrial I(to) and cloned hKv4.3 channels are modulated by EGFR kinase via phosphorylation of the Y136 residue and by Src-family kinases via phosphorylation of the Y108 residue|We found that human atrial I(to) was inhibited by the broad-spectrum PTK inhibitor genistein, the selective epidermal growth factor receptor (EGFR) kinase inhibitor AG556, and the Src-family kinases inhibitor PP2." SIGNOR-275566 PRKCA protein P17252 UNIPROT SHOC2 protein Q9UQ13 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser297 GLRYNRLsAIPRSLA 29383184 t lperfetto "PKCalpha/delta phosphorylate Sur8 at Thr-71 and Ser-297, respectively. This phosphorylation is essential for polyubiquitin-dependent degradation of Sur8." SIGNOR-275567 PRKCA protein P17252 UNIPROT SHOC2 protein Q9UQ13 UNIPROT "down-regulates quantity by destabilization" phosphorylation Thr71 VAFSVDNtIKRPNPA 29383184 t lperfetto "PKCalpha/delta phosphorylate Sur8 at Thr-71 and Ser-297, respectively. This phosphorylation is essential for polyubiquitin-dependent degradation of Sur8." SIGNOR-275568 CSNK2A1 protein P68400 UNIPROT XRCC1 protein P18887 UNIPROT up-regulates phosphorylation Ser518 GEDPYAGsTDENTDS 9606 20471329 t lperfetto "Xrcc1 phosphorylation by ck2 is required for its stability and efficient dna repair. Rcc1 is phosphorylated in vivo and in vitro by ck2, and ck2 phosphorylation of xrcc1 on s518, t519, and t523" SIGNOR-165423 MAPKAPK2 protein P49137 UNIPROT YWHAZ protein P63104 UNIPROT "down-regulates activity" phosphorylation Ser58 VVGARRSsWRVVSSI 9606 BTO:0000007 12861023 t miannu "We confirmed that MAPKAPK2 interacted with and phosphorylated 14-3-3zeta in vitro and in HEK293 cells. Mutation analysis showed that MAPKAPK2 phosphorylated 14-3-3zeta at Ser-58. S58D mutation significantly impaired both 14-3-3zeta dimerization and binding to Raf-1." SIGNOR-250151 belinostat chemical CHEBI:61076 ChEBI HDAC7 protein Q8WUI4 UNIPROT "down-regulates activity" "chemical inhibition" -1 17868033 t Luana "Our findings suggest that hydroxamic acid-derived compounds such as TSA, NVP-LAQ824, panobinostat, ITF2357, vorinostat and belinostat act as potent pan-HDAC isoform inhibitors. A notable observation was the similarity between belinostat and vorinostat in the biochemical isoform assays; both compounds exhibit similar EC50 values in all but the HDAC8 assay." SIGNOR-257741 CDK8 protein P49336 UNIPROT E2F1 protein Q01094 UNIPROT down-regulates phosphorylation Ser375 PVDEDRLsPLVAADS 9606 18794899 t lperfetto "E2F1 activity is also repressed by cyclin-dependent kinase-8 (CDK8), a colorectal oncoprotein. Elevated levels of CDK8 protect beta-catenin/TCF-dependent transcription from inhibition by E2F1." SIGNOR-181078 FBXW7 protein Q969H0 UNIPROT NOTCH1 protein P46531 UNIPROT "down-regulates quantity by destabilization" ubiquitination 9606 15546612 t lperfetto "Purified recombinant cycc:cdk8 phosphorylates the notch icd within the tad and pest domains, and expression of cycc:cdk8 strongly enhances notch icd hyperphosphorylation and pest-dependent degradation by the fbw7/sel10 ubiquitin ligase in vivo." SIGNOR-130706 Ub:E2 complex SIGNOR-C497 SIGNOR RNF10 protein Q8N5U6 UNIPROT "up-regulates activity" ubiquitination 9606 34199813 t miannu "The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t" SIGNOR-271064 NRXN1 protein Q9ULB1 UNIPROT NLGN2 protein Q8NFZ4 UNIPROT "up-regulates activity" binding 9606 BTO:0000142 22626542 t miannu "The neurexin–NL2 interaction is sufficient to induce GABAergic differentiation and clustering of GABAARs at postsynaptic sites." SIGNOR-265452 POMC protein P01189 UNIPROT MC3R protein P41968 UNIPROT "up-regulates activity" binding 9606 BTO:0000142 20371771 t lperfetto "The melanocortin (MC) receptor family consists of five Gs-coupled receptors that control various physiological functions in response to four distinct agonists, adrenocorticotropic hormone (ACTH, also known as corticotrophin) and alpha, beta, and gamma melanocyte-stimulating hormone (MSH), which are derived from the proopiomelanocortin precursor protein, and two inverse agonists, agouti and agouti-related proteins" SIGNOR-268705 EGFR protein P00533 UNIPROT ERBB3 protein P21860 UNIPROT up-regulates phosphorylation Tyr1289 CPASEQGyEEMRAFQ 9606 BTO:0000150 7929151 t lperfetto "The erbb3 protein which possesses little or no intrinsic protein tyrosine kinase activiity is phosphorylated by the activated egf receptor protein tyrosine kinase on tyrosine residues within the yxxm sequence motif. These phosphorylated tyrosine residues interact with the p85 regulatory subunit of pi 3-kinase, which could result in the activation of the p110 catalytic subunit via a conformational mechanism." SIGNOR-34752 H2BC11 protein P06899 UNIPROT "Nucleosome_H3.3 variant" complex SIGNOR-C339 SIGNOR "form complex" binding 9606 15776021 t miannu "Variant histone H3.3 is incorporated into nucleosomes by a mechanism that does not require DNA replication and has also been implicated as a potential mediator of epigenetic memory of active transcriptional states. In this study, we have used chromatin immunoprecipitation analysis to show that H3.3 is found mainly at the promoters of transcriptionally active genes." SIGNOR-263875 VPS39 protein Q96JC1 UNIPROT SMAD3/SMAD4 complex SIGNOR-C9 SIGNOR "down-regulates quantity" binding 9534 12941698 t miannu "Overexpression of TLP blocks TGF-β-induced formation of Smad3/4 complexes while it does not alter Smad2/4 complex levels." SIGNOR-261378 N-[2-(4-bromocinnamylamino)ethyl]isoquinoline-5-sulfonamide chemical CHEBI:47495 ChEBI PRKACA protein P17612 UNIPROT "down-regulates activity" "chemical inhibition" 10116 2156866 t "Simone Vumbaca" "Kinetic analysis indicated that H-89 inhibits protein kinase A, in competitive fashion against ATP." SIGNOR-261087 AR protein P10275 UNIPROT UCN protein P55089 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0001509 23801677 t lperfetto "When cells were treated with DHT alone, AR was upregulated and translocated into the nuclei, which might repress UCN1 expression via a potential androgen-responsive element found in human CRF family promoter|These data suggest that DHT differentially influences UCN1 levels under normal and inflammatory conditions in human umbilical vein endothelial cells, which involves AR-dependent and -independent mechanisms respectively." SIGNOR-253688 RHEB protein Q15382 UNIPROT FKBP8 protein Q14318 UNIPROT "down-regulates activity" "gtpase-activating protein" 9606 19222999 t lperfetto "Recent studies document that Rheb activates mTORC1 via direct, GTP-dependent interaction with the peptidyl-prolyl-cis/trans-isomerase FKBP38, which is proposed to act as an inhibitor of mTORC1." SIGNOR-233568 MUL1 protein Q969V5 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR "down-regulates quantity by destabilization" ubiquitination Lys284 LENLMLDkDGHIKIT 9606 22410793 t gcesareni "The results of the functional studies suggest that the degradation of Akt by MULAN suppresses cell proliferation and viability." SIGNOR-252460 2-formamido-N(1)-(5-O-phosphonato-beta-D-ribosyl)acetamidine smallmolecule CHEBI:147287 ChEBI 5-amino-1-(5-phosphonato-beta-D-ribosyl)imidazol-3-ium smallmolecule CHEBI:137981 ChEBI "up-regulates quantity" "precursor of" 9606 33179964 t miannu "The second enzyme in the DNPB pathway is trifunc tional GART (TGART), whose domains and activities include: glycinamide ribonucleotide synthase (GARS) that catalyzes the ATP-dependent process that uses 5- PRA and Gly to make glycinamide ribonucleotide (GAR); glycinamide ribonucleotide transformylase (GART) that transfers the formyl group of N10-formyltetrahydrofolate to GAR, generating formylglycinamide ribonucleotide (FGAR); and aminoimidazole ribonucleotide synthase (AIRS) that converts formylglycinamidine ribonucleotide (FGAM) to aminoimidazole ribonucleotide (AIR) in an ATP-dependent manner." SIGNOR-267313 MMP7 protein P09237 UNIPROT HAPLN1 protein P10915 UNIPROT "down-regulates quantity by destabilization" cleavage Leu40 QAENGPHlLVEAEQA -1 7694569 t miannu "Matrix metalloproteinases cleave at two distinct sites on human cartilage link protein. Sequencing studies of modified link protein components revealed that stromelysins-1 and -2, gelatinases A and B and collagenase cleaved specifically between His16 and Ile17, and matrilysin, stromelysin-2 and gelatinase A cleaved between Leu25 and Leu26. Based on previously determined in situ cleavage sites it is evident that matrix metalloproteinases are not solely responsible for the accumulation of link protein degradation products in adult human cartilage, indicating that additional proteolytic agents are involved in the normal catabolism of human cartilage matrix." SIGNOR-256329 CDK1 protein P06493 UNIPROT UBXN2B protein Q14CS0 UNIPROT "down-regulates activity" phosphorylation Thr59 TVFKSPRtPPQRFYS 23500464 t lperfetto "At mitosis, Cdc2 kinase phosphorylates p47 on Serine-140 and p37 on Serine-56 and Threonine-59, respectively. The phosphorylated p47 and p37 are unable to bind to Golgi membranes, resulting in mitotic inhibition of the p97/p47 and the p97/p37 pathways, respectively." SIGNOR-265041 COL1A2 protein P08123 UNIPROT ECM_synthesis phenotype SIGNOR-PH8 SIGNOR up-regulates 9606 21949456 t "Collagen is the major structural protein in skeletal muscle ECM;...Several studies suggest that perimysial collagen is predominantly type I" SIGNOR-254663 FOXO proteinfamily SIGNOR-PF27 SIGNOR IGFBP1 protein P08833 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 10358076 f miannu "Reporter gene studies in hepg2 hepatoma cells show that fkhr stimulates insulin-like growth factor-binding protein-1 promoter activity through an irs" SIGNOR-252925 ATP6AP1 protein Q15904 UNIPROT RAB7A protein P51149 UNIPROT "up-regulates activity" binding 22467241 t lperfetto "We found that Ac45 colocalized with Rab7 in resorbing osteoclasts cultured on bone slices (Fig. 6A). In addition, a co-immunoprecipitation assay revealed that Ac45 directly interacted with Rab7| Therefore, Ac45’s role in extracellular acidification, lysosomal trafficking, and cathepsin K exocytosis may be through the Rab7 pathway." SIGNOR-261484 HYDIN protein Q4G0P3 UNIPROT GATA4 protein P43694 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0001086 32376282 t miannu "HYDIN promotes expression of Gata4 in cardiomyocyte differentiation. HYDIN functions as a positive regulator of human cardiomyocyte differentiation and promotes expression of cardiac contractile genes in hESC cells. This is mediated through GATA4, a critical transcription factor in heart development. Cardiac-specific Hydin knockdown in vivo leads to Gata4 downregulation and enhanced atrial septal defect (ASD) risk in mice. GATA4 is a fundamental TF in embryonic heart development and cardiac differentiation, and reduction in GATA4 function results in a diverse range of CHDs" SIGNOR-265479 TIMM44 protein O43615 UNIPROT "TIM23 complex" complex SIGNOR-C423 SIGNOR "form complex" binding 32074073 t lperfetto "The human TIM23 complex is formed by the core components TIM50 (50), TIM23 (23) and TIM17A/B (17A/B). The sorting elements are TIM21 (21) and ROMO1, and the motor elements include TIM44 (44), PAM18 (18; DNAJC15 and DNAJC19), PAM16 (16; MAGMAS), mtHSP70 (Mortalin) and GrpE." SIGNOR-267689 FOXN4 protein Q96NZ1 UNIPROT PTF1A protein Q7RTS3 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 BTO:0001175 17075007 f Luana " We conclude that Foxn4 functions upstream of Ptf1a to activate its expression, thereby regulating the generation of amacrine and horizontal cells during retinogenesis." SIGNOR-261608 TYK2 protein P29597 UNIPROT TYK2 protein P29597 UNIPROT "up-regulates activity" phosphorylation Tyr1054 AVPEGHEyYRVREDG 9606 BTO:0000452 8702790 t lperfetto "These results indicate that tyk2 is activated by phosphorylation on tyr-1054 and/or tyr-1055The K930R mutant, bearing a mutation in the ATP binding site, is catalytically inactive (Fig. 3B, lanes 5 and 6). This protein is not basally phosphorylated, while the wt and the Y1054F/Y1055F proteins are (Fig. 3A), suggesting that autophosphorylation is responsible for the basal level of phosphorylation." SIGNOR-43088 ezogabine chemical CHEBI:68584 ChEBI KCNQ3 protein O43525 UNIPROT up-regulates "chemical activation" 9606 Other t "Selleck;anticonvulsant for KCNQ2/3 currents" gcesareni SIGNOR-206541 MAPKAPK2 protein P49137 UNIPROT KRT20 protein P35900 UNIPROT "up-regulates activity" phosphorylation Ser13 RSFHRSLsSSLQAPV -1 20724476 t miannu "P38 phosphorylates the type II keratin, K8 at Ser73, whereas MK2 phosphorylates the binding partners K18 at Ser52 and K20 at Ser13." SIGNOR-263072 GFPT1 protein Q06210 UNIPROT Hexosamine_biosynthesis phenotype SIGNOR-PH194 SIGNOR up-regulates 9606 21310273 f miannu "GFPT1 is the key enzyme of the hexosamine pathway yielding the amino sugar UDP-N-acetylglucosamine, an essential substrate for protein glycosylation." SIGNOR-267819 SRC protein P12931 UNIPROT IKBKB protein O14920 UNIPROT up-regulates phosphorylation Tyr188 SFVGTLQyLAPELLE 9606 SIGNOR-C14 12645577 t gcesareni "These results indicate that c-src can associate with ikkbeta and phosphorylate its tyrosine residues after tnf-alfa or tpa stimulation." SIGNOR-99314 NBN protein O60934 UNIPROT MRE11/RAD50/NBS1 complex SIGNOR-C147 SIGNOR "form complex" binding 17713585 t lperfetto "The mre11_rad50_nbs1 (mrn) complex is among the earliest respondents to dna double-strand breaks (dsbs). To organize the mrn complex, the mre11 exonuclease directly binds nbs1, dna, and rad50." SIGNOR-251505 CyclinD3/CDK11B complex SIGNOR-C543 SIGNOR AR protein P10275 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser310 TEDTAEYsPFKGGYT 9534 17698582 t "phosphorylation site remapping based on Fig 7D" lperfetto "We found that AR was phosphorylated at Ser-308 by cyclin D3/CDK11p58 in vitro and in vivo, leading to the repressed activity of AR transcriptional activation unit 1 (TAU1)." SIGNOR-273130 TOR1AIP1 protein Q5JTV8 UNIPROT VIM protein P08670 UNIPROT "up-regulates activity" binding 9606 BTO:0000452 16361107 t Sara "Co-immune precipitation studies revealed association between vimentin and torsinA in a complex. these studies suggest that mutant torsinA interferes with cytoskeletal events involving vimentin, possibly by restricting movement of these particles/filaments, and hence may affect development of neuronal pathways in the brain." SIGNOR-261313 MAPK3 protein P27361 UNIPROT RPS3 protein P23396 UNIPROT unknown phosphorylation Thr42 SGVEVRVtPTRTEII 9606 15950189 t llicata "Erk phosphorylates threonine 42 residue of ribosomal protein s3." SIGNOR-137959 MED25 protein Q71SY5 UNIPROT "Core mediator complex" complex SIGNOR-C405 SIGNOR "form complex" binding 9606 28467824 t miannu "Mediator is a multiprotein co-activator that binds the transcription pre-initiation complex (PIC) and regulates RNA polymerase (Pol) II. The Mediator head and middle modules form the essential core Mediator (cMed), whereas the tail and kinase modules play regulatory roles." SIGNOR-266681 GPKOW protein Q92917 UNIPROT DHX16 protein O60231 UNIPROT "up-regulates quantity" binding 9606 BTO:0000567 25296192 t miannu "In this report, we showed that GPKOW interacted directly with the DHX16/hPRP2 and with RNA. Immuno-depletion of GPKOW from HeLa nuclear extracts resulted in an inactive spliceosome that still bound DHX16." SIGNOR-266312 CDK2 protein P24941 UNIPROT CDC6 protein Q99741 UNIPROT up-regulates phosphorylation Ser106 DNQLTIKsPSKRELA 9606 SIGNOR-C83 10339564 t lperfetto "Based on these results, we propose that phosphorylation of hscdc6 by cdks regulates dna replication of at least two steps: first, by promoting initiation of dna replication and, second, through nuclear exclusion preventing dna rereplication. hscdc6 is an excellent substrate for cdk2 in vitro and is phosphorylated in vivo at three sites (ser-54, ser-74, and ser-106)" SIGNOR-67540 HIF1A protein Q16665 UNIPROT TM9SF4 protein Q92544 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0001545 25961573 t miannu "Here, we investigated the impact of hypoxia on TM9SF4 expression in leukemic cells and identified TM9SF4 as a direct target of HIF-1α, downregulated in these cells by hypoxia. Then, we found that the hypoxia-mediated downregulation of TM9SF4 expression is associated with a decrease of cell adhesion of leukemic cells to fibronectin, thus demonstrating that human TM9SF4 is a new molecule involved in leukemic cell adhesion." SIGNOR-266705 GRIK1 protein P39086 UNIPROT Excitatory_synaptic_transmission phenotype SIGNOR-PH133 SIGNOR up-regulates 9606 BTO:0000938 24564659 f miannu "Excitatory synaptic transmission in the mammalian brain is mediated primarily by the amino acid glutamate, activating two different groups of glutamate receptors: ionotropic and metabotropic." SIGNOR-264342 PAK1 protein Q13153 UNIPROT PAK1 protein Q13153 UNIPROT "down-regulates activity" binding 9606 BTO:0000007 11804587 t lperfetto "We show that pak1 forms homodimers in vivo and that its dimerization is regulated by the intracellular level of gtp-cdc42 or gtp-rac1. The dimerized pak1 adopts a trans-inhibited conformation." SIGNOR-236338 C3 protein P01024 UNIPROT "C5 convertase complex" complex SIGNOR-C312 SIGNOR "form complex" binding cleavage:Arg748 ASHLGLArSNLDEDI 31331124 t "complement C3b fragment: PRO_0000005911" lperfetto "C3b associates with C3 convertase to form C5 convertase and cleaves C5." SIGNOR-263448 CAMK2B protein Q13554 UNIPROT GSK3A protein P49840 UNIPROT down-regulates phosphorylation Ser21 SGRARTSsFAEPGGG 9606 BTO:0000938 20841359 t gcesareni "Inhibitory phosphorylation of gsk-3 by camkii couples depolarization to neuronal survival." SIGNOR-167962 MAPK1 protein P28482 UNIPROT RPS6KB1 protein P23443 UNIPROT up-regulates phosphorylation Ser434 SFEPKIRsPRRFIGS 9606 7545671 t gcesareni "Erk phosphorylates multiple cytoplasmatic and cytoskeletal proteins, including mapk-activated protein kinases and the ribosomal p70-s6 kinase" SIGNOR-28796 TGFB1 protein P01137 UNIPROT ITGA2 protein P17301 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0001596 1744142 f lperfetto "TGF-beta 1 decreases the biosynthesis of alpha 3 subunit but increases the production of alpha 2 subunit. IL-1 beta potentiates the effects of TGF-beta 1. Furthermore, in the presence of TGF-beta 1 the increase in the expression of alpha 1 subunit by IL-1 beta is even larger. Thus, IL-1 beta and TGF-beta 1, which usually have antagonistic functions in connective tissue, can regulate integrin expression in a synergistic way." SIGNOR-253354 TET1 protein Q8NFU7 UNIPROT SLIT2 protein O94813 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 27708339 t irozzo "Furthermore, TET1 catalytic domain possessed demethylase activity in cancer cells, being able to inhibit the CpG methylation of tumor suppressor gene (TSG) promoters and reactivate their expression, such as SLIT2, ZNF382 and HOXA9." SIGNOR-259093 HSF2 protein Q03933 UNIPROT HSPA6 protein P17066 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 12813038 f miannu "These experiments suggest that HSF2 is involved in the stress response, but unlike the ubiquitous HSF1 operates in a cell-line specific manner through differential expression of alternatively spliced isoforms. Curiously, HSF2A could not be activated by heat shock in cells deficient in functional HSF1 and required the expression of HSF1 for heat induction of the hsp70B gene in cells." SIGNOR-254478 PRKCA protein P17252 UNIPROT CSPG4 protein Q6UVK1 UNIPROT "up-regulates activity" phosphorylation Thr2252 YLRKRNKtGKHDVQV 9606 BTO:0002035 15504744 t miannu "Protein kinase C (PKC)-alpha phosphorylation of recombinant NG2 cytoplasmic domain and phorbol ester-induced PKC-dependent phosphorylation of full-length NG2 expressed in U251 cells are both blocked by mutation of Thr(2256), identifying this residue as a primary phosphorylation site. PKC-alpha-mediated NG2 phosphorylation at Thr(2256) is therefore a key step for initiating cell polarization and motility." SIGNOR-263162 MRPL16 protein Q9NX20 UNIPROT "39S mitochondrial large ribosomal subunit" complex SIGNOR-C285 SIGNOR "form complex" binding -1 25838379 t lperfetto "We have determined the structure of the intact mitoribosome to 3.5 angstrom resolution by single-particle electron cryo-microscopy. It reveals 80 extensively interconnected proteins, 36 of which are specific to mitochondria, and three rRNA molecules" SIGNOR-262377 MAPK1 protein P28482 UNIPROT SREBF2 protein Q12772 UNIPROT up-regulates phosphorylation Ser432 NQNVLLMsPPASDSG 9606 14988395 t lperfetto "Insulin-activated erk-mitogen-activated protein kinases phosphorylate sterol regulatory element-binding protein-2 at serine residues 432 and 455 in vivo.Further characterization by electrophoretic mobility shift assay and promoter reporter gene analyses revealed that phosphorylation does not influence protein/dna interaction, but enhances trans-activity." SIGNOR-123041 CLU protein P10909 UNIPROT IKBKB protein O14920 UNIPROT "down-regulates quantity by destabilization" binding 9606 BTO:0001321 20068069 t miannu "CLU-2 is a ubiquitin binding protein (UBP) that enhances proteasome activity. sCLU promotes degradation of COMMD1. sCLU interacts with the SCF-βTrCP E3 ligase complex, serving as a scaffolding chaperone to form a multimeric protein complex that facilitates COMMD1 and I-κB ubiquitination and proteasomal degradation." SIGNOR-271433 FLT3 protein P36888 UNIPROT SHC1 protein P29353 UNIPROT "up-regulates activity" phosphorylation Tyr349 EEPPDHQyYNDFPGK 9606 10482988 t miannu "Intracellular FLT3 signaling involves tyrosine phosphorylation of several cytoplasmic proteins including SHC. We have found that upon FLT3 activation SHC phosphorylation occurs at tyrosine 239/240 and 313." SIGNOR-251146 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR IL16 protein Q14005 UNIPROT up-regulates phosphorylation 9606 BTO:0000782 14768064 t "inferred from 70% family members" lperfetto "The precursor form of the cytokine il-16 (proil-16) was shown to be phosphorylated on ser144 in antigen receptor-, sdf1alpha- and il-2-activated t cells. Genetic and pharmacological-inhibitor experiments showed that the phosphorylation of proil-16 is dependent on activation of the kinases erk1/2. Il-16 is secreted by mitogen-activated t cells, and the biochemical link between proil-16 and erk1/2, revealed by studies with pap-1, prompted analysis of the role of map kinases in this response." SIGNOR-270168 MAP2K4 protein P45985 UNIPROT MAPK10 protein P53779 UNIPROT "up-regulates activity" phosphorylation Tyr223 TSFMMTPyVVTRYYR -1 10715136 t "Activation of JNK3 alpha 1 requires both MKK4 and MKK7. both MKK4 and MKK7 were required for bisphosphorylation and maximal enzyme activity. a processive mechanism for JNK3R1 activation that requires phosphorylation of Thr 221 by MKK7 prior to phosphorylation of Tyr 223 by MKK4" SIGNOR-251423 "A8/b1 integrin" complex SIGNOR-C165 SIGNOR PTK2 protein Q05397 UNIPROT up-regulates 15721307 f lperfetto "We previously showed that α8β1-mediated adhesion of cells to fibronectin resulted in phosphorylation of FAK | FAK can activate PI3 kinase, either directly or indirectly through Src kinase [23]." SIGNOR-253309 CyclinA2/CDK1 complex SIGNOR-C420 SIGNOR G2/M_transition phenotype SIGNOR-PH52 SIGNOR up-regulates 9606 29870721 f lperfetto "Here we show that cyclin A/cdk1 kinase is the factor triggering mitosis." SIGNOR-267572 CD3D protein P04234 UNIPROT CD3 complex SIGNOR-C432 SIGNOR "form complex" binding 9606 12507424 t miannu "The T cell receptor-CD3 complex (TCR-CD3) serves a critical role in the differentiation, survival, and function of T cells, and receptor triggering elicits a complex set of biological responses that serve to protect the organism from infectious agents. The receptor is composed of six different chains that form the TCR heterodimer responsible for ligand recognition, as well as the CD3γε, CD3δε, and ζζ signaling modules." SIGNOR-255295 CASP3 protein P42574 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR "down-regulates activity" cleavage -1 10579725 t lperfetto "P53 can inhibit the survival function of integrins by inducing the caspase-dependent cleavage and inactivation of the serine/threonine kinase akt/pkb;the involvement of caspase 3 in akt/pkb regulation was indicated by the ability of z-devd-fmk, a caspase 3 inhibitor, to block the alpha6beta4-associated reduction in akt/pkb levels in vivo, and by the ability of recombinant caspase 3 to promote the cleavage of akt/pkb in vitro" SIGNOR-72677 MRPL53 protein Q96EL3 UNIPROT "39S mitochondrial large ribosomal subunit" complex SIGNOR-C285 SIGNOR "form complex" binding -1 25838379 t lperfetto "We have determined the structure of the intact mitoribosome to 3.5 angstrom resolution by single-particle electron cryo-microscopy. It reveals 80 extensively interconnected proteins, 36 of which are specific to mitochondria, and three rRNA molecules" SIGNOR-262345 SPOP protein O43791 UNIPROT DAXX protein Q9UER7 UNIPROT "down-regulates quantity" ubiquitination 9606 BTO:0002181 16524876 t Gianni "These results suggest that SPOP/Cul3-ubiquitin ligase plays an essential role in the control of Daxx level and, thus, in the regulation of Daxx-mediated cellular processes, including transcriptional regulation and apoptosis." SIGNOR-268858 PKA proteinfamily SIGNOR-PF17 SIGNOR PHF2 protein O75151 UNIPROT "up-regulates activity" phosphorylation Ser954 QKSKKKKsAKRKLTP 9606 BTO:0000007 21532585 t miannu "PHF2, a jmjC demethylase, is enzymatically inactive by itself, but becomes an active H3K9Me2 demethylase through PKA-mediated phosphorylation. We found that phosphorylated PHF2 then associates with ARID5B, a DNA-binding protein, and induce demethylation of methylated ARID5B. This modification leads to targeting of the PHF2-ARID5B complex to its target promoters, where it removes the repressive H3K9Me2 mark. Replacement of all of four serine residues by alanines (4SA: Ser 757/Ser 899/Ser 954/Ser 1056) fully abrogated PKA phosphorylation of PHF2 (Fig. 2h)." SIGNOR-264512 DMXL2 protein Q8TDJ6 UNIPROT MADD protein Q8WXG6 UNIPROT "up-regulates quantity" binding 10116 BTO:0000142 11809763 t miannu "We isolated here a novel protein that was co-immunoprecipitated with Rab3 GEP and GAP by their respective antibodies from the crude synaptic vesicle fraction of rat brain. The protein, named rabconnectin-3, bound both Rab3 GEP and GAP. These results indicate that rabconnectin-3 serves as a scaffold molecule for both Rab3 GEP and GAP on synaptic vesicles." SIGNOR-265581 CACNA2D3 protein Q8IZS8 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR down-regulates 9606 31746409 f miannu "Overexpression of CACNA2D3 reduced proliferation and migration, but increased apoptosis and Ca2+ influx in Ishikawa and RL95-2 cells." SIGNOR-266854 GART protein P22102 UNIPROT N(1)-(5-phospho-beta-D-ribosyl)glycinamide(1-) smallmolecule CHEBI:143788 ChEBI "down-regulates quantity" "chemical modification" 9606 34283828 t miannu "In humans, GART [phosphoribosylglycinamide formyltransferase (EC 2.1.2.2) / phosphoribosylglycinamide synthetase (EC 6.3.4.13) / phosphoribosylaminoimidazole synthetase (EC 6.3.3.1)] is a trifunctional protein which catalyzes the second, third, and fifth reactions of the ten step de novo purine synthesis (DNPS) pathway. The second step of DNPS is conversion of phosphoribosylamine (5-PRA) to glycineamide ribonucleotide (GAR)." SIGNOR-268101 "Cullin 1-RBX1-Skp1" complex SIGNOR-C529 SIGNOR SNAI1 protein O95863 UNIPROT "down-regulates quantity by destabilization" polyubiquitination -1 24157836 t miannu "FBXL5 is located in the nucleus where it interacts with Snail1 promoting its polyubiquitination and affecting Snail1 protein stability and function by impairing DNA binding. Snail1 is ubiquitinated by the SCFFBXL5 complex. Snail1 downregulation by FBXL5 is prevented by Lats2, a protein kinase that phosphorylates Snail1 precluding its nuclear export but not its polyubiquitination. To demonstrate that FBXL5 has a direct activity on Snail1, we carried out polyubiquitination reactions in vitro. For this we purified Snail1 and the SCFFBXL5 complex from Sf9 insect cells infected with different baculoviruses corresponding to Flag-FBXL5, His-Skp1, HA-Cullin1 and Rbx1 (Supplementary Figure S3C)." SIGNOR-272137 ZNF804A protein Q7Z570 UNIPROT BIRC3 protein Q13489 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0000007 23434502 t miannu "ZNF804A has been implicated in susceptibility to schizophrenia by several genome-wide association studies (GWAS), follow-up association studies and meta-analyses. ZNF804A was identified as a schizophrenia-associated gene by GWAS and was predicted to play a role in DNA binding and transcription To identify the genes that are affected by ZNF804A, we manipulated the expression of the ZNF804A protein in HEK293 human embryonic kidney cell lines and performed a cDNA microarray analysis followed by qPCR. We found that ZNF804A-overexpression up-regulated four genes (ANKRD1, INHBE, PIK3AP1, and DDIT3) and down-regulated three genes (CLIC2, MGAM, and BIRC3)." SIGNOR-269467 FZD2 protein Q14332 UNIPROT PPARG protein P37231 UNIPROT down-regulates 9606 BTO:0000222 10937998 f fspada "Wnt signaling maintains preadipocytes in an undifferentiated state through inhibition of the adipogenic transcription factors ccaat/enhancer binding protein alpha (c/ebpalpha) and peroxisome proliferator- activated receptor gamma (ppargamma)" SIGNOR-80604 PRKCA protein P17252 UNIPROT HLA-A protein P04439 UNIPROT unknown phosphorylation Ser359 SAQGSDVsLTACKV 2941417 t lperfetto "As shown in Fig. 6A, the HLA heavy chain was phosphorylated by kinase C. | The major site of in vivo phosphorylation of the HLA-B7 heavy chain was localized to Ser-335 which is conserved in all specificitie" SIGNOR-248891 SMURF1 protein Q9HCE7 UNIPROT ASCC2 protein Q9H1I8 UNIPROT unknown ubiquitination -1 20804422 t miannu "Recombinant proteins were used to profile substrate ubiquitination by the Smurf1 ubiquitin ligase on a global scale using protein microarrays. T Proteins ubiquitinated on the protein microarray were confirmed as potential substrates of the Smurf1 activity using an off chip in vitro ubiquitination assay." SIGNOR-272692 "MSL acetyltransferase" complex SIGNOR-C344 SIGNOR "Histone H2B" proteinfamily SIGNOR-PF68 SIGNOR "down-regulates activity" monoubiquitination 9606 BTO:0000567 21726816 t miannu "MSL1/2 ubiquitylates histone H2B on K 34. Importantly, only mono-ubiquitylation of H2B by MSL1/2 was detected in cells (data not shown), suggesting that MSL1/2, like RNF20/RNF40, was mainly a mono-ubiquitylase under physiological conditions.the MOF-MSL complex functions to promote both H4 K16ac and H2B K34ub. H2B K34ub, in turn, promotes H2B K120ub, H3 K4me3 and K79me2 to facilitate transcription elongation." SIGNOR-271978 MMP14 protein P50281 UNIPROT FGA protein P02671 UNIPROT "down-regulates quantity by destabilization" cleavage Leu433 REYHTEKlVTSKGDK -1 10930399 t lperfetto "Matrix metalloproteinases collagenase-2, macrophage elastase, collagenase-3, and membrane type 1-matrix metalloproteinase impair clotting by degradation of fibrinogen and factor XII| We have now investigated the role of collagenase-2 (MMP-8), macrophage elastase (MMP-12), collagenase-3 (MMP-13), and membrane type 1-matrix metalloproteinase (MT1-MMP, MMP-14) in the degradation of fibrinogen and Factor XII of the plasma clotting system.|MMP-14 27YVATRDN g-chain| 105XDAATLKSR g-chain | 92LTYNPDES g-chain |105LTTNIXEXL a-chain|433LVTSKGDKE a-chain| 117FXSANNRD a-chain" SIGNOR-263620 MIPOL1 protein Q8TD10 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR "down-regulates activity" 9606 31609475 f miannu "In our results, we also showed that re-expression of MIPOL1 is associated with suppression phosphorylation of AKT and p65, a subunit of NF-ҡB. This suggests that MIPOL1 may inhibit invasion by suppression of phosphorylation of AKT and p65 to further inhibit the expression of MMP-9" SIGNOR-261135 PPP2R2C protein Q9Y2T4 UNIPROT SRC protein P12931 UNIPROT "down-regulates activity" binding 9606 BTO:0001938 18069897 t gcesareni "We show that PR55gamma binds c-SRC and modulates the phosphorylation of serine 12 of c-SRC, a residue we demonstrate to be required for JNK activation by c-SRC" SIGNOR-247966 MAP2K1 protein Q02750 UNIPROT MAPK3 protein P27361 UNIPROT "up-regulates activity" phosphorylation 10090 11730323 t "Raf proteins have been shown to phosphorylate and activate MAPKKs (MAP kinase kinases) called MEKs (MAPK or ERK kinases) which in turn phosphorylate and activate MAPKs (MAP kinases) called ERKs" SIGNOR-258994 Gbeta proteinfamily SIGNOR-PF4 SIGNOR PLA2G4A protein P47712 UNIPROT up-regulates phosphorylation 9606 8381049 t "inferred from 70% family members" gcesareni "Activated map kinase phosphorylates cpla2 at ser-505, causing increased enzymatic activity of cpla2, which is only realized upon translocation of cpla2 to the membrane." SIGNOR-270096 Ub:E2 complex SIGNOR-C497 SIGNOR NEURL1B protein A8MQ27 UNIPROT "up-regulates activity" ubiquitination 9606 34199813 t miannu "The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t" SIGNOR-271252 PI3K complex SIGNOR-C156 SIGNOR AKT1 protein P31749 UNIPROT "up-regulates activity" 9606 BTO:0000150 19573809 f lperfetto "However, here we show through phosphoprotein profiling and functional genomic studies that many PIK3CA mutant cancer cell lines and human breast tumors exhibit only minimal AKT activation and a diminished reliance on AKT for anchorage-independent growth" SIGNOR-252704 ZNF423 protein Q2M1K9 UNIPROT Adipogenesis phenotype SIGNOR-PH26 SIGNOR "up-regulates activity" 10090 BTO:0000011 20200519 f "Ectopic expression of Zfp423 in non-adipogenic NIH 3T3 fibroblasts robustly activates expression of Pparg in undifferentiated cells and permits cells to undergo adipocyte differentiation under permissive conditions. Short hairpin RNA (shRNA)-mediated reduction of Zfp423 expression in 3T3-L1 cells blunts preadipocyte Pparg expression and diminishes the ability of these cells to differentiate." SIGNOR-255928 MAP2K7 protein O14733 UNIPROT MAPK9 protein P45984 UNIPROT up-regulates phosphorylation Thr183 ACTNFMMtPYVVTRY 9606 11062067 t "phosphorylation of a threonine and a tyrosine residue in a Thr-Pro-Tyr motif" gcesareni "Here we report that mkk4 shows a striking preference for the tyrosine residue (tyr-185), and mkk7 a striking preference for the threonine residue (thr-183) in three sapk1/jnk1 isoforms tested (jnk1 alpha 1, jnk2 alpha 2 and jnk3 alpha 1). These results indicate that hgk, a novel activator of the jnk pathway, may function through tak1, and that the hgk --> tak1 --> mkk4, mkk7 --> jnk kinase cascade may mediate the TNF-alphalpha signaling pathway." SIGNOR-83744 GHSR protein Q92847 UNIPROT GNAO1 protein P09471 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257255 PHKG1 protein Q16816 UNIPROT MAPT protein P10636 UNIPROT "down-regulates activity" phosphorylation Ser669 DFKDRVQsKIGSLDN -1 8999860 t miannu "Muscle phosphorylase kinase phosphorylates Ser237, Ser262, Ser285, Ser305, and Ser352 of human tau. in vitro phosphorylation of tau on Ser262 alone strongly reduced the ability of tau to bind microtubules whereas the phosphorylation of many Ser/Thr-Pro motif sites of tau showed moderate effects on the binding of tau to microtubules" SIGNOR-250287 SRC protein P12931 UNIPROT GSN protein P06396 UNIPROT unknown phosphorylation Tyr603 LKTPSAAyLWVGTGA -1 10210201 t llicata "Gelsolin phosphorylation by c-Src in the presence of lysophosphatidic acid also revealed Tyr438 as the most prominent site. Additional minor sites were found using the anti-phosphotyrosine bead immunoprecipitation method followed by MALDI-MS and PSD analysis. These sites, representing approximately 5% of the total phosphate incorporation, were identified as Tyr59, Tyr382, Tyr576, and Tyr624." SIGNOR-250782 PTPRD protein P23468 UNIPROT Synaptic_plasticity phenotype SIGNOR-PH158 SIGNOR up-regulates 9606 BTO:0000938 27225731 f miannu "LAR (for leukocyte common antigen-related) is a family of receptor protein tyrosine phosphatases (LAR-RPTPs) with three known members: LAR/PTPRF, PTPδ/PTPRD, and PTPσ/PTPRS. In mammals, LAR-RPTPs have been shown to regulate dendrite and excitatory synapse development and maintenance" SIGNOR-264089 CDK9 protein P50750 UNIPROT POLR2A protein P24928 UNIPROT up-regulates phosphorylation Ser1868 SPTSPKYsPTSPKYS 9606 24385927 t lperfetto "Cyclin-dependent kinase 9 (cdk9) promotes elongation by rna polymerase ii (rnapii), mrna processing, and co-transcriptional histone modification. Cdk9 phosphorylates multiple targets, including the conserved rnapii elongation factor spt5 and rnapii itself" SIGNOR-203564 PRKAA1 protein Q13131 UNIPROT GLI1 protein P08151 UNIPROT "down-regulates activity" phosphorylation Ser408 GPLPRAPsISTVEPK 9606 26190112 t Luana "AMPK phosphorylates GLI1 at serines 102 and 408 and threonine 1074. Mutation of these three sites into alanine prevents phosphorylation by AMPK. This in turn leads to increased GLI1 protein stability, transcriptional activity, and oncogenic potency." SIGNOR-259860 L-arginine chemical CHEBI:16467 ChEBI ARG1 protein P05089 UNIPROT up-regulates BTO:0000801 BTO:0001103 25386178 f apalma "In mammalian cells, arginine can be catabolized by four classes of enzymes (Figure ​(Figure1):1): NOS, arginase, arginine decarboxylase (ADC), and arginine:glycine amidinotransferase (AGAT)" SIGNOR-255555 ULK1 protein O75385 UNIPROT RB1CC1 protein Q8TDY2 UNIPROT up-regulates phosphorylation 9606 19597335 t gcesareni "Ulk1 and ulk2 are the kinase phosphorylating their binding proteins atg13 and fip200. Atg13 directly binds fip200 and mediates the interaction between fip200 and ulks." SIGNOR-186992 PLRG1 protein O43660 UNIPROT PRP19-CDC5L complex SIGNOR-C534 SIGNOR "form complex" binding 9606 BTO:0000567 20176811 t miannu "In this study, we affinity purified the human Prp19/CDC5L complex from HeLa cell lines stably expressing FLAG-AD002 or FLAG-SPF27 and determined its molecular architecture and EM structure. To learn more about the spatial organization of the human Prp19 (hPrp19)/CDC5L complex, which is comprised of hPrp19, CDC5L, PRL1, AD002, SPF27, CTNNBL1, and HSP73, we purified native hPrp19/CDC5L complexes from HeLa cells stably expressing FLAG-tagged AD002 or SPF27." SIGNOR-271969 androst-4-ene-3,17-dione smallmolecule CHEBI:16422 ChEBI testosterone smallmolecule CHEBI:17347 ChEBI "up-regulates quantity" "precursor of" 9606 BTO:0001363 16166196 t lperfetto "A novel 17beta-hydroxysteroid dehydrogenase (17beta-HSD) chronologically named type 12 17beta-HSD (17beta-HSD12), that transforms estrone (E1) into estradiol (E2) was identified by sequence similarity with type 3 17beta-HSD (17beta-HSD3) that catalyzes the formation of testosterone from androstenedione in the testis." SIGNOR-268665 CAMK2G protein Q13555 UNIPROT PLCB3 protein Q01970 UNIPROT unknown phosphorylation Ser537 PSLEPQKsLGDEGLN 11325525 t llicata "CaMK II phosphorylated PLCbeta3 but not PLCbeta1 in vitro. Phosphorylation occurred exclusively on 537Ser in the X-Y linker region of PLCbeta3. 537Ser was also phosphorylated in the basal state in cells and phosphorylation was enhanced by ionomycin treatment" SIGNOR-250702 PIK3AP1 protein Q6ZUJ8 UNIPROT PIK3CA protein P42336 UNIPROT up-regulates binding 9606 BTO:0000801 22187458 t gcesareni "This accumulation of tyrosine-phosphorylated bcap at the membrane with its associated pi3k would then allow for the catalysis of ptd ins p2 to ptd ins p3 and downstream pi3k-dependent signals. Therefore, bcap is an essential activator of the pi3k pathway downstream of tlr signaling, providing a brake to limit potentially pathogenic excessive tlr responses." SIGNOR-191664 PDX1 protein P52945 UNIPROT Hexokinase proteinfamily SIGNOR-PF76 SIGNOR "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000627 8866550 f "inferred from family member" miannu "The glycolytic enzyme glucokinase plays a primary role in the glucose-responsive secretion of insulin, and defects of this enzyme can cause NIDDM. As a step toward understanding the molecular basis of glucokinase (GK) gene regulation, we assessed the structure and regulation of the human GK gene beta-cell-type promoter. The results of reporter gene analyses using HIT-T15 cells revealed that the gene promoter was comprised of multiple cis-acting elements, including two primarily important cis-motifs: a palindrome structure, hPal-1, and the insulin gene cis-motif A element-like hUPE3. While both elements were bound specifically by nuclear proteins, it was the homeodomain-containing transcription factor insulin promoter factor 1 (IPF1)/STF-1/PDX-1 that bound to the hUPE3 site: IPF1, when expressed in CHO-K1 cells, became bound to the hUPE3 site and activated transcription." SIGNOR-270264 SREBF2 protein Q12772 UNIPROT PCSK9 protein Q8NBP7 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 17921436 t miannu "Expression of nuclear forms of sterol-regulatory element binding protein-1 (SREBP-1) and SREBP-2 dramatically increased the promoter activity of PCSK9." SIGNOR-255223 CDK13 protein Q14004 UNIPROT EIF4EBP1 protein Q13541 UNIPROT "up-regulates activity" phosphorylation Thr46 GGTLFSTtPGGTRII 9606 BTO:0001109 36882522 t lperfetto "CDK13 directly phosphorylates 4E-BP1 at Thr46 and eIF4B at Ser422; genetically or pharmacologically inhibiting CDK13 disrupts mRNA translation." SIGNOR-273113 PER2 protein O15055 UNIPROT CLOCK/BMAL1 complex SIGNOR-C195 SIGNOR "down-regulates activity" binding 9606 20817722 t miannu "The mammalian clock is regulated at the cellular level by a transcriptional/translational feedback loop. BMAL1/clock (or NPAS2) heterodimers activate the expression of the period (PER) and cryptochrome (CRY) genes acting as transcription factors directed to the PER and CRY promoters via E-box elements. PER and CRY proteins form heterodimers and suppress the activity of the BMAL1/clock (or NPAS2) completing the feedback loop." SIGNOR-267977 IL1B protein P01584 UNIPROT IL6 protein P05231 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 32446778 f "doi: 10.1016/j.cytogfr.2020.05.003" miannu "Interleukin-6 (IL-6) deserves a more extensive discussion in view of its involvement in the coronavirus-induced cytokine storm. The production of this cytokine is increased by IL-1β and tumor necrosis factor (TNF- α)" SIGNOR-260855 CMA1 protein P23946 UNIPROT EDN3 protein P14138 UNIPROT "up-regulates activity" cleavage Tyr127 TPEQTVPyGLSNYRG 9606 BTO:0000830 9257865 t miannu "Chymase from human mast cells selectively cleaved big endothelins (ETs) at the Tyr31-Gly32 bond and produced novel trachea-constricting 31-amino acid-length endothelins, ETs(1-31), without any further degradation products." SIGNOR-256355 (+)-pilocarpine chemical CHEBI:8207 ChEBI CHRM2 protein P08172 UNIPROT "up-regulates activity" "chemical activation" 10029 BTO:0000246 9224827 t miannu "We investigated whether the allosteric modulators can also increase the affinity of receptors for their agonists. Twelve agonists and five allosteric modulators were tested in experiments on membranes of CHO cells that had been stably transfected with genes for the M1-M4 receptor subtypes. Affinities of agonists for the M1–M4 receptor subtypes were determined according to the ability of the agonist to inhibit [3H]NMS binding in the presence of 0.5 mM GTP; in this way, the low affinity binding of agonists was measured.The computed pKi and nH values are summarized in Table 2." SIGNOR-258629 axitinib chemical CHEBI:66910 ChEBI FLT4 protein P35916 UNIPROT down-regulates "chemical inhibition" 9606 BTO:0000150 21297102 t gcesareni "Axitinib , a highly selective inhibitor of vascular endothelial growth factor receptors taken orally, is approved for second-line treatment of advanced renal cell carcinoma (rcc) after failure of prior treatment with sunitinib or a cytokine." SIGNOR-171860 HIF1A protein Q16665 UNIPROT PKG proteinfamily SIGNOR-PF77 SIGNOR "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000567;BTO:0000972 8089148 f "inferred from family member" miannu "Hypoxia-inducible factor 1 (HIF-1) activates erythropoietin gene transcription in Hep3B cells subjected to hypoxia. HIF-1 activity is also induced by hypoxia in non-erythropoietin-producing cells, suggesting a more general regulatory role. We now report that RNAs encoding the glycolytic enzymes aldolase A (ALDA), phosphoglycerate kinase 1 (PGK1), and pyruvate kinase M were induced by exposure of Hep3B or HeLa cells to inducers of HIF-1 (1% O2, cobalt chloride, or desferrioxamine). Sequences from the ALDA, PFKL, and PGK1 genes containing HIF-1 binding sites mediated hypoxia-inducible transcription in transient expression assays." SIGNOR-270291 SMARCD2 protein Q92925 UNIPROT "SWI/SNF ACTL6A-ARID1A-SMARCA2 variant" complex SIGNOR-C470 SIGNOR "form complex" binding 9606 30397315 t miannu "Mammalian SWI/SNF (mSWI/SNF) complexes are ATP-dependent chromatin remodelers that modulate genomic architecture and DNA accessibility, enabling timely and appropriate control of gene expression. They are combinatorially assembled from the products of 29 total genes into three final-form complexes: canonical BAF, PBAF (polybromo-associated BAF complexes), and a newly-defined non-canonical BAF (ncBAF), with specific subunits specifying distinct complexes, such as PBRM1, ARID2, and BRD7 in PBAF complexes, ARID1A/ARID1B and DPF2 in canonical BAF (cBAF) complexes, and GLTSCR1/GLTSCR1L and BRD9 in ncBAF complexes" SIGNOR-269821 FLT4 protein P35916 UNIPROT FLT4 protein P35916 UNIPROT "up-regulates activity" phosphorylation Tyr1231 HSLAARYyNWVSFPG 9606 12881528 t lperfetto "Trans-phosphorylation of activated, dimerized receptor tyrosine kinases is known to be critical for the regulation of kinase activity and for receptor interaction with signal transduction molecules. In this study, we have identified five tyrosyl phosphorylation sites in the vegfr-3 carboxyl-terminal tail." SIGNOR-104076 NFIB protein O00712 UNIPROT NFIB protein O00712 UNIPROT "down-regulates activity" binding 9606 9099724 t 2 miannu "Coexpression of NFI-B3 with other isoforms of the NFI-B, -C, and -X family, however, led to a strong reduction of transcriptional activation compared with the expression of these factors alone. NFI-B3 apparently forms heterodimers with other NFI proteins thereby interfering with their function." SIGNOR-240883 CSNK2A1 protein P68400 UNIPROT SERINC3 protein Q13530 UNIPROT "up-regulates activity" phosphorylation Ser383 DTTTSGAsDEEDGQP -1 30135209 t miannu "The two serines within the PSAC of Serinc3 are phosphorylated by casein kinase II and mediate interaction with the μ subunits in vitro." SIGNOR-273632 EGFR protein P00533 UNIPROT NIBAN2 protein Q96TA1 UNIPROT "up-regulates activity" phosphorylation Tyr593 PIDWGEEySNSGGGG 9606 BTO:0002035 26721396 t miannu " We demonstrate here that activated EGFR phosphorylates the Y593 residue of the protein known as family with sequence similarity 129, member B (FAM129B), which is overexpressed in many types of human cancer. FAM129B phosphorylation increased the interaction between FAM129B and Ras, resulting in reduced binding of p120-RasGAP to Ras." SIGNOR-273637 EGFR protein P00533 UNIPROT SPRED1 protein Q7Z699 UNIPROT "down-regulates activity" phosphorylation Ser105 KFGLTFQsPADARAF 9606 BTO:0000007 32697994 t miannu "We show that oncogenic EGFR(L858R) signaling leads to the phosphorylation of SPRED1 on serine 105, disrupting the SPRED1-neurofibromin complex. The structural, biochemical, and biological results provide new mechanistic insights about how SPRED1 interacts with neurofibromin and regulates active KRAS levels in normal and pathologic conditions." SIGNOR-273638 TOP2A protein P11388 UNIPROT Survival phenotype SIGNOR-PH13 SIGNOR down-regulates 9606 15942022 f lperfetto "Down-regulation of DNA topoisomerase IIalpha leads to prolonged cell cycle transit in G2 and early M phases and increased survival to microtubule-interacting agents" SIGNOR-242537 GLI2 protein P10070 UNIPROT PTCH1 protein Q13635 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 BTO:0002572 16571352 f lperfetto "Primary mouse embryonic fibroblasts responded to Shh stimulation with the induction of Hh target genes Gli1, Ptc1, and Hip1.These observations support the previously advanced notion of a functional redundancy or cooperativity between Gli2 and Gli1 in activation of target genes [18] and [43] and indicate a functional cooperation between Gli3 and Gli1." SIGNOR-209632 HMOX1 protein P09601 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 BTO:0000848 17148680 f irozzo "Here we investigated the effects of HO-1 overexpression in murine and human melanoma cells. The most important findings of our study are that 1) overexpression of HO-1 augments the proliferation [.]" SIGNOR-256295 SPRED1 protein Q7Z699 UNIPROT NF1 protein P21359 UNIPROT "up-regulates quantity" binding 9606 BTO:0000007 32697994 t miannu "Sprouty-related, EVH1 domain-containing (SPRED) proteins negatively regulate RAS/mitogen-activated protein kinase (MAPK) signaling following growth factor stimulation. This inhibition of RAS is thought to occur primarily through SPRED1 binding and recruitment of neurofibromin, a RasGAP, to the plasma membrane. Here, we report the structure of neurofibromin (GTPase-activating protein [GAP]-related domain) complexed with SPRED1 (EVH1 domain) and KRAS. The structure provides insight into how the membrane targeting of neurofibromin by SPRED1 allows simultaneous interaction with activated KRAS." SIGNOR-273660 PRKCA protein P17252 UNIPROT TNNI3 protein P19429 UNIPROT unknown phosphorylation Ser77 GEKGRALsTRCQPLE -1 2584239 t lperfetto "We have now determined that PKC phosphorylated serine 43 (and/or serine 45), serine 78, and threonine 144 in the free Tn-I subunit" SIGNOR-248890 MAPK14 protein Q16539 UNIPROT CDKN1A protein P38936 UNIPROT "up-regulates quantity by stabilization" phosphorylation Ser130 SGEQAEGsPGGPGDS 9606 12058028 t gcesareni "The stress-activated protein kinases p38 alpha and jnk1 stabilize p21(cip1) by phosphorylation.|p38 alpha and JNK1 phosphorylated p21 in vivo, and both p38 alpha and JNK1 phosphorylated p21 at Ser(130) in vitro." SIGNOR-89436 PHKA1 protein P46020 UNIPROT PHKA1 protein P46020 UNIPROT "up-regulates activity" phosphorylation Ser972 KEFGVERsVRPTDSN -1 10487978 t miannu "Phk is activated in vitro by autophosphorylation. Ser1018 and at least three of the other six serine residues (Ser972, -985, and -1007) can be phosphorylated in vitro by Phk itself (autophosphorylation)" SIGNOR-250281 prazosin chemical CHEBI:8364 ChEBI ADRA1D protein P25100 UNIPROT "down-regulates activity" "chemical inhibition" 10029 BTO:0000246 7651358 t miannu "Membrane preparations from CHO cells stably transfected with the cloned human a1-AR genes showed saturable binding of [‘251]HEAT; Bm,,ı values were 1.3 ± 0.2, 5.5 ± 0.1, and 1.1 ± 0.1 pmol/mg of protein, with Kd values of 110 ± 21, 60 ± 1, and 300 ± 26 ıM (three experiments each), for the ala-, alb-, and ald-ARS, respectively. The potencies of a1-AR agonists and antagonists at the cloned human a1-ARs are shown in Table 1." SIGNOR-258468 SHANK3 protein Q9BYB0 UNIPROT GRIA2 protein P42262 UNIPROT "up-regulates quantity" binding 9606 BTO:0000938 28179641 t miannu "SHANK proteins are ‘master’ scaffolding proteins that tether and organize intermediate scaffolding proteins. They are located at excitatory synapses, where they are crucial for proper synaptic development and function. SAPAP proteins subsequently bind to the PDZ domain of members of the SHANK protein family. SHANK proteins then bind to the actin cytoskeleton and to Homer protein, which in turn interacts with mGluRs. Through these extended links, PSD95, SAPAP, SHANK and Homer proteins form a quaternary complex that brings together mGluR and NMDAR complexes in the PSD (FIG. 3)." SIGNOR-264602 COL4A5 protein P29400 UNIPROT "A1/b1 integrin" complex SIGNOR-C159 SIGNOR "up-regulates activity" binding 35267698 t lperfetto "Integrins constitute a major group of receptors for extracellular matrix components, including collagens.|Among the four types, the signaling mechanism of α1β1 and α2β1 integrins has especially been reported. These integrins bind to both collagen types I and IV; however, their affinities differ: α1β1 has a higher affinity for collagen type IV, while α2β1 preferentially binds to collagen type I [13,23]." SIGNOR-272349 SMARCA4 protein P51532 UNIPROT "SWI/SNF ACTL6B varian" complex SIGNOR-C476 SIGNOR "form complex" binding 9606 30397315 t miannu "Mammalian SWI/SNF (mSWI/SNF) complexes are ATP-dependent chromatin remodelers that modulate genomic architecture and DNA accessibility, enabling timely and appropriate control of gene expression. They are combinatorially assembled from the products of 29 total genes into three final-form complexes: canonical BAF, PBAF (polybromo-associated BAF complexes), and a newly-defined non-canonical BAF (ncBAF), with specific subunits specifying distinct complexes, such as PBRM1, ARID2, and BRD7 in PBAF complexes, ARID1A/ARID1B and DPF2 in canonical BAF (cBAF) complexes, and GLTSCR1/GLTSCR1L and BRD9 in ncBAF complexes" SIGNOR-270608 SMAD3 protein P84022 UNIPROT SMAD3 protein P84022 UNIPROT "up-regulates activity" binding 9534 9670020 t lperfetto "Smad2 and Smad3 form homo-oligomers upon phosphorylation by the constitutively active TGF-beta type I receptor, and this oligomerization does not require Smad4" SIGNOR-217227 Ub:E2 complex SIGNOR-C497 SIGNOR ZBTB12 protein Q9Y330 UNIPROT "up-regulates activity" ubiquitination 9606 34199813 t miannu "The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t" SIGNOR-271022 "tacrolimus (anhydrous)" chemical CHEBI:61049 ChEBI PPP3CB protein P16298 UNIPROT down-regulates "chemical inhibition" 9606 15276472 t gcesareni "Calcineurin catalytic activity is inhibited by the immunosuppressive drugs cyclosporine and fk506 through complexes with immunophilin proteins." SIGNOR-127242 GAST protein P01350 UNIPROT CCKBR protein P32239 UNIPROT up-regulates binding 9606 BTO:0000142 10368033 t gcesareni "A segment of five amino acids in the second extracellular loop of the cck-b receptor was shown to be essential for the high affinity of the natural peptide agonits, gastrin," SIGNOR-66987 RBKS protein Q9H477 UNIPROT "D-ribofuranose 5-phosphate(2-)" smallmolecule CHEBI:78346 ChEBI "up-regulates quantity" "chemical modification" 9606 25749547 t miannu "Human ribokinase (RK) is a member of the ribokinase family, and is the first enzyme responsible for D-ribose metabolism, since D-ribose must first be converted into D-ribose-5-phosphate to be further metabolized and incorporated into ATP or other high energy phosphorylated compounds." SIGNOR-267073 Ub:E2 complex SIGNOR-C497 SIGNOR RNF183 protein Q96D59 UNIPROT "up-regulates activity" ubiquitination 9606 34199813 t miannu "The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t" SIGNOR-271209 AMPK complex SIGNOR-C15 SIGNOR NR2C2 protein P49116 UNIPROT down-regulates phosphorylation Ser351 HVISRDQsTPIIEVE 9606 21478464 t lperfetto "Tr4 transactivation is inhibited via phosphorylation bymetformin-induced amp-activated protein kinase (ampk) at the amino acid serine 351, which results in the suppression of scd1 gene expression" SIGNOR-216537 CNR2 protein P34972 UNIPROT GNAI1 protein P63096 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-256700 MLL-AF4 "fusion protein" SIGNOR-FP4 SIGNOR DOT1L protein Q8TEK3 UNIPROT "up-regulates activity" binding 9606 BTO:0005014 27856324 t irozzo "Previously, we found that MLL-AF4 binds to the BCL-2 gene and directly activates it through DOT1L recruitment and increased H3K79me2/3 levels. MLL-AF4 directly controls the active transcription of both BCL-2 and MCL-1 […]. Of all the BCL-2 family members, only BCL-2 and MCL-1 are directly activated by MLL-AF4." SIGNOR-255882 GRK2 protein P25098 UNIPROT FPR1 protein P21462 UNIPROT "down-regulates activity" phosphorylation Thr329 RALTEDStQTSDTAT -1 7836371 t gcesareni "Kinetic studies demonstrated that GRK2 has a Km for the carboxyl-terminal domain of the FPR of approximately 1.5 microM and that denaturation of the substrate results in an almost complete loss of phosphorylation [€] simultaneous substitution of the upstream Ser328, Thr329, Thr331, and Ser332 or merely the Ser328 and Thr329 residues resulted in an approximately 80% reduction in phosphorylation." SIGNOR-249664 EP300 protein Q09472 UNIPROT PCK1 protein P35558 UNIPROT "down-regulates quantity by destabilization" acetylation Lys70 EGILRRLkKYDNCWL 9606 BTO:0000007 21726808 t lperfetto "Acetylation Regulates Gluconeogenesis by Promoting PEPCK1 Degradation via Recruiting the UBR5 Ubiquitin Ligase|P300 Acetylates and Destabilizes PEPCK1|Furthermore, coexpression of P300 increased acetylation levels of wild-type PEPCK1, but not PEPCK13K/R, indicating that P300 acts on these lysine residues of PEPCK1" SIGNOR-267597 ABL1 protein P00519 UNIPROT STX17 protein P56962 UNIPROT "down-regulates activity" phosphorylation Tyr157 SQSLTQIyALPEIPQ 9534 BTO:0001538 23006999 t miannu "C-Abl was identified as one of the kinases, which phosphorylates syntaxin 17.Western blot shows phosphorylation of syntaxin 17 on Tyr-156 by overexpression and activation of c-Abl. A phospho-mimicking mutant (Y156E) of syntaxin 17 showed reduced interaction with COPI vesicles. These results suggest that tyrosine phosphorylation of syntaxin 17 is likely to have a role in regulating syntaxin 17 dependent membrane trafficking in the early secretory pathway." SIGNOR-273538 SRC protein P12931 UNIPROT WASF1 protein Q92558 UNIPROT up-regulates phosphorylation Tyr125 PIPLQETyDVCEQPP 9606 16317717 t lperfetto "The wave/scar proteins regulate actin polymerisation at the leading edge of motile cells via activation of the arp2/3 complex in response to extracellular cues.Src-dependent phosphorylation of scar1 promotes its association with the arp2/3 complex" SIGNOR-142724 CHD4 protein Q14839 UNIPROT "MBD3/NuRD complex" complex SIGNOR-C338 SIGNOR "form complex" binding 9606 27098840 t miannu "The NuRD complex is a multi-protein transcriptional corepressor that couples histone deacetylase and ATP-dependent chromatin remodelling activities.In humans, an assembly of proteins called the NuRD complex makes chromatin more compact by removing acetyl groups from nucleosomes. This complex is important for early development and for the stability and repair of our genes. Three proteins make up its core: HDAC1, which removes the acetyl group from the nucleosome; MTA1, which acts as a scaffold to hold the complex together; and RBBP4, which enables the complex to interact with nucleosomes. MBD2 and MBD3 are members of the methyl cytosine-guanosine (CpG)-binding domain (MBD) family of proteins42; 43. Of the five MBD members, only MBD2 and MBD3 associate with NuRD and are required for the complex formation and gene repression." SIGNOR-263856 clozapine chemical CHEBI:3766 ChEBI HTR1A protein P08908 UNIPROT "up-regulates activity" "chemical activation" 10116 BTO:0000601 8935801 t miannu "Risperidone and its active metabolite 9-OH-risperidone were compared to reference antipsychotic drugs (haloperidol, pipamperone, fluspirilene, clozapine, zotepine) and compounds under development (olanzapine, seroquel, sertindole, ORG-5222, ziprasidone) for in vitro binding to neurotransmitter receptors in brain tissue and on membranes of recombinant cells expressing cloned human receptors and for in vivo occupancy of neurotransmitter receptors in rat and guinea-pig brain following acute treatment (2 h., s.c.). The binding affinities of the compounds for various neurotransmitter receptors were measured using membrane preparations of animal brain regions and of recombinant cells expressing cloned, mostly human receptors. Receptors, tissues and cells are indicated in Table I; results are shown in Table 4A-B." SIGNOR-258517 NPFFR2 protein Q9Y5X5 UNIPROT GNAO1 protein P09471 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-256988 PTGER4 protein P35408 UNIPROT GNAL protein P38405 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-256903 STAT3 protein P40763 UNIPROT FOXP3 protein Q9BZS1 UNIPROT down-regulates 9606 18156621 f "Our results demonstrate that IL-27 inhibits the acquisition of the Treg phenotype at the level of Foxp3. The inhibitory effect of IL-27 on Treg generation was at least partially signal transducer and activator of transcription 3 (STAT3) dependent as examined by targeted STAT3 protein inhibition using small interfering RNA (siRNA)" SIGNOR-254304 PRKACA protein P17612 UNIPROT PKD2L1 protein Q9P0L9 UNIPROT "up-regulates activity" phosphorylation Ser685 KLGRSIVsSPQGKSG -1 29230552 t miannu "PKD2L1 channel activation by PKA phosphorylation. In this study, we observed the activity of PKD2L1 channel increased by the downstream cascades of β2AR and found the clustered phosphorylation sites, Ser-682, Ser-685, and Ser-686 that are significant in the channel regulation by phosphorylation." SIGNOR-273562 prednisone chemical CHEBI:8382 ChEBI NR3C1 protein P04150 UNIPROT up-regulates "chemical activation" 9606 4344326 t "Bell's palsy" gcesareni SIGNOR-251704 RPE protein Q96AT9 UNIPROT "D-xylulose 5-phosphate(2-)" smallmolecule CHEBI:57737 ChEBI "up-regulates quantity" "chemical modification" 9606 34775382 t miannu "The reversible nonoxidative phase starts with Ru5P that is transformed into ribose-5-phosphate (R5P) by ribulose-5-phosphate isomerase. R5P is an essential component of purine and pyrimidine nucleotides biosynthesis. Ru5P may also be converted into xylulose-5-phosphate by ribulose-5-phosphate-3-epimerase, which was reported to enhance glycolytic flux." SIGNOR-267068 PLPPR1 protein Q8TBJ4 UNIPROT RASGEF1B protein Q0VAM2 UNIPROT "up-regulates activity" binding 9606 27058420 t miannu "Oncogenic effects of imbalanced PRG3 are mediated via PRG3-RasGEF1 interaction and Ras activation. PRG3 interacts with RasGEF1 in vivo.We could further show that PRG3 executes the binding to RasGEF1 predominantly via its C-terminal domain (CT) and in the consequence causes Ras activation." SIGNOR-261806 VRK2 protein Q86Y07 UNIPROT BANF1 protein O75531 UNIPROT down-regulates phosphorylation Thr3 tSQKHRDF 9606 16495336 t gcesareni "We demonstrate that phosphorylation of ser4 and/or thr2/thr3 abrogates the interaction of baf with dna and reduces its interaction with the lem domain. Coexpression of vrk1 and gfp-baf greatly diminishes the association of baf with the nuclear chromatin/matrix and leads to its dispersal throughout the cell" SIGNOR-144803 EIF3E protein P60228 UNIPROT MCM7 protein P33993 UNIPROT "up-regulates quantity by stabilization" binding 9606 BTO:0002181 17310990 t irozzo "Our data show that INT6 interacts with a C-terminal domain of MCM7. Collectively, our observations suggest that INT6 restrains the increased degradation of MCM7 occurring during DNA replication by protecting its polyubiquitylated derivatives from the proteasome activity." SIGNOR-259154 PIAS1 protein O75925 UNIPROT STAT1 protein P42224 UNIPROT down-regulates binding 9606 BTO:0000887;BTO:0001103 23663276 t milica "Socs1 and socs3 target jak1 and gp130, respectively, near the plasma membrane to prevent cytoplasmic stats from being activated, whereas pias1 principally targets activated stat1 in the cell nucleus and prevents it from binding to dna." SIGNOR-202039 "tamoxifen citrate" chemical CHEBI:9397 ChEBI ESR2 protein Q92731 UNIPROT "down-regulates activity" "chemical inhibition" 9606 20512796 t miannu "Estrogen receptor-alpha (ER) antagonists have been widely used for breast cancer therapy. Despite initial responsiveness, hormone-sensitive ER-positive cancer cells eventually develop resistance to ER antagonists. It has been shown that in most of these resistant tumor cells, the ER is expressed and continues to regulate tumor growth. Recent studies indicate that tamoxifen initially acts as an antagonist, but later functions as an ER agonist, promoting tumor growth." SIGNOR-259300 MAPK14 protein Q16539 UNIPROT SMAD3 protein P84022 UNIPROT "up-regulates activity" phosphorylation Ser208 DAGSPNLsPNPMSPA 9606 BTO:0001939 15520018 t miannu "Smad3 was phosphorylated at both Ser203 and Ser207 in untreated MCF10CA1h cells and the p38 and ROCK inhibitors each down-regulated phosphorylation at these sites. we demonstrate that phosphorylation at Ser203 and Ser207 residues is required for the full transactivation potential of Smad3, and that these residues are targets of the p38 and Rho/ROCK pathways." SIGNOR-250112 ABL1 protein P00519 UNIPROT ABL1 protein P00519 UNIPROT "up-regulates activity" phosphorylation Tyr393 RLMTGDTyTAHAGAK 9606 BTO:0001271 8441409 t lperfetto "Sh1 domain autophosphorylation of p210 bcr/abl is required for transformation but not growth factor independence." SIGNOR-39142 GSK3B protein P49841 UNIPROT CAMKK2 protein Q96RR4 UNIPROT down-regulates phosphorylation Ser129 ICPSLPYsPVSSPQS 9606 22778263 t lperfetto "Cdk5 and gsk3 phosphorylate ser-129, ser-133, and ser-137. Mutation of ser-129, ser-133, and ser-137 increases autonomous activity with little change in ca2 /cam-dependent activity." SIGNOR-198134 MAPK1 protein P28482 UNIPROT GAB1 protein Q13480 UNIPROT "up-regulates activity" phosphorylation Ser567 DSSRFPMsPRPDSVH 10029 BTO:0000246 15379552 t lperfetto "Our results demonstrate that ERK1/2 phosphorylate Gab1 at six serine/threonine residues (T312, S381, S454, T476, S581, S597) in consensus motifs for MAP kinase phosphorylation. |serine and threonine phosphorylation are capable of modulating the initial signal" SIGNOR-249398 SIK2 protein Q9H0K1 UNIPROT CRTC2 protein Q53ET0 UNIPROT down-regulates phosphorylation Ser171 SALNRTSsDSALHTS 9606 20577053 t gcesareni "Phosphorylation on the ser171 residue of crtc2 by ampk and ampk-related kinases, including the salt-inducible kinases (siks), is critical for determining the activity, cellular localization, and degradation of crtc2" SIGNOR-166372 SP1 protein P08047 UNIPROT PHGDH protein O43175 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 18378410 f miannu "Positive regulation of promoter activity of human 3-phosphoglycerate dehydrogenase (PHGDH) gene is mediated by transcription factors Sp1 and NF-Y." SIGNOR-255208 CASP3 protein P42574 UNIPROT Muscle_atrophy phenotype SIGNOR-PH40 SIGNOR up-regulates 10090 25787076 f miannu "The UPS by itself degrades actomyosin and myofibrillar proteins slowly, but when caspase-3 is activated, it cleaves actomyosin and the myofibrillar proteins to provide substrates for degradation in the UPS . Caspase-3 also can cleave specific subunits of the 19 S proteasome particle, which stimulates the proteolytic activity of the 26S proteasome[...] These results indicate that caspase-3 participates in the muscle proteolysis that is present in tumor-bearing mice" SIGNOR-255336 RPS6KA5 protein O75582 UNIPROT EIF4EBP1 protein Q13541 UNIPROT "down-regulates activity" phosphorylation Ser65 FLMECRNsPVTKTPP 12213813 t lperfetto "In response to UV-B irradiation, the translation factor 4E-BP1 (eukaryotic initiation factor 4E [eIF4E]-binding protein 1) was phosphorylated at Thr36, Thr45, Ser64 and Thr69. Using either p38 MAPK inhibitors or the MSK inhibitor H89, UV-B-irradiation-induced phosphorylation was blocked [43]. 4E-BP1 binds to eIF4E in resting cells to prevent formation of a functional eIF4F complex, which is essential for cap-dependent initiation of translation. Phosphorylation of 4E-BP1 leads to dissociation from eIF4E" SIGNOR-262993 GSK3B protein P49841 UNIPROT MAPT protein P10636 UNIPROT "down-regulates activity" phosphorylation Ser512 PPKSGDRsGYSSPGS 9606 BTO:0000590 9771888 t lperfetto "Sequencing of 32P-labeled trypsin phosphopeptides from tau prephosphorylated by A-kinase (using unlabeled ATP) and further phosphorylated by GSK-3 in the presence of [gamma-32P]ATP revealed that Ser-195, Ser-198, Ser-199, Ser-202, Thr-205, Thr-231, Ser-235, Ser-262, Ser-356 and Ser-404 are phosphorylated, whereas if tau is not prephosphorylated by A-kinase, GSK-3 phosphorylates it at Thr-181, Ser-184, Ser-262, Ser-356 and Ser-400. These data suggest that (i) prephosphorylation of tau by A-kinase makes additional and different sites accessible for phosphorylation by GSK-3; (ii) phosphorylation of tau at these additional sites further inhibits the biological activity of tau in its ability to bind to microtubules and promote microtubule assembly." SIGNOR-249353 PPP2CA protein P67775 UNIPROT EEF2 protein P13639 UNIPROT up-regulates dephosphorylation Thr57 RAGETRFtDTRKDEQ 9606 phosphorylation:Thr57 RAGETRFtDTRKDEQ 8386634 t gcesareni "Protein phosphatases-2a and -2c (pp-2a and pp-2c) can each efficiently dephosphorylate phosphorylated eef-2" SIGNOR-38561 RIPK3 protein Q9Y572 UNIPROT MLKL protein Q8NB16 UNIPROT "up-regulates activity" phosphorylation Ser360 RKTQTSMsLGTTREK -1 24012422 t gianni "MLKL comprises a four-helical bundle tethered to the pseudokinase domain, which contains an unusual pseudoactive site. Although the pseudokinase domain binds ATP, it is catalytically inactive and its essential nonenzymatic role in necroptotic signaling is induced by receptor-interacting serine-threonine kinase 3 (RIPK3)-mediated phosphorylation.[...]S345, S347, and T349 in the MLKL activation loop were phosphorylated by RIPK3 in in vitro kinase assays" SIGNOR-266440 NFYA protein P23511 UNIPROT SOX18 protein P35713 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000567 18496767 f miannu "co-transfection experiments revealed that over-expression of Sp3 and ZBP-89 down-regulate, while over-expression of NF-Y up-regulates SOX18 promoter activity in HeLa cells" SIGNOR-254818 HIPK2 protein Q9H2X6 UNIPROT HMGA1 protein P17096 UNIPROT down-regulates phosphorylation Ser36 PRKQPPVsPGTALVG 9606 17960875 t gcesareni "Here, we found that hipk2 phosphorylates hmga1a at ser-35, thr-52, and thr-77, and hmga1b at thr-41 and thr-66. In addition, we demonstrated that cdc2, which is known to phosphorylate hmga1 proteins, could induce the phosphorylation of hmga1 proteins at the same ser/thr sites. we found that the hipk2-phosphorylated hmga1a reduced the binding affinity of hmga1a to human germ line promoter, and the drop in binding affinity induced by hipk2 phosphorylation was lower than that introduced by cdc2 phosphorylation." SIGNOR-158616 CSNK1A1L protein Q8N752 UNIPROT GLI3 protein P10071 UNIPROT up-regulates phosphorylation 9606 16481469 t gcesareni "Ci is phosphorylated by pka at multiple sites priming phosphorylation by both gsk3 and cki, leading to partial proteolysis. The pka, gsk3, and cki sites are conserved in gli2 and gli3, vertebrate homologs of ci that are similarly processed" SIGNOR-144554 MAPK8 protein P45983 UNIPROT EIF4ENIF1 protein Q9NRA8 UNIPROT up-regulates phosphorylation Ser587 YLRPRIPsPIGFTPG 9606 22966201 t llicata "Identification of 4e-t phosphorylation sites regulated by jnk. identification of these residues as phosphorylation sites (ser301, ser374, ser513, ser587, ser693, and ser752) was obtained by ms/ms sequencing, these results demonstrate that jnk activity is required to stimulate the assembly of pbs in response to oxidative stress." SIGNOR-198996 MAPK1 protein P28482 UNIPROT TSC1 protein Q92574 UNIPROT down-regulates phosphorylation 9606 15851026 t gcesareni "Here, we show that erk may play a critical role in tsc progression through posttranslational inactivation of tsc2. Erk-dependent phosphorylation leads to tsc1-tsc2 dissociation and markedly impairs tsc2 ability to inhibit mtor signalin." SIGNOR-135692 TRIM27 protein P14373 UNIPROT ULK1 protein O75385 UNIPROT "down-regulates quantity" ubiquitination 10090 35670107 t "STK38L ubiquitination promotes its activation and phosphorylation of ULK1 at Ser495, rendering ULK1 in a permissive state for TRIM27-mediated hyper-ubiquitination" SIGNOR-270349 ZAP70 protein P43403 UNIPROT LAT protein O43561 UNIPROT "up-regulates activity" phosphorylation Tyr255 EEEGAPDyENLQELN 9606 11368773 t lperfetto "In the present study we reconstituted the LAT signalling pathway by demonstrating that a direct tyrosine phosphorylation of LAT with activated protein-tyrosine kinase Zap70 is necessary and sufficient for the association and activation of signalling proteins. Zap-70 efficiently phosphorylates LAT on tyrosine residues at positions 226, 191, 171, 132 and 127." SIGNOR-247034 PAX7 protein P23759 UNIPROT Differentiation phenotype SIGNOR-PH37 SIGNOR down-regulates BTO:0001103 15501225 f svumbaca "We found that ectopic expression of Pax-7 prevented myogenic differentiation and the induction of myogenin protein." SIGNOR-255367 "Cullin 1-RBX1-Skp1" complex SIGNOR-C529 SIGNOR CHUK protein O15111 UNIPROT "down-regulates quantity by destabilization" polyubiquitination 9606 BTO:0000007 10321728 t miannu "We identified a human F-box/WD40 repeats protein (HOS), which is homologous to Slimb/h betaTrCP. Being a part of SCF complex with Skp1 and Cullin1, HOS specifically interacted with the phosphorylated IkappaB and beta-catenin, targeting these proteins for proteasome-dependent degradation in vivo. " SIGNOR-272548 PEA15 protein Q15121 UNIPROT ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR down-regulates 9606 11702783 f "inferred from 70% of family members" gcesareni "Here, we report that pea-15, a protein variably expressed in multiple cell types, blocks erk-dependent transcription and proliferation by binding erks and preventing their localization in the nucleus._ Pea-15 can redirect the biological outcome of map kinase signaling by regulating the subcellular localization of erk map kinase." SIGNOR-269925 NARS1 protein O43776 UNIPROT ATP(4-) smallmolecule CHEBI:30616 ChEBI "down-regulates quantity" "chemical modification" 9606 32788587 t miannu "Asparaginyl-tRNA synthetase1 (NARS1) is a member of the ubiquitously expressed cytoplasmic Class IIa family of tRNA synthetases required for protein translation. Asparaginyl-tRNA synthetase1 (NARS1) belongs to the class IIa family, based upon a 7 beta-strand protein structure. There are two NARS genes: NARS1 functions in the cytoplasm while NARS2 functions in mitochondria, solely responsible for asparagine tRNA charging in these locations." SIGNOR-270455 NBN protein O60934 UNIPROT ATM protein Q13315 UNIPROT up-regulates binding 9606 18854157 t gcesareni "Nbs1 can also immobilize atm at the site of the dsb via direct binding of atm to a c-terminal atm interaction motif on nbs1 . the mre11/rad50/nbs1 (mrn) complex maintains genomic stability by bridging dna ends and initiating dna damage signaling through activation of the atm" SIGNOR-181631 SENP1 protein Q9P0U3 UNIPROT GCM1 protein Q9NP62 UNIPROT "up-regulates activity" desumoylation 9606 BTO:0000007 21791615 t miannu "We show that Epac1 and Rap1, in response to cAMP, activate CaMKI to phosphorylate Ser47 in GCM1. This phosphorylation facilitates the interaction between GCM1 and the desumoylating enzyme SENP1 and thereby leads to GCM1 desumoylation and activation." SIGNOR-262681 NOG protein Q13253 UNIPROT BMP2 protein P12643 UNIPROT down-regulates binding 9606 12700180 t lperfetto "Noggin acts by binding bmps, thus preventing them from binding to their receptors (180). Noggin binds with various degrees of affinity bmp-2, -4, -5, -6, and -7, gdf-5, gdf-6, and vg1, but not other members of the tgf- family of peptides" SIGNOR-100657 LPAR1 protein Q92633 UNIPROT GNA12 protein Q03113 UNIPROT up-regulates binding 9606 20331961 t milica "The receptor, now called lpa1, is a gpcr that couples to heterotrimeric g proteins (gi, gq, g12/13alpha subunits)." SIGNOR-164679 ATM protein Q13315 UNIPROT MCM3 protein P25205 UNIPROT unknown phosphorylation Ser535 ATDDPNFsQEDQQDT 9606 15210935 t lperfetto "Atm phosphorylates mcm3 on s535 in response to ionizing radiation. Second, atr phosphorylates mcm2 on s108 in response to multiple forms of dna damage and stalling of replication forksthe functional consequences of mcm2 s108 and mcm3 s535 phosphorylation are not clear" SIGNOR-126308 HES1 protein Q14469 UNIPROT RBPJ protein Q06330 UNIPROT down-regulates binding 9606 16682003 t gcesareni "Here we show that hrt2 and hes1 interact with rbp-jkappa to negatively regulate notch-dependent activation of hrt and hes expression." SIGNOR-146684 FLT3 protein P36888 UNIPROT PTPRJ protein Q12913 UNIPROT "down-regulates activity" 10090 22438257 f "Taken together, the described findings supported the notion that FLT3 ITD causes reduced DEP-1 activity compared with cells expressing WT FLT3 rather than alterations in mRNA or protein levels." SIGNOR-261553 CTCF protein P49711 UNIPROT MGAT5B protein Q3V5L5 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 BTO:0001976 21771782 f miannu "By EMSA and ChIP analyses we identified two regulatory proteins, NeuroD1 and CTCF that bind to and activate the GnT-IX promoter. We also revealed that GnT-IX expression was suppressed in CTCF- and NeuroD1-depleted cells, indicating that a NeuroD1- and CTCF-dependent epigenetic mechanism governs brain-specific GnT-IX expression." SIGNOR-253826 Ub:E2 complex SIGNOR-C497 SIGNOR RNF166 protein Q96A37 UNIPROT "up-regulates activity" ubiquitination 9606 34199813 t miannu "The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t" SIGNOR-271065 NFIL3 protein Q16649 UNIPROT PER1 protein O15534 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 11316793 t miannu "E4BP4, a basic leucine zipper transcription factor, contains a DNA-binding domain closely related to DBP, HLF, and TEF, which are PAR proteins. Here, we show that the phase of e4bp4 mRNA rhythm is opposite to that of the dbp, hlf, and tef rhythms in the suprachiasmatic nucleus (SCN), the mammalian circadian center, and the liver. The protein levels of E4BP4 and DBP also fluctuate in almost the opposite phase. All PAR proteins activate, whereas E4BP4 suppresses the mPer1 promoter through the same sequence" SIGNOR-268056 ESCRT-III complex SIGNOR-C379 SIGNOR Membrane_fusion phenotype SIGNOR-PH122 SIGNOR up-regulates 9606 26775243 f miannu "The ESCRT machinery drives a diverse collection of membrane remodeling events, including multivesicular body biogenesis, release of enveloped retroviruses and both reformation of the nuclear envelope and cytokinetic abscission during mitotic exit." SIGNOR-265536 TUBA1B protein P68363 UNIPROT Neuron_migration phenotype SIGNOR-PH67 SIGNOR up-regulates 9606 BTO:0000007 19185337 f miannu "We show here that Elongator regulates corticogenesis because an acute disruption of its activity in dorsal progenitors results in radial migration delays and defective terminal branching of projection neurons that come with a reduction in α-tubulin acetylation. Importantly, this complex interacts with the microtubule cytoskeleton, where Elp3 may directly acetylate α-tubulin, a posttranslational modification known to regulate the intracellular trafficking that is critical for cell shape remodeling during migration and terminal branching." SIGNOR-269727 ZMYND8 protein Q9ULU4 UNIPROT EGFR protein P00533 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0001033 27477906 t lperfetto "Our quantitative ChIP experiments confirmed that ZMYND8 and JARID1D were co-localized at Slug, CD44, VEGFA, and EGFR genes (Figures 4F–4I). Our ChIP results also showed that ZMYND8 repressed and occupied other JARID1D target genes, such as the matrix metalloproteinase 1 (MMP1) and MMP3, that we previously reported" SIGNOR-262040 SMURF1 protein Q9HCE7 UNIPROT PARD6/SMURF1 complex SIGNOR-C112 SIGNOR "form complex" binding 9606 BTO:0004183 15761148 t lperfetto "The Par6-Smurf1 complex then mediates the localized ubiquitination of RhoA to enable the TGF_-dependent dissolution of tight junctions during EMT." SIGNOR-227562 NFKB1 protein P19838 UNIPROT THBD protein P07204 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 17211835 f miannu "Blocking the transcriptional activation of NF-kappaB prevented the TNFalpha-induced downregulation of TM." SIGNOR-254811 GSK3B protein P49841 UNIPROT MAPT protein P10636 UNIPROT "down-regulates activity" phosphorylation Thr529 TPGSRSRtPSLPTPP 9606 BTO:0000590 12387894 t lperfetto "We found that cdk5 phosphorylated tau(441) at Thr-181, Ser-199, Ser-202, Thr-205, Thr-212, Ser-214, Thr-217, Thr-231, Ser-235, Ser-396, and Ser-404, but not at Ser-262, Ser-400, Thr-403, Ser-409, Ser-413, or Ser-422. GSK-3beta phosphorylated all the cdk5-catalyzed sites above except Ser-235." SIGNOR-249348 ADORA2B protein P29275 UNIPROT GNAI3 protein P08754 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257152 "Neuropeptide W-30" smallmolecule CHEBI:80256 ChEBI NPBWR1 protein P48145 UNIPROT "up-regulates activity" "chemical activation" 9606 BTO:0002524 31160049 t "Ligand-GPCR dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257548 MTOR protein P42345 UNIPROT AKT1 protein P31749 UNIPROT "up-regulates activity" phosphorylation Ser473 RPHFPQFsYSASGTA 9606 BTO:0000132 SIGNOR-C2 21592956 t lperfetto "Protein kinase B (PKB, Akt) is a Ser/Thr kinase involved in the regulation of cell survival, proliferation, and metabolism and is activated by dual phosphorylation on Thr(308) in the activation loop and Ser(473) in the hydrophobic motif. It plays a contributory role to platelet function, although little is known about its regulation. In this study, we investigated the role of the mammalian target of rapamycin complex (mTORC)-2 in Akt regulation using the recently identified small molecule ATP competitive mTOR inhibitors PP242 and Torin1." SIGNOR-217869 SLC9A4 protein Q6AI14 UNIPROT sodium(1+) chemical CHEBI:29101 ChEBI "up-regulates quantity" relocalization 9606 BTO:0000938 31507243 t miannu "Na+/H+ exchangers play pivotal roles in the control of cell and tissue pH by mediating the electroneutral exchange of Na+ and H+ across cellular membranes. " SIGNOR-265603 CDK9 protein P50750 UNIPROT POLR2A protein P24928 UNIPROT up-regulates phosphorylation Ser1941 SPKGSTYsPTSPGYS 9606 24385927 t lperfetto "Cyclin-dependent kinase 9 (cdk9) promotes elongation by rna polymerase ii (rnapii), mrna processing, and co-transcriptional histone modification. Cdk9 phosphorylates multiple targets, including the conserved rnapii elongation factor spt5 and rnapii itself" SIGNOR-203604 paracetamol chemical CHEBI:46195 ChEBI PTGS2 protein P35354 UNIPROT "down-regulates activity" "chemical inhibition" 9606 BTO:0000876 17884974 t Luana "Acetaminophen (paracetamol) is a selective cyclooxygenase-2 inhibitor in man" SIGNOR-257757 MLNR protein O43193 UNIPROT GNAQ protein P50148 UNIPROT "up-regulates activity" binding 9606 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257016 HECTD3 protein Q5T447 UNIPROT TRIOBP protein Q9H2D6 UNIPROT "down-regulates quantity by destabilization" polyubiquitination 9606 BTO:0000007 18194665 t miannu "Here, we identify a novel Tara-binding protein HECTD3, a putative member of HECT E3 ubiquitin ligases. HECTD3 directly binds Tara in vitro and forms a complex with Tara in vivo. Overexpression of HECTD3 enhances the ubiquitination of Tara in vivo and promotes the turnover of Tara, whereas depletion of HECTD3 by small interfering RNA decreases Tara degradation." SIGNOR-271770 DAPK1 protein P53355 UNIPROT BECN1 protein Q14457 UNIPROT up-regulates phosphorylation Thr119 LSRRLKVtGDLFDIM 9606 19395874 t gcesareni "We found that DAPk phosphorylates Beclin 1 on T119, a critical residue within its BH3 domain, and thus promotes Beclin 1 dissociation from Bcl-X(L) and autophagy induction. Here we report that T119 phosphorylation also reduces the interaction between Beclin 1 and Bcl-2, in line with the high degree of structural homology between the BH3 binding pockets of Bcl-2 and Bcl-X(L) proteins." SIGNOR-185589 SOX11 protein P35716 UNIPROT SPAST protein Q9UBP0 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 22574173 f miannu "we demonstrate that SPAST transcription is positively regulated by NRF1 and SOX11." SIGNOR-254886 IHH protein Q14623 UNIPROT BMP2 protein P12643 UNIPROT up-regulates 9606 22298955 f gcesareni "Ihh is found to be required for bmp-induced os-teogenesis of a limb-bud cell line in culture. Ihh sig-naling is directly required for the osteoblast lineage in developing long bones. Ihh functions in conjunction with other factors such as bmps to induce osteoblast differentiation. In vivo, ihh acts on potential progeni-tor cells to promote osteoblast differentiation and prevent chondrocyte differentiation." SIGNOR-195609 LFNG protein Q8NES3 UNIPROT DLL3 protein Q9NYJ7 UNIPROT up-regulates binding 9606 10934472 t gcesareni "We find that mammalian lunatic fringe (lfng) inhibits jagged1-mediated signalling and potentiates delta1-mediated signalling through notch1." SIGNOR-80524 PRKAA1 protein Q13131 UNIPROT CFTR protein P13569 UNIPROT "down-regulates activity" phosphorylation Ser737 EPLERRLsLVPDSEQ 9606 19095655 t Luana "AMPK phosphorylates CFTR¬†in vitro¬†at two essential serines (Ser737and Ser768) in the R domain, formerly identified as ""inhibitory"" PKA sites.|Interestingly two of these sites, namely Ser737 and Ser768, have been identified as “inhibitory” R domain sites, i.e. when mutated to alanines they augment the open probability of CFTR relative to wild type|Our present results suggest that it might be AMPK rather than PKA that is phosphorylating Ser737 and Ser768 under baseline conditions" SIGNOR-259858 NME1 protein P15531 UNIPROT NETO2 protein Q8NC67 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 17671192 f miannu "To elucidate the molecular mechanism of Nm23-H1 motility suppression, expression microarray analysis of an MDA-MB-435 cancer cell line overexpressing wild-type Nm23-H1 was done and cross-compared with expression profiles from lines expressing the P96S and S120G mutants. Nine genes, MET, PTN, SMO, FZD1, L1CAM, MMP2, NETO2, CTGF, and EDG2, were down-regulated by wild-type but not by mutant Nm23-H1 expression." SIGNOR-255166 MSX2 protein P35548 UNIPROT DLX5 protein P56178 UNIPROT "down-regulates activity" binding 10090 BTO:0000947 9111364 t 2 miannu "We demonstrate that dimerization by Msx and Dlx proteins is mediated through their homeodomains and that the residues required for this interaction correspond to those necessary for DNA binding. Unlike most other known examples of homeoprotein interactions, association of Msx and Dlx proteins does not promote cooperative DNA binding; instead, dimerization and DNA binding are mutually exclusive activities. Msx proteins act as transcriptional repressors and Dlx proteins act as activators, while in combination, Msx and Dlx proteins counteract each other's transcriptional activities." SIGNOR-240990 SRP54 protein P61011 UNIPROT SRPRA protein P08240 UNIPROT "up-regulates activity" binding -1 30649417 t miannu "The multi-domain SRP GTPase SRP54 recognizes the signal with its M domain and establishes the targeting complex consisting of its NG domain bound to the homologous NG domain of the SRP receptor SRα at a proximal ribosome binding site." SIGNOR-261163 KRAS protein P01116 UNIPROT RAF1 protein P04049 UNIPROT up-regulates binding 9606 10882715 t gcesareni "Among other effectors, active ras binds and activates the raf kinase, iniziating a kinase cascade involving serine phosporylation of mek1/2 (mapkk) and tyrosine and threonine phosphorylation of erk1/2. the raf family of proteins (raf-1, a-raf, and b-raf) is serine/threonine kinases that bind to the effector region of ras-gtp, thus inducing translocation of the protein to the plasma membrane. Once there, raf proteins are activated and phosphorylated by different protein kinases.. Association of ras with the mapk kinase kinase, raf, initiates the raf mek erk map kinase cascade." SIGNOR-78911 RFC4 protein P35249 UNIPROT "RF-C complex" complex SIGNOR-C375 SIGNOR "form complex" binding 12930972 t lperfetto "RF‐C, a complex of five subunits, is conserved in all eukaryotes (reviewed in 5). In yeast, all subunits of RF‐C are essential for viability. The genes encoding all five subunits of mammalian RF‐C (145, 40, 38, 37 and 36 kDa) have been cloned" SIGNOR-265508 MELK protein Q14680 UNIPROT MELK protein Q14680 UNIPROT up-regulates phosphorylation Thr167 NKDYHLQtCCGSLAY 9606 16216881 t gcesareni "We have mapped no less than 16 autophosphorylation sites including serines, threonines, and a tyrosine residue and show that the phosphorylation of thr167 and ser171 is required for the activation of melk." SIGNOR-141022 tibolone chemical CHEBI:32223 ChEBI AR protein P10275 UNIPROT "up-regulates activity" "chemical activation" 9606 19464167 t Luana "In this study, we have assessed the potential hormonal profile of tibolone and its primary metabolites on all human steroid receptors (PR, AR, GR, MR, ERα and ERβ) using HeLa or PC3 cells stably transfected with a given receptor and a luciferase reporter gene. We show that tibolone and its ∆ 4 -isomer predominantly bind and activate PR and AR whereas 3α and 3β-OH-tibolone predominantly bind and activate ERα (Table 1)." SIGNOR-257823 COL4A1 protein P02462 UNIPROT ECM_synthesis phenotype SIGNOR-PH8 SIGNOR up-regulates 9606 12778132 t "Type IV collagen is the most abundant Type IV collagen is the most abundant constituent of the BM…All of the type IV collagen in mammals is derived from six genetically distinct alpha-chain polypeptides (alpha1-alpha6)" SIGNOR-254665 NRAS protein P01111 UNIPROT PIK3CG protein P48736 UNIPROT up-regulates binding 9606 21779497 t gcesareni "Grb2 binds and activates sos, which then activates ras, and this activates p110 independently of p85. It was also described that ras interacts with pi3k in a direct manner.llysine residue 227 is essential for the interaction of ras with pi3k" SIGNOR-175228 NFATC4 protein Q14934 UNIPROT GPC6 protein Q9Y625 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000150 21871017 t miannu "NFAT transcriptionally regulates GPC6 induction in breast cancer cells and binds to three regulatory elements in the GPC6 proximal promoter. Expression of GPC6 in response to NFAT signalling promotes invasive migration, whereas GPC6 silencing with shRNA (small-hairpin RNA) potently blocks this phenotype." SIGNOR-264023 MMP1 protein P03956 UNIPROT ECM_disassembly phenotype SIGNOR-PH80 SIGNOR up-regulates 17318226 f lperfetto "Historically, MMPs were thought to function mainly as enzymes that degrade structural components of the ECM." SIGNOR-272354 "MLL/SET subcomplex" complex SIGNOR-C87 SIGNOR "MLL3 complex" complex SIGNOR-C446 SIGNOR "form complex" binding 9606 34156443 t miannu "MLL3/KMT2C and MLL4/KMT2D are two paralogous histone modifiers that belong to the SET1/MLL (also named COMPASS) family of lysine methyltransferases and play critical roles in enhancer-regulated gene activation. MLL3 and MLL4 form identical multi-protein complexes for modifying mono-methylation of histone H3 lysine 4 (H3K4) at enhancers, which together with the p300/CBP-mediated H3K27 acetylation can generate an active enhancer landscape for long-range target gene activation." SIGNOR-268808 CASP9 protein P55211 UNIPROT CASP3 protein P42574 UNIPROT "up-regulates activity" cleavage 9606 BTO:0000567 9390557 t lperfetto "Activated caspase-9 in turn cleaves and activates caspase-3. Mutation of the active site of caspase-9 attenuated the activation of caspase-3 and cellular apoptotic response in vivo, indicating that caspase-9 is the most upstream member of the apoptotic protease cascade." SIGNOR-53582 PRKCB protein P05771 UNIPROT CHAT protein P28329 UNIPROT up-regulates phosphorylation Ser594 HKAAVPAsEKLLLLK 9606 15381704 t "The effect has been demonstrated using P28329-3" gcesareni "We show that chat is differentially phosphorylated by protein kinase c (pkc) isoforms on four serines (ser-440, ser-346, ser-347, and ser-476) and one threonine (thr-255). This phosphorylation is hierarchical, with phosphorylation at ser-476 required for phosphorylation at other serines. Phosphorylation at some, but not all, sites regulates basal catalysis and activation." SIGNOR-129292 Phenelzine chemical CHEBI:8060 ChEBI MAOA protein P21397 UNIPROT "down-regulates activity" "chemical inhibition" -1 18426226 t Luana "Phenylethylhydrazine stoichiometrically reduces the covalent FAD moieties of MAO A and of MAO B. Molecular oxygen is required for the inhibition reactions, and the level of O2 consumption for phenylethylhydrazine is 6-7-fold higher with either MAO A or MAO B than for the corresponding reactions with benzylhydrazine or phenylhydrazine." SIGNOR-257777 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR CIITA protein P33076 UNIPROT down-regulates phosphorylation 9606 18245089 t "inferred from 70% family members" gcesareni "In this study we show that the extracellular signal-regulated kinases 1 and 2 (erk1/2) interact directly with ciita, targeting serine residues in the amino terminus of the protein, including serine 288. These data suggest a model whereby erk1/2-mediated phosphorylation of ciita down-regulates ciita activity by priming it for nuclear export, thus providing a means for cells to tightly regulate the extent of antigen presentation." SIGNOR-270173 CDK7 protein P50613 UNIPROT POLR2A protein P24928 UNIPROT down-regulates phosphorylation Ser1899 SPTYSPTsPVYTPTS 9606 14662762 t lperfetto "Although there is some inconsistency in the literature, it is generally thought that cdk7, a component of the transcription factor (tf) iih, is a major ser-5 kinase, whereas cdk9, a component of positive transcription elongation factor (p-tef) b, is a major ser-2 kinase within cells. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination." SIGNOR-120056 SRC protein P12931 UNIPROT PRKCI protein P41743 UNIPROT up-regulates phosphorylation Tyr265 RVIGRGSyAKVLLVR 9606 11713277 t llicata "Nerve growth factor stimulates multisite tyrosine phosphorylation and activation of the atypical protein kinase c's via a src kinase pathway. tyrosine 256, 271, and 325 were identified as major sites phosphorylated by src in the catalytic domain." SIGNOR-111920 AKAP12 protein Q02952 UNIPROT PRKACA protein P17612 UNIPROT "up-regulates activity" relocalization 14657015 t lperfetto "A-kinase-anchoring protein 250 (AKAP250; gravin) acts as a scaffold that binds protein kinase A (PKA), protein kinase C and protein phosphatases, associating reversibly with the beta(2)-adrenergic receptor." SIGNOR-271835 CDK2 protein P24941 UNIPROT SMAD3 protein P84022 UNIPROT down-regulates phosphorylation Ser213 NLSPNPMsPAHNNLD 9606 15241418 t gcesareni "We have mapped cdk4 and cdk2 phosphorylation sites to thr 8, thr 178 and ser 212 in smad3. taken together, these findings indicate that cdk phosphorylation of smad3 inhibits its transcriptional activity and antiproliferative function" SIGNOR-126732 WWTR1 protein Q9GZV5 UNIPROT SMAD3 protein P84022 UNIPROT "up-regulates activity" binding 9606 21084559 t lperfetto "Taz has been shown to interact with smad2 and smad3 through its coiled-coil region, and to be important in maintaining the nuclear localization of smad2 and smad3 as well as the expression of their target genes in response to tgf-b signaling and, thus, in the maintenance of human esc self-renewal." SIGNOR-232098 ESR2 protein Q92731 UNIPROT SCN9A protein Q15858 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 10090 BTO:0000938 BTO:0001264 22169964 f miannu "17β-Estradiol regulates the gene expression of voltage-gated sodium channels. . In this study, we investigate the mRNA expressions of Nav channel subtypes mediated differentially by the ERs in the DRGs of wild-type (WT) and estrogen receptor knockout (αERKO and βERKO) mice. In the present study, by means of quantitative real-time PCR, we found that the expressions of Nav1.1, Nav1.7, Nav1.8, and Nav1.9 subtypes were elevated in αERKO and βERKO mice" SIGNOR-253473 ARID1A protein O14497 UNIPROT "Brain-specific SWI/SNF SMARCA4 variant" complex SIGNOR-C486 SIGNOR "form complex" binding 9606 BTO:0000142 11790558 t miannu " Whereas chromatin-remodeling complexes are generally thought to promote gene expression, recent genetic and biochemical studies suggest that the SWI/SNF complex may also be involved in transcriptional repression . The subunit composition of the different human complexes that belong to this family is listed in Table 1. Several of the subunits, including SNF5/INI1, are common to all complexes and may constitute its core." SIGNOR-270751 MMP15 protein P51511 UNIPROT ECM stimulus SIGNOR-ST20 SIGNOR down-regulates 17318226 f lperfetto "Historically, MMPs were thought to function mainly as enzymes that degrade structural components of the ECM." SIGNOR-272383 EEF1A1 protein P68104 UNIPROT Tyr-tRNA(Tyr) smallmolecule CHEBI:29161 ChEBI up-regulates relocalization 9606 23699257 t lperfetto "During protein synthesis, eEF1A binds to and delivers aminoacylated tRNAs (aa-tRNAs) to the elongating ribosome (Fig. 1). GTP bound to eEF1A is hydrolyzed upon codon-anticodon match between an aa-tRNA in the A site of the ribosome and mRNA bound to the ribosome." SIGNOR-269518 ATG9A protein Q7Z3C6 UNIPROT YWHAE protein P62258 UNIPROT "up-regulates activity" binding 9606 25266655 t miannu "Our data suggest that the localization of mammalian Atg9A to autophagosomes requires phosphorylation on the C terminus of Atg9A at S761, which creates a 14-3-3ζ docking site. Under basal conditions, this phosphorylation is maintained at a low level and is dependent on both ULK1 and AMPK." SIGNOR-266368 GALR2 protein O43603 UNIPROT GNAQ protein P50148 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257020 HDAC1 protein Q13547 UNIPROT UBE2D3 protein P61077 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0000356 21044962 f miannu "knockdown of SLUG in SLUG-high breast cancer cells elevated the levels of UbcH5c while decreasing the level of cyclin D1 protein. SLUG is recruited at the E2-box sequence at the UbcH5c gene promoter along with the corepressor CtBP1 and the effector HDAC1 to silence the expression of this gene." SIGNOR-255175 PPP1R15A protein O75807 UNIPROT PPP1CC protein P36873 UNIPROT up-regulates relocalization 9606 14718519 t lpetrilli "We found smad7 interacts with growth arrest and dna damage protein, gadd34, a regulatory subunit of the protein phosphatase 1 (pp1) holoenzyme, which subsequently recruits catalytic subunit of pp1 (pp1c) to dephosphorylate t?RI." SIGNOR-120734 SLBP protein Q14493 UNIPROT H2BC3 protein P33778 UNIPROT "up-regulates quantity by expression" "translation regulation" 9606 BTO:0001938 19155325 t lperfetto "Synthesis of mature histone mRNA requires only a single processing reaction: an endonucleolytic cleavage between a conserved stem-loop and a purine-rich downstream element to form the 3' end. The stem-loop binding protein (SLBP) is required for processing, and following processing, histone mRNA is transported to the cytoplasm, where SLBP participates in translation of the histone mRNA|We used radiolabeled probes generated by PCR targeting the open reading frame (ORF) to detect histones H2A, H2B, H3, H4, and H1 and used 7SK snRNA as a loading control (Fig. 2A). The abundance of histone H2A, H2B, H3, and H4 mRNAs is reduced to 37% to 70% of control levels in the SLBP knockdown cells when compared to the C2 control." SIGNOR-265385 gemcitabine chemical CHEBI:175901 ChEBI RRM2 protein P31350 UNIPROT "down-regulates activity" "chemical inhibition" -1 2233693 t miannu "Direct assays of partially purified ribonucleoside diphosphate reductase (EC 1.17.4.1) demonstrated 50% inhibition by 4 microM dFdC 5'-diphosphate; dFdC 5'-triphosphate was much less inhibitory. We conclude that dFdC 5'-diphosphate acts as an inhibitor of ribonucleoside diphosphate reductase." SIGNOR-258387 MTMR4 protein Q9NYA4 UNIPROT SMAD3 protein P84022 UNIPROT down-regulates dephosphorylation 9606 20061380 t gcesareni "Here we demonstrate that myotubularin-related protein 4" SIGNOR-163034 HSBP1 protein O75506 UNIPROT HSF1 protein Q00613 UNIPROT "down-regulates activity" binding 9606 BTO:0000567 9649501 t Monia "HSBP1 is nuclear-localized and interacts in vivo with the active trimeric state of HSF1 that appears during heat shock. During attenuation of HSF1 to the inert monomer, HSBP1 associates with Hsp70. HSBP1 negatively affects HSF1 DNA-binding activity, and overexpression of HSBP1 in mammalian cells represses the transactivation activity of HSF1. HSF1 interacts with HSBP1 in vivo and is a nuclear localized protein." SIGNOR-261181 TFDP1 protein Q14186 UNIPROT CDK1 protein P06493 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000972 14618416 f miannu "To assess transactivating activity of E2F1/DP-1, we also analyzed expression of ten putative transcriptional targets of this complex in HCCs. Expression levels of TFDP1 and E2F1 correlated with those of seven transcriptional targets ( TYMS, DHFR, PCNA, RRM1, CCNE1, CDC2, and MYBL2) that play important roles in the G1/S transition, and down-regulation of TFDP1 inhibited growth of Hep3B cells." SIGNOR-253859 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR RAF1 protein P04049 UNIPROT down-regulates phosphorylation Ser301 SSSPNNLsPTGWSQP 9606 16407412 t lperfetto "Using mass spectrometry, we identified raf-1 phosphorylation on three sp motif sites: s289/s296/s301. These sites were phosphorylated by extracellular signal-regulated kinase (erk)-1 in vitro, and their phosphorylation in vivo was dependent on endogenous erk activity. Functionally, erk-1 expression sustains raf-1 activation in a manner dependent on raf-1 phosphorylation on the identified sites, and s289/296/301a substitution markedly decreases the in vivo activity of raf-1 s259a." SIGNOR-244685 USP7 protein Q93009 UNIPROT RPS27A protein P62979 UNIPROT "up-regulates quantity" cleavage 9606 BTO:0000567 26235645 t miannu "Here we provide data suggesting that two of the four mammalian ubiquitin precursors, UBA52 and UBA80, are processed mostly post-translationally whereas the other two, UBB and UBC, probably undergo a combination of co- and post-translational processing. Using an unbiased biochemical approach we found that UCHL3, USP9X, USP7, USP5 and Otulin/Gumby/FAM105b are by far the most active DUBs acting on these precursors." SIGNOR-270824 "prostaglandin E2(1-)" smallmolecule CHEBI:606564 ChEBI PTGER1 protein P34995 UNIPROT "up-regulates activity" "chemical activation" 9606 BTO:0002524 31160049 t "Ligand-GPCR dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257569 7-[4-[4-(2,3-Dichlorophenyl)-1,4-diazepan-1-yl]butoxy]-3,4-dihydro-1H-quinolin-2-one chemical CID:56597938 PUBCHEM DRD2 protein P14416 UNIPROT "up-regulates activity" "chemical activation" 9606 BTO:0002181 22025698 t Luana "Through a robust diversity-oriented modification of the scaffold represented by aripiprazole (1), we discovered UNC9975 (2), UNC0006 (3), and UNC9994 (4) as unprecedented β-arrestin–biased D2R ligands. " SIGNOR-258320 PD173955 chemical CHEBI:49791 ChEBI ABL1 protein P00519 UNIPROT "down-regulates activity" "chemical inhibition" -1 22037378 t Luana "Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here." SIGNOR-258263 PI3K complex SIGNOR-C156 SIGNOR PIP3 smallmolecule CHEBI:16618 ChEBI "up-regulates quantity" 9606 21798082 t lperfetto "Phosphorylated irs then acts as docking site to recruit and activate phosphatidylinositol-3-kinase (pi3k) which phosphorylates membrane phospholipids, generating phosphoinositide-3,4,5-triphosphate (pip3) from phosphoinositide-4,5-biphosphate. (pip2)." SIGNOR-252722 PAXIP1 protein Q6ZW49 UNIPROT PAX2 protein Q02962 UNIPROT "up-regulates activity" binding 10090 BTO:0000944 10908331 t miannu "PTIP, a novel BRCT domain-containing protein interacts with Pax2 and is associated with active chromatin. The degree of interaction with the Pax2 C-terminal polypeptides correlates with their transcription transactivation potential and we have therefore designated this factor PTIP for Pax transactivation-domain interacting protein." SIGNOR-236965 AKT proteinfamily SIGNOR-PF24 SIGNOR CDKN1C protein P49918 UNIPROT down-regulates phosphorylation Thr310 GVGSVEQtPRKRLR 9606 BTO:0000150 23421998 t lperfetto "Cdk inhibitor p57 (kip2) is downregulated by akt during her2-mediated tumorigenicityakt phosphorylates p57 on ser 282 or thr310. Akt activity results in destabilization of p57 by accelerating turnover rate of p57 and enhancing p57 ubiquitination" SIGNOR-201046 Goserelin chemical CHEBI:5523 ChEBI GNRHR protein P30968 UNIPROT "up-regulates activity" "chemical activation" 9606 BTO:0001033 22416801 t miannu "The efficacy of degarelix compared with a GnRH agonist (goserelin, plus flare protection with bicalutamide) was evaluated in a 12‐week trial in men with lower urinary tract symptoms secondary to prostate cancer." SIGNOR-259161 GSK3B protein P49841 UNIPROT CCND3 protein P30281 UNIPROT down-regulates phosphorylation Thr283 QGPSQTStPTDVTAI 9606 16331257 t lperfetto "We have previously shown that both basal and camp-induced degradation of cyclin d3 in reh cells is dependent on thr-283 phosphorylation by glycogen synthase kinase-3beta (gsk-3beta)." SIGNOR-142880 CDK1 protein P06493 UNIPROT MAPK6 protein Q16659 UNIPROT up-regulates phosphorylation Thr698 KSIQATLtPSAMKSS 9606 SIGNOR-C17 20236090 t lperfetto "Using ms analysis, we identified four novel phosphorylation sites, ser684, ser688, thr698 and ser705, located at the extreme c-terminus of erk3. All four sites are followed by a proline residue. We have shown that purified cyclin b-cdk1 (cyclindependent kinase 1) phosphorylates these sitesalanine substitution of the four c-terminal phosphorylation sites markedly decreased the half-life of erk3 in mitosis, thereby linking phosphorylation to the stabilization of the kinase." SIGNOR-164499 RPAP2 protein Q8IXW5 UNIPROT POLR2A protein P24928 UNIPROT "up-regulates activity" dephosphorylation Ser1721 SPTSPSYsPTSPSYS 9606 BTO:0000567 22137580 t "In addition, we show that RPAP2 is a CTD Ser5 phosphatase. Taken together, our results indicate that during transcription of snRNA genes, Ser7 phosphorylation facilitates recruitment of RPAP2, which in turn both recruits Integrator and dephosphorylates Ser5.|The Pol II CTD is first phosphorylated on Ser5 and then on Ser7 by CDK7. RPAP2 associates with the Pol II CTD after Ser7 phosphorylation and tethers a subcomplex of Integrator to snRNA genes. RPAP2 dephosphorylates Ser5P of the CTD, facilitating transcription and the subsequent recruitment of the Int11 catalytic subunit of Integrator" SIGNOR-248754 PAK5 protein Q9P286 UNIPROT BAD protein Q92934 UNIPROT "down-regulates activity" phosphorylation Ser75 EIRSRHSsYPAGTED 9534 BTO:0000298 12897128 t miannu "P21-Activated kinase 5 (Pak5) localizes to mitochondria and inhibits apoptosis by phosphorylating BAD. Pak5 phosphorylates BAD Ser-112" SIGNOR-250247 F2R protein P25116 UNIPROT GNA12 protein Q03113 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257403 SOSTDC1 protein Q6X4U4 UNIPROT WNT3 protein P56703 UNIPROT "down-regulates activity" 10090 22829579 f lperfetto "Our laboratory identified an almost twofold upregulation of sclerostin domain-containing 1 (Sostdc1; also referred to as WISE, USAG-1, ectodin), a dual Bmp/Wnt inhibitor, in postnatal day (P)1 pancreata from transgenic mice misexpressing hepatocyte nuclear factor (Hnf)6 in islet endocrine cells." SIGNOR-242730 UHMK1 protein Q8TAS1 UNIPROT SF1 protein Q15637 UNIPROT up-regulates phosphorylation Ser82 NPEDRSPsPEPIYNS 9606 16420481 t "The effect has been demonstrated using Q15637-2" gcesareni "Sf1 is phosphorylated on serines 80 and 82 in vitro and in vivo. Kis can phosphorylate sf1f on serine 80 and 82 with a high efficiency that particularly relies on the anchoring of its uhm domain to sf1. Serine phosphorylation of a conserved ser80-pro81-ser82-pro83 motif rigidifies a long unstructured linker in the sf1 helix hairpin and slightly enhances rna binding." SIGNOR-143841 UTS2R protein Q9UKP6 UNIPROT GNAI1 protein P63096 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257051 mTORC2 complex SIGNOR-C2 SIGNOR AKT proteinfamily SIGNOR-PF24 SIGNOR "up-regulates activity" phosphorylation Ser477 PQFSYSAsGTA 9606 BTO:0000093 24670654 t gcesareni "Phosphorylation of S477 and T479 at the Akt extreme carboxy terminus by cyclin-dependent kinase 2 (Cdk2)/cyclin A or mTORC2, under distinct physiological conditions, promotes Akt activation through facilitating, or functionally compensating for, S473 phosphorylation" SIGNOR-252451 RPL39 protein P62891 UNIPROT "60S cytosolic large ribosomal subunit" complex SIGNOR-C287 SIGNOR "form complex" binding -1 25901680 t lperfetto "Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins." SIGNOR-262490 HMGB2 protein P26583 UNIPROT POU2F1 protein P14859 UNIPROT "up-regulates activity" binding 10090 BTO:0002910 7720710 t 2 miannu "HMG2 and Oct2 interact via their HMG domains and POU homeodomains, respectively. This interaction is not restricted to Oct2, as other members of the octamer transcription factor family like Oct1 and Oct6 also interact with HMG2. The interaction with HMG2 results in a marked increase in the sequence-specific DNA binding activity of the Oct proteins" SIGNOR-240151 MED17 protein Q9NVC6 UNIPROT "Core mediator complex" complex SIGNOR-C405 SIGNOR "form complex" binding 9606 28467824 t miannu "Mediator is a multiprotein co-activator that binds the transcription pre-initiation complex (PIC) and regulates RNA polymerase (Pol) II. The Mediator head and middle modules form the essential core Mediator (cMed), whereas the tail and kinase modules play regulatory roles." SIGNOR-266669 ARRB1 protein P49407 UNIPROT KIF3A protein Q9Y496 UNIPROT up-regulates binding 9606 18497258 t gcesareni "Kif3a is essential for shh-mediated signaling in mammalian systems (5), and we identified kif3a as a arr1 binding partner in a proteomics screen (18). To test whether arrs, smo, and kif3a might work in concert." SIGNOR-178672 PTK2 protein Q05397 UNIPROT TRIO protein O75962 UNIPROT "up-regulates activity" phosphorylation Tyr2796 KDNFDSFySEVAELG 9534 12551902 t lperfetto "A FAK phosphorylation site, tyrosine residue 2737, was identified in subdomain I of the Trio kinase domain. Additionally, in vitro phosphorylation assays and in vivo co-expression studies indicated that Trio enhances FAK kinase activity." SIGNOR-249188 STK38 protein Q15208 UNIPROT STK38 protein Q15208 UNIPROT up-regulates phosphorylation Thr444 DWVFINYtYKRFEGL 9606 12493777 t lperfetto "We found that ndr1 autophosphorylates in vitro predominantly on ser-281 and to a lesser extent on thr-74 and thr-444. All of these residues proved to be crucial also for ndr1 activity in vivo" SIGNOR-96683 CSNK2B protein P67870 UNIPROT EIF5 protein P55010 UNIPROT "up-regulates activity" phosphorylation Ser174 DKENGSVsSSETPPP 9606 BTO:0001938 11861906 t llicata "Mass spectrometric analysis of maximally in vitro phosphorylated eIF5 localized the major phosphorylation sites at Ser-387 and Ser-388 near the C-terminus of eIF5. These serine residues are embedded within a cluster of acidic amino acid residues and account for nearly 90% of the total in vitro eIF5 phosphorylation. A minor phosphorylation site at Ser-174 was also observed. | The results suggest that phosphorylation of eIF5 may have a role in stimulating the rate of eIF5-promoted GTP hydrolysis." SIGNOR-251068 RIPK3 protein Q9Y572 UNIPROT MLKL protein Q8NB16 UNIPROT "up-regulates activity" phosphorylation Ser358 ELRKTQTsMSLGTTR 10090 24012422 t gianni "MLKL comprises a four-helical bundle tethered to the pseudokinase domain, which contains an unusual pseudoactive site. Although the pseudokinase domain binds ATP, it is catalytically inactive and its essential nonenzymatic role in necroptotic signaling is induced by receptor-interacting serine-threonine kinase 3 (RIPK3)-mediated phosphorylation.[...]S345, S347, and T349 in the MLKL activation loop were phosphorylated by RIPK3 in in vitro kinase assays" SIGNOR-266427 MAPKAPK2 protein P49137 UNIPROT ZFP36 protein P26651 UNIPROT "down-regulates activity" phosphorylation Ser113 TELCRTFsESGRCRY -1 14688255 t miannu "We confirm phosphorylation of TTP by MK2 and identify specific phosphorylation sites at Ser52, Ser105, Ser58, Ser176, Ser178, and Ser316. If MK2 regulates translation in part by TTP phosphorylation, TTP should be a repressor of translation when dephosphorylated and an activator of (or neutral to) translation when phosphorylated." SIGNOR-250156 MAPK1 protein P28482 UNIPROT DYNC1LI1 protein Q9Y6G9 UNIPROT unknown phosphorylation Ser516 VSPTTPTsPTEGEAS 10090 BTO:0000944 22028470 t miannu "We have optimized a chemical genetic system using analog-sensitive ERK2, a form of ERK2 engineered to use an analog of adenosine 5'-triphosphate (ATP), to tag and isolate ERK2 substrates in vitro. This approach identified 80 proteins phosphorylated by ERK2, 13 of which are known ERK2 substrates. With this improved methodology, we detected 98 sites directly phosphorylated by ERK2 on 80 proteins from NIH 3T3-L1 fibroblasts. Thirteen of these proteins are known substrates and the rest represent previously unknown kinase/substrate interactions. (table1)" SIGNOR-262773 ZNF165 protein P49910 UNIPROT SMURF2 protein Q9HAU4 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0000356 26567849 t Luana "ZNF165 drives the unrestrained activation of transforming growth factor β (TGFβ) signalling by directly inactivating the expression of negative feedback pathway regulators, SMURF2, SMAD7 and PMEPA1." SIGNOR-266095 MAPK3 protein P27361 UNIPROT CTTN protein Q14247 UNIPROT up-regulates phosphorylation Ser418 TEERLPSsPVYEDAA 9606 BTO:0000938 21079800 t gcesareni "Cortactin is regulated by multiple phosphorylation events, including phosphorylation of s405 and s418 by extracellular regulated kinases (erk)1/2. Erk1/2 phosphorylation of cortactin has emerged as an important positive regulatory modification, enabling cortactin to bind and activate the arp2/3 regulator neuronal wiskott-aldrich syndrome protein (n-wasp), promoting actin polymerization and enhancing tumor cell movement." SIGNOR-169686 SPRY2 protein O43597 UNIPROT CBLC protein Q9ULV8 UNIPROT down-regulates 9606 12234920 f gcesareni "Hspry2 prevents c-cbl-mediated ubiquitylation of egfrs. hspry2 interacts specifically with the c-cbl ring finger domain and displaces ubch7 from its binding site on the e3 ligase." SIGNOR-92926 CFL1 protein P23528 UNIPROT Axonal_growth_cone_formation phenotype SIGNOR-PH199 SIGNOR down-regulates 9606 16226035 f miannu "This observation suggests that Slit2 may require the Robo2 and Robo3 receptors in this process . Slit2 causes the miRNA miR-182 to release cofilin1 mRNA, potentiating cofilin1 local translation and resulting in growth cone collapse. The use of morpholinos or RNAi to knockdown robo2 and robo3 in X. laevis RGCs, would be useful to further confirm that Robo2 and Robo3 are the receptors involved in Slit2-dependent cofilin1 translation." SIGNOR-268382 MAPK1 protein P28482 UNIPROT PML protein P29590 UNIPROT up-regulates phosphorylation Ser530 DGPPSPRsPVIGSEV 9606 BTO:0001271 15093545 t "The effect has been demonstrated using P29590-4" gcesareni "We conclude that phosphorylation by map kinase cascades potentiates the antiproliferative functions of pml and helps mediate the proapoptotic effects of as(2)o(3)." SIGNOR-124056 PPP2R1A protein P30153 UNIPROT PPP2CB protein P62714 UNIPROT up-regulates binding 9606 16039140 t miannu "Pr65/a acts as a scaffold protein for binding pp2ac and regulatory b subunits in a heterotrimeric holoenzyme" SIGNOR-138886 ITGA8 protein P53708 UNIPROT "A8/b1 integrin" complex SIGNOR-C165 SIGNOR "form complex" binding 16988024 t lperfetto "Integrins are one of the major families of cell adhesion receptors (Humphries, 2000; Hynes, 2002). All integrins are non-covalently-linked, heterodimeric molecules containing an α and a β subunit. Both subunits are type I transmembrane proteins, containing large extracellular domains and mostly short cytoplasmic domains (Springer and Wang, 2004; Arnaout et al., 2005). Mammalian genomes contain 18 α subunit and 8 β subunit genes, and to date 24 different α,β combinations have been identified at the protein level. Although some subunits only appear in a single heterodimer, twelve integrins contain the β1 subunit, and five contain αV." SIGNOR-253181 INSR protein P06213 UNIPROT GAB1 protein Q13480 UNIPROT "up-regulates activity" phosphorylation Tyr659 VADERVDyVVVDQQK 10090 BTO:0000944 10978177 t "HGab-1 was phosphorylated by IR at eight tyrosine residues (Y242, Y285, Y373, Y447, Y472, Y619, Y657, and Y689). t Gab-1 is the major binding partner of PI-3 kinase in 3T3L1 cells when stimulated with insulin" SIGNOR-251317 SUZ12 protein Q15022 UNIPROT SNAI2 protein O43623 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 23836662 f miannu "We further demonstrated that PER2 served as a transcriptional corepressor, which recruited polycomb proteins EZH2 and SUZ12 as well as HDAC2 to octamer transcription factor 1 (OCT1) (POU2F1) binding sites of the TWIST1 and SLUG promoters to repress expression of these EMT genes." SIGNOR-254150 SRC protein P12931 UNIPROT SRC protein P12931 UNIPROT up-regulates phosphorylation Tyr216 KLDSGGFyITSRTQF 9606 BTO:0000150 12753909 t lperfetto "This study establishes that her2/hrg signaling selectively upregulates tyr phosphorylation of c-src at tyr-215 located within the sh2 domain, increases c-src kinase activity" SIGNOR-236246 Nutlin-3 smallmolecule CID:216345 PUBCHEM TP73 protein O15350 UNIPROT up-regulates 9606 17700533 t miannu "These results provide the first evidence that Nutlin-3 disrupts endogenous p73-HDM2 interaction and enhances the stability and proapoptotic activities of p73 and thus, provides a rationale for the use of Nutlin-3 in the large number of human tumors in which p53 is inactivated." SIGNOR-255472 PPP2CB protein P62714 UNIPROT PRKCB protein P05771 UNIPROT "down-regulates activity" dephosphorylation Thr500 WDGVTTKtFCGTPDY 10116 8749392 t "Specifically, the threonine at position 500 (T500) on the activation loop, and T641 and S660 on the carboxyl terminus of protein kinase C beta II are phosphorylated in vivo. T500 and S660 are selectively dephosphorylated in vitro by protein phosphatase 2A to yield an enzyme that is still capable of lipid-dependent activation, whereas all three residues are dephosphorylated by protein phosphatase 1 to yield an inactive enzyme." SIGNOR-248585 GPR119 protein Q8TDV5 UNIPROT GNAI1 protein P63096 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257040 Ub:E2 complex SIGNOR-C497 SIGNOR TRIM31 protein Q9BZY9 UNIPROT "up-regulates activity" ubiquitination 9606 34199813 t miannu "The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t" SIGNOR-270979 Adechlorin chemical CID:125913 PUBCHEM ADA protein P00813 UNIPROT "down-regulates activity" "chemical inhibition" 9606 2433905 t miannu "2'-Chloropentostatin is a new inhibitor of adenosine deaminase isolated from the fermentation broth of an unidentified actinomycete, ATCC 39365. It contains the aglycone of coformycin, i.e. 3,6,7,8-tetrahydroimidazo[4,5-d][1,3]diazepin-8-o1, coupled to the unusual carbohydrate, 2'-chloro-2'-deoxyribose. 2'-Chloropentostatin is a slightly weaker inhibitor of rat and human adenosine deaminases than coformycin, and considerably weaker than pentostatin. Unlike pentostatin, which appears to undergo a two-stage interaction with adenosine deaminase, 2'-chloropentostatin forms a single enzyme-inhibitor complex. The enzyme-inhibitor complex between adenosine deaminase and 2'-chloropentostatin was much more rapidly dissociable than the complex with pentostatin." SIGNOR-259262 PRKCZ protein Q05513 UNIPROT NCF1 protein P14598 UNIPROT up-regulates phosphorylation Ser315 AHSIHQRsRKRLSQD 9606 12056906 t lperfetto "Phosphopeptide mapping of p47(phox) showed that, as opposed to pkc zeta, pkc alpha, beta ii, and delta are able to phosphorylate all the major pkc sites. The use of p47(phox) mutants identified serines 303, 304, 315, 320, 328, 359, 370, and 379 as targets of pkc alpha, beta ii, and delta.Taken together, these results suggest that pkc alpha, beta ii, delta, and zeta expressed in human neutrophils can individually phosphorylate p47(phox) and induce both its translocation and nadph oxidase activation." SIGNOR-89264 ZMYND8 protein Q9ULU4 UNIPROT SNAI2 protein O43623 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 27477906 t lperfetto "Our quantitative ChIP experiments confirmed that ZMYND8 and JARID1D were co-localized at Slug, CD44, VEGFA, and EGFR genes (Figures 4F–4I). Our ChIP results also showed that ZMYND8 repressed and occupied other JARID1D target genes, such as the matrix metalloproteinase 1 (MMP1) and MMP3, that we previously reported" SIGNOR-262038 "ER stress" stimulus SIGNOR-ST9 SIGNOR ERN1 protein O75460 UNIPROT up-regulates 9606 18065414 f miannu "Our findings suggest that MTHFR is up-regulated by ER stress and that this effect is mediated by IRE1 and c-Jun." SIGNOR-253145 ID1 protein P41134 UNIPROT AKT1 protein P31749 UNIPROT up-regulates binding 9606 BTO:0004136 26084673 t apalma "We have determined that Id1 physically interacts with AKT1, through its C-terminal region, and promotes AKT1 phosphorylation;" SIGNOR-255658 RNGTT protein O60942 UNIPROT "messenger RNA" smallmolecule CHEBI:33699 ChEBI "up-regulates quantity" "chemical modification" 9606 9512541 t lperfetto "The human mRNA 5'-capping enzyme cDNA was identified. Three highly related cDNAs, HCE1 (human mRNAcappingenzyme1), HCE1A and HCE1B , were isolated from a HeLa cDNA library. The HCE1 cDNA has the longest ORF, which can encode a 69 kDa protein. A short region of 69 bp in the 3'-half of the HCE1 ORF was missing in HCE1A and HCE1B , and, additionally, HCE1B has an early translation termi" SIGNOR-268357 bromocriptine chemical CHEBI:3181 ChEBI DRD2 protein P14416 UNIPROT "up-regulates activity" "chemical activation" 10029 BTO:0000246 8301582 t miannu "The most selective compound from this group were (+)butaclamol and domperidone which showed 5-fold D3 selectivity. A number of high affinity dopamine receptor agonists, including apomorphine and bromocriptine, also failed to demonstrate selectivity. In contrast, the natural ligand dopamine and the efficacious synthetic agonists quinpirole, (+)4-propyl-9-hydroxynapthoxazine (PHNO), 2-amino-6,7-dihydroxy-1,2,3,4-tetrahydronaphthalene (6,7-ADTN), 7-OH DPAT and N-0434 showed marked apparent human dopamine D3 (hD3) receptor selectivity. In the aminotetralin series, this selectivity was observed preferentially with analogs of the 6,7-rotamer compared with compounds from the 5,6-rotamer series. Functional coupling of the hD3 receptor was investigated in a number of cell lines in which the hD3 receptor was stably expressed, including CHO cells, the neuroblastoma-glioma hybrid cell line NG108-15 and a rat 1 fibroblast cell line." SIGNOR-258723 CTNNB1 protein P35222 UNIPROT CCND1 protein P24385 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 12589056 f gcesareni "The resulting accumulation of beta-catenin leads to its nuclear translocation and binding to tcf/lef transcription factors to induce target genes including cyclin d1." SIGNOR-98379 GAS6 protein Q14393 UNIPROT TYRO3 protein Q06418 UNIPROT up-regulates binding 9606 7867073 t gcesareni "We report the identification of ligands for tyro 3 (alternatively called sky, rse, brt, or tif) and axl (alternatively, ark or ufo), members of a previously orphan family of receptor-like tyrosine kinases. These ligands correspond to protein s, a protease regulator that is a potent anticoagulant, and gas6, a protein related to protein s but lacking any known function." SIGNOR-34414 PHLPP1 protein O60346 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR down-regulates dephosphorylation Ser473 RPHFPQFsYSASGTA 9606 BTO:0000527 15808505 t gcesareni "Here, we identify a protein_ phosphatase, ph domain leucine-rich repeat protein_ phosphatase_ (phlpp), that specifically_ dephosphorylates_ the hydrophobic motif of_ akt_ (ser473 in akt1), triggering_ apoptosis_ and suppressing_ tumor_ growth." SIGNOR-135005 DMPK protein Q09013 UNIPROT SRF protein P11831 UNIPROT up-regulates phosphorylation Thr159 DNKLRRYtTFSKRKT 10090 12809504 t llicata "Myotonic dystrophy protein kinase (DMPK), a muscle- and neuron-restricted kinase, enhanced SRF-mediated promoter activity of the skeletal and cardiac alpha-actin genes in C2C12 myoblasts as well as in nonmyogenic cells. | Threonine 159 in the MADS box alphaI coil was a specific phosphorylation target in vitro as well as in vivo of both DMPK and protein kinase C-alpha. " SIGNOR-236982 ORC3 protein Q9UBD5 UNIPROT ORC complex SIGNOR-C419 SIGNOR "form complex" binding 9606 32808929 t lperfetto "The dynamic nature of the human origin recognition complex revealed through five cryoEM structures|Genome replication is initiated from specific origin sites established by dynamic events. The Origin Recognition Complex (ORC) is necessary for orchestrating the initiation process by binding to origin DNA, recruiting CDC6, and assembling the MCM replicative helicase on DNA. Here we report five cryoEM structures of the human ORC (HsORC) that illustrate the native flexibility of the complex. |The very first step of this initiation process is accomplished by DNA association with the Origin Recognition Complex (ORC), a six-subunit protein that forms a partial ring around origin DNA" SIGNOR-267565 P2RY13 protein Q9BPV8 UNIPROT GNAO1 protein P09471 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-256749 GART protein P22102 UNIPROT glycine smallmolecule CHEBI:15428 ChEBI "down-regulates quantity" "chemical modification" 9606 34283828 t miannu "In humans, GART [phosphoribosylglycinamide formyltransferase (EC 2.1.2.2) / phosphoribosylglycinamide synthetase (EC 6.3.4.13) / phosphoribosylaminoimidazole synthetase (EC 6.3.3.1)] is a trifunctional protein which catalyzes the second, third, and fifth reactions of the ten step de novo purine synthesis (DNPS) pathway. The second step of DNPS is conversion of phosphoribosylamine (5-PRA) to glycineamide ribonucleotide (GAR)." SIGNOR-267299 PBRM1 protein Q86U86 UNIPROT RARB protein P10826 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 15601824 f miannu "We found that baf180 deficiency leads to a decreased expression of select target genes, such as s100a13 and ra targets rar_2 and crabpii in heart tissues." SIGNOR-132378 AKT1 protein P31749 UNIPROT MVD protein P53602 UNIPROT "up-regulates activity" phosphorylation Ser96 LARKRRNsRDGDPLP 10090 25378391 t miannu "Akt modulated the pathway by phosphorylating mevalonate diphosphate decarboxylase (MDD) at Ser96. These data suggest that Akt regulates Rac1 activity by directly phosphorylating MDD at Ser96, which augments Rac1 geranylgeranylation." SIGNOR-265891 PCDHA10 protein Q9Y5I2 UNIPROT PCDHGC5 protein Q9Y5F6 UNIPROT "up-regulates activity" binding 9606 BTO:0000227 16697637 t miannu "The clustered protocadherins comprise the largest subfamily of the cadherin superfamily and are predominantly expressed in the nervous system. Pcdh-alpha proteins interact with beta1-integrin to promote cell adhesion. They also form oligomers with Pcdh-gamma proteins at the same membrane sites." SIGNOR-265705 "A5/b1 integrin" complex SIGNOR-C163 SIGNOR JAG1 protein P78504 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 BTO:0004093 25786978 f lperfetto "First, EPCs incorporated into the neovascular region recognize the TGFBIp secreted by cells in the environment via binding to integrins a4 and a5. Second, binding of TGFBIp to integrins in EPCs induces phosphorylation of intracellular signaling molecules in a pathway necessary for TGFBIp-mediated angiogenic activity of EPCs. In addition, binding of TGFBIp to integrins activates the NF-kappaB signaling pathway that induces expression of DLL1 and JAG1 in EPCs." SIGNOR-253288 MAPK3 protein P27361 UNIPROT STAT5A protein P42229 UNIPROT up-regulates phosphorylation Ser780 DSLDSRLsPPAGLFT 9606 BTO:0000975 10194762 t gcesareni "Serine 780 is the only substrate in full-length stat5a for active erk" SIGNOR-66247 AURKB protein Q96GD4 UNIPROT NINL protein Q9Y2I6 UNIPROT up-regulates phosphorylation Ser185 WDSEDFGsPQKSCSP 9606 20864540 t lperfetto "Importantly, nlp is characterized as a novel substrate of aurora b and can be phosphorylated by aurora b. The specific phosphorylation sites are mapped at ser-185, ser-448, and ser-585. The phosphorylation at ser-448 and ser-585 is likely required for nlp association with aurora b and localization at midbody. Meanwhile, the phosphorylation at ser-185 is vital to nlp protein stability. Disruptions of these phosphorylation sites abolish cytokinesis and lead to chromosomal instability." SIGNOR-168045 NUDT3 protein O95989 UNIPROT AKT2 protein P31751 UNIPROT up-regulates binding 9606 BTO:0000782;BTO:0001271 10983986 t miannu "Full-length tcl1 and its isoforms bind to akt / in in vitro kinase assays using gsk-3_ as a substrate, we found that the presence of any of the tcl1 family proteins (tcl1, mtcp1, or tcl1b) as gst fusion proteins significantly enhanced akt-induced gsk-3_ phosphorylation" SIGNOR-81759 GATA3 protein P23771 UNIPROT Adipogenesis phenotype SIGNOR-PH26 SIGNOR down-regulates 10090 11021798 f fspada "Constitutive gata-2 and gata-3 expression suppressed adipocyte differentiation and trapped cells at the preadipocyte stage." SIGNOR-78830 GPR17 protein Q13304 UNIPROT GNAO1 protein P09471 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-256971 E2F5 protein Q15329 UNIPROT CBP/p300 complex SIGNOR-C6 SIGNOR "up-regulates activity" binding 9606 BTO:0001938 10783242 t miannu "Here we show that E2F-5 is phosphorylated by the cyclin E-Cdk2 complex, which functions in the late G1 phase, but not by the early-G1-phase-acting cyclin D-CDK complex. A phosphorylation site in the trans-activation domain of E2F-5 stimulates transcription and cell-cycle progression by the recruitment of the p300/CBP family of co-activators, whose binding to E2F-5 is stabilized upon phosphorylation by cyclin E-Cdk2. These results indicate that phosphorylation of E2F-5 at the CDK site at position 251 by cyclin E–Cdk2 augments transcription by enhancing the interaction of E2F-5 with p300/CBP co-activator proteins." SIGNOR-262733 SMURF proteinfamily SIGNOR-PF29 SIGNOR SMAD5 protein Q99717 UNIPROT down-regulates ubiquitination 9606 22298955 t "inferred from 70% family members" gcesareni "Smurf1 and smurf2 are e3 ubiquitin ligases known to suppress tgf-beta signaling through degra-dation of smads and receptors for tgf-beta and bmps" SIGNOR-270213 PCBD1 protein P61457 UNIPROT HNF1B protein P35680 UNIPROT "up-regulates activity" binding 9606 BTO:0000482 24204001 t miannu "Overexpression in a human kidney cell line showed that wild-type PCBD1 binds HNF1B to costimulate the FXYD2 promoter, the activity of which is instrumental in Mg(2+) reabsorption in the DCT." SIGNOR-254910 PIM proteinfamily SIGNOR-PF34 SIGNOR FOXO3 protein O43524 UNIPROT "down-regulates activity" phosphorylation Thr32 QSRPRSCtWPLQRPE 9606 18593906 t fspada "Pim1s expression induced the phosphorylation of foxo3a (fig. 5a and b) and inactivated its transcriptional activity (fig. 5c). A previous report showed that phosphorylation at t32, s253, and s315 residues in foxo3a induced 14-3-3 binding, nuclear export, and proteasomemediated degradation (42)." SIGNOR-259428 MAPK1 protein P28482 UNIPROT RPS6KA1 protein Q15418 UNIPROT "up-regulates activity" phosphorylation Thr359 DTEFTSRtPKDSPGI 9534 BTO:0004055 9430688 t lperfetto "Several lines of evidence indicate that the mapkap-k1 isoforms are also activated by mapks in vivo via the ras-dependent protein kinase cascade that is triggered by growth factors or tumor-promoting phorbol esters, such as phorbol 12-myristate 13-acetate (pma). here we identify six sites in mapkap-k1a that become phosphorylated in transfected cos-1 cells. The inactive form of mapkap-k1a in unstimulated cells is partially phosphorylated at ser222 and ser733. Stimulation with phorbol 12-myristate 13-acetate induces the phosphorylation of thr360, ser364, thr574, and ser381 and increases the phosphorylation of ser222 and ser733." SIGNOR-219324 WDFY3 protein Q8IZQ1 UNIPROT GABARAP protein O95166 UNIPROT "down-regulates quantity by destabilization" binding 9606 BTO:0000567 24668264 t miannu "Here, we show that ALFY binds selectively to LC3C and the GABARAPs through a LIR in its WD40 domain. Binding of ALFY to GABARAP is indispensable for its recruitment to LC3B-positive structures and, thus, for the clearance of certain p62 structures by autophagy." SIGNOR-266796 "pazopanib hydrochloride" chemical CHEBI:71217 ChEBI CSF1R protein P07333 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-199527 PTPRJ protein Q12913 UNIPROT KDR protein P35968 UNIPROT "down-regulates activity" dephosphorylation Tyr1059 DIYKDPDyVRKGDAR 9606 18936167 t "These results therefore suggest that the autoactivation residues Y1054 and Y1059 are targeted by DEP-1 and that this results in the inhibition of kinase activity and the consequent general dephosphorylation of VEGFR2." SIGNOR-248710 AKT1 protein P31749 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR down-regulates phosphorylation Thr32 QSRPRSCtWPLPRPE 9606 16272144 t lperfetto "Foxo4 transcription factor, also referred to afx, contains three putative phosphorylation motif sites for protein kinase b (pkb), thr32, ser197, and ser262, and it is proposed that phosphorylated foxo4 stays in the cytosol and is imported to the nucleus through dephosphorylation to induce target gene expression" SIGNOR-252855 RPS6K proteinfamily SIGNOR-PF26 SIGNOR PPP1R3A protein Q16821 UNIPROT "up-regulates activity" phosphorylation Ser46 PQPSRRGsDSSEDIY -1 10648825 t lperfetto "The protein G(M), which targets protein phosphatase 1 (PP1) to the glycogen particles and sarcoplasmic reticulum (SR) of striated muscles, is known to be phosphorylated at Ser48 and Ser67 in vitro by adenosine 3',5' cyclic monophosphate-dependent protein kinase (PKA) and at Ser48 by MAP kinase-activated protein kinase-1 (MAPKAP-K1, also called p90 RSK). The phosphorylation of Ser48 increases the rate at which the glycogen-associated PP1.G(M) complex dephosphorylates (activates) glycogen synthase, but the phosphorylation of Ser67 has the opposite effect, suppressing the activity of PP1 toward glycogen-bound substrates." SIGNOR-252777 PPP3CC protein P48454 UNIPROT NFATC2 protein Q13469 UNIPROT "up-regulates activity" dephosphorylation Ser274 ASPQRSRsPSPQPSS 9606 BTO:0000567 11030334 t "NFAT1 is phosphorylated on fourteen conserved phosphoserine residues in its regulatory domain, thirteen of which are dephosphorylated upon stimulation. Dephosphorylation of all thirteen residues is required to mask a nuclear export signal (NES), cause full exposure of a nuclear localization signal (NLS), and promote transcriptional activity" SIGNOR-248520 FMR1 protein Q06787 UNIPROT DLG4 protein P78352 UNIPROT "up-regulates quantity" "post transcriptional regulation" 10090 BTO:0000142 32118033 t lperfetto "These results point toward a novel mechanism by which FUS targets neuronal mRNA and given that these PSD-95 and Shank1 3'-UTR G quadruplex structures are also targeted by the fragile X mental retardation protein (FMRP), they raise the possibility that FUS and FMRP might work together to regulate the translation of these neuronal mRNA targets." SIGNOR-262108 Gbeta proteinfamily SIGNOR-PF4 SIGNOR ESR1 protein P03372 UNIPROT up-regulates phosphorylation 9606 BTO:0000567 17615152 t "inferred from 70% family members" gcesareni "In several estrogen response element-containing genes, the s118a mutation strongly reduced induction by e(2), and u0126 did not further reduce expression. Here, we show that serines 104 (s104) and 106 (s106) are also phosphorylated by mapk in vitro and upon stimulation of mapk activity in vivo.Phosphorylation at serines 104 and 106 by erk1/2 mapk is important for estrogen receptor-alpha activity" SIGNOR-270023 CHMP5 protein Q9NZZ3 UNIPROT ESCRT-III complex SIGNOR-C379 SIGNOR "form complex" binding -1 26775243 t miannu "The ESCRT machinery drives a diverse collection of membrane remodeling events, including multivesicular body biogenesis, release of enveloped retroviruses and both reformation of the nuclear envelope and cytokinetic abscission during mitotic exit. ESCRT-III subunits (CHMPs, for Charged Multivesicular Body Proteins [32], or Chromatin Modifying Proteins [33]) transition between soluble and polymerising states, and assemble in a defined order to form a membrane-remodeling filament that brings about membrane fission." SIGNOR-265527 TLN1 protein Q9Y490 UNIPROT "A3/b1 integrin" complex SIGNOR-C161 SIGNOR "up-regulates activity" binding 10090 BTO:0000132 19118207 t miannu "Over the past 10 years, the binding of talin to the cytoplasmic tail of integrin-β subunits has been established to have a key role in integrin activation. Binding of the phosphotyrosinebinding (PTB)-domain-like subdomain of the protein 4.1, ezrin, radixin, moesin (FERM) domain of talin to the conserved WxxxNP(I/L)Y motif of the β-integrin tail permits additional weaker interactions between talin and the membrane-proximal region of the tail that trigger integrin activation, probably through the disruption of inhibitory interactions between α- and β-subunit cytoplasmic tails." SIGNOR-257610 CDK9 protein P50750 UNIPROT SMAD1 protein Q15797 UNIPROT down-regulates phosphorylation Ser187 NSHPFPHsPNSSYPN 9606 19914161 t lpetrilli "Phosphorylation of the linker region of smad1, a receptor-activated smad (r-smad), at serine 206 (s206) and s214 induced by bmp and mediated by cdk8/9 is critical for binding of the e3 ubiquitin ligase smurf1. Binding of smurf1 leads to polyubiquitination of smad1 and its degradation by the proteasome;cdk8 and cyclint-cdk9 showed a preference for s206 and s214 but also phosphorylated s186 and s195 in the case of smad1;and t179, s208 and s213 in the case of smad3." SIGNOR-161565 PDPK1 protein O15530 UNIPROT PDPK1 protein O15530 UNIPROT unknown phosphorylation Ser396 SSSSSSHsLSASDTG 9606 10455013 t lperfetto "3-phosphoinositide-dependent protein kinase-1 (pdk1) expressed in unstimulated 293 cells was phosphorylated at ser-25, ser-241, ser-393, ser-396 and ser-410 and the level of phosphorylation of each site was unaffected by stimulation with insulin-like growth factor-1. Mutation of ser-241 to ala abolished pdk1 activity, whereas mutation of the other phosphorylation sites individually to ala did not affect pdk1 activity" SIGNOR-236764 PFKP protein Q01813 UNIPROT ATG4B protein Q9Y4P1 UNIPROT "up-regulates activity" phosphorylation Ser34 WILGRKYsIFTEKDE 9606 BTO:0000007 33607258 t lperfetto "In vitro kinase assay validated that PFKP functioning as a protein kinase phosphorylated ATG4B at S34. This phosphorylation could enhance ATG4B activity and p62 degradation. In addition, PFKP S386 phosphorylation was important to ATG4B S34 phosphorylation and autophagy in HEK293T cells." SIGNOR-275832 STK26 protein Q9P289 UNIPROT ATG4B protein Q9Y4P1 UNIPROT "up-regulates activity" phosphorylation Ser383 RLERFFDsEDEDFEI 29232556 t lperfetto "ATG4B stimulates autophagy by promoting autophagosome formation through reversible modification of ATG8. We identify ATG4B as a substrate of mammalian sterile20-like kinase (STK) 26/MST4. MST4 phosphorylates ATG4B at serine residue 383, which stimulates ATG4B activity and increases autophagic flux." SIGNOR-275833 AKT1 protein P31749 UNIPROT ATG4B protein Q9Y4P1 UNIPROT "up-regulates activity" phosphorylation Ser34 WILGRKYsIFTEKDE 9606 BTO:0000586 29165041 t lperfetto "In this study, we identified a novel phosphorylation site at Ser34 of ATG4B induced by AKT in HCC cells.| In brief, our results demonstrate for the first time that the phosphorylation of ATG4B at Ser34 participates in the metabolic reprogramming of HCC cells via repressing mitochondrial function, which possibly results from the Ser34 phosphorylation-induced mitochondrial enrichment of ATG4B and the subsequent inhibition of F1Fo-ATP synthase activity." SIGNOR-275834 PAK1 protein Q13153 UNIPROT ATG5 protein Q9H1Y0 UNIPROT "up-regulates quantity by stabilization" phosphorylation Thr101 SALPWNItVHFKSFP 36528756 t lperfetto "Here, we identified USP13 as an essential deubiquitinase that stabilizes ATG5 in a process that depends on the PAK1 serine/threonine-protein kinase and which enhances autophagy and promotes IM resistance in GIST cells. |As PAK1-mediated phosphorylation at residue T101 protects ATG5 from ubiquitination-dependent degradation" SIGNOR-275835 AKT proteinfamily SIGNOR-PF24 SIGNOR ATG4B protein Q9Y4P1 UNIPROT "up-regulates activity" phosphorylation Ser34 WILGRKYsIFTEKDE 9606 BTO:0000586 29165041 t lperfetto "In this study, we identified a novel phosphorylation site at Ser34 of ATG4B induced by AKT in HCC cells.| In brief, our results demonstrate for the first time that the phosphorylation of ATG4B at Ser34 participates in the metabolic reprogramming of HCC cells via repressing mitochondrial function, which possibly results from the Ser34 phosphorylation-induced mitochondrial enrichment of ATG4B and the subsequent inhibition of F1Fo-ATP synthase activity." SIGNOR-275836 GTF3C4 protein Q9UKN8 UNIPROT TFIIIC complex SIGNOR-C392 SIGNOR "form complex" binding 9606 29378333 t lperfetto "Both yeast and human TFIIIC consist of six polypeptides organized into two globular domains" SIGNOR-266185 calcium(2+) smallmolecule CHEBI:29108 ChEBI PRKCA protein P17252 UNIPROT up-regulates "chemical activation" 9606 BTO:0000887;BTO:0001103 22944199 t gcesareni "The wnt/ca2+ signaling pathway is defined by the activation of plc (phospholipase c) through wnt/fzd resulting in an increase in intracellular ca2+ levels, which activate pkcs (protein kinase c) and camkii (calcium-calmodulin-dependent kinase ii) or cn (calcineurin), a phosphatase that activates the transcription factor nfat (nuclear factor of activated t cell)." SIGNOR-198822 CSNK1D protein P48730 UNIPROT WWTR1 protein Q9GZV5 UNIPROT down-regulates phosphorylation Ser314 SREQSTDsGLGLGCY 9606 24715453 t lperfetto "LATS1/2-mediated phosphorylation of a conserved serine in this region (Ser311 in human TAZ; Ser397 in human YAP) primes for further phosphorylation by CK1_/_ kinases (Ser314 on human TAZ; Ser400/403 in human YAP)" SIGNOR-234438 ATG4B protein Q9Y4P1 UNIPROT "ATP synthase" complex SIGNOR-C264 SIGNOR "down-regulates activity" 9606 BTO:0000586 29165041 f lperfetto "In this study, we identified a novel phosphorylation site at Ser34 of ATG4B induced by AKT in HCC cells.| In brief, our results demonstrate for the first time that the phosphorylation of ATG4B at Ser34 participates in the metabolic reprogramming of HCC cells via repressing mitochondrial function, which possibly results from the Ser34 phosphorylation-induced mitochondrial enrichment of ATG4B and the subsequent inhibition of F1Fo-ATP synthase activity." SIGNOR-275837 USP13 protein Q92995 UNIPROT ATG5 protein Q9H1Y0 UNIPROT "up-regulates quantity by stabilization" deubiquitination 36528756 t lperfetto "Here, we identified USP13 as an essential deubiquitinase that stabilizes ATG5 in a process that depends on the PAK1 serine/threonine-protein kinase and which enhances autophagy and promotes IM resistance in GIST cells." SIGNOR-275838 METTL3 protein Q86U44 UNIPROT USP13 protein Q92995 UNIPROT "up-regulates quantity by stabilization" "post transcriptional regulation" 36528756 t lperfetto "Furthermore, N6-methyladenosine methyltransferase-like 3 (METTL3) mediated stabilization of USP13 mRNA that required the m6A reader IGF2BP2." SIGNOR-275839 TLK1 protein Q9UKI8 UNIPROT NEK1 protein Q96PY6 UNIPROT "up-regulates activity" phosphorylation Thr141 IFLTKDGtVQLGDFG 28426283 t lperfetto "TLK1 phosphorylated NEK1 at T141, which lies in the kinase domain, and caused an increase in its activity. " SIGNOR-275840 NEK1 protein Q96PY6 UNIPROT ATR protein Q13535 UNIPROT "up-regulates activity" binding 28426283 t lperfetto "It was reported that NEK1 associates with ATR/ATRIP and primes it for activation in response to a variety of genotoxic agents" SIGNOR-275841 NEK1 protein Q96PY6 UNIPROT ATRIP protein Q8WXE1 UNIPROT "up-regulates activity" binding 28426283 t lperfetto "It was reported that NEK1 associates with ATR/ATRIP and primes it for activation in response to a variety of genotoxic agents" SIGNOR-275842 hydroxyurea chemical CHEBI:44423 ChEBI RRM2 protein P31350 UNIPROT "down-regulates activity" "chemical inhibition" 9606 14583450 t miannu "In PC3 cells, hydroxyurea inhibited hRRM2 and resulted in increased sensitivity to UV irradiation." SIGNOR-259355 LATS1 protein O95835 UNIPROT AMOT protein Q4VCS5 UNIPROT "up-regulates quantity by stabilization" phosphorylation Ser175 QGHVRSLsERLMQMS 24101513 t lperfetto "Here low serum and high LATS1 activity are found to enhance the levels of the 130-kDa isoform of angiomotin (Amot130) through phosphorylation by LATS1/2 at serine 175, which then forms a binding site for 14-3-3. Such phosphorylation, in turn, enables the ubiquitin ligase atrophin-1 interacting protein (AIP)4 to bind, ubiquitinate, and stabilize Amot130" SIGNOR-275843 BLK protein P51451 UNIPROT CGAS protein Q8N884 UNIPROT "down-regulates activity" phosphorylation Tyr215 LLNTGSYyEHVKISA 30356214 t lperfetto "DNA damage induces nuclear translocation of cGAS in a manner that is dependent on importin-α, and the phosphorylation of cGAS at tyrosine 215-mediated by B-lymphoid tyrosine kinase-facilitates the cytosolic retention of cGAS." SIGNOR-275844 DYRK2 protein Q92630 UNIPROT PSMC4 protein P43686 UNIPROT "down-regulates quantity by destabilization" phosphorylation Thr25 LSVSRPQtGLSFLGP 26655835 t lperfetto "Through a kinome-wide screen, we have identified dual-specificity tyrosine-regulated kinase 2 (DYRK2) as the primary kinase that phosphorylates Rpt3-Thr25, leading to enhanced substrate translocation and degradation." SIGNOR-275845 NEK2 protein P51955 UNIPROT CCDC102B protein Q68D86 UNIPROT "down-regulates activity" phosphorylation 30404835 t lperfetto "CCDC102B is recruited to the centrosome by C-Nap1 (also known as CEP250) and interacts with the centrosome linker components rootletin and LRRC45. CCDC102B decorates and facilitates the formation of rootletin filaments. Furthermore, CCDC102B is phosphorylated by Nek2A (an isoform encoded by NEK2) and is disassociated from the centrosome at the onset of mitosis." SIGNOR-275626 SSU72 protein Q9NP77 UNIPROT POLR2A protein P24928 UNIPROT "up-regulates activity" dephosphorylation Ser1717 SPSYSPTsPSYSPTS -1 15125841 t "Phosphorylation of serine-2 (S2) and serine-5 (S5) of the C-terminal domain (CTD) of RNA polymerase II (RNAP II) is a dynamic process that regulates the transcription cycle and coordinates recruitment of RNA processing factors. The Fcp1 CTD phosphatase catalyzes dephosphorylation of S2-P.| Depletion of Ssu72 impairs transcription in vitro" SIGNOR-248811 LRRK2 protein Q5S007 UNIPROT SNCA protein P37840 UNIPROT "down-regulates activity" phosphorylation Ser129 NEAYEMPsEEGYQDY 9606 19576176 t lperfetto "Here we show that full-length Lrrk2 or fragments containing its kinase domain have a significant capacity to phosphorylate recombinant alpha synuclein (Asyn) at serine 129. Such phosphorylated Asyn is the major component of pathological deposits in PD." SIGNOR-249690 PRKCH protein P24723 UNIPROT PRKD1 protein Q15139 UNIPROT up-regulates phosphorylation Ser738 ARIIGEKsFRRSVVG 9606 10197446 t llicata "These results provide direct evidence that pkd becomes activated in vivo as a consequence of pkc-mediated phosphorylation of serines 744 and 748." SIGNOR-66730 TGFB3 protein P10600 UNIPROT TGFB3 protein P10600 UNIPROT up-regulates binding 9606 16885528 t gcesareni "The active form of tgf-b is a dimer stabilized by hydrophobic interactions and usually further strengthened by an intersubunit disulfide bridge" SIGNOR-148611 LATS2 protein Q9NRM7 UNIPROT AMOT protein Q4VCS5 UNIPROT "up-regulates quantity by stabilization" phosphorylation Ser175 QGHVRSLsERLMQMS 24101513 t lperfetto "Here low serum and high LATS1 activity are found to enhance the levels of the 130-kDa isoform of angiomotin (Amot130) through phosphorylation by LATS1/2 at serine 175, which then forms a binding site for 14-3-3. Such phosphorylation, in turn, enables the ubiquitin ligase atrophin-1 interacting protein (AIP)4 to bind, ubiquitinate, and stabilize Amot130" SIGNOR-275846 WWP1 protein Q9H0M0 UNIPROT AMOT protein Q4VCS5 UNIPROT "up-regulates quantity by stabilization" ubiquitination 24101513 t lperfetto "Here low serum and high LATS1 activity are found to enhance the levels of the 130-kDa isoform of angiomotin (Amot130) through phosphorylation by LATS1/2 at serine 175, which then forms a binding site for 14-3-3. Such phosphorylation, in turn, enables the ubiquitin ligase atrophin-1 interacting protein (AIP)4 to bind, ubiquitinate, and stabilize Amot130" SIGNOR-275847 RUNX1 protein Q01196 UNIPROT CCL3 protein P10147 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000661 12771199 t lperfetto "We show that RUNX1 can specifically bind to both RUNX sites but that only the proximal RUNX site is essential for PMA/ PHA stimulation of the MIP-1a promoter in Jurkat T-cells. We also show that the endogenous MIP-1a promoter is constitutively bound by RUNX1." SIGNOR-251738 SRC protein P12931 UNIPROT VCL protein P18206 UNIPROT "down-regulates activity" phosphorylation Tyr100 QMLQSDPySVPARDY 9534 15229287 t lperfetto "The phosphorylation of vinculin on tyrosine residues 100 and 1065, mediated by SRC kinases, affects cell spreadingWhen phosphorylated, the vinculin tail exhibited significantly less binding to the vinculin head domain than the unphosphorylated tail." SIGNOR-247424 CNTRL protein Q7Z7A1 UNIPROT CEP290 protein O15078 UNIPROT "down-regulates activity" binding 9606 18694559 t miannu "CEP290 cooperates with Rab8a to promote ciliogenesis and this function is antagonized by CP110. CP110 in this complex is to keep CEP290 inactive in growing cells until cells are ready to undergo ciliogenesis as they transit into the quiescent state" SIGNOR-252149 (2S)-N1-[5-(2-tert-butyl-4-thiazolyl)-4-methyl-2-thiazolyl]pyrrolidine-1,2-dicarboxamide chemical CHEBI:91449 ChEBI PIK3CA protein P42336 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-204490 DOK1 protein Q99704 UNIPROT "A3/b1 integrin" complex SIGNOR-C161 SIGNOR "down-regulates activity" binding 9606 19118207 t miannu "Integrins also bind to many PTBdomain-containing proteins (Calderwood et al., 2003) – including Dok1 and integrincytoplasmic-domain-associated protein 1 (ICAP1) – and these can compete with talin for binding to integrin and so can impair activation" SIGNOR-257672 SETD5 protein Q9C0A6 UNIPROT Epigenetic_regulation phenotype SIGNOR-PH203 SIGNOR up-regulates 9606 32299058 f "The Autism-Related Protein SETD5 Controls Neural Cell Proliferation through Epigenetic Regulation of rDNA Expression" SIGNOR-268627 AURKB protein Q96GD4 UNIPROT H1-4 protein P10412 UNIPROT "up-regulates quantity by stabilization" phosphorylation Ser27 VKKKARKsAGAAKRK 9606 BTO:0000093 21511733 t miannu "we showed previously that phosphorylation of S27 in human histone H1.4 (H1.4S27-P), prevents binding of heterochromatin protein 1 (HP1) family members (officially known as chromobox protein homologs) to the neighboring dimethylated K26. Here, we present the first functional characterization of H1.4S27-P in vivo and in vitro. We show that H1.4S27 phosphorylation is cell-cycle-regulated and its levels peak on metaphase chromosomes. We identify further Aurora B as the kinase phosphorylating H1.4S27." SIGNOR-262658 PRKACA protein P17612 UNIPROT AMPK complex SIGNOR-C15 SIGNOR "down-regulates activity" phosphorylation 10116 17023420 t "These agents also enhanced phosphorylation of alpha-Ser(485/491) by the cAMP-dependent protein kinase. AMPK alpha-Ser(485/491) phosphorylation was necessary but not sufficient for inhibition of AMPK activity in response to forskolin/isobutylmethylxanthine." SIGNOR-256111 BTRC protein Q9Y297 UNIPROT RAP1GAP protein P47736 UNIPROT down-regulates ubiquitination 9606 25329897 t lperfetto "Here, we demonstrated that rap1gap is ubiquitinated and degraded through proteasome pathway in mitosis. Proteolysis of rap1gap requires the plk1 kinase and _-trcp ubiquitin ligase complex." SIGNOR-203548 Ub:E2 complex SIGNOR-C497 SIGNOR RNF208 protein Q9H0X6 UNIPROT "up-regulates activity" ubiquitination 9606 34199813 t miannu "The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t" SIGNOR-271013 SMURF1 protein Q9HCE7 UNIPROT FKBP3 protein Q00688 UNIPROT unknown ubiquitination -1 20804422 t miannu "Recombinant proteins were used to profile substrate ubiquitination by the Smurf1 ubiquitin ligase on a global scale using protein microarrays. T Proteins ubiquitinated on the protein microarray were confirmed as potential substrates of the Smurf1 activity using an off chip in vitro ubiquitination assay." SIGNOR-272694 APC-c complex SIGNOR-C150 SIGNOR KIFC1 protein Q9BW19 UNIPROT "down-regulates quantity by destabilization" ubiquitination -1 24510915 t miannu "Biochemical studies on the kinesins confirmed KIFC1, KIF18A, KIF2C, and KIF4A as APC/C substrates. Furthermore, we showed that the APC/CCDH1-dependent degradation of KIFC1 regulates the bipolar spindle formation and proper cell division. Our in vitro degradation assays showed a time-dependent degradation for four of the five potential substrates tested: KIF18A, KIF2C, KIFC1 and KIF4A were readily degraded in vitro, however remained stable in the presence of either APC/C inhibitor (Fig​(Fig4A4A and Supplementary Fig S3A)." SIGNOR-266109 serotonin smallmolecule CHEBI:28790 ChEBI HTR3B protein O95264 UNIPROT "up-regulates activity" "chemical activation" 9606 BTO:0000938 25601315 t miannu "Serotonin or 5-hydroxytryptamine (5-HT) remains one of the most widely studied chemical messengers. Serotonin produces a myriad of physiological effects in humans, mediated through 14 distinct receptor subtypes, of which 13 are G protein coupled receptors (GPCRs), and one ligand-gated cation channel" SIGNOR-264290 FZD5 protein Q13467 UNIPROT DVL2 protein O14641 UNIPROT "up-regulates activity" binding 9606 23151663 t areggio "Upon ligand binding, DVL proteins are recruited to Frizzled receptors at the plasma membrane and co-recruit cytoplasmic transducers, such as Axin, CK1 and GSK3 binding protein (GBP), presumably along with their partners, to promote ?-catenin-dependent signalling. " SIGNOR-258960 RAB14 protein P61106 UNIPROT "Early Endosome" complex SIGNOR-C246 SIGNOR "form complex" binding 9606 19924646 t lperfetto "The Rab proteins primarily localized to the EE include Rab5 and Rab4, which regulate distinct early endocytic events. In addition to these two Rab proteins, some of the other less well-characterized Rabs at the EE include Rab10 , Rab14 , Rab21 and Rab22" SIGNOR-260619 PBX1 protein P40424 UNIPROT CDKN2A protein P42771 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000093 21746878 t miannu "We show that the Pbx1 and Meis2 homeodomain proteins interact with Klf4 and can be recruited to DNA elements comprising a Klf4 site or G C box, with adjacent Meis and Pbx sites. Meis2d and Pbx1a activate expression of p15(Ink4a) and E-cadherin, dependent on the Meis2d transcriptional activation domain. We suggest a model in which genes with Klf4 sites can be cooperatively activated by Meis2/Pbx1 and Klf4, dependent primarily on recruitment by Klf4." SIGNOR-267239 telmisartan chemical CHEBI:9434 ChEBI AGTR1 protein P30556 UNIPROT "down-regulates activity" "chemical inhibition" 9606 9878991 t miannu "Telmisartan is a nonpeptide angiotensin II receptor antagonist which selectively and insurmountably inhibits the angiotensin II AT1 receptor subtype without affecting other receptor systems involved in cardiovascular regulation." SIGNOR-259072 E2F1 protein Q01094 UNIPROT SMAD7/HDAC1/E2F-1 complex SIGNOR-C12 SIGNOR "form complex" binding 9606 23213415 t gcesareni "Furthermore, smad7 caused hdac-1 bind to e2f-1 to form a ternary complex on chromosomal dna containing an e2f-binding motif and leading to repression in the activity of the e2f target genes" SIGNOR-199955 TBK1 protein Q9UHD2 UNIPROT STAT6 protein P42226 UNIPROT up-regulates phosphorylation Tyr641 MGKDGRGyVPATIKM 9606 22000020 t gcesareni "We now show that stat6 is required for innate immune signaling in response to virus infection. Viruses or cytoplasmic nucleic acids trigger sting (also named mita/eris) to recruit stat6 to the endoplasmic reticulum, leading to stat6 phosphorylation on ser(407) by tbk1 and tyr(641), independent of jaks. Phosphorylated stat6 then dimerizes and translocates to the nucleus to induce specific target genes responsible for immune cell homing." SIGNOR-176775 dothiepin chemical CHEBI:36798 ChEBI CHRM1 protein P11229 UNIPROT "down-regulates activity" "chemical inhibition" 10029 BTO:0000246 8100134 t miannu "Antagonism of the five cloned human muscarinic cholinergic receptors expressed in CHO-K1 cells by antidepressants and antihistaminics. Competition between [‘H]QNB and the antidepressant compounds (Table 1) showed that at the ml subtype the most potent drugs were amitriptyline > dothiepin > doxepin = nortriptyline; at the m2 receptor, amitriptyline > imipramine > nortriptyline = dothiepin; at the m3 recep- tor, amitriptyline > dothiepin > nortriptyline; at the m4 receptor, amitriptyline > dothiepin > doxepin = nortrip- tyline; and at the m5 receptor, amitriptyline > doxepin > imipramine." SIGNOR-258697 EP300 protein Q09472 UNIPROT XBP1 protein P17861-2 UNIPROT "up-regulates quantity by stabilization" acetylation 9606 BTO:0000007 20955178 t miannu "P300 increases the acetylation and protein stability of XBP1s, and enhances its transcriptional activity, whereas SIRT1 deacetylates XBP1s and inhibits its transcriptional activity.. The mRNA encoding the active spliced form of XBP1 (XBP1s) is generated from the unspliced form by IRE1 (inositol-requiring enzyme 1) during the UPR." SIGNOR-260429 EEF1A2 protein Q05639 UNIPROT Translational_elongation phenotype SIGNOR-PH210 SIGNOR up-regulates 9606 23699257 f lperfetto "During protein synthesis, eEF1A binds to and delivers aminoacylated tRNAs (aa-tRNAs) to the elongating ribosome (Fig. 1). GTP bound to eEF1A is hydrolyzed upon codon-anticodon match between an aa-tRNA in the A site of the ribosome and mRNA bound to the ribosome." SIGNOR-269394 LCK protein P06239 UNIPROT SIGLEC10 protein Q96LC7 UNIPROT up-regulates phosphorylation Tyr667 ESQEELHyATLNFPG 9606 11733002 t lperfetto "These results suggest that the tyrosines at positions 597 and 667, contained within itim-like motifs, are likely targets of phosphorylation by several classes of signaling molecules, including lck, jak3, and emt. The tyrosine located at position y691 was also contributing to the phosphorylation of the wild-type siglec tail by lck and jak3 kinases. Phosphorylation of the tyrosine located at position 667 in an itim motif appears to be necessary for the recruitment of shp-1 and partial recruitment of shp-2" SIGNOR-112495 "Neurokinin A" smallmolecule CHEBI:80311 ChEBI TACR2 protein P21452 UNIPROT "up-regulates activity" "chemical activation" 9606 BTO:0002524 31160049 t "Ligand-GPCR dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257587 PPP2CA protein P67775 UNIPROT MAPK1 protein P28482 UNIPROT down-regulates dephosphorylation 9606 20626350 t gcesareni "In particular, p38 mapk activity stimulates the physical association between ppa2 and mkk1/2- erk1/2 complex, leading to mkk1/2 dephosphorilation by pp2a . p38 mapks activity stimulates the physical association between pp2a and erk complex, leading to mkk1/2 dephosphorylation by pp2a." SIGNOR-166655 DISC1 protein Q9NRI5 UNIPROT KIF5B protein P33176 UNIPROT "up-regulates activity" binding 9606 BTO:0000938 17202468 t miannu "We identified Kinesin-1, a microtubule-dependent and plus-end directed motor, as a DISC1-interacting molecule. Our results show that DISC1 links Kinesin-1 to the NUDEL/LIS1/14-3-3ε complex, serves as the cargo receptor, and regulates the transport of the complex to axons, leading to axon elongation. DISC1 directly interacted with kinesin heavy chain of Kinesin-1. Kinesin-1 interacted with the NUDEL/LIS1/14-3-3ε complex through DISC1" SIGNOR-252161 "Multiaminoacyl-tRNA synthetase" complex SIGNOR-C472 SIGNOR AMP smallmolecule CHEBI:456215 ChEBI "up-regulates quantity" "chemical modification" 9606 28271488 t miannu "Aminoacyl-tRNA synthetases (AARSs) are essential enzymes that specifically aminoacylate one tRNA molecule by the cognate amino acid. In mammals, nine synthetases, those specific for amino acids Arg, Asp, Gln, Glu, Ile, Leu, Lys, Met and Pro, associate into a multi-aminoacyl-tRNA synthetase complex, an association which is believed to play a key role in the cellular organization of translation, but also in the regulation of the translational and nontranslational functions of these enzymes." SIGNOR-270408 "Phenylalanyl-tRNA synthetase" complex SIGNOR-C473 SIGNOR Phe-tRNA(Phe) smallmolecule CHEBI:29153 ChEBI "up-regulates quantity" "chemical modification" 9606 20223217 t miannu "Here we report crystal structure of hcPheRS complexed with phenylalanine at 3.3 Å resolution. An essential feature of hcPheRS is a novel fold formed by the N-terminal part of the α subunit, whose functional role in tRNAPhe binding and complex formation was studied by truncation mutagenesis. Phenylalanine activation and formation of Phe-tRNAPhe catalyzed by modified hcPheRS have been compared with those of the wild-type enzyme. HcPheRS is a heterotetramer built of two αβ heterodimers." SIGNOR-270442 MAP2K6 protein P52564 UNIPROT MAPK14 protein Q16539 UNIPROT "up-regulates activity" phosphorylation Tyr182 TDDEMTGyVATRWYR 9534 8622669 t lperfetto "These data indicate that mkk6 phosphorylates p38 map kinase on thr-180 and tyr-182, the sites of phosphorylation that activate p38 map kinase" SIGNOR-40427 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR RUNX1 protein Q01196 UNIPROT up-regulates phosphorylation Ser397 SMVGGERsPPRILPP 9606 21059642 t "The effect has been demonstrated using Q01196-8" lperfetto "Phosphorylation of runx1 on ser-303 by cdks leads its ubiquitin-mediated degradation during g2/m (19). We developed additional evidence that cdks phosphorylate ser-303 and found that ser-48 and ser-424 are also substrates of cdk1/cyclin b and cdk6/cyclin d3. Moreover, we demonstrated that phosphorylation of ser-48, ser-303, and ser-424 strengthens the ability of runx1 to activate transcription and to stimulate proliferation of the ba/f3 hematopoietic cell line (20)." SIGNOR-216912 MLL-AF9 "fusion protein" SIGNOR-FP5 SIGNOR RUNX1 protein Q01196 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 24449215 f irozzo "However, the functional consequence of MLL fusions on RUNX1/CBFβ activity has not been fully understood. In this report, we show that MLL fusion proteins and the N-terminal MLL portion of MLL fusions downregulate RUNX1 and CBFβ protein expression via the MLL CXXC domain and flanking regions. We found that MLL-BP and the 3 MLL fusion proteins all decreased RUNX1 levels, and MLL-eleven nineteen leukemia (ENL) caused a greater decrease in RUNX1 compared with MLL-AF9 and MLL-AF4 fusion proteins." SIGNOR-255851 cyproheptadine chemical CHEBI:4046 ChEBI HRH1 protein P35367 UNIPROT "down-regulates activity" "chemical inhibition" 10029 BTO:0000246 7925364 t miannu "The human H1-receptor cDNA was transfected into Chinese hamster ovary cells (CHO) via an eukaryotic expression vector; the receptor protein present on cell membranes specifically bound [3H]mepyramine with a Kd of 3.7 nM. The binding was displaced by H1-histamine-receptor antagonists and histamine. Affinity of histamine and selected histamine antagonists for human H, receptors expressed in CHO cells (CHO H,-30) and a comparison with HI receptors found in guinea pig cerebellum." SIGNOR-258869 Ub:E2 complex SIGNOR-C497 SIGNOR TRIM64C protein A6NLI5 UNIPROT "up-regulates activity" ubiquitination 9606 34199813 t miannu "The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t" SIGNOR-271272 CHD8 protein Q9HCK8 UNIPROT NEFM protein P07197 UNIPROT "down-regulates quantity" "transcriptional regulation" 10090 32839322 t Gianni "Many of the most significantly up-regulated genes in Chd8+/− and Chd8−/− NPCs are involved in later stages of neuronal development, including Ascl1 [a central driver of neural reprogramming (29)], Dcx, Map2, Nefm, Neurod4, and Neurog1 (Fig. 2 E and F). Additionally, we found that Sox3 is derepressed in both Chd8+/− and Chd8−/− NPCs, and several other Sox TF members (Sox2, Sox7, and Sox11) became derepressed in the Chd8−/− cells" SIGNOR-268917 MAP3K1 protein Q13233 UNIPROT ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR "down-regulates quantity by destabilization" polyubiquitination 9606 BTO:0000007 12049732 t miannu "ERK1/2 MAP kinases are important regulators in cellular signaling, whose activity is normally reversibly regulated by threonine-tyrosine phosphorylation. In contrast, we have found that stress-induced ERK1/2 activity is downregulated by ubiquitin/proteasome-mediated degradation of ERK1/2. The PHD domain of MEKK1, a RING finger-like structure, exhibited E3 ubiquitin ligase activity toward ERK2 in vitro and in vivo. Therefore, MEKK1 functions not only as an upstream activator of the ERK and JNK through its kinase domain, but also as an E3 ligase through its PHD domain, providing a negative regulatory mechanism for decreasing ERK1/2 activity." SIGNOR-272609 MMP3 protein P08254 UNIPROT ACAN protein P16112 UNIPROT "down-regulates quantity by destabilization" cleavage Asn360 DFVDIPEnFFGVGGE 9606 BTO:0000206 9202061 t lperfetto "Aggrecan Degradation in Human Cartilage Evidence for both Matrix Metalloproteinase and Aggrecanase Activity in Normal, Osteoarthritic, and Rheumatoid Joints|Stromelysin-1 (MMP-3), as well as other MMPs, cleave aggrecan in the interglobular domain between Asn341 and Phe342 to generate a G1 fragment with the COOH terminus VDIPEN341 (11–13). This fragment has been isolated and identified by NH2-terminal sequence analysis from human OA cartilage (11). A second proteolytic activity identified as “aggrecanase” also cleaves aggrecan in the interglobular domain, but between Glu373 and Ala374 (19–24), generating a G1 fragment with a COOH terminus of NITEGE374" SIGNOR-266986 FREM1 protein Q5H8C1 UNIPROT NPNT protein Q6UXI9 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 22613833 t lperfetto "The loss of QBRICK significantly diminished the expression of nephronectin, an integrin α8β1 ligand necessary for renal development. In vivo, nephronectin associated with QBRICK and localized at the sublamina densa region, where QBRICK was also located. Collectively, these findings indicate that QBRICK facilitates the integrin α8β1-dependent interactions of cells with basement membranes by regulating the basement membrane assembly of nephronectin and explain why renal defects occur in Fraser syndrome." SIGNOR-253308 GRK2 protein P25098 UNIPROT FPR1 protein P21462 UNIPROT "down-regulates activity" phosphorylation Thr339 SDTATNStLPSAEVE -1 7836371 t "Phosphorylation of the FPR carboxyl terminus by GRK2 is the result of a high affinity interaction and proceeds in a hierarchical manner. sequential mechanism of phosphorylation beginning with residues 328 and/or 329, followed by residues 331 and/or 332, and finally residues 334 through 339. Attenuation of receptor-mediated signal amplification in response to external stimuli, an essential step in the balance of cellular activation, may be mediated by receptor phosphorylation." SIGNOR-251452 MAPK1 protein P28482 UNIPROT APBB1 protein O00213 UNIPROT unknown phosphorylation Thr709 PKRLGAHtP 9606 14697653 t lperfetto "Thus, fe65 has at least two apparently disparate functions and may also be involved in the pathogenesis of alzheimer's disease. The mechanisms by which fe65 trafficking and metabolism are regulated to fulfil these different roles are unclear. Our findings reported here, which demonstrate that fe65 is a phosphoprotein that is targeted by erk1/2 and which identify four in vivo phosphorylation sites, provide one possible mechanism whereby functional diversity might be achieved." SIGNOR-120463 "Cullin 1-RBX1-Skp1" complex SIGNOR-C529 SIGNOR SQSTM1 protein Q13501 UNIPROT "down-regulates quantity by destabilization" polyubiquitination 9606 BTO:0000007 25721664 t miannu "F-box protein Fbxo3 targets Smurf1 ubiquitin ligase for ubiquitination and degradation. Here we show that another F-box protein Fbxo3, belonging to the FBXO type protein family, also interacts with and targets Smurf1 for poly-ubiquitination and proteasomal degradation. The SCF complex is composed of F-box protein, Skp1, Cullin1 (Cul1) and ROC1. Fbxo3, whose substrates are few, forms SCF Fbxo3 ubiquitin ligase and regulates the degradations of Fbxl2, p62, HIPK2 and p300 through the ubiquitin-proteasome pathway." SIGNOR-272446 EREG protein O14944 UNIPROT EGFR protein P00533 UNIPROT up-regulates binding 9606 BTO:0000150 9419975 t "Epiregulin may be a mediator of localized cell proliferation" gcesareni "Chemical cross-linking experiments showed that [125i]epiregulin directly bound to each of egfr and erbb-4 but not to erbb-2 and erbb-3. remarkably, three members of the epidermal growth factor (egf) family (ereg, areg, and epgn) showed increased expression that was associated with elevated epidermal activation of the egf receptor (egfr) and stat3, a downstream effector of egfr signaling." SIGNOR-54351 WNT1 protein P04628 UNIPROT MYF5 protein P13349 UNIPROT "up-regulates activity" 10090 BTO:0000887;BTO:0001103 9753670 f gcesareni "Differential activation of Myf5 and MyoD by different Wnts in explants of mouse paraxial mesoderm and the later activation of myogenesis in the absence of Myf5" SIGNOR-60285 ACTL6B protein O94805 UNIPROT "Muscle cell-specific SWI/SNF SMARCA4 variant" complex SIGNOR-C483 SIGNOR "form complex" binding 9606 BTO:0000887 11073988 t miannu "We have also found that, of the two human SWI/2/SNF2 family-related ATPases, the PBAF complex contains only BRG1 but not hbrm (Xue et al., submitted). In contrast, the BAF complex isolated by BAF250 can include either BRG1 or hbrm (Fig. ​(Fig.4b).4b). These data underscore the distinctness of the two human complexes and suggest that BAF250 is a signature subunit that may confer specificity to the BAF complex." SIGNOR-270740 FASN protein P49327 UNIPROT CTNNB1 protein P35222 UNIPROT "up-regulates quantity by stabilization" 9606 BTO:0001130 18838960 f lperfetto "Overexpression of fatty acid synthase is associated with palmitoylation of Wnt1 and cytoplasmic stabilization of beta-catenin in prostate cancer" SIGNOR-242878 MELK protein Q14680 UNIPROT MELK protein Q14680 UNIPROT up-regulates phosphorylation Ser431 ENVYTPKsAVKNEEY 9606 16216881 t lperfetto "We have mapped no less than 16 autophosphorylation sites including serines, threonines, and a tyrosine residue and show that the phosphorylation of thr167 and ser171 is required for the activation of melk.We have not yet explored the role of autophosphorylation of nine residues in the c-terminal, autoinhibitory domain (fig. 4c). An enticing hypothesis is that these autophosphorylations decrease the inhibitory potency of this domain and thereby contribute to the activation of the kinase." SIGNOR-141010 YY1 protein P25490 UNIPROT NOTCH proteinfamily SIGNOR-PF30 SIGNOR "down-regulates activity" binding 9606 BTO:0000664 12913000 t "Taken together, these results indicate that transcription factor YY1 may modulate Notch signaling via association with the high molecular weight Notch complex [..] both YY1 and N1IC were present in a large complex of the nucleus to suppress the luciferase reporter activity transactivated by Notch signaling." SIGNOR-254305 LRRK2 protein Q5S007 UNIPROT SH3GL2 protein Q99962 UNIPROT down-regulates phosphorylation Ser75 LSMINTMsKIRGQEK 9606 22998870 t gcesareni "We show that lrrk2 affects synaptic endocytosis by phosphorylating endophilin-a1 at s75." SIGNOR-192072 B4GALT1 protein P15291 UNIPROT UDP(3-) smallmolecule CHEBI:58223 ChEBI "up-regulates quantity" "chemical modification" 9606 16157350 t miannu "Beta-1,4-Galactosyltransferase-I (beta4Gal-T1) transfers galactose from UDP-galactose to N-acetylglucosamine (GlcNAc) residues of the branched N-linked oligosaccharide chains of glycoproteins." SIGNOR-268470 CDK1 protein P06493 UNIPROT LMNA protein P02545 UNIPROT up-regulates phosphorylation Ser22 QASSTPLsPTRITRL 9606 18815303 t gcesareni "Phosphorylation by mitotic cdc2 kinase at ser-22, ser-390, and ser-392 residues on lamin a/c, or by protein kinase c (pkc) during apoptosis, leads to the depolymerization of lamin (disassembly of the nuclear lamina), which may lead to their release from the inm" SIGNOR-181310 ADNP protein Q9H2P0 UNIPROT BECN1 protein Q14457 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10116 24365867 f miannu "Here, we show for the first time that hippocampal ADNP deficiency paralleled reduced beclin1 expression which, in turn, parallels increased tauopathy and cell death. We now show that ADNP directly interacts with LC3B, implicating the requirement of a healthy ADNP system for the apoptotic/autophagy processes." SIGNOR-266760 MAPK1 protein P28482 UNIPROT GABRR1 protein P24046 UNIPROT unknown phosphorylation Ser434 LTLASERsSPQRKSQ -1 12175859 t miannu "Here, we have identified phosphorylation sites on the human ρ1 GABA receptor for six protein kinases widely expressed in the brain: protein kinase C (PKC); cAMP‐dependent protein kinase (PKA); calmodulin‐dependent kinase (CaMKII); casein kinase (CKII); mitogen‐activated protein kinase (MAPK); and cGMP‐dependent protein kinase (PKG). From these data we conclude that T373 is the predominant site of phosphorylation, with a low level of phosphorylation at S413 and/or S414.An extensive functional analysis comparing wild type 1 receptors and receptors with select or multiple phosphorylation sites removed as well as pharmacological manipulation of five kinase pathways failed to reveal any functional effects of phosphorylation" SIGNOR-262748 GLI2 protein P10070 UNIPROT IFITM5 protein A6NNB3 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 23530031 f miannu "Regulation of the bone-restricted IFITM-like (Bril) gene transcription by Sp and Gli family members and CpG methylation. Bril transcription is activated by Sp1, Sp3, OSX, and GLI2 and by CpG demethylation." SIGNOR-254217 CDR2 protein Q01850 UNIPROT CENPE protein Q02224 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 20383333 f lperfetto "Additionally, cdr2 knockdown lead to a decrease (Table 3) in four other transcripts (AURKA, CENPE, SPC25 and TTK), which are involved in kinetochore and spindle biology" SIGNOR-252020 RPS6KA3 protein P51812 UNIPROT H3C1 protein P68431 UNIPROT "down-regulates activity" phosphorylation Ser11 TKQTARKsTGGKAPR 9606 15994958 t "Ser 11 phosphorylation of H3 is either activatory and inhibitory as promotes DNA condensation (activatory) and induce transcription (inhibitory)." gcesareni "Phosphorylation at ser-11 (h3s10ph) by rps6ka4 and rps6ka5 is important during interphase because it enables the transcription of genes following external stimulation, like mitogens, stress, growth factors or uv irradiation and result in the activation of genes, such as c-fos and c-jun." SIGNOR-138475 ARHGAP23 protein Q9P227 UNIPROT RHOA protein P61586 UNIPROT "down-regulates activity" "gtpase-activating protein" 9606 BTO:0000007 32203420 t Luana "We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2)." SIGNOR-260479 SMAD1 protein Q15797 UNIPROT SMAD4 protein Q13485 UNIPROT up-regulates phosphorylation 9606 SIGNOR-C85 20957627 t lperfetto "Whereas alk5 signalling is mediated by phosphorylation of smad2 and smad3 proteins, alk1 signalling is mediated by smad1, smad5, and smad8. Activated smads form a complex with the common(co-Smad; Smad4 in mammals) and shuttle into the nucleus." SIGNOR-168734 3,5-dichloro-N-[[(2S)-1-ethyl-2-pyrrolidinyl]methyl]-2-hydroxy-6-methoxybenzamide chemical CHEBI:92070 ChEBI HTR1A protein P08908 UNIPROT "down-regulates activity" "chemical inhibition" 10029 BTO:0000246 9760039 t miannu "Marked differences were observed between the actions of ‘antagonists’ (Table 2; Fig. 2D ). methiothepin and butaclamol, as well asspiperone, exhibited negative efficacy by concentration-dependently inhibiting S GTPgS binding below basal levels, indicating that they act as inverse agonists in this system.WAY 100,135, yUH 301 and the 5-HTreceptor1A and b-adrenergic receptor antagonist ,ytertatolol, acted as ‘neutral’ antagonists, exhibiting antagonist activity without any detectable agonist or inverse agonist effects." SIGNOR-258856 HRH3 protein Q9Y5N1 UNIPROT GNAO1 protein P09471 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-256968 AKT2 protein P31751 UNIPROT PCBP1 protein Q15365 UNIPROT "down-regulates activity" phosphorylation Ser43 VKRIREEsGARINIS 10090 BTO:0004183 20154680 t miannu "We show that heterogeneous nuclear ribonucleoprotein E1 (hnRNP E1) binds a structural, 33-nucleotide TGF-beta-activated translation (BAT) element in the 3' untranslated region of disabled-2 (Dab2) and interleukin-like EMT inducer (ILEI) transcripts, and represses their translation.TGF-beta activation leads to phosphorylation at Ser 43 of hnRNP E1 by protein kinase Bbeta/Akt2, inducing its release from the BAT element and translational activation of Dab2 and ILEI messenger RNAs." SIGNOR-262625 RAF1 protein P04049 UNIPROT BAD protein Q92934 UNIPROT down-regulates phosphorylation Ser118 GRELRRMsDEFVDSF 9606 17535812 t lperfetto "The activation of several major anti-apoptotic signaling pathways correlates with an increase in the phosphorylation of bad on ser-112, ser-136, and ser-155. These phosphorylation events result in bad inactivation through sequestration by 14-3-3 proteins" SIGNOR-155293 PTPRC protein P08575 UNIPROT JAK2 protein O60674 UNIPROT "down-regulates activity" dephosphorylation 9606 24252238 t miannu "Src homology-2 (SH2) containing tyrosine phosphatase and CD45 tyrosine phosphatase play a major role in modulating JAK-STAT pathway. SH2 containing tyrosine phosphatases include SHP1 and SHP2 (shatterproof 1 & 2). Their SH2 domains allow attachment to the phospho-tyrosine residues present on activated receptors, JAKs or STAT proteins, leading to dephosphorylation of the substrates." SIGNOR-255679 POU5F1 protein Q01860 UNIPROT ID2 protein Q02363 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0001086 17068183 f miannu "To enhance our understanding of the molecular basis of this differentiation event in humans, we used a functional genomics approach involving RNA interference-mediated suppression of OCT4 function in a human ESC line and analysis of the resulting transcriptional profiles to identify OCT4-dependent genes in human cells. We detected altered expression of >1,000 genes, including targets regulated directly by OCT4 either positively (NANOG, SOX2, REX1, LEFTB, LEFTA/EBAF DPPA4, THY1, and TDGF1) or negatively (CDX2, EOMES, BMP4, TBX18, Brachyury [T], DKK1, HLX1, GATA6, ID2, and DLX5), as well as targets for the OCT4-associated stem cell regulators SOX2 and NANOG." SIGNOR-254937 ASB8 protein Q9H765 UNIPROT IKBKB protein O14920 UNIPROT "down-regulates quantity by destabilization" ubiquitination 9606 BTO:0000007 31009856 t lperfetto "In turn, ASB8 facilitated K48-linked ubiquitination and degradation of IKKbeta via the ubiquitin-proteasome pathway, resulting in remarkable inhibition of I-kappa-B-alpha (IkappaBalpha) and of p65 phosphorylation, consequently suppressing NF-kappaB activity." SIGNOR-272253 EGFR protein P00533 UNIPROT STAT5B protein P51692 UNIPROT up-regulates phosphorylation Tyr725 AGGGSATyMDQAPSP 9606 11751923 t llicata "Novel activation of stat5b in response to epidermal growth factor. novel activation of stat5b in response to epidermal growth factor." SIGNOR-113393 PTHLH protein P12272 UNIPROT PTH1R protein Q03431 UNIPROT "up-regulates activity" binding -1 8683730 t lperfetto "Prostate-specific antigen was found to specifically cleave PTHrP 1-141 in a time- and dose-dependent manner.|The preferred PSA cleavage site of PTHrP 1-141 was determined to be at the carboxyl-terminus of phenylalanine 23, consistent with chymotryptic-like enzymatic activity of PSA. Cleavage of PTHrP by PSA completely abolished the ability of PTHrP to stimulate cAMP production." SIGNOR-270549 PHB protein P35232 UNIPROT AR protein P10275 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 16964284 f lperfetto "We now present evidence that PHB, which has 54% homology at the protein level to the oestrogen receptor corepressor REA (repressor of oestrogen receptor activity), can repress androgen receptor (AR)-mediated transcription and androgen-dependent cell growth." SIGNOR-268977 GRIA2 protein P42262 UNIPROT Excitatory_synaptic_transmission phenotype SIGNOR-PH133 SIGNOR up-regulates 9606 BTO:0000938 30825796 f miannu "In the mammalian brain the majority of fast excitatory neurotransmission is carried out by α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA)-sensitive ionotropic glutamate receptors located within the post-synaptic density of glutamatergic synapses" SIGNOR-264612 IL22RA1 protein Q8N6P7 UNIPROT STAT3 protein P40763 UNIPROT up-regulates 9606 12087100 f gcesareni "Il-22 also induced serine phosphorylation of stat3 on ser(727)." SIGNOR-90162 GEM protein P55040 UNIPROT ROCK2 protein O75116 UNIPROT "down-regulates activity" binding 9606 14701738 t miannu "Two functions for Gem have been demonstrated, including inhibition of voltage-gated calcium channel activity and inhibition of Rho kinase-mediated cytoskeletal reorganization, such as stress fiber formation and neurite retraction. These functions for Gem have been ascribed to its interaction with the calcium channel Β subunit and Rho kinase Β, respectively." SIGNOR-261711 AKT proteinfamily SIGNOR-PF24 SIGNOR ESR1 protein P03372 UNIPROT up-regulates phosphorylation Ser118 LHPPPQLsPFLQPHG 9606 11108261 t lperfetto "Studies using mutants of er-alpha demonstrated that akt increased estrogen receptor activity through the amino-terminal activation function-1 (af-1). Serines s104 s106, s118, and s167 appear to play a role in the activation of er-alpha by akt." SIGNOR-244255 FBXW8 protein Q8N3Y1 UNIPROT "Cullin 7-RBX1-Skp1" complex SIGNOR-C528 SIGNOR "up-regulates activity" binding 10090 BTO:0002572 23142081 t miannu "Defective IRS-1 degradation was due to attenuated expression and phosphorylation of the ubiquitin ligase substrate-targeting subunit, Fbw8. mTORC2 stabilizes Fbw8 by phosphorylation at Ser86, allowing the insulin-induced translocation of Fbw8 to the cytosol where it mediates IRS-1 degradation.  We provide evidence that mTORC2 can stabilize Fbw8, the substrate-targeting subunit of the CUL7 E3 ligase complex that has been shown to mediate degradation of IRS-1 ." SIGNOR-271942 RPTOR protein Q8N122 UNIPROT mTORC1 complex SIGNOR-C3 SIGNOR "form complex" binding 9606 25628925 t lperfetto "Depending on their binding partners and sensitivities to rapamycin, mtor resides in at least two distinct complexes, termed mtor complex 1 (mtorc1, containing raptor, fkbp12, pras40 and mlst8) and mtor complex 2 (mtorc2, containing rictor, sin1, protor and mlst8)" SIGNOR-205627 PTPN11 protein Q06124 UNIPROT ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR "up-regulates activity" 9606 11085989 f miannu "We show here that leptin can activate ERK signaling in thehypothalamus and that this stimulation is likely to occur viatwo pathways, both involving SHP-2.We have shown above that SHP-2 is a positive mediator of ERK activation by ObRb and that this requires both the phosphatase activity and tyrosine phosphorylation of SHP-2. Furthermore,Tyr-985 is required for maximal ERK phosphorylation." SIGNOR-263500 EZH2 protein Q15910 UNIPROT SNAI2 protein O43623 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 23836662 f miannu "We further demonstrated that PER2 served as a transcriptional corepressor, which recruited polycomb proteins EZH2 and SUZ12 as well as HDAC2 to octamer transcription factor 1 (OCT1) (POU2F1) binding sites of the TWIST1 and SLUG promoters to repress expression of these EMT genes." SIGNOR-254146 PRKCA protein P17252 UNIPROT THOC5 protein Q13769 UNIPROT up-regulates phosphorylation Ser6 sKKRKPKV 9606 BTO:0000801;BTO:0000876 15221008 t llicata "We conclude m-csf-mediated activation of pkcalpha can potentiate fmip action to initiate survival/differentiation signaling." SIGNOR-126572 Ub:E2 complex SIGNOR-C497 SIGNOR RNF175 protein Q8N4F7 UNIPROT "up-regulates activity" ubiquitination 9606 34199813 t miannu "The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t" SIGNOR-271196 GRP protein P07492 UNIPROT GRPR protein P30550 UNIPROT up-regulates binding 9606 17251915 t gcesareni "Indeed, many potent mitogens such as thrombin, lysophosphatidic acid (lpa), gastrin-releasing peptide (grp), endothelin and prostaglandins stimulate cell proliferation by acting on their cognate gpcrs in various cell types." SIGNOR-152676 MAPK14 protein Q16539 UNIPROT TP53 protein P04637 UNIPROT "up-regulates activity" phosphorylation Ser33 LPENNVLsPLPSQAM 9606 BTO:0000093 10581258 t lperfetto "P38 regulates p53, but also in p53-defective tumor cells rewire their checkpoint response and become dependent in the p38/mk2 pathway in mcf-7 cells, p38 kinase activated p53 more effectively than other members of the ras pathway. p53 and p38 kinase exist in the same physical complex, and co-expression of p38 stabilized p53 protein. In vitro, p38 kinase phosphorylated p53 at ser33 and ser46, a newly identified site." SIGNOR-72699 F2R protein P25116 UNIPROT GNAZ protein P19086 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257127 CyclinK/CDK12 complex SIGNOR-C37 SIGNOR POLR2A protein P24928 UNIPROT "up-regulates activity" phosphorylation Ser1941 SPKGSTYsPTSPGYS 9606 BTO:0006413 32917631 t "Ser2 in CTD of PolII" lperfetto "Together, these studies demonstrate the important, yet largely redundant, role for CDK12 and CDK13 for the regulation of POLII CTD phosphorylation at multiple residues, as well as the global role for both of these kinases in regulating POLII occupancy across the genome.|CDK12 and CDK13 are thus evolutionarily related and structurally similar kinases, and biochemical assays have demonstrated that both have POLII C-terminal domain (CTD) kinase activity and the ability to phosphorylate the Ser2 residue of the repetitive CTD heptad sequence" SIGNOR-273084 MAPK1 protein P28482 UNIPROT GJA1 protein P17302 UNIPROT "down-regulates activity" phosphorylation Ser255 HATSGALsPAKDCGS 9606 BTO:0000567 9535909 t lperfetto "These studies confirm that connexin-43 is a MAP kinase substrate in vivo and that phosphorylation on Ser255, Ser279, and/or Ser282 initiates the down-regulation of gap junctional communication. Studies with connexin-43 mutants suggest that MAP kinase phosphorylation at one or more of the tandem Ser279/Ser282 sites is sufficient to disrupt gap junctional intercellular communication." SIGNOR-249401 SGK2 protein Q9HBY8 UNIPROT FOXO3 protein O43524 UNIPROT "down-regulates activity" phosphorylation Ser253 APRRRAVsMDNSNKY 9606 11154281 t lperfetto "Protein kinase SGK mediates survival signals by phosphorylating the forkhead transcription factor FKHRL1 (FOXO3a)|However, SGK and Akt display differences with respect to the efficacy with which they phosphorylate the three regulatory sites on FKHRL1. While both kinases can phosphorylate Thr-32, SGK displays a marked preference for Ser-315 whereas Akt favors Ser-253. These findings suggest that SGK and Akt may coordinately regulate the function of FKHRL1 by phosphorylating this transcription factor at distinct sites. The efficient phosphorylation of these three sites on FKHRL1 by SGK and Akt appears to be critical to the ability of growth factors to suppress FKHRL1-dependent transcription, thereby preventing FKHRL1 from inducing cell cycle arrest and apoptosis." SIGNOR-249130 TOP2B protein Q02880 UNIPROT CDH13 protein P55290 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 24463367 f lperfetto "While Top2a is essential in proliferating cells and has been linked to DNA replication and chromosome condensation/segregation, Top2b has been clearly indicated in regulating gene expression (e.g. Reln, Dab1, Catna2, Cdh13, Sst, Pbx3, and Epha7) during brain development" SIGNOR-242302 PPP3CB protein P16298 UNIPROT IL6 protein P05231 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 18177723 f lperfetto "Interestingly, since IL-6 production by nerve-mediated skeletal muscle contraction has recently been shown to be partly dependent on the activation of the calcineurin pathway |The fact that IL-6 is produced not only by proliferating satellite cells but also by growing myofibers during hypertrophy" SIGNOR-251734 "MLL/SET subcomplex" complex SIGNOR-C87 SIGNOR "MLL1 complex" complex SIGNOR-C89 SIGNOR "form complex" binding 9606 24680668 t miannu "The mixed lineage leukemia-1 (mll1) enzyme is a histone h3 lysine 4 (h3k4) monomethyltransferase and has served as a paradigm for understanding the mechanism of action of the human set1 family of enzymes that include mll1_Mll4 and setd1a,b. Dimethylation of h3k4 requires a sub-complex including wrad (wdr5, rbbp5, ash2l, and dpy-30), which binds to each set1 family member forming a minimal core complex that is required for multiple lysine methylation." SIGNOR-204819 CyclinK/CDK12 complex SIGNOR-C37 SIGNOR POLR2A protein P24928 UNIPROT "up-regulates activity" phosphorylation Ser1878 SPKYSPTsPTYSPTT 9606 BTO:0006413 32917631 t "Ser2 in CTD of PolII" lperfetto "Together, these studies demonstrate the important, yet largely redundant, role for CDK12 and CDK13 for the regulation of POLII CTD phosphorylation at multiple residues, as well as the global role for both of these kinases in regulating POLII occupancy across the genome.|CDK12 and CDK13 are thus evolutionarily related and structurally similar kinases, and biochemical assays have demonstrated that both have POLII C-terminal domain (CTD) kinase activity and the ability to phosphorylate the Ser2 residue of the repetitive CTD heptad sequence" SIGNOR-273085 CNR1 protein P21554 UNIPROT GNAZ protein P19086 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257119 HDAC7 protein Q8WUI4 UNIPROT PLAG1 protein Q6DJT9 UNIPROT down-regulates deacetylation 9606 16207715 t miannu "Plag1 and plagl2 are also regulated by acetylation. They are acetylated and activated by p300 and deacetylated and repressed by hdac7." SIGNOR-140950 Ub:E2 complex SIGNOR-C497 SIGNOR TRIM38 protein O00635 UNIPROT "up-regulates activity" ubiquitination 9606 34199813 t miannu "The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t" SIGNOR-271141 HIF1A protein Q16665 UNIPROT KDM3A protein Q9Y4C1 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 32938217 t SaraGualdi "To this end, we confirm that KDM3A, KDM4B, KDM4C, KDM5B, KDM5C, and KDM62 are direct targets of HIF-1a while extent the list of known targets to KDM2A, KDM2B, KDM4D, KDM5A, and KDM6A. The results demonstrated that majority of the KDMs were similarly induced (KDM2A, KDM2B, KDM3A, KDM4B, KDM4C, KDM4D, KDM5A, KDM5B, KDM5C, KDM6B, and KDM7A) or repressed (KDM NO66 and KDM1A) by both HIF-1a and HIF-2a." SIGNOR-271568 CTSG protein P08311 UNIPROT F2RL1 protein P55085 UNIPROT "down-regulates activity" cleavage Phe59 GVTVETVfSVDEFSA -1 10978167 t lperfetto "PAR1E and PAR2E (10 microM) were incubated in the presence of the different proteases | The enzymes were used at the following concentrations: 0.5 unit/mL thrombin, 2.5 nM trypsin, 20 nM plasmin, 20 nM cathepsin G, 20 nM elastase, 20 nM proteinase 3, and 2 units/mL calpain I and II|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus.|Mass spectrometry studies of PAR2E predicted activation of PAR2 by trypsin through cleavage at the Arg36-Ser37 site, no effect of thrombin, and inactivation of the receptor by plasmin, calpain and leukocyte elastase, cathepsin G, and proteinase 3" SIGNOR-263585 PARD6A protein Q9NPB6 UNIPROT RAC1 protein P63000 UNIPROT up-regulates 9606 23151663 f gcesareni "In pcp , dvl binds to proteins such as pkc, atypical pkc (apkc), dvl?associated Activator of morphogenesis 1 (daam1), dvl-associating protein with a high frequency of leu residues (daple) and partitioning defective 6 (par6), which are important for the regulation of small gtpases such as rho and rac and, consequently, the cytoskeleton and cell polarity58." SIGNOR-199530 ACACA protein Q13085 UNIPROT "Food intake" phenotype SIGNOR-PH152 SIGNOR down-regulates 9606 BTO:0003336 25343030 f miannu "Leptin exerts an inhibitory effect on AMPK in the hypothalamus, thereby stimulating ACC and subsequently suppressing food intake." SIGNOR-263509 CSNK2A2 protein P19784 UNIPROT SPIB protein Q01892 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser146 PALEVSDsESDEALV 9606 BTO:0000567 10618498 t llicata "Phosphorylation of the Spi-B transcription factor reduces its intrinsic stability. | Serine residues 37 in the transactivation domain and 129, 144 and 146 in the PEST domain of Spi-B are phosphorylated by CKII in vitro | The CKII phosphorylation sites mapped in vitro are phosphorylated in vivo" SIGNOR-251041 CAMK2D protein Q13557 UNIPROT ANKRD28 protein O15084 UNIPROT "down-regulates activity" phosphorylation Ser1011 TNTSKTVsFEALPIM -1 17023142 t lperfetto "We provide evidence for a dual kinase-mediated regulation of the PITK holoenzyme whereby PITK phosphorylation at S1017 is catalyzed by calcium/calmodulin-dependent kinase II-delta (CaMKIIdelta), promoting the subsequent phosphorylation of S1013 by glycogen synthase kinase-3 (GSK3) in vitro.|the phosphorylation of PITK at these specific residues altered PP1 binding and subsequent PITK-directed dephosphorylation of hnRNP K" SIGNOR-264793 PPP2CA protein P67775 UNIPROT DDHD1 protein Q8NEL9 UNIPROT unknown dephosphorylation Ser727 TIPSPVTsPVLSRRH -1 11328814 t miannu "Here we incubated a recombinant preparation of the phospholipase in vitro with several enzymes including protein kinase CK2 (CK2), extracellular signal-regulated kinase 2 (ERK2), and protein phosphatase 2A (PP2A) to identify effects that might be of regulatory importance in vivo.Major findings were that 1) CK2 phosphorylated the phospholipase on serines 93, 105, and 716; 2) ERK2 phosphorylated the enzyme on serine 730; 3) there was cross-antagonism between the reactions that phosphorylated serines 716 and 730; 4) PP2A selectively hydrolyzed phosphate groups that were esterified to serines 716 and 730. The results of two independent experiments with each type of assay indicated that the incubation caused a 50% loss of phospholipase activity (TableV). These results differed from those of corresponding incubation experiments with PA-PLA1α plus ERK2 and MgATP (see “Experimental Procedures”), which provided no evidence for complex formation or phosphorylation-dependent loss of phospholipase activity" SIGNOR-262976 EEF2K protein O00418 UNIPROT EEF2 protein P13639 UNIPROT down-regulates phosphorylation Thr59 GETRFTDtRKDEQER 9606 2261989 t gcesareni "Ef-2 kinase phosphorylates ef-2 at 3 threonine residues: thr-53, thr-56, thr-58. Phosphorylation of thr56 and thr58 was found to be an ordered process, modification of thr56 preceding, and apparently being required for, phosphorylation of thr58." SIGNOR-22928 DNM2 protein P50570 UNIPROT MYO1C protein O00159 UNIPROT up-regulates binding 9606 17257598 t miannu "Dynamin bind directly to the sh3 domain of myo1e / an intriguing possibility is that binding of dynamin and synaptojanin to myo1e tail may activate motor activity since it has been demonstrated that myo1e atpase activity is autoinhibited by its sh3 domain" SIGNOR-152910 serotonin(1+) smallmolecule CHEBI:350546 ChEBI HTR2C protein P28335 UNIPROT "up-regulates activity" "chemical activation" 9606 BTO:0002524 31160049 t "Ligand-GPCR dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257523 "Cullin 3-RBX1-Skp1" complex SIGNOR-C526 SIGNOR WNK4 protein Q96J92 UNIPROT "down-regulates quantity by destabilization" polyubiquitination 9606 BTO:0000007 23838290 t miannu "We found that KLHL2, as well as KLHL3, was co-immunoprecipitated with all four WNK isoforms. The direct interaction of KLHL2 with WNKs was confirmed on fluorescence correlation spectroscopy. Co-expression of KLHL2 and Cullin3 decreased the abundance of WNK1, WNK3 and WNK4 within HEK293T cells, and a significant increase of WNK4 ubiquitination by KLHL2 and Cullin3 was observed both in HEK293T cells and in an in vitro ubiquitination assay. These results suggest that KLHL2-Cullin3 also functions as an E3-ligase for WNK isoforms within the body." SIGNOR-272123 CSK protein P41240 UNIPROT LCK protein P06239 UNIPROT down-regulates phosphorylation Tyr505 FTATEGQyQPQP 9606 BTO:0000782 1639064 t gcesareni "P50csk tyrosine kinase phosphorylates p56lck at tyr-505 and down regulates its catalytic activity." SIGNOR-20371 MAPK1 protein P28482 UNIPROT RPS6KB1 protein P23443 UNIPROT up-regulates phosphorylation Thr444 RFIGSPRtPVSPVKF 9606 15774499 t gcesareni "The principal target of rapamycin-induced p70s6k inactivation is a novel phosphorylation site within a conserved hydrophobic domain." SIGNOR-134658 PLCG2 protein P16885 UNIPROT "1D-myo-inositol 1,4,5-trisphosphate" smallmolecule CHEBI:16595 ChEBI "up-regulates quantity" "chemical modification" 9606 23000145 t scontino "Upon stimulation with various immune receptors, PLCγ2 cleaves the membrane-bound phospholipid phosphatidyl inositol-4, 5-biphosphate (PIP2) into the second messenger molecules inositol-1,4,5-trisphosphate (IP3) and diacylglycerol (DAG)." SIGNOR-268453 EHMT2 protein Q96KQ7 UNIPROT HBB protein P68871 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 19822740 f "Regulation of transcription" miannu "G9a activation of the βmaj globin gene was shown to be independent of G9a MT activity." SIGNOR-251788 KLHL9 protein Q9P2J3 UNIPROT "Cullin 3-RBX1-Skp1" complex SIGNOR-C526 SIGNOR "up-regulates activity" binding 9606 BTO:0000527 25303533 t miannu "KLHL9 mediates poly-ubiquitylation of C/EBPβ and C/EBPδ isoforms. We confirmed KLHL9 deletions in an independent cohort and showed that this protein is necessary for Cul3-ligase mediated ubiquitylation and proteasomal degradation of established MES-GBM MRs, C/EBPβ and C/EBPδ." SIGNOR-272455 Ub:E2 complex SIGNOR-C497 SIGNOR TRIM62 protein Q9BVG3 UNIPROT "up-regulates activity" ubiquitination 9606 34199813 t miannu "The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t" SIGNOR-270964 PRKAA1 protein Q13131 UNIPROT PPARGC1A protein Q9UBK2 UNIPROT "up-regulates activity" phosphorylation Ser539 SLFNVSPsCSSFNSP 10090 BTO:0001103 SIGNOR-C15 17609368 t lperfetto "AMPK phosphorylates PGC-1alpha directly both in vitro and in cells. These direct phosphorylations of the PGC-1alpha protein at threonine-177 and serine-538 are required for the PGC-1alpha-dependent induction of the PGC-1alpha promoter" SIGNOR-228654 SPI1 protein P17947 UNIPROT Differentiation phenotype SIGNOR-PH37 SIGNOR up-regulates 10090 BTO:0004730 12130514 f lperfetto "The transcription factor PU.1 is required for normal blood cell development. PU.1 regulates the expression of a number of crucial myeloid genes, such as the macrophage colony-stimulating factor (M-CSF) receptor, the granulocyte colony-stimulating factor (G-CSF) receptor, and the granulocyte-macrophage colony-stimulating factor (GM-CSF) receptor. Myeloid cells derived from PU.1(-/-) mice are blocked at the earliest stage of myeloid differentiation, similar to the blast cells that are the hallmark of human acute myeloid leukemia (AML). These facts led us to hypothesize that molecular abnormalities involving the PU.1 gene could contribute to the development of AML." SIGNOR-249633 KLHL21 protein Q9UJP4 UNIPROT EB1/MLL protein Q5UEC6 UNIPROT "up-regulates activity" binding 9606 BTO:0000567 27641145 t miannu "Indeed, KLHL21 localizes to FA structures preferentially at the leading edge, and in complex with Cul3, ubiquitylates EB1 within its microtubule-interacting CH-domain. Cells lacking CRL3(KLHL21) activity or expressing a non-ubiquitylatable EB1 mutant protein are unable to migrate and exhibit strong defects in FA dynamics, lamellipodia formation and cortical plasticity. Our study thus reveals an important mechanism to regulate cortical dynamics during cell migration that involves ubiquitylation of EB1 at focal adhesions." SIGNOR-272407 MMP7 protein P09237 UNIPROT ECM_disassembly phenotype SIGNOR-PH80 SIGNOR up-regulates 17318226 f lperfetto "Historically, MMPs were thought to function mainly as enzymes that degrade structural components of the ECM." SIGNOR-272374 EIF2AK2 protein P19525 UNIPROT EIF2AK2 protein P19525 UNIPROT "up-regulates activity" phosphorylation Tyr162 QLAAKLAyLQILSEE -1 16373505 t Manara "PKR autophosphorylates on Y101, Y162, and Y293 in vitro. Site-specific tyrosine phosphorylation is essential for efficient dsRNA-binding, dimerization, kinase activation and eIF2alpha phosphorylation of PKR." SIGNOR-260783 carvedilol chemical CHEBI:3441 ChEBI UGT1A1 protein P22309 UNIPROT "down-regulates activity" "chemical inhibition" 9606 BTO:0000007 21030469 t Luana "Fourteen of the compounds studied inhibited both bilirubin and estradiol glucuronidation (Table 1). Among these 14 compounds, ritonavir, anthraflavic acid, levothyroxine, riluzole, baicalein, farnesol, 4′-OH-phenytoin, 4-methylumbelliferone, raltegravir, and 1-naphthol exhibited very similar IC50 values (differences less than 2-fold) on both bilirubin glucuronidation and estradiol-3-glucuronidation (Table 1). Ketoconazole, carvedilol, and niflumic acid exhibited more disparity with respect to inhibition of the two reactions in that these compounds exhibited at least a 2-fold higher IC50 value against bilirubin glucuronidation than against estradiol-3-glucuronidation. SN-38 only weakly inhibited bilirubin glucuronidation (IC50 = 356 μM) and seemed to be a partial inhibitor of estradiol-3-glucuronidation." SIGNOR-258165 PPP2CB protein P62714 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR "down-regulates activity" dephosphorylation 9606 18160256 t "Overexpression of BTBD10 increased phosphorylation levels of Akts at both Thr(308) and Ser(473) while the reduction of the endogenous BTBD10 level resulted in a decrease in the phosphorylation levels of Akts. In vitro analysis indicated that BTBD10 bound to protein phosphatase 2A (PP2A) and inhibited dephosphorylation of Akts by PP2A." SIGNOR-248614 WNT7B protein P56706 UNIPROT LRP5 protein O75197 UNIPROT up-regulates binding 9606 15578921 t gcesareni "Wnt proteins bind to the frizzled receptors and lrp5/6 co-receptors, and through stabilizing the critical mediator betBeta-catenin, initiate a complex signaling cascade that plays an important role in regulating cell proliferation and differentiation." SIGNOR-131981 IKBKE protein Q14164 UNIPROT STAT1 protein P42224 UNIPROT up-regulates phosphorylation Ser727 TDNLLPMsPEEFDEV 9606 17502367 t gcesareni "All stats are phosphorylated on at least one serine residue in their tad specifically, ser727 in stats 1 and 3 and ser721 in stat4. Stat serine kinases have been identified through the use of inhibitors, dominant-negative alleles, and in vitro kinase assays. They include mapk (p38mapk: stats 1, 3, 4;erk: stat3, 5;jnk: stat3), pkc_ (stat1, stat3), mtor (stat3), nlk (stat3 (42)), and camkii and ikk_ (stat1 (39, 40, 43)).STAT Serine phosphorylation regulates transcriptional activity (see below)." SIGNOR-154775 PRKN protein O60260 UNIPROT EPS15 protein P42566 UNIPROT up-regulates ubiquitination 9606 BTO:0000938 BTO:0000142 16862145 t gcesareni "Treatment of cells with egf stimulates parkin binding to both eps15 and the egfr and promotes parkin-mediated ubiquitination of eps15" SIGNOR-148218 CLOCK protein O15516 UNIPROT BMAL1/NPAS2 complex SIGNOR-C431 SIGNOR "form complex" binding 9606 20817722 t miannu "The mammalian clock is regulated at the cellular level by a transcriptional/translational feedback loop. BMAL1/clock (or NPAS2) heterodimers activate the expression of the period (PER) and cryptochrome (CRY) genes acting as transcription factors directed to the PER and CRY promoters via E-box elements." SIGNOR-267965 PAK1 protein Q13153 UNIPROT SNAI1 protein O95863 UNIPROT up-regulates phosphorylation Ser246 QACARTFsRMSLLHK 9606 BTO:0000150 15833848 t lperfetto "Pak1 regulates the repressor activity of snail by phosphorylating on ser(246). Pak1 phosphorylation of snail supports snail's accumulation in the nucleus as well as its repressor functions." SIGNOR-135605 LPAR3 protein Q9UBY5 UNIPROT GNA13 protein Q14344 UNIPROT up-regulates binding 9606 22863277 t gcesareni "Serum-borne lysophosphatidic acid (lpa) and sphingosine 1-phosphophate (s1p) act through g12/13-coupled receptors to inhibit the hippo pathway kinases lats1/2 thereby activating yap and taz transcription co-activators, which are oncoproteins repressed by lats1/2." SIGNOR-198547 DYRK1A protein Q13627 UNIPROT FOXO1 protein Q12778 UNIPROT "down-regulates activity" phosphorylation Ser329 STISGRLsPIMTEQD 9606 BTO:0000887;BTO:0001103 11311120 t lperfetto "The kinase dyrk1a phosphorylates the transcription factor fkhr at ser329 in vitro, a novel in vivo phosphorylation siteser(329) phosphorylation also decreases the ability of fkhr to stimulate gene transactivation and reduces the proportion of fkhr present in the nucleus" SIGNOR-106829 TWIST2 protein Q8WVJ9 UNIPROT F2R protein P25116 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0004828 19051271 f miannu "we performed microarray analysis to compare the gene expression profiles in HGC-27 cells, with or without small interfering RNA (siRNA)-mediated depletion of TWIST. Our results showed that NF1, RAP1A, SRPX, RBL2, PFDN4, ILK, F2R, ERBB3, and MYB were up-regulated, whereas AKR1C2, FOS, GDF15, NR2F1, ATM, and CTPS were down-regulated after TWIST depletion" SIGNOR-255502 MRGPRX2 protein Q96LB1 UNIPROT GNAZ protein P19086 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257327 MAP3K1 protein Q13233 UNIPROT MAP2K6 protein P52564 UNIPROT up-regulates phosphorylation Thr211 LVDSVAKtIDAGCKP 9606 9712898 t gcesareni "Both wild type and kinase-inactive mutant rip immunoprecipitates can active mkk6 in vitrohe sapks are activated by at least two meks, sapk/erk kinase-1 (sek1, also called mapk-kinase (mkk)) and mkk7" SIGNOR-59679 TBKBP1 protein A7MCY6 UNIPROT TBK1 protein Q9UHD2 UNIPROT "up-regulates activity" relocalization 9606 31792381 t "TBKBP1 recruits TBK1 to protein kinase C-theta (PKCθ) through a scaffold protein, CARD10. This enables PKCθ to phosphorylate TBK1 at Ser 716, a crucial step for TBK1 activation" SIGNOR-272469 TBKBP1 protein A7MCY6 UNIPROT CARD10 protein Q9BWT7 UNIPROT "up-regulates activity" relocalization 9606 31792381 t "TBKBP1 recruits TBK1 to protein kinase C-theta (PKCθ) through a scaffold protein, CARD10. This enables PKCθ to phosphorylate TBK1 at Ser 716, a crucial step for TBK1 activation" SIGNOR-272470 IRF7 protein Q92985 UNIPROT Interferon-type-I proteinfamily SIGNOR-PF50 SIGNOR "up-regulates quantity by expression" "transcriptional regulation" 9606 16612387 f miannu "Ikkalfa can also phosphorylate and activate interferon regulatory factor-7 (irf7), which is required for interferon-alfa (ifnalfa) production." SIGNOR-263128 TRH protein P20396 UNIPROT TRHR protein P34981 UNIPROT "up-regulates activity" binding 9606 BTO:0001379 27515033 t scontino "When TRH reaches the pars distalis of the pituitary, it regulates cells that express TRH receptor-1 (TRH-R1), such as the thyrotrophs. These cell types are subject to a multifactorial regulation that determines the extent and specificity of their response to TRH." SIGNOR-267200 CSNK2A1 protein P68400 UNIPROT AKT1 protein P31749 UNIPROT up-regulates phosphorylation Ser129 SGSPSDNsGAEEMEV 9606 15818404 t gcesareni "Akt/pkb ser129 is phosphorylated by ck2 in vitro and in vivo;(4) such a phosphorylation of activated akt/pkb correlates with a further increase in catalytic activity." SIGNOR-135203 RPN2 protein P04844 UNIPROT "OST-B complex" complex SIGNOR-C536 SIGNOR "form complex" binding 9606 31831667 t miannu "Oligosaccharyltransferase (OST) catalyzes the transfer of a high-mannose glycan onto secretory proteins in the endoplasmic reticulum. Mammals express two distinct OST complexes that act in a cotranslational (OST-A) or posttranslocational (OST-B) manner. Here, we present high-resolution cryo-electron microscopy structures of human OST-A and OST-B. Although they have similar overall architectures, structural differences in the catalytic subunits STT3A and STT3B facilitate contacts to distinct OST subunits, DC2 in OST-A and MAGT1 in OST-B. In OST-A, interactions with TMEM258 and STT3A allow ribophorin-I to form a four-helix bundle that can bind to a translating ribosome, whereas the equivalent region is disordered in OST-B. " SIGNOR-272074 ANKRD11 protein Q6UB99 UNIPROT Neurite_outgrowth phenotype SIGNOR-PH134 SIGNOR up-regulates 10090 BTO:0000142 29274743 f miannu "We showed that ANKRD11 regulates dendrite outgrowth, arborization, and spine formation via Trkb transcription and activation of its downstream effectors in the developing mouse brain." SIGNOR-266733 CyclinD/CDK4 complex SIGNOR-C18 SIGNOR TSC2 protein P49815 UNIPROT "up-regulates activity" phosphorylation Ser1217 MSLENPLsPFSSDIN 9606 BTO:0000007 32294430 t done miannu "We show here that CyclinD-Cdk4/6 activates mTORC1 by binding and phosphorylating TSC2 on Ser1217 and Ser1452. " SIGNOR-274099 TBK1 protein Q9UHD2 UNIPROT IRF3 protein Q14653 UNIPROT "up-regulates activity" phosphorylation Ser386 ARVGGASsLENTVDL -1 18440553 t lperfetto "Virus-induced phosphoactivation of irf-3, thought to be mediated directly or indirectly by ikk? And/or tbk1 occurs in the c-terminal region of irf-3 at seven ser/thr residues, 385sslentvdlhisnshplslts405 (fig. 1a).Within This region, irf-3 has two phosphorylation sites: site 1 includes ser385 and ser386, whereas site 2 includes ser396, ser398, ser402, ser405, and thr404." SIGNOR-178395 JAK1 protein P23458 UNIPROT STAT1 protein P42224 UNIPROT "up-regulates activity" phosphorylation Tyr701 DGPKGTGyIKTELIS -1 7657660 t lperfetto "Stat1 was phosphorylated at tyr 701 in jak immune complex kinase reaction. The stat1 and stat2 proteins are present in the cytoplasm of untreated cells;upon stimulation with ifn-g, They become rapidly activated by tyrosine phosphorylation at a single site catalyzed by receptor associated jak (janus) kinases." SIGNOR-30905 TACR1 protein P25103 UNIPROT GNAQ protein P50148 UNIPROT "up-regulates activity" binding 9606 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257374 PRKACG protein P22612 UNIPROT PHKA2 protein P46019 UNIPROT "down-regulates activity" phosphorylation 9606 10487978 t "Phosphorylation of the alpha and beta subunits by the 3',5'-cyclic adenosine monophosphate (cAMP)-dependent protein kinase (PKA) also relieves inhibition of the gamma subunit and thereby activates the enzyme." SIGNOR-267414 F3 protein P13726 UNIPROT "Factor FVIIa:TF" complex SIGNOR-C319 SIGNOR "form complex" binding 9606 BTO:0000131 32665005 t lperfetto "During vascular injury, TF is exposed to the blood, where it functions as a cofactor for the circulating zymogen factor VII (FVII). This TF:FVIIa complex can then bind and activate either factor IX (FIX) or factor X (FX), triggering a cascade that generates fibrin and activates platelets, resulting in a hemostatic plug at the site of injury." SIGNOR-263556 UBE2D1 protein P51668 UNIPROT MGRN1 protein O60291 UNIPROT "up-regulates activity" binding 9606 BTO:0000567 17229889 t miannu "Our in vivo and in vitro ubiquitylation studies demonstrate that the binding of TSG101 to Mahogunin targets the substrate TSG101 for ubiquitylation by Mahogunin E3 ligase in cooperation with its cognate E2 enzyme Ubc5a" SIGNOR-271637 oxybutynin chemical CHEBI:7856 ChEBI CHRM3 protein P20309 UNIPROT "down-regulates activity" "chemical inhibition" 10030 BTO:0000246 22243489 t Luana " Interestingly, unlike the methiodide 5, the tertiary amine 17 and to a lesser extent its (S)-eutomer preferentially block the M3 receptor subtype with respect to the M2, with an M3/M2 selectivity ratio slightly higher than those of oxybutynin and the conventional M3selective antagonist 4-DAMP. " SIGNOR-258327 MRPL38 protein Q96DV4 UNIPROT "39S mitochondrial large ribosomal subunit" complex SIGNOR-C285 SIGNOR "form complex" binding -1 25838379 t lperfetto "We have determined the structure of the intact mitoribosome to 3.5 angstrom resolution by single-particle electron cryo-microscopy. It reveals 80 extensively interconnected proteins, 36 of which are specific to mitochondria, and three rRNA molecules" SIGNOR-262359 CHEK2 protein O96017 UNIPROT E2F1 protein Q01094 UNIPROT "up-regulates activity" phosphorylation Ser364 PLLSRMGsLRAPVDE 9606 12717439 t Manara "Therefore, Chk2 phosphorylates and activates E2F-1 in response to DNA damage, resulting in apoptosis. | These results suggest that the Ser 364 site is phosphorylated by Chk2 and that anti-P-Ser 364 recognises the phosphorylated site in E2F-1." SIGNOR-260822 PTPN2 protein P17706 UNIPROT MET protein P08581 UNIPROT "down-regulates activity" dephosphorylation Tyr1234 RDMYDKEyYSVHNKT 9606 18819921 t "Using substrate trapping mutants of PTP1B or TCPTP, we have demonstrated that both phosphatases interact with Met and that these interactions require phosphorylation of twin tyrosines (Tyr-1234/1235) in the activation loop of the Met kinase domain.|Using small interfering RNA against PTP1B and TCPTP, we demonstrate that phosphorylation of Tyr-1234/1235 in the activation loop of the Met receptor is elevated in the absence of either PTP1B or TCPTP and further elevated upon loss of both phosphatases." SIGNOR-248387 PTPN12 protein Q05209 UNIPROT SHC1 protein P29353 UNIPROT down-regulates dephosphorylation Tyr350 EPPDHQYyNDFPGKE 9606 8939605 t gcesareni "The shc adaptor protein is highly phosphorylated at conserved, twin tyrosine residues (y239/240) that mediate protein-protein interactions." SIGNOR-44862 KDM6A protein O15550 UNIPROT HOXA9 protein P31269 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 24561908 t miannu "Evidence for direct involvement of UTX in regulation of HOX gene activity was demonstrated through UTX knockdown experiments in HEK293T cells in which loss of UTX induced transcriptional repression of HOXA and HOXC clusters." SIGNOR-260025 UBE4B protein O95155 UNIPROT FEZ1 protein Q99689 UNIPROT "up-regulates activity" polyubiquitination 10116 BTO:0001009 15466860 t K27 miannu " E4B mediated the polyubiquitylation of FEZ1 but did not affect its intracellular stability, suggesting that such modification of FEZ1 is not a signal for its proteolysis. Polyubiquitylation of FEZ1 by E4B required Lys(27) of ubiquitin. Expression of a dominant-negative mutant of E4B in rat pheochromocytoma PC12 cells resulted in inhibition of neurite extension induced either by nerve growth factor or by coexpression of FEZ1 and constitutively active PKCzeta. These findings indicate that E4B serves as a ubiquitin ligase for FEZ1 and thereby regulates its function but not its degradation. The polyubiquitin chain attached by E4B to FEZ1 might therefore facilitate the interaction of FEZ1 with an unidentified target that functions in neuritogenesis." SIGNOR-271510 PTPN2 protein P17706 UNIPROT PDGFRB protein P09619 UNIPROT "down-regulates activity" dephosphorylation Tyr771 ADIESSNyMAPYDNY 10090 BTO:0002572 14966296 t "The PDGF beta receptor is negatively regulated by protein tyrosine phosphatases (PTPs).|In summary, our findings identify TC-PTP as a previously unrecognized negative regulator of PDGF beta receptor signaling and support the general notion that PTPs display site selectivity in their action on tyrosine kinase receptors.The fact that two of the investigated PDGF β receptor sites, Y1021 and Y771, displayed a larger increase in phosphorylation than Y579 and Y751 in TC-PTP ko MEFs indicated that these two sites are preferred substrates for TC-PTP." SIGNOR-248389 SRC protein P12931 UNIPROT PRKD1 protein Q15139 UNIPROT "up-regulates activity" phosphorylation Tyr432 KEGWMVHyTSKDTLR 9606 BTO:0000567 12637538 t lperfetto "Here we report that PKD is tyrosine-phosphorylated within the PH domain, leading to activation. This phosphorylation is mediated by a pathway that consists of the Src and Abl tyrosine kinases and occurs in response to stimulation with pervanadate and oxidative stress. Mutational analysis revealed three tyrosine phosphorylation sites (Tyr(432), Tyr(463), and Tyr(502)), which are regulated by the Src-Abl pathway, and phosphorylation of only one of these (Tyr(463)) leads to PKD activation." SIGNOR-247320 MAPK1 protein P28482 UNIPROT NEFH protein P12036 UNIPROT "up-regulates activity" phosphorylation Ser526 PVKEEAKsPAEAKSP 10116 BTO:0000938 9592082 t lperfetto "The fraction containing Erk2, as well as bacterially expressed Erk1 and Erk2, phosphorylated all types of KSP motifs in peptides (KSPXK, KSPXXK, KSPXXXK, and KSPXXXXK) derived from NF-M and NF-H. They also phosphorylated an expressed 24 KSPXXXK repeat NF-H polypeptide, an expressed NF-H as well as dephosphorylated native rat NF-H, and NF-M proteins with accompanying decreases in their respective electrophoretic mobilities. |Our data on primary hippocampal cells also showed an inhibition of neurite outgrowth by the drug that was accompanied by inhibition of MAP, NF-H, and NF-M phosphorylation." SIGNOR-249424 "Multiaminoacyl-tRNA synthetase" complex SIGNOR-C472 SIGNOR diphosphate(3-) smallmolecule CHEBI:33019 ChEBI "up-regulates quantity" "chemical modification" 9606 28271488 t miannu "Aminoacyl-tRNA synthetases (AARSs) are essential enzymes that specifically aminoacylate one tRNA molecule by the cognate amino acid. In mammals, nine synthetases, those specific for amino acids Arg, Asp, Gln, Glu, Ile, Leu, Lys, Met and Pro, associate into a multi-aminoacyl-tRNA synthetase complex, an association which is believed to play a key role in the cellular organization of translation, but also in the regulation of the translational and nontranslational functions of these enzymes." SIGNOR-270375 RCAN1 protein P53805 UNIPROT PPP3CA protein Q08209 UNIPROT "down-regulates activity" binding 9606 12554096 t "MCIP proteins can bind to and inhibit calcineurin, a calcium/calmodulin-regulated serine/threonine protein phosphatase that is activated during cardiac hypertrophy and failure" SIGNOR-252025 "aspartic acid" smallmolecule CHEBI:22660 ChEBI AminoAcids stimulus SIGNOR-ST5 SIGNOR "up-regulates quantity" 29259120 t lperfetto "All extant life employs the same 20 amino acids for protein biosynthesis" SIGNOR-264754 HLX protein Q14774 UNIPROT CDKN1C protein P49918 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0003980 20008130 t Luana "In this study, we have identified cell cycle regulatory genes as downstream targets of the homeobox gene HLX in cultured trophoblast cells, namely RB1, MYC, EGR1, CDKN1C, ELK1, CCNB1, and JUN. RB1 and MYC mRNA expression was increased with HLX inactivation, whereas EGR1, CDKN1C, ELK1, CCNB1, and JUN mRNA expression was decreased compared with mock-transfected control cells." SIGNOR-261620 MDC1 protein Q14676 UNIPROT RNF8 protein O76064 UNIPROT up-regulates relocalization 9606 18678647 t gcesareni "Rnf8 relocalizes to dna damage sites via a phospho-dependent interaction with mdc1" SIGNOR-179820 LPAR6 protein P43657 UNIPROT GNA12 protein Q03113 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257286 "glutamic acid" smallmolecule CHEBI:18237 ChEBI GRIK3 protein Q13003 UNIPROT "up-regulates activity" "chemical activation" 9606 27586965 t miannu "Glutamate is the major excitatory neurotransmitter in the mammalian central nervous system (CNS) and exerts its biological activity through a variety of receptors. Glutamate receptors (GluRs) are divided into two major classes on the basis of the mechanism by which they relay their signal: the ionotropic glutamate receptors (iGluRs), which are ligand-gated cation channels, and the metabotropic glutamate receptors (mGluRs) that are G protein-coupled receptors" SIGNOR-264472 CUL3 protein Q13618 UNIPROT HSF2 protein Q03933 UNIPROT "down-regulates quantity by destabilization" ubiquitination 10090 BTO:0002572 19768582 t 1 miannu "Here we show that the PEST sequences of a short-lived protein called HSF2 interact with Cullin3, a subunit of a Cullin-RING E3 ubiquitin ligase, and that this interaction mediates the Cul3-dependent ubiquitination and degradation of HSF2" SIGNOR-239129 MAPK3 protein P27361 UNIPROT TP53 protein P04637 UNIPROT up-regulates phosphorylation Ser15 PSVEPPLsQETFSDL 9606 12955074 t gcesareni "Mutant p53 is constitutively phosphorylated at serine 15 in uv-induced mouse skin tumors: involvement of erk1/2 map kinase." SIGNOR-100270 CDK2 protein P24941 UNIPROT ZBTB16 protein Q05516 UNIPROT down-regulates phosphorylation Ser197 SFGLSAMsPTKAAVD 9606 BTO:0001271 18246121 t llicata "Here we show that the main cyclin-dependent kinase involved at the g(1) to s transition (cdk2) phosphorylates plzf at two consensus sites found within pest domains present in the hinge region of the protein. This phosphorylation triggers the ubiquitination and subsequent degradation of plzf, which impairs plzf transcriptional repression ability and antagonizes its growth inhibitory effects." SIGNOR-160626 NTRK1 protein P04629 UNIPROT PLCG1 protein P19174 UNIPROT up-regulates binding 9606 BTO:0000938 10708759 t esanto "Autophosphorylated trka binds directly to plc?, Abl, and shc." SIGNOR-75405 PTPN2 protein P17706 UNIPROT INSR protein P06213 UNIPROT "down-regulates activity" dephosphorylation Tyr1189 RDIYETDyYRKGGKG 9606 BTO:0000007 12612081 t "In this study, we investigated the downregulation of insulin receptor (IR) signaling by TCPTP. In response to insulin stimulation, the TC48-D182A and TC45-D182A substrate-trapping mutants formed stable complexes with the endogenous tyrosine-phosphorylated IR beta-subunit in 293 cells.|IR β-subunit phosphorylated on tyrosine and specifically on tyrosines 1162 and 1163 could be coimmunoprecipitated with the TC48-D182A and TC45-D182A mutants but not the wild-type TC48 or TC45 in response to insulin" SIGNOR-248385 RPGRIP1L protein Q68CZ1 UNIPROT RELA protein Q04206 UNIPROT down-regulates demethylation Lys221 LLCDKVQkEDIEVYF 9606 SIGNOR-C13 20080798 t miannu "Fbxl11 and nsd1 have opposite effects on nf-kb; both bind to p65 subunit after activation of nf-kb. / nsd1 activates nf-kb and reverses the inhibitory effect of fbxl11 / these data confirm that fbxl11 and nsd1 constitute an enzyme pair that methylates and demethylates p65 on k218 and 221 in response to cytokine stimulation." SIGNOR-163320 DUX4 protein Q9UBX2 UNIPROT PITX1 protein P78337 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 17984056 t Luana "DUX4, a candidate gene of facioscapulohumeral muscular dystrophy, encodes a transcriptional activator of PITX1" SIGNOR-261590 MEF2C protein Q06413 UNIPROT MYOD1 protein P15172 UNIPROT "up-regulates activity" binding 9606 9418854 t lperfetto "Myod-e protein heterodimers interact with mef2 proteins to synergistically activate myogenesis." SIGNOR-54089 CyclinK/CDK12 complex SIGNOR-C37 SIGNOR POLR2A protein P24928 UNIPROT "up-regulates activity" phosphorylation Ser1948 SPTSPGYsPTSPTYS 9606 BTO:0006413 32917631 t "Ser2 in CTD of PolII" lperfetto "Together, these studies demonstrate the important, yet largely redundant, role for CDK12 and CDK13 for the regulation of POLII CTD phosphorylation at multiple residues, as well as the global role for both of these kinases in regulating POLII occupancy across the genome.|CDK12 and CDK13 are thus evolutionarily related and structurally similar kinases, and biochemical assays have demonstrated that both have POLII C-terminal domain (CTD) kinase activity and the ability to phosphorylate the Ser2 residue of the repetitive CTD heptad sequence" SIGNOR-273086 CyclinK/CDK12 complex SIGNOR-C37 SIGNOR POLR2A protein P24928 UNIPROT "up-regulates activity" phosphorylation Ser1868 SPTSPKYsPTSPKYS 9606 BTO:0006413 32917631 t "Ser2 in CTD of PolII" lperfetto "Together, these studies demonstrate the important, yet largely redundant, role for CDK12 and CDK13 for the regulation of POLII CTD phosphorylation at multiple residues, as well as the global role for both of these kinases in regulating POLII occupancy across the genome.|CDK12 and CDK13 are thus evolutionarily related and structurally similar kinases, and biochemical assays have demonstrated that both have POLII C-terminal domain (CTD) kinase activity and the ability to phosphorylate the Ser2 residue of the repetitive CTD heptad sequence" SIGNOR-273087 "SWI/SNF complex" complex SIGNOR-C92 SIGNOR CDKN2A protein P42771 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 18332116 f irozzo "HSNF5 reexpression in MRT cells caused SWI/SNF recruitment and activation of p15INK4b and p16INK4a, but not of p14ARF.Reexpression of hSNF5 in MRT cells overcomes epigenetic silencing and mediates transcriptional activation of p15INK4b and p16INK4a" SIGNOR-256299 IFI30 protein P13284 UNIPROT "peptide antigen" smallmolecule CHEBI:166824 ChEBI "up-regulates quantity" "chemical modification" 9606 31810556 t scontino "Within the phagosome, the internalized antigens are partially degraded by Cathepsin S and the GILT complex, a necessary step for further export to cytosol." SIGNOR-267864 CSK protein P41240 UNIPROT PECAM1 protein P16284 UNIPROT "up-regulates activity" phosphorylation Tyr713 KKDTETVySEVRKAV 9534 BTO:0001538 9624175 t miannu "We demonstrated that phosphorylation of PECAM-1 by Src or Csk family kinases was sufficient to trigger its association with SHP-2. Moreover, it was able to promote binding of PECAM-1 to SHP-1, a SHP-2-related protein-tyrosine phosphatase expressed in hemopoietic cells. Taken together, these findings indicated that the Src and Csk families of kinases are strong candidates for mediating tyrosine phosphorylation of PECAM-1 and triggering its association with SH2 domain-containing phosphatases under physiological circumstances." SIGNOR-262741 MARCHF5 protein Q9NX47 UNIPROT MFN1 protein Q8IWA4 UNIPROT "down-regulates quantity by destabilization" ubiquitination 9606 BTO:0000567 20103533 t lperfetto "MARCH5, a mitochondrial E3 ubiquitin ligase, has been identified as a molecule that binds mitochondrial fission 1 protein (hFis1), dynamin-related protein 1 (Drp1) and mitofusin 2 (Mfn2), key proteins in the control of mitochondrial fission and fusion.|Notably, a significant increase in Mfn1 level, but not Mfn2, Drp1 or hFis1 levels, was observed in MARCH5-depleted cells, indicating that Mfn1 is a major ubiquitylation substrate." SIGNOR-272981 AKT proteinfamily SIGNOR-PF24 SIGNOR PDCD4 protein Q53EL6 UNIPROT down-regulates phosphorylation Ser457 RGRKRFVsEGDGGRL 9606 16357133 t gcesareni "Our results show that akt specifically phosphorylates ser(67) and ser(457) residues of pdcd4 in vitro and in vivo. We further show that phosphorylation of pdcd4 by akt causes nuclear translocation of pdcd4." SIGNOR-143098 GADD45G protein O95257 UNIPROT CDK11A protein Q9UQ88 UNIPROT "down-regulates activity" binding 9606 BTO:0000007 26885618 t lperfetto "Western blot analysis for SPDEF revealed that overexpression of GADD45α, β and γ prevents SPDEF degradation mediated by CDK11p58 |We identified CDK11p58 as an interaction partner of GADD45α by co-immunoprecipitation analysis. We corroborated these data by co-immunoprecipitation in vitro translation assays, showing that all three members of the GADD45 family interact with CDK11p58." SIGNOR-273025 Gbeta proteinfamily SIGNOR-PF4 SIGNOR NCF1 protein P14598 UNIPROT up-regulates phosphorylation 9606 BTO:0000130 16778989 t "inferred from 70% family members" gcesareni "Inhibitors of the erk1/2 pathway abrogated gm-csf-induced phosphorylation of ser345, while p38 mapk inhibitor abrogated tnf-alpha-induced phosphorylation of ser345.These results show that the ala-mutated p47phox acts as a dominant-negative inhibitor of endogenous p47phox and clearly indicate that phosphorylation of ser345 is required for the priming of nadph oxidase activity in neutrophil-like cells." SIGNOR-270091 NARS2 protein Q96I59 UNIPROT Asn-tRNA(Asn) smallmolecule CHEBI:29265 ChEBI "up-regulates quantity" "chemical modification" 9606 32788587 t miannu "Asparaginyl-tRNA synthetase1 (NARS1) is a member of the ubiquitously expressed cytoplasmic Class IIa family of tRNA synthetases required for protein translation. Asparaginyl-tRNA synthetase1 (NARS1) belongs to the class IIa family, based upon a 7 beta-strand protein structure. There are two NARS genes: NARS1 functions in the cytoplasm while NARS2 functions in mitochondria, solely responsible for asparagine tRNA charging in these locations." SIGNOR-270464 alvimopan chemical CHEBI:135686 ChEBI OPRK1 protein P41145 UNIPROT "down-regulates activity" "chemical inhibition" -1 18313920 t Luana "A series of N-substituted trans-3,4-dimethyl-4-(3-hydroxyphenyl)piperidines, l opioid receptor antagonists, analogs of alvimopan, were prepared using solid phase methodology. This study led to the identification of a highly selective l opioid receptor antagonist, which interacts selectively with l peripheral receptors." SIGNOR-257774 ROCK2 protein O75116 UNIPROT PPP1R14A protein Q96A00 UNIPROT "up-regulates activity" phosphorylation Thr38 QKRHARVtVKYDRRE 9606 32471307 t lperfetto "A major kinase for GPCR‐induced CPI‐17 phosphorylation is PKC which is activated by the PLCbeta‐produced signaling messenger diacylglycerol (DAG). It phosphorylates CPI‐17 at Thr38 residue that directly docks at the active site of MLCP, thereby inhibiting its activity and promoting an increase of phosphorylation of myosin and of other MLCP.| CPI-17 can be also directly phosphorylated at Thr38 residue by MYPT1-associated kinase [222], by PAK, which is downstream of Rac and/or Cdc42 cascade [223], by Rho-associated coiled-coil kinase (ROCK) [224] and by PKN [225]." SIGNOR-90832 Ub:E2 complex SIGNOR-C497 SIGNOR SYVN1 protein Q86TM6 UNIPROT "up-regulates activity" ubiquitination 9606 34199813 t miannu "The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t" SIGNOR-271126 MAPK14 protein Q16539 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR "up-regulates activity" 9606 12181443 f lperfetto "We show [] that the kinase activity and s473 phosphorylation of akt induced by lpa and s1p requires both mitogen-activated protein (map) kinase kinase (mek) and p38 map kinase. [] among different stimuli tested, platelet-derived growth factor stimulates s473 phosphorylation of akt in a mek- and p38-dependent manner. However, epidermal growth factor, thrombin, and endothelin-1?stimulated Akt s473 phosphorylation require p38 but not mek." SIGNOR-244465 "Cullin 1-RBX1-Skp1" complex SIGNOR-C529 SIGNOR FBXL2 protein Q9UKC9 UNIPROT "down-regulates quantity by destabilization" polyubiquitination 9606 BTO:0000007 25721664 t miannu "F-box protein Fbxo3 targets Smurf1 ubiquitin ligase for ubiquitination and degradation. Here we show that another F-box protein Fbxo3, belonging to the FBXO type protein family, also interacts with and targets Smurf1 for poly-ubiquitination and proteasomal degradation. The SCF complex is composed of F-box protein, Skp1, Cullin1 (Cul1) and ROC1. Fbxo3, whose substrates are few, forms SCF Fbxo3 ubiquitin ligase and regulates the degradations of Fbxl2, p62, HIPK2 and p300 through the ubiquitin-proteasome pathway." SIGNOR-272447 calcium(2+) smallmolecule CHEBI:29108 ChEBI CAMK2G protein Q13555 UNIPROT up-regulates "chemical activation" 9606 22944199 t lperfetto "Non-canonical Wnt/Ca2+ pathway has also been implicated in multiple functions including cell adhesion and cell movements during gastrulation. In this signaling cascade, binding of Wnt to the Fzd receptor leads to the release of intracellular Ca2+, a process which is mediated through heterotrimeric G proteins, PLC (phospholipase C) and CamKII (calcium-calmodulin-dependent kinae II) as well as PKC (protein kinase C). The increased intracellular Ca2+ concentration also activates the calcineurin phosphatase, leading to activation of the transcription factor NFAT (nuclear factor of activated T cell)." SIGNOR-198816 CDK12 protein Q9NYV4 UNIPROT POLR2A protein P24928 UNIPROT up-regulates phosphorylation Ser1875 SPTSPKYsPTSPTYS 9606 22012619 t miannu "Cyck/cdk12 can activate transcription and phosphorylate ser2 in the ctd of rnapii / phosphorylation of serine at position 2 (ser2) is thought to be responsible for productive transcriptional elongation and synthesis of full-length mature mrna" SIGNOR-176801 WT1 protein P19544 UNIPROT SRY protein Q05066 UNIPROT up-regulates binding 9606 12970737 t miannu "Here we report that wt1 binds to and acts synergistically with sry to activate transcription from a promoter containing sry-binding sites" SIGNOR-100345 2''-O-acetyl-ADP-D-ribose(2-) smallmolecule CHEBI:83767 ChEBI ADP-D-ribose(2-) smallmolecule CHEBI:57967 ChEBI "up-regulates quantity" "precursor of" 9606 32257385 t miannu "MACROD2 is a protein-coding gene located at a fragile site on human chromosome 20. The MACROD2 protein is a deacetylase involved in the removal of ADP-ribose from mono-ADP-ribosylated proteins" SIGNOR-269841 ECSIT protein Q9BQ95 UNIPROT MAVS protein Q7Z434 UNIPROT "up-regulates activity" binding 9606 22588174 t Giorgia "ECSIT interacts with IPS-1|ECSIT enhances IPS-1-mediated IFN-Beta promoter activation" SIGNOR-260371 Calcineurin complex SIGNOR-C155 SIGNOR NFATC2 protein Q13469 UNIPROT "up-regulates activity" dephosphorylation Ser274 ASPQRSRsPSPQPSS 9606 BTO:0000567 11030334 t "NFAT1 is phosphorylated on fourteen conserved phosphoserine residues in its regulatory domain, thirteen of which are dephosphorylated upon stimulation. Dephosphorylation of all thirteen residues is required to mask a nuclear export signal (NES), cause full exposure of a nuclear localization signal (NLS), and promote transcriptional activity" SIGNOR-252328 SLC6A4 protein P31645 UNIPROT serotonin smallmolecule CHEBI:28790 ChEBI "up-regulates quantity" relocalization 9606 BTO:0000227 16789923 t miannu "The function of the serotonin transporter (SERT) is to take up and release serotonin (5-hydroxytyptamine (5-HT)) from cells and this function of SERT in the central nervous system (CNS) is well-documented; SERT is the target of selective serotonin reuptake inhibitors used in the treatment of CNS disorders, such as depression." SIGNOR-263953 CDON/SPAG9 complex SIGNOR-C21 SIGNOR MAP3K5 protein Q99683 UNIPROT unknown binding 10090 BTO:0000165;BTO:0000222;BTO:0002181 22337877 t lperfetto "Cdo and jlp interacted with ask1 or tak1 in 293t cells and c2c12 myoblasts" SIGNOR-235557 CASP3 protein P42574 UNIPROT IKBKB protein O14920 UNIPROT down-regulates cleavage Asp78 PNVVAARdVPEGMQN 9606 11741536 t gcesareni "Ikappab kinase (ikk) beta was specifically proteolyzed by caspase-3-related caspases at aspartic acid residues 78, 242, 373, and 546 during tumor necrosis factor (tnf)-alpha-induced apoptosis." SIGNOR-112800 IL10 protein P22301 UNIPROT SCN2A protein Q99250 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 10116 23357618 f miannu "Interleukin-10 down-regulates voltage gated sodium channels in rat dorsal root ganglion neurons. Consistent with the electrophysiological results, real-time PCR and western blot revealed that IL-10 (200 pg/ml) down-regulated VGSCs in both mRNA and protein levels and reversed the up-regulation of VGSCs by TNF-α." SIGNOR-253499 TRAF6 protein Q9Y4K3 UNIPROT ULK1 protein O75385 UNIPROT "up-regulates quantity by stabilization" ubiquitination 9606 BTO:0000007 23524951 t lperfetto "AMBRA1, interacting with the E3-ligase TRAF6, supports ULK1 ubiquitylation by LYS-63-linked chains, and its subsequent stabilization, self-association and function." SIGNOR-273000 LARP7 protein Q4G0J3 UNIPROT P-TEFb complex SIGNOR-C238 SIGNOR "down-regulates activity" binding 9606 BTO:0000567 30824372 t Monia "To investigate whether LARP7 is part of the known 7SK RNP implicated in the regulation of transcription, co‐immunoprecipitation studies were performed using the nuclear extracts of HeLa cells (Fig 3A, lanes 1–4). Antibodies against LARP7, CDK9 and HEXIM1 efficiently precipitated 7SK RNA, whereas no RNA was found in the control (Fig 3A, lower panel, lanes 1–4). Interestingly, HEXIM1, CDK9, CYCT1 and LARP7 were present in all immunopurifications, as determined by mass spectrometry of silver‐stained gels (Fig 3A; data not shown) and western blotting. In conclusion, these experiments show that LARP7 negatively regulates not only viral but also cellular POLII class genes through the 7SK P‐TEFb system." SIGNOR-261184 CASP9 protein P55211 UNIPROT Apoptosome complex SIGNOR-C230 SIGNOR "form complex" binding -1 10206961 t lperfetto " APAF-1 binds and hydrolyzes ATP or dATP to ADP or dADP, respectively. The hydrolysis of ATP/dATP and the binding of cytochrome c promote APAF-1 oligomerization, forming a large multimeric APAF-1.cytochrome c complex. Such a complex can be isolated using gel filtration chromatography and is by itself sufficient to recruit and activate procaspase-9. " SIGNOR-256429 AKT2 protein P31751 UNIPROT TSC2 protein P49815 UNIPROT down-regulates phosphorylation Ser939 SFRARSTsLNERPKS 9606 12150915 t gcesareni "We demonstrate here that tuberin is phosphorylated on s939 and t1462 in response to pi3k activation. Our results are consistent with akt being the pi3k-depen-dent tuberin kinase. The pi3k-akt-mediated phosphorylation of tuberin would inhibit the function of the tuberin-hamartin complex." SIGNOR-91041 isoleucine smallmolecule CHEBI:24898 ChEBI AminoAcids stimulus SIGNOR-ST5 SIGNOR "up-regulates quantity" 29259120 t lperfetto "All extant life employs the same 20 amino acids for protein biosynthesis" SIGNOR-264749 FZD7 protein O75084 UNIPROT FZD7/SDC4 complex SIGNOR-C216 SIGNOR "form complex" binding 9606 BTO:0002314 BTO:0001103 23290138 t apalma "We next examined whether endogenous Fzd7 and Sdc4 form a receptor complex in satellite cells […] Therefore, we conclude that Fzd7 and Sdc4 form a co-receptor complex in activated satellite cells." SIGNOR-255848 NMBR protein P28336 UNIPROT GNAS protein Q5JWF2 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-256775 PCNA protein P12004 UNIPROT NCR2 protein O95944 UNIPROT "down-regulates activity" binding 9606 22021614 t miannu "NK cells play an important role in the early immune response to cancer. The NKp44 activating receptor is the only natural cytotoxicity receptor that is expressed exclusively by primate NK cells, yet its cellular ligands remain largely unknown." SIGNOR-260043 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR BCL2L11 protein O43521 UNIPROT "down-regulates quantity by destabilization" phosphorylation 9606 15486195 t "inferred from 70% family members" lperfetto "In vitro, bimel was phosphorylated by extracellular signal-regulated kinase on ser(69), which resides in the bimel-specific insert region. Using phosphospecific antibody against this site, we show that this residue is actually phosphorylated in cells. We also show that phosphorylation of ser(69) promotes ubiquitination of bimel. We conclude that mek inhibitors sensitize mda-mb231 and hbc4 cells to anoikis by blocking phosphorylation and hence degradation of bimel" SIGNOR-270152 2-(6-Bromo-1,3-benzodioxol-5-yl)-N-(4-cyanophenyl)-1-[(1S)-1-cyclohexylethyl]benzimidazole-5-carboxamide chemical CID:126961335 PUBCHEM F2RL1 protein P55085 UNIPROT "down-regulates activity" "chemical inhibition" -1 28445455 t "Simone Vumbaca" "The antagonist AZ8838 binds in a fully occluded pocket near the extracellular surface. | Antagonist AZ3451 binds to a remote allosteric site outside the helical bundle. We propose that antagonist binding prevents structural rearrangements required for receptor activation and signalling." SIGNOR-261119 "3-phenanthryl hydrogen sulfate" chemical CHEBI:37459 ChEBI DRD2 protein P14416 UNIPROT "down-regulates activity" "chemical inhibition" -1 7576010 t miannu "The affinities of D2 receptors for agonists and antagonists were compared for receptors labeled with [1251]-7-OHPIPAT and with [*251]-NCQ-298 under conditions that promote, respectively, coupling or uncoupling of receptors to G proteins. Table 1." SIGNOR-258439 "Ub:E1 (UBA1 substrate)" complex SIGNOR-C495 SIGNOR UBE2D3 protein P61077 UNIPROT "up-regulates activity" ubiquitination 9606 34199813 t miannu "The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t" SIGNOR-271314 CSNK1E protein P49674 UNIPROT PER3 protein P56645 UNIPROT "down-regulates activity" phosphorylation Ser634 ISQCGYSsTIVHVPP 9534 BTO:0000298 11865049 t llicata "The CKI phosphorylation of mPer1 and mPer3 proteins results in their rapid degradation, which is dependent on the ubiquitin-proteasome pathway. Moreover, CKIepsilon and CKIdelta are able to induce nuclear translocation of mPer3, which requires its nuclear localization signal. The mutation in potential phosphorylation sites on mPer3 decreased the extent of both nuclear translocation and degradation of mPer3 that are stimulated by CKIepsilon. | In mut7 in which all of the conserved serine and threonine residues in this region were mutated, the ratio of the shifted band was greatly reduced reproducibly. " SIGNOR-250819 TGFBR2 protein P37173 UNIPROT PIK3R2 protein O00459 UNIPROT up-regulates binding 9606 9435577 t lperfetto "These studies revealed that PI 3-kinase is associated in vivo with both TGF-_ receptor subtypes and that TGF-_1 stimulation enhances PI 3-kinase activity associated with type I TGF-_ receptor in hASM cells." SIGNOR-227528 CD300LB protein A8K4G0 UNIPROT GRB2 protein P62993 UNIPROT "up-regulates activity" binding 9534 BTO:0004055 20959446 t lperfetto "The CD300b receptor is a non-classical activating receptor able to deliver signals by associating with the transmembrane adaptor protein DAP-12 and the intracellular mediator Grb-2." SIGNOR-264833 "C5 convertase complex" complex SIGNOR-C312 SIGNOR C5 protein P01031 UNIPROT "up-regulates activity" cleavage Arg677 KEILRPRrTLQKKIE 31331124 t lperfetto "Association of C3b with C3 convertases (C3bBb or C4b2a) results in formation of C5 convertases, C3bBbC3b and C4b2aC3b, which initiate the lytic pathway by cleavage of C5 to C5a and C5b" SIGNOR-263452 IL10 protein P22301 UNIPROT SCN8A protein Q9UQD0 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 10116 BTO:0000938 BTO:0001264 23357618 f miannu "Interleukin-10 down-regulates voltage gated sodium channels in rat dorsal root ganglion neurons. Consistent with the electrophysiological results, real-time PCR and western blot revealed that IL-10 (200 pg/ml) down-regulated VGSCs in both mRNA and protein levels and reversed the up-regulation of VGSCs by TNF-α." SIGNOR-253501 PRKACA protein P17612 UNIPROT "Histone H3" proteinfamily SIGNOR-PF69 SIGNOR up-regulates phosphorylation 9606 10464286 t gcesareni "Identification of a novel phosphorylation site on histone h3 coupled with mitotic chromosome condensation." SIGNOR-265344 OXTR protein P30559 UNIPROT GNAI1 protein P63096 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257065 BRSK1 protein Q8TDC3 UNIPROT CAST protein P20810 UNIPROT "up-regulates activity" phosphorylation Ser45 KSQSTKLsVVHEKKS 10090 BTO:0000142 27626661 t miannu "Here, we show that an AZ cytomatrix protein CAST and an AZ-associated protein kinase SAD-B coordinately regulate STD by controlling reloading of the AZ with release-ready synaptic vesicles. SAD-B phosphorylates the N-terminal serine (S45) of CAST, and S45 phosphorylation increases with higher firing rate." SIGNOR-263051 PRKCB protein P05771 UNIPROT ITGB7 protein P26010 UNIPROT unknown phosphorylation Thr783 PLYKSAItTTINPRF 10090 BTO:0001825 12682249 t lperfetto "Beta7 subunit is phosphorylated even in unstimulated TK-1 cells. Activation of TK-1 cells with anti-CD3 (Fig. 5_A) and PDBu (Fig. 5_B) increased the phosphorylation 15€“20%. | The result shows that the fourth amino acid of the tryptic peptide was phosphorylated. This phosphorylated threonine residue is most likely the first threonine (Thr782) of threonine triplet (Thr782€“784)." SIGNOR-249200 MMP9 protein P14780 UNIPROT HAPLN1 protein P10915 UNIPROT "down-regulates quantity by destabilization" cleavage His31 LDHDRAIhIQAENGP -1 7694569 t miannu "Matrix metalloproteinases cleave at two distinct sites on human cartilage link protein. Sequencing studies of modified link protein components revealed that stromelysins-1 and -2, gelatinases A and B and collagenase cleaved specifically between His16 and Ile17, and matrilysin, stromelysin-2 and gelatinase A cleaved between Leu25 and Leu26. Based on previously determined in situ cleavage sites it is evident that matrix metalloproteinases are not solely responsible for the accumulation of link protein degradation products in adult human cartilage, indicating that additional proteolytic agents are involved in the normal catabolism of human cartilage matrix." SIGNOR-256328 AREL1 protein O15033 UNIPROT SEPTIN4 protein O43236 UNIPROT "down-regulates quantity by destabilization" ubiquitination 9606 23479728 t lperfetto "Furthermore, the ubiquitination and degradation of SMAC, HtrA2, and ARTS were significantly enhanced in AREL1-expressing cells following apoptotic stimulation, indicating that AREL1 binds to and ubiquitinates cytosolic but not mitochondria-associated forms of IAP antagonists" SIGNOR-267670 MAPK1 protein P28482 UNIPROT EP300 protein Q09472 UNIPROT up-regulates phosphorylation Ser2279 PVQPNPMsPQQHMLP 9606 17623675 t lperfetto "Serine residues (ser-2279, ser-2315, and ser-2366) on the c terminus of p300 were the major signaling targets of egf. Furthermore, the c-terminal serine phosphorylation of p300 stimulated its histone acetyltransferase activity these results also constituted the first report identifying the unique p300 phosphorylation sites induced by erk2 in vivo." SIGNOR-156887 AMPD1 protein P23109 UNIPROT "adenosine 5'-monophosphate" smallmolecule CHEBI:16027 ChEBI "down-regulates quantity" "chemical modification" 9606 BTO:0001103 1631143 t miannu "AMP deaminase (AMPD; EC 3.5.4.6) is encoded by a multigene family in mammals. The AMPD1 gene is expressed at high levels in skeletal muscle, where this enzyme is thought to play an important role in energy metabolism. AMP deaminase (AMPD; EC 3.5.4.6), an enzyme that catalyzes deamination of AMP to IMP, and the purine nucleotide cycle, of which AMPD is one component, play a central role in purine nucleotide interconversion in eukaryotic cells." SIGNOR-269772 INS protein P01308 UNIPROT IGF1R protein P08069 UNIPROT up-regulates binding 9606 BTO:0000887 1851182 t fspada "Because of the sequence homology and tertiary structure similarities between proinsulin (pi) and insulin-like growth factor-i (igf-i), it is possible that pi interacts with the igf-i receptor with higher affinity than insulin." SIGNOR-22083 Mob1 proteinfamily SIGNOR-PF42 SIGNOR LATS1/2 proteinfamily SIGNOR-PF43 SIGNOR "up-regulates activity" binding 9606 21084559 t miannu "Lats1/2 are activated by association with the highly homologous scaffold proteins mps one binder kinase activator-like 1a (mobkl1a) and 1b (mobkl1b), which are collectively referred to as mob1." SIGNOR-256186 ZNF384 protein Q8TF68 UNIPROT MMP1 protein P03956 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 BTO:0000944 10669742 t Luana "Luciferase activity driven by the MMP-1 promoter also increased by 2.5- to 3-fold. In contrast, CIZ had no effect on the luciferase activity from the MMP-1 promoter that was mutated at the CIZ binding consensus sequence. These results show that the CIZ transactivates the MMP-1 promoter through this sequence." SIGNOR-266229 PRKCA protein P17252 UNIPROT SRF protein P11831 UNIPROT down-regulates phosphorylation Ser162 LRRYTTFsKRKTGIM 10090 16537394 t lperfetto "Mimicking phosphorylation of serine-162, a target of protein kinase c-alpha, with an aspartic acid substitution (srf-s162d) completely inhibited srf-dna binding and blocked alpha-actin gene transcription pkc? Highly phosphorylated serine-162." SIGNOR-234461 P2RY12 protein Q9H244 UNIPROT GNAZ protein P19086 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257107 CDK9 protein P50750 UNIPROT SMAD1 protein Q15797 UNIPROT down-regulates phosphorylation Ser195 PNSSYPNsPGSSSST 9606 19914161 t lpetrilli "Phosphorylation of the linker region of smad1, a receptor-activated smad (r-smad), at serine 206 (s206) and s214 induced by bmp and mediated by cdk8/9 is critical for binding of the e3 ubiquitin ligase smurf1. Binding of smurf1 leads to polyubiquitination of smad1 and its degradation by the proteasome;cdk8 and cyclint-cdk9 showed a preference for s206 and s214 but also phosphorylated s186 and s195 in the case of smad1;and t179, s208 and s213 in the case of smad3." SIGNOR-161569 PTPN7 protein P35236 UNIPROT MAPK14 protein Q16539 UNIPROT down-regulates binding 9606 BTO:0000776 19047375 t gcesareni "Thus, beta(2)ar stimulation on a b cell phosphorylates and inactivates heptp in a gs/camp/pka-dependent manner to release bound p38 mapk, making more available for phosphorylation and subsequent ige regulation" SIGNOR-182525 PRKCA protein P17252 UNIPROT GRIA2 protein P42262 UNIPROT unknown phosphorylation Ser880 YNVYGIEsVKI 9606 BTO:0000007 10501226 t lperfetto "Here, we show that the C terminus of GluR2 of the alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA) receptor is phosphorylated by protein kinase C and that serine-880 is the major phosphorylation site. This phosphorylation also occurs in human embryonic kidney (HEK) cells by addition of 12-O-tetradecanoylphorbol 13-acetate." SIGNOR-249022 CDK2 protein P24941 UNIPROT ORC2 protein Q13416 UNIPROT up-regulates phosphorylation Thr116 LASELAKtPQKSVSF 9606 SIGNOR-C83 11931757 t lperfetto "We also found that horc2p is phosphorylated in vitro by cyclin a/cdk2, specifically at residues thr116 and thr226. These data combined strongly suggest that skp2 promotes horc1p turnover and that the n-terminal domain of horc1p, containing most of the phosphorylation sites and overlapping with one of the skp2-interacting domains, is a regulatory element for horc1p stability." SIGNOR-116364 GPI protein P06744 UNIPROT AMFR protein Q9UKV5 UNIPROT up-regulates binding 9606 12527360 t gcesareni "Pgi is a housekeeping gene encoding phosphoglucose isomerase (pgi) a glycolytic enzyme that also functions as a cytokine (autocrine motility factor (amf)/neuroleukin/maturation factor) upon secretion from the cell and binding to its 78 kda seven-transmembrane domain receptor (gp78/amf-r)" SIGNOR-97270 MLNR protein O43193 UNIPROT GNAI1 protein P63096 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-256737 PRKACA protein P17612 UNIPROT PRKAA1 protein Q13131 UNIPROT "down-regulates activity" phosphorylation Ser491 SSTPQRSCsAAGLHRPR 10116 BTO:0002135 17023420 t "These agents also enhanced phosphorylation of alpha-Ser(485/491) by the cAMP-dependent protein kinase. AMPK alpha-Ser(485/491) phosphorylation was necessary but not sufficient for inhibition of AMPK activity in response to forskolin/isobutylmethylxanthine." SIGNOR-256112 panobinostat chemical CHEBI:85990 ChEBI HDAC9 protein Q9UKV0 UNIPROT "down-regulates activity" "chemical inhibition" -1 17868033 t Luana "Our findings suggest that hydroxamic acid-derived compounds such as TSA, NVP-LAQ824, panobinostat, ITF2357, vorinostat and belinostat act as potent pan-HDAC isoform inhibitors. A notable observation was the similarity between belinostat and vorinostat in the biochemical isoform assays; both compounds exhibit similar EC50 values in all but the HDAC8 assay." SIGNOR-257750 HIF1A protein Q16665 UNIPROT KDM4B protein O94953 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0001248 20682797 f miannu "Here, we show the histone demethylase JMJD2B is regulated by both ERalpha and HIF-1alpha, drives breast cancer cell proliferation in normoxia and hypoxia, and epigenetically regulates the expression of cell cycle genes such as CCND1, CCNA1, and WEE1." SIGNOR-263738 GRPR protein P30550 UNIPROT GNAQ protein P50148 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257372 SMAD2 protein Q15796 UNIPROT SMAD2/SMAD4 complex SIGNOR-C8 SIGNOR "form complex" binding 9606 phosphorylation:Ser465;Ser467 SPSVRCSsMS;SVRCSSMs 11274206 t gcesareni "the receptor-regulated Smad, such as Smad2, forms a heterocomplex with the co-mediator Smad, Smad4" SIGNOR-235188 MRPL50 protein Q8N5N7 UNIPROT "39S mitochondrial large ribosomal subunit" complex SIGNOR-C285 SIGNOR "form complex" binding -1 25838379 t lperfetto "We have determined the structure of the intact mitoribosome to 3.5 angstrom resolution by single-particle electron cryo-microscopy. It reveals 80 extensively interconnected proteins, 36 of which are specific to mitochondria, and three rRNA molecules" SIGNOR-262338 ICAM3 protein P32942 UNIPROT "AD/b2 integrin" complex SIGNOR-C172 SIGNOR "up-regulates activity" binding 8777714 t lperfetto "A novel leukointegrin, alpha d beta 2, binds preferentially to ICAM-3." SIGNOR-253371 WNT5B protein Q9H1J7 UNIPROT FZD3 protein Q9NPG1 UNIPROT up-regulates binding 9606 15578921 t gcesareni "Wnt proteins bind to the frizzled receptors and lrp5/6 co-receptors, and through stabilizing the critical mediator betBeta-catenin, initiate a complex signaling cascade that plays an important role in regulating cell proliferation and differentiation." SIGNOR-131882 AKT proteinfamily SIGNOR-PF24 SIGNOR PRKAA1 protein Q13131 UNIPROT "down-regulates activity" phosphorylation -1 16340011 t gcesareni "It is proposed that the effect of insulin to antagonize AMP-activated protein kinase activation involves a hierarchical mechanism whereby Ser 485/Ser 491 phosphorylation by protein kinase B reduces subsequent phosphorylation of Thr 172 by LKB1 and the resulting activation of AMP-activated protein kinase." SIGNOR-252740 RUNX2 protein Q13950 UNIPROT SPP1 protein P10451 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 11331591 f gcesareni "In addition to osteocalcin, cbfa1 regulates expression of several other genes that are activated during osteoblast" SIGNOR-107175 PRKAA1 protein Q13131 UNIPROT SREBF1 protein P36956 UNIPROT "down-regulates activity" phosphorylation 9606 SIGNOR-C15 21892142 t lperfetto "Ampk was recently found to phosphorylate a conserved serine near the cleavage site within srebp1, suppressing its activation" SIGNOR-176497 "sphingosine 1-phosphate" smallmolecule CHEBI:37550 ChEBI S1PR2 protein O95136 UNIPROT up-regulates "chemical activation" 9606 16794003 t gcesareni "The evidence suggests that s1p acting on s1p receptors coupled to gq." SIGNOR-147230 CSNK2A1 protein P68400 UNIPROT DDHD1 protein Q8NEL9 UNIPROT "down-regulates activity" phosphorylation Ser104 GSSLRYYsEGESGGG -1 11328814 t miannu "Here we incubated a recombinant preparation of the phospholipase in vitro with several enzymes including protein kinase CK2 (CK2), extracellular signal-regulated kinase 2 (ERK2), and protein phosphatase 2A (PP2A) to identify effects that might be of regulatory importance in vivo.Major findings were that 1) CK2 phosphorylated the phospholipase on serines 93, 105, and 716; 2) ERK2 phosphorylated the enzyme on serine 730; 3) there was cross-antagonism between the reactions that phosphorylated serines 716 and 730; 4) PP2A selectively hydrolyzed phosphate groups that were esterified to serines 716 and 730. The results of two independent experiments with each type of assay indicated that the incubation caused a 50% loss of phospholipase activity (TableV). These results differed from those of corresponding incubation experiments with PA-PLA1α plus ERK2 and MgATP (see “Experimental Procedures”), which provided no evidence for complex formation or phosphorylation-dependent loss of phospholipase activity" SIGNOR-262974 L-arginine chemical CHEBI:16467 ChEBI NOS2 protein P35228 UNIPROT up-regulates BTO:0000801 BTO:0001103 25386178 f apalma "In mammalian cells, arginine can be catabolized by four classes of enzymes (Figure ​(Figure1):1): NOS, arginase, arginine decarboxylase (ADC), and arginine:glycine amidinotransferase (AGAT)" SIGNOR-255554 WNT3A protein P56704 UNIPROT FZD2 protein Q14332 UNIPROT up-regulates binding 9606 19910923 t gcesareni "It was also shown that wnt5a inhibits the beta-catenin pathway by competing with wnt3a for binding to fz2, and that the impairment of clathrin-mediated internalization does not affect this wnt5a inhibitory action." SIGNOR-189117 CDK6 protein Q00534 UNIPROT RUNX1 protein Q01196 UNIPROT up-regulates phosphorylation Ser21 TPPSTALsPGKMSEA 9606 21059642 t "The effect has been demonstrated using Q01196-8" gcesareni "Phosphorylation of runx1 on ser-303 by cdks leads its ubiquitin-mediated degradation during g2/m (19). We developed additional evidence that cdks phosphorylate ser-303 and found that ser-48 and ser-424 are also substrates of cdk1/cyclin b and cdk6/cyclin d3. Moreover, we demonstrated that phosphorylation of ser-48, ser-303, and ser-424 strengthens the ability of runx1 to activate transcription and to stimulate proliferation of the ba/f3 hematopoietic cell line (20)." SIGNOR-169326 Ub:E2 complex SIGNOR-C497 SIGNOR NEURL3 protein Q96EH8 UNIPROT "up-regulates activity" ubiquitination 9606 34199813 t miannu "The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t" SIGNOR-271211 HTR2A protein P28223 UNIPROT GNAQ protein P50148 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257137 BCOR protein Q6W2J9 UNIPROT HOXA9 protein P31269 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 10090 26847029 f irozzo "Importantly, our results showed that BCOR is a repressor of HoxA cluster of genes (HoxA5, HoxA7 and HoxA9) in myeloid cells. Knock-down of HoxA5, HoxA7 and HoxA9 significantly decreased the clonogenic growth of Bcor mutant and wild type cells, demonstrating the Hox genes, as targets of BCOR, played an important role in mediating BCOR’s function in regulating myeloid cell proliferation." SIGNOR-256014 CyclinK/CDK12 complex SIGNOR-C37 SIGNOR POLR2A protein P24928 UNIPROT "up-regulates activity" phosphorylation Ser1924 SPTSPKYsPTSPTYS 9606 BTO:0006413 32917631 t "Ser2 in CTD of PolII" lperfetto "Together, these studies demonstrate the important, yet largely redundant, role for CDK12 and CDK13 for the regulation of POLII CTD phosphorylation at multiple residues, as well as the global role for both of these kinases in regulating POLII occupancy across the genome.|CDK12 and CDK13 are thus evolutionarily related and structurally similar kinases, and biochemical assays have demonstrated that both have POLII C-terminal domain (CTD) kinase activity and the ability to phosphorylate the Ser2 residue of the repetitive CTD heptad sequence" SIGNOR-273088 IFTAP protein Q86VG3 UNIPROT BTF3 protein P20290 UNIPROT "down-regulates activity" binding 9606 BTO:0000567 18433331 t lperfetto "Furthermore, we co-immunoprecipitated HEPIS with BTF3, a component of the RNA pol II initiation complex, and observed reduced proliferation of HeLa cells transfected with the HEPIS gene." SIGNOR-260252 LCK protein P06239 UNIPROT VAV1 protein P15498 UNIPROT unknown phosphorylation Tyr142 SVGDEDIySGLSDQI -1 10669745 t "Lck recognizes preferentially the tyrosine residue of Vav located at position 174 and, with significantly less affinity, those present at positions 142 and 160. It is now clear that this posttranslational modification will be involved in the activation of Vav, in the regulation of the strength of the signals emanating from this molecule, and also in the negative regulation of its function." SIGNOR-251389 CEBPE protein Q15744 UNIPROT LTF protein P02788 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000007 15588942 f miannu "C/EBP_ interacts with C/EBP_ through the leucine-zipper–containing domain. C/EBP_ and C/EBP_ synergistically activate transcription of lactoferrin promoter" SIGNOR-225012 PRKCD protein Q05655 UNIPROT DAP3 protein P51398 UNIPROT up-regulates phosphorylation Thr237 ITRVRNAtDAVGIVL 9606 18227431 t amattioni "Dap3 is phosphorylated by protein kinase cdelta on thr237. Dap3 was originally identified as a pro-apoptotic protein. The mutation of the phosphorylation site thr237 to alanine reversed the cell death caused by the wild-type dap3" SIGNOR-160488 5-amino-1-(5-phospho-D-ribosyl)imidazole-4-carboxamide(2-) smallmolecule CHEBI:58475 ChEBI (6S)-5,6,7,8-tetrahydrofolate(2-) smallmolecule CHEBI:57453 ChEBI "up-regulates quantity" "precursor of" 9606 33179964 t miannu "The last two steps in the pathway are catalyzed by the bifunctional AICAR transformylase/IMP cyclohydrolase (ATIC). The transformylase domain of the enzyme first catalyzes the conversion of AICAR to formylaminoimida zole-4-carboxamide ribonucleotide (FAICAR) using the N10-formyltetrahydrofolate. Then, the cyclohydrolase domain closes the purine ring to form IMP." SIGNOR-267323 INPP5D protein Q92835 UNIPROT SYK protein P43405 UNIPROT "down-regulates activity" dephosphorylation 9606 32323266 t scontino "An adaptor protein Dok-3 mediates the suppressive function of LYN. The Dok-3 phosphorylated by LYN upon BCR stimulation forms a complex with GRB2, which allows it to enter into the signalosome and associate with activation of SHIP protein. This translocation facilitates the efficient inhibition of PLCc2 and SYK from activation, subsequently resulting in the suppression of downstream Ca2+ signaling." SIGNOR-268456 CTNNB1 protein P35222 UNIPROT CEBPA protein P49715 UNIPROT down-regulates 9606 BTO:0000222 10937998 f fspada "Wnt-10b, is a molecular switch that governs adipogenesis. Wnt signaling maintains preadipocytes in an undifferentiated state through inhibition of the adipogenic transcription factors ccaat/enhancer binding protein alpha (c/ebpalpha) and peroxisome proliferator- activated receptor gamma (ppargamma)." SIGNOR-80589 SLBP protein Q14493 UNIPROT H2BS1 protein P57053 UNIPROT "up-regulates quantity by expression" "translation regulation" 9606 BTO:0001938 19155325 t lperfetto "Synthesis of mature histone mRNA requires only a single processing reaction: an endonucleolytic cleavage between a conserved stem-loop and a purine-rich downstream element to form the 3' end. The stem-loop binding protein (SLBP) is required for processing, and following processing, histone mRNA is transported to the cytoplasm, where SLBP participates in translation of the histone mRNA|We used radiolabeled probes generated by PCR targeting the open reading frame (ORF) to detect histones H2A, H2B, H3, H4, and H1 and used 7SK snRNA as a loading control (Fig. 2A). The abundance of histone H2A, H2B, H3, and H4 mRNAs is reduced to 37% to 70% of control levels in the SLBP knockdown cells when compared to the C2 control." SIGNOR-265384 GUCY1A2 protein P33402 UNIPROT GUCY1A2-B3 complex SIGNOR-C138 SIGNOR "form complex" binding 9606 10977868 t gcesareni "This enzyme is a heterodimeric protein consisting of - and ²-subunits, and expression of both subunits is required for catalytic activity" SIGNOR-243977 CSNK2A1 protein P68400 UNIPROT EEF1D protein P29692 UNIPROT unknown phosphorylation Ser162 DDIDLFGsDNEEEDK 9606 BTO:0000567 21936567 t lperfetto "Direct phosphorylation of eef1d by ck2 was shown by performing ck2 assays with eef1d -flag from hela cells. Dramatic increases in eef1d phosphorylation following _-phosphatase treatment and phospho- eef1d antibody recognizing eef1d ps162 indicated phosphorylation at the ck2 site in cells." SIGNOR-176632 FLT3 protein P36888 UNIPROT SHC1 protein P29353 UNIPROT "up-regulates activity" phosphorylation Tyr350 EPPDHQYyNDFPGKE 9606 10482988 t miannu "Intracellular FLT3 signaling involves tyrosine phosphorylation of several cytoplasmic proteins including SHC. We have found that upon FLT3 activation SHC phosphorylation occurs at tyrosine 239/240 and 313." SIGNOR-251147 PRKACA protein P17612 UNIPROT CUL5 protein Q93034 UNIPROT "up-regulates activity" phosphorylation Ser730 MKMRKKIsNAQLQTE 9534 BTO:0000298 10898738 t miannu "Elimination of the S730 but not the T325 PKA phosphorylation site of VACM-1 resulted in a complete inhibition of the VACM-1 activity, thus suggesting a direct effect of PKA on the VACM-1 receptor." SIGNOR-250352 CyclinK/CDK12 complex SIGNOR-C37 SIGNOR POLR2A protein P24928 UNIPROT "up-regulates activity" phosphorylation Ser1651 SPTSPSYsPTSPSYS 9606 BTO:0006413 32917631 t "Ser2 in CTD of PolII" lperfetto "Together, these studies demonstrate the important, yet largely redundant, role for CDK12 and CDK13 for the regulation of POLII CTD phosphorylation at multiple residues, as well as the global role for both of these kinases in regulating POLII occupancy across the genome.|CDK12 and CDK13 are thus evolutionarily related and structurally similar kinases, and biochemical assays have demonstrated that both have POLII C-terminal domain (CTD) kinase activity and the ability to phosphorylate the Ser2 residue of the repetitive CTD heptad sequence" SIGNOR-273090 Ub:E2 complex SIGNOR-C497 SIGNOR MIB2 protein Q96AX9 UNIPROT "up-regulates activity" ubiquitination 9606 34199813 t miannu "The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t" SIGNOR-270989 DCN protein P07585 UNIPROT FBN1 protein P35555 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10116 BTO:0000951 17200203 f Regulation miannu "Decorin Induces Fibrillin-1 Protein Expression in NRK Cells via IGF-IR. we report a novel mechanism of action that involves two key molecules: decorin, a small leucine-rich proteoglycan, and the IGF-IR. These two players, together with the downstream signaling pathway evoked by decorin-mediated activation of the receptor, lead to an enhanced translation of fibrillin-1 and its deposition in the extracellular environment both in vitro and in vivo." SIGNOR-251893 NOTCH proteinfamily SIGNOR-PF30 SIGNOR MAML2 protein Q8IZL2 UNIPROT up-regulates binding 9606 12386158 t gcesareni "Other than a role in t-cell development, the hox genes may be involved in alternative notchregulated processes in hematopoietic stem cells. Notch signaling is clearly important for self-renewal of hematopoietic progenitors (reviewed by radkte et al. 57). Interestingly, hoxa5, a9 and a10 were found to be part of the stem cell profile'" SIGNOR-254347 PPP1CA protein P62136 UNIPROT CASP9 protein P55211 UNIPROT "up-regulates activity" dephosphorylation Thr125 PEVLRPEtPRPVDIG 9606 16888006 t "ERK/MAPK phosphorylates caspase-9 at Thr(125), and this phosphorylation is crucial for caspase-9 inhibition. Until now, the phosphatase responsible for Thr(125) dephosphorylation has not been described. Here, we demonstrate that in IL-2-proliferating cells, phosphorylated serine/threonine phosphatase type 1alpha (PP1alpha) associates with phosphorylated caspase-9." SIGNOR-248565 PRKCB protein P05771 UNIPROT MARCKS protein P29966 UNIPROT unknown phosphorylation Ser170 SFKLSGFsFKKNKKE -1 8422248 t lperfetto "These results indicate that in vitro, PKC phosphorylates MARCKS only at three sites, but not at Ser160 as that reported previously, and there was no preferential phosphorylation of MARCKS by either PKC isozyme I, II or III." SIGNOR-248929 ACP1 protein P24666 UNIPROT PDGFRB protein P09619 UNIPROT "down-regulates activity" dephosphorylation Tyr857 DIMRDSNyISKGSTF 9606 12149261 t "Insight into the role of low molecular weight phosphotyrosine phosphatase (LMW-PTP) on platelet-derived growth factor receptor (PDGF-r) signaling. LMW-PTP controls PDGF-r kinase activity through TYR-857 dephosphorylation|On the basis of these results, we propose a key role for LMW-PTP in PDGF-r down-regulation through the dephosphorylation of the activation loop Tyr-857, thus determining a general negative regulation of all downstream signals, with the exception of those elicited by internalized receptors." SIGNOR-248452 CDS2 protein O95674 UNIPROT "phosphatidic acid" smallmolecule CHEBI:16337 ChEBI "down-regulates quantity" "chemical modification" 9606 25375833 t lperfetto "CDP-diacylglycerol synthases (CDS) are critical enzymes that catalyze the formation of CDP-diacylglycerol (CDP-DAG) from phosphatidic acid (PA)." SIGNOR-267021 CRK protein P46108 UNIPROT PTK2 protein Q05397 UNIPROT "up-regulates activity" phosphorylation Tyr397 SVSETDDyAEIIDEE 9606 BTO:0000007 11314030 t llicata "Tyrosine phosphorylation FAK was strictly dependent upon c-Crk II expression | Crk-inducible FAK tyrosine phosphorylation was completely abrogated by co-expression with R38K Crk (lane 2), and decreased by co-expression with W170K Crk (lane 3), indicating that the SH2 domain of c-Crk is absolutely essential for this effect. In contrast, mutants in the C-terminus of Crk that include Y222F c-Crk, which abrogates the c-Abl phosphorylation site, and W276K Crk, which mutates the C-terminal SH3 domain, modestly increased FAK activation compared to wild-type c-Crk II." SIGNOR-250777 5-chloro-N2-[2-methoxy-4-[4-(4-methyl-1-piperazinyl)-1-piperidinyl]phenyl]-N4-(2-propan-2-ylsulfonylphenyl)pyrimidine-2,4-diamine chemical CHEBI:91338 ChEBI ALK protein Q9UM73 UNIPROT "down-regulates activity" "chemical inhibition" -1 22037378 t Luana "Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here." SIGNOR-258293 MAPK3 protein P27361 UNIPROT RPS6KA1 protein Q15418 UNIPROT "up-regulates activity" phosphorylation Ser380 HQLFRGFsFVATGLM 9534 9430688 t lperfetto "Several lines of evidence indicate that the mapkap-k1 isoforms are also activated by mapks in vivo via the ras-dependent protein kinase cascade that is triggered by growth factors or tumor-promoting phorbol esters, such as phorbol 12-myristate 13-acetate (pma). here we identify six sites in mapkap-k1a that become phosphorylated in transfected cos-1 cells. The inactive form of mapkap-k1a in unstimulated cells is partially phosphorylated at ser222 and ser733. Stimulation with phorbol 12-myristate 13-acetate induces the phosphorylation of thr360, ser364, thr574, and ser381 and increases the phosphorylation of ser222 and ser733." SIGNOR-219341 AKT proteinfamily SIGNOR-PF24 SIGNOR ARFIP2 protein P53365 UNIPROT unknown phosphorylation Ser260 GTRGRLEsAQATFQA 9606 BTO:0000938 15809304 t llicata "Akt phosphorylated arfaptin 2 at ser(260). we have also demonstrated that arfaptin 2 phosphorylation restores proteasome activity that is inhibited by the presence of polyq-huntingtin in cells." SIGNOR-135105 GPR17 protein Q13304 UNIPROT GNAI1 protein P63096 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-256692 TP53 protein P04637 UNIPROT CCNG1 protein P51959 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10116 9688532 t lperfetto "Individual promoter and intron p53-binding motifs from the rat Cyclin G1 promoter region support transcriptional activation by p53 but do not show co-operative activation." SIGNOR-268961 RITA1 protein Q96K30 UNIPROT RBPJ protein Q06330 UNIPROT down-regulates binding 9606 21102556 t gcesareni "Thus, we propose that rita acts as a negative modulator of the notch signalling pathway, controlling the level of nuclear rbp-j/cbf-1, where its amounts are limiting." SIGNOR-170089 MAPK8 protein P45983 UNIPROT NFATC3 protein Q12968 UNIPROT down-regulates phosphorylation 9606 14517246 t gcesareni "Jnks directly phosphorylate nuclear factor of activated t-cell (nfat) transcription factors, thus antagonizing the effects of calcium-regulated signaling through the protein phosphatase calcineurin" SIGNOR-118220 CSF2RA protein P15509 UNIPROT STAT5A protein P42229 UNIPROT up-regulates 9606 7716810 f gcesareni "A major pathway which mediates the effects of gm-csf on macrophages involves activation of the latent transcription factor stat5a via a janus kinase 2 (jak2)-dependent pathway." SIGNOR-32220 PAK1 protein Q13153 UNIPROT NET1 protein Q7Z628 UNIPROT "down-regulates activity" phosphorylation Ser152 PTPAKRRsSALWSEM -1 15684429 t miannu "In this work we show that the Rac/Cdc42hs-regulated protein kinase PAK1 down-regulates the activity of the RhoA-specific guanine nucleotide exchange factor NET1. Specifically, PAK1 phosphorylates NET1 on three sites in vitro: serines 152, 153, and 538. Replacement of serines 152 and 153 with glutamate residues down-regulates the activity of NET1 as an exchange factor in vitro and its ability to stimulate actin stress fiber formation in cells. Using a phospho-specific antibody that recognizes NET1 phosphorylated on serine 152, we show that PAK1 phosphorylates NET1 on this site in cells and that Rac1 stimulates serine 152 phosphorylation in a PAK1-dependent manner." SIGNOR-263017 "GABA-A (a6-b3-d) receptor" complex SIGNOR-C329 SIGNOR Excitatory_synaptic_transmission phenotype SIGNOR-PH133 SIGNOR down-regulates 9606 BTO:0000227 18790874 f brain lperfetto "GABAA receptors (GABAA-Rs) are the major inhibitory receptors in the central nervous system (CNS). |Mammalian GABAA-Rs are all anion-selective channels. Increased chloride permeability generally reduces neuronal excitability (inhibition)" SIGNOR-263783 EP300 protein Q09472 UNIPROT RELA protein Q04206 UNIPROT "up-regulates activity" acetylation Lys310 KRTYETFkSIMKKSP 9606 BTO:0002207 15152190 t gcesareni "Using acetylation assays, p300 was found to effectively acetylate RelA/p65 across the amino-acid region containing 1€“317" SIGNOR-238778 NTNG1 protein Q9Y2I2 UNIPROT LRRC4C protein Q9HCJ2 UNIPROT "up-regulates activity" binding 9606 BTO:0000938 19467332 t miannu "The NGL (netrin-G ligand; LRRC4) family of synaptic cell adhesion molecules belongs to the superfamily of leucine-rich repeat (LRR) proteins. The three known members of the NGL family, NGL-1, NGL-2, and NGL-3, are mainly localized to the postsynaptic side of excitatory synapses, and interact with the presynaptic ligands, netrin-G1, netrin-G2, and LAR, respectively." SIGNOR-264047 EPHB1 protein P54762 UNIPROT EPHB1 protein P54762 UNIPROT "up-regulates activity" phosphorylation Tyr928 SAIKMVQyRDSFLTA 10029 BTO:0000246 12223469 t " Co-immunoprecipitation was used to confirm the interaction of Grb7 with the cytoplasmic domain of EphB1 as well as the full-length receptor in intact cells. This interaction is mediated by the SH2 domain of Grb7 and requires tyrosine autophosphorylation of EphB1. We also found that EphB1 could phosphorylate Grb7 and mutation of either Tyr-928 or Tyr-594 to Phe decreased this activity." SIGNOR-251123 TCL1A protein P56279 UNIPROT AKT3 protein Q9Y243 UNIPROT up-regulates binding 9606 10983986 t miannu "Full-length tcl1 and its isoforms bind to akt / in in vitro kinase assays using gsk-3_ as a substrate, we found that the presence of any of the tcl1 family proteins (tcl1, mtcp1, or tcl1b) as gst fusion proteins significantly enhanced akt-induced gsk-3_ phosphorylation" SIGNOR-81434 TANK protein Q92844 UNIPROT DUSP14 protein O95147 UNIPROT "up-regulates activity" ubiquitination lys103 9606 BTO:0000007 26521044 t miannu "TRAF2-mediated Lys63-linked ubiquitination of DUSP14/MKP6 is essential for its phosphatase activity. Mass spectrometry and mutational analyses identified that DUSP14 was Lys63-linked ubiquitinated at lysine 103 residue.Here we report that DUSP14 was Lys63-linked ubiquitinated at Lys103 residue by the E3 ligase TRAF2 during TCR signaling. Furthermore, ubiquitination of DUSP14 was essential for its phosphatase activity." SIGNOR-272811 ADP chemical CHEBI:16761 ChEBI P2RY12 protein Q9H244 UNIPROT "up-regulates activity" "chemical activation" 9606 BTO:0002524 31160049 t "Ligand-GPCR dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257560 JAK2 protein O60674 UNIPROT JAK2 protein O60674 UNIPROT "down-regulates activity" phosphorylation Tyr570 VRREVGDyGQLHETE 9606 21841788 t lperfetto "The jak2 jh2 domain functions as a negative regulator and is presumed to be a catalytically inactive pseudokinase, but the mechanism(s) for its inhibition of jak2 remains unknown. Here we show that jh2 is a dual-specificity protein kinase that phosphorylates two negative regulatory sites in jak2: ser523 and tyr570." SIGNOR-176058 RPS6KA1 protein Q15418 UNIPROT RANBP3 protein Q9H6Z4 UNIPROT unknown phosphorylation Ser126 VKRERTSsLTQFPPS 9606 18280241 t llicata "Rsk phosphorylates serine 58 of ranbp3 in vitro and in vivo" SIGNOR-160904 GSK3B protein P49841 UNIPROT GYS1 protein P13807 UNIPROT "down-regulates activity" phosphorylation Ser649 VPPSPSLsRHSSPHQ -1 6772446 t "Glycogen synthase kinase-3 phosphorylates three serine residues on glycogen synthase (sites 3a, 3b and 3c) which are all located in the same nine-amino-acid segment of the polypeptide chain. The sequence in this region is: Arg-Tyr-Pro-Arg-Pro-Ala-Ser(P)-Val-Pro-Pro-Ser(P)-Pro-Ser-Leu-Ser(P)-Arg-." SIGNOR-253007 BMP2 protein P12643 UNIPROT BMPR1A protein P36894 UNIPROT "up-regulates activity" binding -1 18937504 t ggiuliani "Here we report the high-resolution NMR structure of BMPR-IA ECD in solution, revealing that a large part of the ligand-binding epitope is unfolded and flexible before formation of the complex. The binding beta4beta5 loop of BMPR-IA passes through a structural rearrangement upon BMP-2 binding." SIGNOR-255771 CDC25C protein P30307 UNIPROT CyclinB/CDK1 complex SIGNOR-C17 SIGNOR "up-regulates activity" dephosphorylation Thr14 IEKIGEGtYGVVYKG 9606 BTO:0001938 10913154 t lperfetto "Cyclin B-Cdc2 complexes are maintained in an inactive state until the end of G2 by phosphorylation of the Thr14/Tyr15 residues. Around the time of nuclear translocation of the complex, these residues are dephosphorylated, resulting in the formation of an active cyclin B-Cdc2 complex (2). As mentioned, this dephosphorylation occurs by a Cdc25 protein phosphatase. Three Cdc25 family members have been identified to date, A, B and C, the last one being the active one at the onset of mitosis. The activity of Cdc25C itself can be enhanced through phosphorylation by cyclin B-Cdc2 (9, 10). Therefore, activation of cyclin B-Cdc2 has been proposed to result in an autocatalytic feedback loop to ensure rapid activation of these complexes at the G2/M transition" SIGNOR-251509 HES1 protein Q14469 UNIPROT NR3C1 protein P04150 UNIPROT "down-regulates activity" 9606 BTO:0001938 24300895 t "Altering the expression of HES1 did not obviously affect GR abundance (Figure 3A). However, genome-wide microarrays revealed that overexpression of HES1 resulted in inhibition of GR-mediated changes in the glucocorticoid regulated transcriptome, as compared to non-overexpressing controls" SIGNOR-253064 FES protein P07332 UNIPROT BCR protein P11274 UNIPROT "down-regulates activity" phosphorylation Tyr246 SCGVDGDyEDAELNP 9606 BTO:0000007 8955135 t "In the present study, we demonstrate that BCR Tyr-246 and at least one of the closely spaced tyrosine residues, Tyr-279, Tyr-283, and Tyr-289 (3Y cluster), are phosphorylated by FES both in vitro and in 32Pi-labeled cells. Co-expression of BCR and FES in human 293T cells stimulated the tyrosine autophosphorylation of FES. By contrast, tyrosine phosphorylation of BCR by FES suppressed BCR serine/threonine kinase activity toward the 14-3-3 protein and BCR substrate, BAP-1. " SIGNOR-251137 CD19 protein P15391 UNIPROT MAPK1 protein P28482 UNIPROT "up-regulates activity" 9606 10706702 f lperfetto "CD19 is a coreceptor on B cells that enhances the increase in cytoplasmic calcium and ERK2 activation when coligated with the B cell Ag receptor." SIGNOR-249609 risperidone chemical CHEBI:8871 ChEBI HTR1A protein P08908 UNIPROT "down-regulates activity" "chemical inhibition" 10029 BTO:0000246 9760039 t miannu "Marked differences were observed between the actions of ‘antagonists’ (Table 2; Fig. 2D ). methiothepin and butaclamol, as well asspiperone, exhibited negative efficacy by concentration-dependently inhibiting S GTPgS binding below basal levels, indicating that they act as inverse agonists in this system.WAY 100,135, yUH 301 and the 5-HTreceptor1A and b-adrenergic receptor antagonist ,ytertatolol, acted as ‘neutral’ antagonists, exhibiting antagonist activity without any detectable agonist or inverse agonist effects." SIGNOR-258840 CDK5 protein Q00535 UNIPROT LMTK2 protein Q8IWU2 UNIPROT up-regulates phosphorylation Ser1450 LQTSKYFsPPPPARS 9606 BTO:0000938 BTO:0000142 22220831 t gcesareni "Here, we demonstrate that lmtk2 is phosphorylated on serine-1418 (lmtk2ser ) by cdk5/p35 and present evidence that this regulates its ability to phosphorylate pp1cthr __" SIGNOR-195329 CHD8 protein Q9HCK8 UNIPROT MAP2 protein P11137 UNIPROT "down-regulates quantity" "transcriptional regulation" 10090 32839322 t Gianni "Many of the most significantly up-regulated genes in Chd8+/− and Chd8−/− NPCs are involved in later stages of neuronal development, including Ascl1 [a central driver of neural reprogramming (29)], Dcx, Map2, Nefm, Neurod4, and Neurog1 (Fig. 2 E and F). Additionally, we found that Sox3 is derepressed in both Chd8+/− and Chd8−/− NPCs, and several other Sox TF members (Sox2, Sox7, and Sox11) became derepressed in the Chd8−/− cells" SIGNOR-268916 ITK protein Q08881 UNIPROT SIGLEC10 protein Q96LC7 UNIPROT up-regulates phosphorylation Tyr597 RHSTILDyINVVPTA 9606 11733002 t lperfetto "These results suggest that the tyrosines at positions 597 and 667, contained within itim-like motifs, are likely targets of phosphorylation by several classes of signaling molecules, including lck, jak3, and emt. The tyrosine located at position y691 was also contributing to the phosphorylation of the wild-type siglec tail by lck and jak3 kinases. Y597 and y667 are likely involved in intracellular signaling" SIGNOR-112471 FES protein P07332 UNIPROT BCR protein P11274 UNIPROT down-regulates phosphorylation Tyr246 SCGVDGDyEDAELNP 9606 BTO:0000007 8955135 t lperfetto "In the present study, we demonstrate that bcr tyr-246 and at least one of the closely spaced tyrosine residues, tyr-279, tyr-283, and tyr- 289 (3y cluster), are phosphorylated by fes both in vitro and in 32p(i)- labeled cells. tyrosine phosphorylation of bcr by fes suppressed bcr serine/threonine kinase activity toward the 14-3-3 protein and bcr substrate, bap-1." SIGNOR-45330 pyruvate smallmolecule CHEBI:15361 ChEBI (S)-lactate smallmolecule CHEBI:16651 ChEBI "up-regulates quantity" "precursor of" 9606 24929216 t lperfetto "Glucose and alanine produce pyruvate which is reduced to lactate by lactate dehydrogenase in the cytoplasm without oxygen consumption. Lactate removal takes place via its oxidation to pyruvate by lactate dehydrogenase." SIGNOR-267655 RHOH protein Q15669 UNIPROT ZAP70 protein P43403 UNIPROT "up-regulates activity" binding 9606 BTO:0000661 17028588 t irozzo "These findings suggest that RhoH is a critical regulator of thymocyte development and TCR signaling by mediating recruitment and activation of Zap70." SIGNOR-259084 CHEK2 protein O96017 UNIPROT VHL protein P40337 UNIPROT up-regulates phosphorylation Ser111 GTGRRIHsYRGHLWL 9606 BTO:0000680 22071692 t llicata "We demonstrated that checkpoint kinase-2 (chk2) binds to the beta-domain of pvhl and phosphorylates ser 111 on dna damage. Notably, this modification enhances pvhl-mediated transactivation of p53 by recruiting p300 and tip60 to the chromatin of p53 target gene" SIGNOR-177091 mTORC2 complex SIGNOR-C2 SIGNOR AKT proteinfamily SIGNOR-PF24 SIGNOR "up-regulates activity" phosphorylation Ser473 RPHFPQFsYSASGTA 9606 BTO:0000182;BTO:0000018 15718470 t lperfetto "The rictor-mtor complex directly phosphorylated akt/pkb on ser473 in vitro and facilitated thr308 phosphorylation by pdk1" SIGNOR-217008 RTKs proteinfamily SIGNOR-PF38 SIGNOR PTK2 protein Q05397 UNIPROT "up-regulates activity" phosphorylation 9606 30889378 t miannu "The RTKs in turn induce phosphorylation of focal adhesion kinase (FAK) or the signaling domain of the b4 integrin. These elements recruit distinct subsets of signaling enzymes and adaptors, refining the specificity of individual partner RTKs." SIGNOR-259030 CARS1 protein P49589 UNIPROT Cys-tRNA(Cys) smallmolecule CHEBI:29152 ChEBI "up-regulates quantity" "chemical modification" 9606 11347887 t miannu "Cysteinyl-tRNA synthetase catalyzes the addition of cysteine to its cognate tRNA. Here we report the isolation of a fulllength cDNA that encodes a protein of 748 amino acids. The predicted protein sequence shows considerable similarity to other eukaryotic cysteinyltRNA synthetases in the carboxylterminus. Expression of the fulllength and alternative forms of the enzyme in E. coli generated functional proteins that were active in aminoacylation of human cytoplasmic tRNA with cysteine." SIGNOR-270474 RIPK1 protein Q13546 UNIPROT IKBKG protein Q9Y6K9 UNIPROT "up-regulates activity" binding 9606 SIGNOR-C14 16603398 t lperfetto "Interestingly, polyubiquitinated rip1 recruits ikk through the binding between the polyubiquitin chains and nemo, a regulatory subunit of the ikk complex. Mutations of nemo that disrupt its polyubiquitin binding also abolish ikk activation." SIGNOR-145858 PPP1R14A protein Q96A00 UNIPROT PPP1CB protein P62140 UNIPROT "down-regulates activity" binding -1 12144526 t lperfetto "We conclude that ILK may activate smooth-muscle contraction both directly, via phosphorylation of myosin, and indirectly, via phosphorylation and activation of CPI-17 and PHI-1, leading to inhibition of MLCP.|CPI-17 and PHI-1 thiophosphorylated by ILK at Thr(38) or Thr(57) respectively inhibited myosin light-chain phosphatase (MLCP) activity bound to myosin" SIGNOR-265742 FGF12 protein P61328 UNIPROT SCN10A protein Q9Y5Y9 UNIPROT "down-regulates activity" binding 9606 BTO:0000938 20679355 t miannu "Sodium channel fast inactivation is modulated by alpha subunit interaction with a family of cytoplasmic proteins termed fibroblast growth factor homologous factors (FHFs). In this paper, we report that all A-type FHFs exert rapid onset long-term inactivation on Nav1.6 and other sodium channels." SIGNOR-253440 PKN3 protein Q6P5Z2 UNIPROT ARHGAP18 protein Q8N392 UNIPROT "up-regulates activity" phosphorylation Ser156 QKRVETVsQTLRKKN -1 33092266 t lperfetto "We present strong evidence that PKN3-ARHGAP18 interaction is increased upon ARHGAP18 phosphorylation and that the phosphorylation of ARHGAP18 by PKN3 enhances its GAP domain activity and contributes to negative regulation of active RhoA.|These results support our data from phosphoproteomic screen and suggest that ARHGAP18 can be phosphorylated by PKN3 on Thr154, Ser156 and Thr158." SIGNOR-264571 CSNK2A1 protein P68400 UNIPROT CASQ2 protein O14958 UNIPROT unknown phosphorylation Ser385 DDDDDDNsDEEDNDD -1 1985907 t llicata "Both cardiac and skeletal muscle calsequestrins were phosphorylated by casein kinase II, but cardiac calsequestrin was phosphorylated to a higher stoichiometry and at least 50 times more rapidly. The site of rapid phosphorylation of cardiac calsequestrin was localized to the distinct COOH terminus, where a cluster of three closely spaced serine residues are found (S378DEESN-DDSDDDDE-COOH)." SIGNOR-250834 PPP1R9B protein Q96SB3 UNIPROT SPATA13 protein Q96N96 UNIPROT "up-regulates activity" binding 9606 BTO:0000007 19151759 t miannu "Here we show that Asef2, but not Asef, interacts with Neurabin2/Spinophilin, a scaffold protein that binds to Filamentous actin (F-actin). Neurabin2 is required for Asef2-induced filopodia formation. RNA interference experiments showed that Asef2, Neurabin2 and APC are involved in HGF-induced cell migration. Furthermore, knockdown of Neurabin2 resulted in the suppression of Asef2-induced filopodia formation." SIGNOR-269174 CDK2 protein P24941 UNIPROT SP1 protein P08047 UNIPROT "up-regulates activity" phosphorylation Ser59 GGQESQPsPLALLAA 10090 BTO:0000944 11598016 t gcesareni "Mutation of Sp1 Ser59 abrogates the cyclin A€“CDK augmentation of Sp1-dependent transcriptional transactivation" SIGNOR-248232 GTF2F1 protein P35269 UNIPROT TFIIF complex SIGNOR-C394 SIGNOR "form complex" binding -1 18218714 t lperfetto "Human general transcription factor IIF (TFIIF), a component of the transcription pre-initiation complex (PIC) associated with RNA polymerase II (Pol II), was characterized by size-exclusion chromatography (SEC), electrospray ionization mass spectrometry (ESI-MS), and chemical cross-linking. Recombinant TFIIF, composed of an equimolar ratio of alpha and beta subunits, was bacterially expressed, purified to homogeneity, and found to have a transcription activity similar to a natural one in the human in vitro transcription system." SIGNOR-266194 PPP3CC protein P48454 UNIPROT NFATC2 protein Q13469 UNIPROT "up-regulates activity" dephosphorylation Ser172 LCLSPASsGSSASFI 9606 BTO:0000567 11030334 t "NFAT1 is phosphorylated on fourteen conserved phosphoserine residues in its regulatory domain, thirteen of which are dephosphorylated upon stimulation. Dephosphorylation of all thirteen residues is required to mask a nuclear export signal (NES), cause full exposure of a nuclear localization signal (NLS), and promote transcriptional activity" SIGNOR-248511 PPP5C protein P53041 UNIPROT ABCB1 protein P08183 UNIPROT "down-regulates activity" dephosphorylation Ser661 SSNDSRSsLIRKRST 9606 BTO:0000007 24333728 t "Protein phosphatase complex PP5/PPP2R3C dephosphorylates P-glycoprotein/ABCB1 and down-regulates the expression and function|P-gp is known to be phosphorylated at Ser667, Ser671, and Ser683 by PKA; at Ser661, Ser667, and Ser671 by PKC; and at Ser683 by Pim-1|simultaneous expression of PP5 and PPP2R3C reduced the phosphorylation detected by the antibodies that specifically recognize serine/threonine phosphorylated by PKA or serine phosphorylated by PKC. These results suggest that the PP5/PPP2R3C complex dephosphorylates PKA- and PKC-phosphorylated serine residues on P-gp" SIGNOR-272505 "EIF4E2/GIGYF2 complex" complex SIGNOR-C257 SIGNOR Protein_synthesis phenotype SIGNOR-PH29 SIGNOR down-regulates 9606 BTO:0000568 22751931 f lperfetto "A Novel 4EHP-GIGYF2 Translational Repressor Complex Is Essential for Mammalian Development|m4EHP and/or GIGYF2 proteins repress translation." SIGNOR-261013 TFIID complex SIGNOR-C343 SIGNOR GTF2B protein Q00403 UNIPROT "up-regulates activity" relocalization 9606 8990153 t lperfetto "Early in PIC assembly, TFIIA can associate with and stabilize the TFIID–DNA or the TFIIB–TFIID–DNA complexes, allowing them to ward off the deleterious effects of inhibitory negative cofactors and enhance the stimulatory effects of transcriptional activators" SIGNOR-269308 ENPP1 protein P22413 UNIPROT INSR protein P06213 UNIPROT "down-regulates activity" binding 9606 10615944 t miannu "Plasma cell membrane glycoprotein-1 (PC-1) inhibits insulin receptor (IR) tyrosine kinase activity and subsequent cellular signaling. PC-1 may inhibit the IR by interacting directly with a specific region in the IR alpha-subunit." SIGNOR-252190 dactolisib chemical CHEBI:71952 ChEBI PIK3CA protein P42336 UNIPROT down-regulates "chemical inhibition" 9606 BTO:0000848 21803746 t "ATP-competitive inhibitor of PI3K and mTOR" gcesareni "The dual pi3k and mtorc1/2 inhibitor bez235 was highly specific" SIGNOR-175706 ADRA2A protein P08913 UNIPROT GNAI1 protein P63096 UNIPROT "up-regulates activity" binding 9606 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-256698 DDIT3 protein P35638 UNIPROT CEBPA protein P49715 UNIPROT "down-regulates quantity" "transcriptional regulation" 10090 7588595 t "We find that expression of CHOP, a nuclear protein that dimerizes avidly with C/EBP isoforms alpha and beta and directs the resulting heterodimer away from classic C/EBP-binding sites, markedly inhibits this differentiation process." SIGNOR-255913 MAPKAPK2 protein P49137 UNIPROT ZFP36L1 protein Q07352 UNIPROT down-regulates phosphorylation Ser203 PRLQHSFsFAGFPSA 9606 18326031 t lperfetto "Mk2-mediated inhibition of brf1 requires phosphorylation at s54, s92, and s203. Phosphorylation of brf1 by mk2 does not appear to alter its ability to interact with ares or to associate with mrna decay enzymes. Thus, mk2 inhibits brf1-dependent amd through direct phosphorylation." SIGNOR-161270 SRGAP2 protein O75044 UNIPROT RAC1 protein P63000 UNIPROT "down-regulates activity" "gtpase-activating protein" 9606 BTO:0000007 32203420 t Luana "We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2)." SIGNOR-260516 FCER1A protein P12319 UNIPROT FCER1 complex SIGNOR-C200 SIGNOR "form complex" binding 9606 BTO:0000830 16470226 t "Alessandro Palma" "FcepsilonRI is a tetrameric receptor that comprises an alpha-chain, which is responsible for binding IgE, as well as a beta-chain and a disulphide-linked gamma-chain homo dimer, which are responsible for initiating signalling." SIGNOR-254959 HACE1 protein Q8IYU2 UNIPROT CCND1 protein P24385 UNIPROT "down-regulates quantity by destabilization" ubiquitination 9606 17694067 t miannu "Mechanistically, the tumor-suppressor function of HACE1 is dependent on its E3 ligase activity and HACE1 controls adhesion-dependent growth and cell cycle progression during cell stress through degradation of cyclin D1." SIGNOR-271405 PP2CA_R1A_R2A complex SIGNOR-C132 SIGNOR AKT1 protein P31749 UNIPROT "down-regulates activity" dephosphorylation Thr308 KDGATMKtFCGTPEY 10090 BTO:0000944 18042541 t gcesareni "Regulation of phosphorylation of Thr-308 of Akt, cell proliferation, and survival by the B55alpha regulatory subunit targeting of the protein phosphatase 2A holoenzyme to Akt.|Phosphorylation of Akt at regulatory residues Thr-308 and Ser-473 leads to its full activation. The protein phosphatase 2A (PP2A) has long been known to negatively regulate Akt activity. The PP2A holoenzyme consists of the structural subunit (A), catalytic subunit (C), and a variable regulatory subunit (B)." SIGNOR-252613 SRC protein P12931 UNIPROT BCAR1 protein P56945 UNIPROT "up-regulates activity" phosphorylation Tyr179 GGPAQDIyQVPPSAG 10090 12972425 t lperfetto "Cas is a member of the focal adhesion complex. Phosphorylation of Cas by Src is an important event leading to cell transformation. Using mass spectrometry, we have mapped 11 sites in Cas that are phosphorylated by Src. These sites are all located between residues 132 and 414 of CasBased on these data, 11 tyrosine residues (132, 169, 183, 196, 238, 253, 271, 291, 301, 391, and 414) were phosphorylated by Src|the biological activity of Cas depends on its phosphorylation by Src (16–18). After phosphorylation, Cas associates with a number of proteins, including Crk, Src, phosphatidylinositol 3-kinase, Nck, and phospholipase Cgamma, via SH2 binding motifs" SIGNOR-246389 COPS3 protein Q9UNS2 UNIPROT SOS1 protein Q07889 UNIPROT "up-regulates quantity by stabilization" binding 9606 30631038 t miannu "Our observations characterizing the interaction between CSN3 and the Sos1 HD suggest that this domain not only functions regulating Sos-GEF autoinhibition but is also involved in other functional roles, such as the control of Sos protein stability and homeostasis by modulating the degradation and intracellular levels of Sos1." SIGNOR-256217 NFIA protein Q12857 UNIPROT MYOG protein P15173 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 32991581 t brain lperfetto "NFIA binds to and activates the brown-fat-specific enhancers even before differentiation and later facilitates the binding of PPARgamma|NFIA has at least three functions on the transcriptional regulation of brown fat [2]. First, NFIA activates adipogenesis per se, through activating the transcription of Pparg, which encodes PPARgamma. Second, NFIA also activates the brown-fat-specific gene expression (such as Ucp1 and Ppargc1a) independent of the degree of adipocyte differentiation, through facilitating the binding of PPARgamma to the brown-fat-specific enhancers. Third, NFIA represses myogenesis through suppression of myogenic transcription factors such as Myod1 as well as Myog," SIGNOR-263983 SMAD4 protein Q13485 UNIPROT MYC protein P01106 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 11689553 t lperfetto "Down-regulation of c-Myc is a critical event for growth inhibition induced by transforming growth factor-β (TGF-β) and is frequently impaired in cancer cells. We determined a Smad-responsive element in the c-mycpromoter." SIGNOR-251493 AURKA protein O14965 UNIPROT WDR62 protein O43379 UNIPROT "up-regulates activity" phosphorylation Ser32 VPARRGQsSPPPAPP -1 25501809 t lperfetto "AURKA activity promotes WDR62 spindle localization|We next purified recombinant full-length WDR62 (GST–WDR62-FL) for in vitro kinase assays with active AURKA and demonstrated that WDR62 was a direct phosphorylation target of AURKA|In addition, our quantitative phosphoproteomic analysis of in-vitro-phosphorylated WDR62 identified S32 and S33 as significantly phosphorylated in the presence of active AURKA|Alanine replacement of the five putative phosphorylation sites (S32/S33/S49/T50/S52-AAAAA) of WDR62 attenuated interphase microtubule association induced by AURKA coexpression" SIGNOR-271712 PKC proteinfamily SIGNOR-PF53 SIGNOR NOXO1 protein Q8NFA2 UNIPROT "up-regulates activity" phosphorylation Ser159 SRAAGRLsIHSLEAQ 9606 28336130 t lperfetto "Importantly, the constitutive activity of NoxO1 can be modulated. NoxO1 phosphorylation by PKC at Ser154 doubles its binding ability to NoxA1, which in turn acts as a molecular switch, allowing optimal interaction of NoxO1 with p22phox" SIGNOR-264728 PRKAA2 protein P54646 UNIPROT ULK1 protein O75385 UNIPROT up-regulates phosphorylation Ser556 GLGCRLHsAPNLSDL 9606 SIGNOR-C15 19584320 t gcesareni "In a screen for conserved substrates of ampk, we identified ulk1 and ulk2, mammalian orthologs of the yeast protein kinase atg1, which is required for autophagy." SIGNOR-186637 DYRK1A protein Q13627 UNIPROT RCAN1 protein P53805 UNIPROT up-regulates phosphorylation Ser167 FLISPPAsPPVGWKQ 9606 12809556 t gcesareni "In the present study, dyrk1a is shown to directly interact with and phosphorylate rcan1 at ser112 and thr192 residues. Dyrk1a-mediated phosphorylation of rcan1 at ser112 primes the protein for the gsk3_-mediated phosphorylation of ser108." SIGNOR-102290 (S,S)-asenapine chemical CHEBI:71257 ChEBI HTR1E protein P28566 UNIPROT "up-regulates activity" "chemical activation" 9534 8935801 t miannu "Risperidone and its active metabolite 9-OH-risperidone were compared to reference antipsychotic drugs (haloperidol, pipamperone, fluspirilene, clozapine, zotepine) and compounds under development (olanzapine, seroquel, sertindole, ORG-5222, ziprasidone) for in vitro binding to neurotransmitter receptors in brain tissue and on membranes of recombinant cells expressing cloned human receptors and for in vivo occupancy of neurotransmitter receptors in rat and guinea-pig brain following acute treatment (2 h., s.c.). The binding affinities of the compounds for various neurotransmitter receptors were measured using membrane preparations of animal brain regions and of recombinant cells expressing cloned, mostly human receptors. Receptors, tissues and cells are indicated in Table I; results are shown in Table 4A-B." SIGNOR-258568 DYRK1B protein Q9Y463 UNIPROT HDAC5 protein Q9UQL6 UNIPROT "down-regulates activity" phosphorylation Ser279 KVAERRSsPLLRRKD 10090 15546868 t lperfetto "Mirk activated mef2 not through direct phosphorylation of mef2 but by phosphorylation of its inhibitors, the class ii histone deacetylases (hdacs). Mef2 is sequestered by class ii hdacs such as hdac5 and mef2-interacting transcriptional repressor (mitr). Mirk antagonized the inhibition of mef2c by mitr, whereas kinase-inactive mirk was ineffective. Mirk phosphorylates class ii hdacs at a conserved site within the nuclear localization region, reducing their nuclear accumulation in a dose-dependent and kinase-dependent mannermirk phosphorylates hdac5 at ser-279" SIGNOR-235809 SMARCD3 protein Q6STE5 UNIPROT "Muscle cell-specific SWI/SNF SMARCA4 variant" complex SIGNOR-C483 SIGNOR "form complex" binding 9606 BTO:0000887 11073988 t miannu "We have also found that, of the two human SWI/2/SNF2 family-related ATPases, the PBAF complex contains only BRG1 but not hbrm (Xue et al., submitted). In contrast, the BAF complex isolated by BAF250 can include either BRG1 or hbrm (Fig. ​(Fig.4b).4b). These data underscore the distinctness of the two human complexes and suggest that BAF250 is a signature subunit that may confer specificity to the BAF complex." SIGNOR-270732 FOS protein P01100 UNIPROT HSD3B2 protein P26439 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 19022561 t miannu "We found that both SF1 and LRH1 can transcriptionally cooperate with the AP-1 family members c-JUN and c-FOS, known to be associated with enhanced proliferation of endometrial carcinoma cells, to further enhance activation of the STAR, HSD3B2, and CYP19A1 PII promoters." SIGNOR-254877 ZMYND8 protein Q9ULU4 UNIPROT CD44 protein P16070 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0001033 27477906 t lperfetto "Our quantitative ChIP experiments confirmed that ZMYND8 and JARID1D were co-localized at Slug, CD44, VEGFA, and EGFR genes (Figures 4F–4I). Our ChIP results also showed that ZMYND8 repressed and occupied other JARID1D target genes, such as the matrix metalloproteinase 1 (MMP1) and MMP3, that we previously reported" SIGNOR-262039 MYC protein P01106 UNIPROT UBTF protein P17480 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000539 15282543 t lperfetto "MAD1 and c-MYC regulate UBF and rDNA transcription during granulocyte differentiation|MAD1 repressed and c-MYC activated rDNA transcription in nuclear run-on assays. Repression of rDNA transcription by MAD1 was associated with its ability to interact directly with the promoter of upstream binding factor (UBF), an rDNA regulatory factor. Conversely, c-MYC activated transcription from the UBF promoter." SIGNOR-269644 INSR protein P06213 UNIPROT GAB1 protein Q13480 UNIPROT "up-regulates activity" phosphorylation Tyr627 KGDKQVEyLDLDLDS 10090 BTO:0000944 10978177 t "HGab-1 was phosphorylated by IR at eight tyrosine residues (Y242, Y285, Y373, Y447, Y472, Y619, Y657, and Y689). t Gab-1 is the major binding partner of PI-3 kinase in 3T3L1 cells when stimulated with insulin" SIGNOR-251316 acetylcholine smallmolecule CHEBI:15355 ChEBI CHRM4 protein P08173 UNIPROT "up-regulates activity" "chemical activation" 9606 BTO:0002524 31160049 t "Ligand-GPCR dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257471 (R)-noradrenaline smallmolecule CHEBI:18357 ChEBI ADRA1D protein P25100 UNIPROT "up-regulates activity" "chemical activation" 10029 BTO:0000246 7651358 t miannu "Membrane preparations from CHO cells stably transfected with the cloned human a1-AR genes showed saturable binding of [‘251]HEAT; Bm,,ı values were 1.3 ± 0.2, 5.5 ± 0.1, and 1.1 ± 0.1 pmol/mg of protein, with Kd values of 110 ± 21, 60 ± 1, and 300 ± 26 ıM (three experiments each), for the ala-, alb-, and ald-ARS, respectively. The potencies of a1-AR agonists and antagonists at the cloned human a1-ARs are shown in Table 1." SIGNOR-258457 SETD5 protein Q9C0A6 UNIPROT H3-3A protein P84243 UNIPROT "up-regulates activity" methylation Lys37 APSTGGVkKPHRYRP -1 31515109 t miannu "SETD5 Exhibits Intrinsic Methyltransferase Activity on H3K36. This assay showed that SETD5 has specific histone methyltransferase activity toward K36 but not for other residues such as K4 and K27 (Figure 8B). we revealed that SETD5 is endowed with H3K36 methyltransferase, which is necessary for RNA elongation and processing and, ultimately, correct gene transcription." SIGNOR-264622 Ub:E2 complex SIGNOR-C497 SIGNOR UBE3C protein Q15386 UNIPROT "up-regulates activity" ubiquitination 9606 34199813 t miannu "The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t" SIGNOR-271296 Ub:E2 complex SIGNOR-C497 SIGNOR TRIM24 protein O15164 UNIPROT "up-regulates activity" ubiquitination 9606 34199813 t miannu "The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t" SIGNOR-271034 KIF1C protein O43896 UNIPROT "Plus-end directed sliding movement" phenotype SIGNOR-PH216 SIGNOR up-regulates 9606 19773780 f "In general, N-kinesins and C-kinesins drive microtubule plus end- and minus end-directed motilities, respectively, and M-kinesins depolymerize microtubules1,9 (Box 1).|Forty-five genes that encode kinesin superfamily proteins (also known as KIFs) have been discovered in the mouse and human genomes.|KIFs are molecular motors that directionally transport various cargos, including membranous organelles, protein complexes and mRNAs, along the microtubule system." SIGNOR-272517 Gbeta proteinfamily SIGNOR-PF4 SIGNOR NCOA1 protein Q15788 UNIPROT up-regulates phosphorylation 9606 BTO:0001130 12163482 t "inferred from 70% family members" lperfetto "Mapk also directly phosphorylates src-1 at thr1179 and ser1185. Phosphorylation of src-1 by mitogen-activated protein kinase (mapk) is required for optimal progesterone receptor-dependent transcription and for functional cooperation with camp response element-binding protein-binding protein" SIGNOR-270099 MCRS1 protein Q96EZ8 UNIPROT "INO80 complex" complex SIGNOR-C498 SIGNOR "form complex" binding 9606 25016522 t miannu "Here, we have systematically investigated the involvement of the catalytic subunit of the human INO80 complex during unchallenged replication and under replication stress by following the effects of its depletion on cell survival, S-phase checkpoint activation, the fate of individual replication forks, and the consequences of fork collapse. We report that INO80 was specifically needed for efficient replication elongation, while it was not required for initiation of replication." SIGNOR-270844 "Melanotan II" chemical CID:92432 PUBCHEM MC4R protein P32245 UNIPROT "up-regulates activity" binding BTO:0000614 17702843 t lperfetto "Centrally administered melanotan II (MTII), a synthetic melanocortin 3/4-receptor agonist, decreases adiposity beyond that accountable by food intake decreases." SIGNOR-253066 LCK protein P06239 UNIPROT SHC1 protein P29353 UNIPROT "up-regulates activity" phosphorylation Tyr427 ELFDDPSyVNVQNLD 9606 BTO:0000782 9710204 t "We show that during TCR signaling, the tyrosines Y239, Y240 and Y317 of Shc are the primary sites of tyrosine phosphorylation. CD4/Lck-dependent tyrosine phosphorylation on Shc was markedly diminished when Y317 was mutated, suggesting a preference of Lck for the Y317 site. tyrosine phosphorylation of Shc may play a key role in T lymphocyte proliferation via interaction of phosphorylated Shc with downstream molecules involved in activation of Ras and Myc proteins" SIGNOR-251388 BID protein P55957 UNIPROT BCL2L1 protein Q07817 UNIPROT "down-regulates activity" binding 9606 BTO:0000093 22464442 t lperfetto "Overexpression of antiapoptotic proteins including Bcl-XL and/or Bcl-2 contributes to tumor initiation, progression, and resistance to therapy by direct interactions with proapoptotic BH3 proteins. Release of BH3 proteins from antiapoptotic proteins kills some cancer cells and sensitizes others to chemotherapy. Binding of Bcl-XL and Bcl-2 to the BH3 proteins Bad, Bid, and the three major isoforms of Bim was measured for fluorescent protein fusions in live cells using fluorescence lifetime imaging microscopy and fluorescence resonance energy transfer." SIGNOR-209675 MAPK8 protein P45983 UNIPROT MCL1 protein Q07820 UNIPROT up-regulates phosphorylation Thr163 TDGSLPStPPPAEEE 9606 12223490 t gcesareni "We found that jnk phosphorylated ser-121 and thr-163 of mcl-1 in response to stimulation with h(2)o(2) and that transfection of unphosphorylatable mcl-1 resulted in an enhanced anti-apoptotic activity in response to stimulation with h(2)o(2). Jnk-dependent phosphorylation and thus inactivation of mcl-1 may be one of the mechanisms through which oxidative stress induces cellular damage." SIGNOR-92597 HTR1A protein P08908 UNIPROT GNA14 protein O95837 UNIPROT "up-regulates activity" binding 9606 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257197 PCDHA2 protein Q9Y5H9 UNIPROT PCDHGA5 protein Q9Y5G8 UNIPROT "up-regulates activity" binding 9606 BTO:0000227 16697637 t miannu "The clustered protocadherins comprise the largest subfamily of the cadherin superfamily and are predominantly expressed in the nervous system. Pcdh-alpha proteins interact with beta1-integrin to promote cell adhesion. They also form oligomers with Pcdh-gamma proteins at the same membrane sites." SIGNOR-265695 AKT1 protein P31749 UNIPROT YBX1 protein P67809 UNIPROT up-regulates phosphorylation Ser102 NPRKYLRsVGDGETV 9606 BTO:0000150 15806160 t lperfetto "Phosphorylation of yb-1 at the serine 102 residue is required for transcriptional activation of growth-enhancing genes, such as egfr. Herein, we illustrate that activated akt binds to and phosphorylates the yb-1 cold shock domain at ser102" SIGNOR-252475 IGF1R protein P08069 UNIPROT IRS1 protein P35568 UNIPROT up-regulates phosphorylation 9606 BTO:0001103 15829723 t apalma "IGF-I binding to its receptor activates the kinase activity of the receptor, which then recruits the insulin response substrate-1, causing activation of phosphatidyl-inositol-3 kinase (PI3K) to phosphorylate Akt." SIGNOR-255104 PPP1CC protein P36873 UNIPROT AXIN1 protein O15169 UNIPROT "down-regulates activity" dephosphorylation Ser469 AHEENPEsILDEHVQ 9606 17318175 t "The data suggest that PP1 controls Wnt signaling through interaction with, and regulated dephosphorylation of, axin| Axin phosphorylation markedly enhances the binding of glycogen synthase kinase 3, leading to a more active beta-catenin destruction complex. Wnt-regulated changes in axin phosphorylation, mediated by PP1, may therefore determine beta-catenin transcriptional activity| Four sites, S80, S82, S222, and S473, were identified to be PP1 regulated" SIGNOR-248497 NfKb-p65/p50 complex SIGNOR-C13 SIGNOR CCND1 protein P24385 UNIPROT "up-regulates quantity by expression" 9606 BTO:0001103 20219869 t apalma "Importantly, NF-kB can promote the expression and stability of cyclin D1 in muscle (4, 35, 39, 132), leading to increased cell proliferation and inhibition of differentiation." SIGNOR-255358 ZBED1 protein O96006 UNIPROT RPS10 protein P46783 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000567 17220279 t Luana "HDRE-like sequences act as positive regulatory elements for RP gene promoter activities in vivo. | Cotransfection of a plasmid expressing hDREF increased luciferase expression directed by each RP gene promoter more than 30% compared with the values obtained without the hDREF-expressing plasmid." SIGNOR-266083 NUP58 protein Q9BVL2 UNIPROT p62_complex complex SIGNOR-C259 SIGNOR "form complex" binding 10116 BTO:0000154 2050741 t Simone "Thus, the p62-p58-p54 complex defines a group of proteins with strong protein-protein interactions that form a unit of pore structure essential for pore function." SIGNOR-261260 HACD proteinfamily SIGNOR-PF86 SIGNOR "very long-chain (R)-3-hydroxyacyl-CoA(4-)" smallmolecule CHEBI:85440 ChEBI "down-regulates quantity" "chemical modification" 9606 18554507 t miannu "Very long-chain fatty acids are produced through a four-step cycle. Mammals have four candidates, HACD1-4, based on sequence similarities to the recently identified yeast Phs1, although HACD3 and HACD4 share relatively weak similarity. We demonstrate that all four of these human proteins are indeed 3-hydroxyacyl-CoA dehydratases.We also established that the HACD proteins interact with ELOVL proteins. Our analyses have completed the identification of mammalian enzymes responsible for the entire VLCFA elongation cycle." SIGNOR-267917 EP300 protein Q09472 UNIPROT SMAD7 protein O15105 UNIPROT up-regulates acetylation Lys64 RAGCCLGkAVRGAKG 9606 12408818 t gcesareni "Here we present evidence that smad7 interacts with the transcriptional coactivator p300, resulting in acetylation of smad7 on two lysine residues in its n terminus. Acetylation or mutation of these lysine residues stabilizes smad7 and protects it from tgfbeta-induced degradation. we have recently shown that smad7 is acetylated on lysine residues 64 and 70 by p300" SIGNOR-95165 EDNRB protein P24530 UNIPROT GNAI1 protein P63096 UNIPROT "up-regulates activity" binding 9606 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257053 "perfluorohexanesulfonic acid" chemical CHEBI:132448 ChEBI AR protein P10275 UNIPROT "down-regulates activity" "chemical inhibition" -1 23764977 t miannu "Seven PFCs [perfluorohexane sulfonate (PFHxS), perfluorooctane sulfonate (PFOS), perfluorooctanoate (PFOA), perfluorononanoate (PFNA), perfluorodecanoate (PFDA), perfluoroundecanoate (PFUnA), and perfluorododecanoate (PFDoA)] were analyzed in vitro for their potential to affect estrogen receptor (ER) and androgen receptor (AR) transactivity as well as aromatase enzyme activity. The PFCs were assessed as single compounds and in an equimolar mixture. PFHxS, PFOS and PFOA significantly induced the ER transactivity, whereas PFHxS, PFOS, PFOA, PFNA and PFDA significantly antagonized the AR activity in a concentration-dependent manner. " SIGNOR-268766 LYN protein P07948 UNIPROT PLCG2 protein P16885 UNIPROT "up-regulates activity" phosphorylation Tyr759 LYDVSRMyVDPSEIN -1 7682059 t lperfetto "The phosphorylation of purified phospholipase C-gamma 1 (PLC-gamma 1) and PLC-gamma 2 by src-family-protein tyrosine kinases (PTKs) P56lck, p53/56lyn, p59hck, p59fyn, and p60src was studied in vitro. All five PTKs phosphorylated PLC-gamma 1 and PLC-gamma 2, suggesting that both PLC-gamma isozymes can be phosphorylated in cells by any of the src-family PTKs in response to the activation of cell surface receptors." SIGNOR-249384 CALM1 protein P0DP23 UNIPROT GEM protein P55040 UNIPROT "up-regulates activity" binding 10116 14701738 t miannu "Inhibition of voltage-gated calcium channels by Gem requires GTP and calmodulin binding, but not phosphorylation of serine 261 or 289. Calmodulin binding in the C-terminal extension of Gem is required for maximal inhibition of HVA Ca2+ channels by ectopically expressed Gem, as determined by measurement of electrical activity in primary neurons and by Ca2+-evoked secretion in PC12 cells." SIGNOR-261726 DDX3X protein O00571 UNIPROT SP1 protein P08047 UNIPROT "up-regulates activity" binding 9606 33627125 t miannu "DDX3X enhances transcription by interacting with transcription factors to promote their binding to the promoter of the target gene. The best characterized mechanism is its cooperation with the transcription factor SP1. The downstream genes of DDX3X-SP1-mediated transactivation include P21, KRAS, and MDM2" SIGNOR-269195 KIF14 protein Q15058 UNIPROT "Plus-end directed sliding movement" phenotype SIGNOR-PH216 SIGNOR up-regulates 9606 19773780 f "In general, N-kinesins and C-kinesins drive microtubule plus end- and minus end-directed motilities, respectively, and M-kinesins depolymerize microtubules1,9 (Box 1).|Forty-five genes that encode kinesin superfamily proteins (also known as KIFs) have been discovered in the mouse and human genomes.|KIFs are molecular motors that directionally transport various cargos, including membranous organelles, protein complexes and mRNAs, along the microtubule system." SIGNOR-272524 KIF18B protein Q86Y91 UNIPROT "Plus-end directed sliding movement" phenotype SIGNOR-PH216 SIGNOR up-regulates 9606 19773780 f "In general, N-kinesins and C-kinesins drive microtubule plus end- and minus end-directed motilities, respectively, and M-kinesins depolymerize microtubules1,9 (Box 1).|Forty-five genes that encode kinesin superfamily proteins (also known as KIFs) have been discovered in the mouse and human genomes.|KIFs are molecular motors that directionally transport various cargos, including membranous organelles, protein complexes and mRNAs, along the microtubule system." SIGNOR-272525 ASXL1 protein Q8IXJ9 UNIPROT CDKN2B protein P42772 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 26470845 t lperfetto "Tumor suppressor ASXL1 is essential for the activation of INK4B expression in response to oncogene activity and anti-proliferative signals" SIGNOR-241759 CITED2 protein Q99967 UNIPROT MMP1 protein P03956 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0003859 12960175 f miannu "CITED2 plays a major role in shear-induced down-regulation of MMP-1 and MMP-13 via a transforming growth factor-beta-dependent pathway." SIGNOR-253778 PKA proteinfamily SIGNOR-PF17 SIGNOR KLHL3 protein Q9UH77 UNIPROT "up-regulates activity" phosphorylation Ser433 PMNTRRSsVGVGVVE -1 26435498 t done miannu "Consistent with the fact that S433 is a component of Akt and PKA phosphorylation motifs, in vitro kinase assay demonstrated that Akt and PKA can phosphorylate KLHL3 at S433, that was previously reported to be phosphorylated by PKC. " SIGNOR-273824 dopamine smallmolecule CHEBI:18243 ChEBI DRD3 protein P35462 UNIPROT "up-regulates activity" "chemical activation" 10029 BTO:0000246 1975644 t miannu "Molecular cloning and characterization of a novel dopamine receptor (D3) as a target for neuroleptics. A dopamine receptor has been characterized which differs in its pharmacology and signalling system from the D1 or D2 receptor and represents both an autoreceptor and a postsynaptic receptor. Table1. pharmacology of D2 and D3 receptors expressed in CHO cells." SIGNOR-258377 SMAD3 protein P84022 UNIPROT SMAD3/PIAS3 complex SIGNOR-C204 SIGNOR "form complex" binding 9606 26194464 t mrosina "In summary, the TGF-b/IL-6/TCR-pERK-Smad2L (Ser255) axis is the positive regulator, whereas unphosphorylated Smad3C-PIAS3 complex is the negative regulator of STAT3-induced transcriptional processes for TH17 differentiation" SIGNOR-255034 NCOA1 protein Q15788 UNIPROT STAT5B protein P51692 UNIPROT up-regulates binding 9606 BTO:0000149 12954634 t miannu "Ncoa-1/src-1 is an essential coactivator of stat5 that binds to the fdl motif in the alpha-helical region of the stat5 transactivation domain." SIGNOR-100261 flutamide chemical CHEBI:5132 ChEBI AR protein P10275 UNIPROT "down-regulates activity" "chemical inhibition" 9606 18571420 t Luana "Among the compounds obtained, N-[4-[(benzyl)(4-nitrophenyl)amino]-1-methylpyrrole-2-carbonyl]pyrrolidine (22) is as potent an AR antagonist as the typical anilide-type AR antagonists hydroxyflutamide and bicalutamide. " SIGNOR-257807 NEFL protein P07196 UNIPROT "Neurofilament L/M" complex SIGNOR-C207 SIGNOR "form complex" binding 9606 19468066 t miannu "Neurofilaments are obligate heteropolymers that are minimally comprised of the low molecular neurofilament protein L (NFL) plus the medium and/or high molecular weight proteins neurofilament protein M (NFM) and neurofilament protein H" SIGNOR-255270 N-(2,6-dimethylphenyl)-5,6-dihydro-4H-1,3-thiazin-2-amine chemical CHEBI:92386 ChEBI ADRA2A protein P08913 UNIPROT "up-regulates activity" "chemical activation" 9606 BTO:0000007 9605427 t miannu "AR agonists stimulated binding of [35S]GTPgS to HEK 293 cell membranes containing the human a2a, a2b, or a2c ARs (Fig. 6). EPI and NE were full agonists; clonidine and oxymetazoline were partial agonists, while antagonists (e.g. rauwolscine, 5 mM) did not stimulate [35S]GTPgS incorporation (Table 3). Although a few agonists showed a great deal of selectivity for a single receptor subtype, the rank order of agonist potency for selected compounds at the human receptors (Table 3) was: a2a: Dexmedetomidine . guanabenz . UK-14304 .clonidine . ST-91 . NE a2b: Dexmedetomidine . clonidine . guanabenz . NE .ST-91 . UK-14304 a2c: Dexmedetomidine . NE . UK-14304 . ST-91 $ clonidine .. guanabenz" SIGNOR-258922 PRKCD protein Q05655 UNIPROT PRKCD protein Q05655 UNIPROT up-regulates phosphorylation Ser645 LNEKARLsYSDKNLI 9606 15731106 t gcesareni "Taken together, our results demonstrate that serine 643 of pkc-delta is a major autophosphorylation site, and phosphorylation of this site plays an important role in controlling its enzymatic activity and biological function. The enzymatic activity of pkc-deltas643a mutant as measured by phosphorylating the pkc-delta pseudosubstrate region-derived substrate was also reduced more than 70% in comparison to that of pkc-deltawt." SIGNOR-134207 PAK4 protein O96013 UNIPROT ITGB5 protein P18084 UNIPROT up-regulates phosphorylation Ser762 AKFQSERsRARYEMA 9606 20507994 t llicata "Pak4 specifically phosphorylated the integrin beta5 subunit at ser-759 and ser-762 within the beta5-sers-motif. Point mutation of these two serine residues abolished the pak4-induced cell migration, indicating a functional role for these phosphorylations in migration." SIGNOR-165706 PRKCD protein Q05655 UNIPROT NCF1 protein P14598 UNIPROT up-regulates phosphorylation Ser315 AHSIHQRsRKRLSQD 9606 BTO:0000130 12056906 t esanto "Pkc alpha, beta ii, delta, and zeta expressed in human neutrophils can individually phosphorylate p47(phox) and induce both its translocation and nadph oxidase activation. The use of p47phox mutants identified serines 303, 304, 315, 320, 328, 359, 370, and 379 as targets of pkc?, ???, And ?." SIGNOR-89225 Jervine chemical CHEBI:6088 ChEBI SMO protein Q99835 UNIPROT down-regulates "chemical inhibition" 9606 BTO:0000527 21679342 t gcesareni "Cyclopamine (c27h41no2) and jervine (c27h39no3) were discovered and in particular, a series of studies with the hh pathway inhibitor, cyclopamine, has brought about this expectation. cyclopamine suppresses the hh signaling pathway through direct interaction with smo." SIGNOR-174420 PCSK1 protein P29120 UNIPROT Corticotropin protein P01189-PRO_0000024969 UNIPROT "up-regulates quantity" cleavage 24631756 t lperfetto "POMC is post-translationally cleaved by prohormone convertase enzymes 1 and 2 (PC1, PC2) into ACTH, an N-terminal glycopeptide" SIGNOR-268724 CDKN3 protein Q16667 UNIPROT CDK2 protein P24941 UNIPROT "down-regulates activity" dephosphorylation Thr160 GVPVRTYtHEVVTLW 9606 11463386 t "The CDK-interacting protein phosphatase KAP dephosphorylates phosphoThr-160 (pThr-160) of the CDK2 activation segment, the site of regulatory phosphorylation that is essential for kinase activity." SIGNOR-248724 CDK5 protein Q00535 UNIPROT NES protein P48681 UNIPROT unknown phosphorylation Thr1299 GETLPDStPLGFYLR 10090 12832492 t llicata "We identify nestin as a novel in vivo target for cdk5 and p35 kinase, a critical signaling determinant in development. Two cdk5-specific phosphorylation sites on nestin, Thr-1495 and Thr-316, were established, the latter of which was used as a marker for cdk5-specific phosphorylation in vivo. | Cdk5 activity is necessary for differentiation and the concomitant nestin reorganization in C2C12 myoblasts." SIGNOR-250669 lovastatin chemical CHEBI:40303 ChEBI HMGCR protein P04035 UNIPROT "down-regulates activity" "chemical inhibition" -1 6933445 t miannu "Mevinolin: a highly potent competitive inhibitor of hydroxymethylglutaryl-coenzyme A reductase and a cholesterol-lowering agent." SIGNOR-258403 MPP5 protein Q8N3R9 UNIPROT AMOT/MPP5/INADL/LIN7C complex SIGNOR-C27 SIGNOR "form complex" binding 9606 24366813 t lperfetto "To gain a more detailed view on the organization of this cell polarity network linked to yap1 we included several proteins of the cell junction complex (amot, mpp5, lin7a)," SIGNOR-203494 GGCX protein P38435 UNIPROT F10 protein P00742 UNIPROT "up-regulates activity" carboxylation Glu46 TRANSFLeEMKKGHL -1 9538022 t lperfetto "This report describes the expression, purification, and characterization of a series of recombinant factor Xa variants bearing aspartate substitutions for each of the glutamate residues which normally undergo gamma-carboxylation. |We have produced fully active recombinant human factor Xa and demonstrated that gla residues 16, 26, and 29 are critical for normal activity of factor Xa.|This observation suggests that, for wild-type r-fX expressed in HEK cells, carboxylation by the gamma-glutamyl carboxylase proceeds to completion once initiated; | 11 amino terminal glutamic acid residues of fX which normally undergo gamma-carboxylation (glas 6, 7, 14, 16, 19, 20, 25, 26, 29, 32, 39)." SIGNOR-263664 PRKAR2A protein P13861 UNIPROT PRKACB protein P22694 UNIPROT "down-regulates activity" binding 9606 26687711 t "Inactive PKA exists as a holoenzyme, comprised of two regulatory (R) subunits and two catalytic subunits . In the presence of cAMP, the holoenzyme becomes active by binding two cAMP molecules cooperatively to each R subunit, resulting in a conformational change in the R subunits, thus releasing the two C subunits to phosphorylate downstream targets" SIGNOR-258757 TLR4 protein O00206 UNIPROT TICAM1 protein Q8IUC6 UNIPROT "up-regulates activity" binding 10090 22664090 t gcesareni "To initiate the innate immune response, Toll-like receptors (TLRs) associate with cytoplasmic adaptor proteins through TIR (Toll/interleukin-1 receptor) domain interactions. The four principal signaling adaptor proteins include MyD88, MAL, TRIF and TRAM, and the fifth protein SARM, involved in negative regulation of TLR pathways, is usually considered a part of the TIR domain-containing adaptor protein group" SIGNOR-252067 NMUR1 protein Q9HB89 UNIPROT GNAQ protein P50148 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-256751 HDAC1 protein Q13547 UNIPROT SERPINB5 protein P36952 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0001570 18247378 t miannu "We found that maspin is selectively upregulated in IFIXα-expressing cells and involved in anti-invasive activity of IFIXα. We also present evidence indicating that IFIXα downregulates histone deacetylase 1 (HDAC1), which is possibly involved in the silencing of the maspin gene in human breast cancer cells. To confirm these results, we performed a luciferase assay using a maspin-promoter-luciferase plasmid. The results showed that HDAC1 overexpression suppressed the activity of the maspin promoter (Figure 3C). Therefore, our results suggest that IFIXα enhances maspin expression through the downregulation of HDAC1." SIGNOR-268494 PKA proteinfamily SIGNOR-PF17 SIGNOR CAMKK2 protein Q96RR4 UNIPROT down-regulates phosphorylation Ser100 HLSGRKLsLQERSQG 9606 22778263 t lperfetto "Pka phosphorylates ser-100, ser-495, and ser-511the camp/pka pathway can inhibit camkk2 activity" SIGNOR-198146 CDK1 protein P06493 UNIPROT BCL2L1 protein Q07817 UNIPROT "down-regulates activity" phosphorylation 9606 BTO:0003918 19917720 t lperfetto "Cyclin-Dependent Kinase 1-Mediated Bcl-xL/Bcl-2 Phosphorylation Acts as a Functional Link Coupling Mitotic Arrest and Apoptosis|These findings suggest a model whereby a switch in the duration of CDK1 activation, from transient during mitosis to sustained during mitotic arrest, dramatically increases the extent of Bcl-xL/Bcl-2 phosphorylation, resulting in inactivation of their antiapoptotic function. Thus, phosphorylation of antiapoptotic Bcl-2 proteins acts as a sensor for CDK1 signal duration and as a functional link coupling mitotic arrest to apoptosis." SIGNOR-267986 UMPS protein P11172 UNIPROT "orotidine 5'-phosphate(3-)" smallmolecule CHEBI:57538 ChEBI "down-regulates quantity" "chemical modification" 9606 18020427 t miannu "Orotate phosphoribosyltransferase (OPRTase, EC 2.4.2.10) catalyzes the Mg2+-dependent condensation of orotic acid (OA) with PRPP (5-alpha-d-phosphorylribose 1-diphosphate) to yield diphosphate (PPi) and the nucleotide OMP (orotidine 5'-monophosphate)." SIGNOR-253581 MAPK3 protein P27361 UNIPROT XPO5 protein Q9HAV4 UNIPROT "down-regulates activity" phosphorylation Ser497 GSLCSVFsPSFVQWE 9606 27846390 t lperfetto "Here we show that ERK suppresses pre-miRNA export from the nucleus through phosphorylation of exportin-5 (XPO5) at T345/S416/S497. After phosphorylation by ERK, conformation of XPO5 is altered by prolyl isomerase Pin1, resulting in reduction of pre-miRNA loading. " SIGNOR-262982 CEP72 protein Q9P209 UNIPROT CDK5RAP2 protein Q96SN8 UNIPROT "up-regulates activity" relocalization 9606 BTO:0000567 26297806 t lperfetto "By bringing CDK5RAP2 to the centrosome, the centriolar satellite proteins CEP72 and SPAG5 are required for the centrosomal localization of the other three MCPH proteins despite not interacting with them biochemically." SIGNOR-271720 fludrocortisone chemical CHEBI:50885 ChEBI NR3C2 protein P08235 UNIPROT "up-regulates activity" "chemical activation" 9534 BTO:0001538 8282004 t miannu "The sex steroid progesterone bound with an affinity (ki < 0.01 nM) even higher than that of aldosterone to the human mineralocorticoid receptor and effectively antagonized the effect of aldosterone via the human mineralocorticoid receptor in functional co-transfection assays. This indicates that progesterone has potent antimineralocorticoid properties, while its antiglucocorticoid effects were less pronounced. The partial agonistic activities of antihormones in this assay suggest a direct interaction of antihormone-receptor complexes with the response elements on the DNA. aldosterone shows a higher functional sensitivity for the human mineralocorticoid receptor than deoxycorticosterone (higher affinity) or cortisol (similar affinity). Moreover, the very high binding affinity of the human mineralocorticoid receptor for progesterone (k i < 0.0l nM) in combination with the very low agonistic activity indicates that progesterone may act as a potent human mineralocorticoid receptor antagonist that is even more effective than spironolactone (k~ = 5.7 nM), which displays no partial agonistic activity (fig. 4)." SIGNOR-258706 SRC protein P12931 UNIPROT FLT4 protein P35916 UNIPROT up-regulates phosphorylation Tyr853 HLGRVLGyGAFGKVV 9606 20431062 t lperfetto "Vegfr-3 is a direct c-src target and mass spectrometry analysis identified the sites phosphorylated by c-src as tyrosine 830, 833, 853, 1063, 1333, and 1337 vegfr-3 phosphorylation activates the recruitment to the receptor of the adaptor proteins crki/ii and shc inducing activation of jnk." SIGNOR-165055 GTF2E1 protein P29083 UNIPROT TFIIE complex SIGNOR-C458 SIGNOR "form complex" binding 9606 31064989 t lperfetto "The heterodimer TFIIE (composed of the TFIIEα and TFIIEβ subunits) seems to play a pivotal role in transcription by directly influencing the transition from initiation to elongation3,4. TFIIE interacts with different factors within the PIC, including Pol II5,6 as well as with DNA immediately upstream of the transcription bubble region7,8. Furthermore, TFIIE seems to influence TFIIH activity9, although it is not clear how this molecular process can occur." SIGNOR-269360 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR SOS1 protein Q07889 UNIPROT "down-regulates activity" phosphorylation 9606 BTO:0000763;BTO:0000149 20724475 t lperfetto "ERK activation was sufficient for the SOS1 phosphorylation and resulting inhibition of EGF-induced Ras activation. This result also showed that SOS1 could be phosphorylated by ERK in the absence of association with EGFR at the plasma membrane, which is a phosphotyrosine-dependent process." SIGNOR-244591 CSNK2A1 protein P68400 UNIPROT JUN protein P05412 UNIPROT down-regulates phosphorylation Ser249 LSPIDMEsQERIKAE 9606 1516134 t lperfetto "Casein kinase ii is a negative regulator of c-jun dna binding and ap-1 activitywe show that two of these sites, thr-231 and ser-249, are phosphorylated by casein kinase ii (ckii)." SIGNOR-19603 HSP90AB1 protein P08238 UNIPROT FLCN protein Q8NFG4 UNIPROT "up-regulates quantity by stabilization" binding 9606 BTO:0000007 27353360 t miannu "Heat shock protein-90 (Hsp90) is an essential molecular chaperone in eukaryotes involved in maintaining the stability and activity of numerous signalling proteins, also known as clients. Hsp90 ATPase activity is essential for its chaperone function and it is regulated by co-chaperones. Here we show that the tumour suppressor FLCN is an Hsp90 client protein and its binding partners FNIP1/FNIP2 function as co-chaperones. FNIPs decelerate the chaperone cycle, facilitating FLCN interaction with Hsp90, consequently ensuring FLCN stability." SIGNOR-261418 FGFR1 protein P11362 UNIPROT FGFR1 protein P11362 UNIPROT up-regulates phosphorylation Tyr605 KDLVSCAyQVARGME 9606 12601080 t lperfetto "Fgfr signaling is under the control of tyrosine phosphorylation to elicit activation of cellular signaling cascades. Ligand binding induces receptor dimerization and transphosphorylation. Fgfr1 contains eleven tyrosine residues (tyr154, tyr280, tyr307, tyr463, tyr585, tyr605, tyr653, tyr654, tyr730 and tyr766), some of which are directly involved regulating the activity of the receptor and others bind to activate substrates leading to the activation of various transduction pathways." SIGNOR-98634 ZFPM1 protein Q8IX07 UNIPROT GATA2 protein P23769 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 21853041 t miannu "GATA-2 induces the expression of GATA-1, which first activates its cofactor FOG-1, and then downregulates GATA-2 cooperatively with FOG-1." SIGNOR-256061 FAM13B protein Q9NYF5 UNIPROT CDC42 protein P60953 UNIPROT "down-regulates activity" "gtpase-activating protein" 9606 BTO:0000007 32203420 t Luana "We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2)." SIGNOR-260504 DDIT3 protein P35638 UNIPROT ASNS protein P08243 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0002181 18940792 f miannu "C/EBP homology protein (CHOP) interacts with activating transcription factor 4 (ATF4) and negatively regulates the stress-dependent induction of the asparagine synthetase gene." SIGNOR-253837 JQ1 chemical CHEBI:137113 ChEBI BRD3 protein Q15059 UNIPROT "down-regulates activity" "chemical inhibition" -1 20871596 t lperfetto "Enantiomerically pure (+)-JQ1 bound with a Kd of about 50 nM and 90 nM to the first and second bromodomains of BRD4, respectively (Fig. 1c, Supplementary Table 3). Comparable binding to both domains of BRD3 was observed, whereas the first bromodomains of BRDT and BRD2 revealed about 3-fold weaker binding.|Here, we present a first, thoroughly characterized inhibitor of the BET-family of bromodomains." SIGNOR-261988 TP53 protein P04637 UNIPROT BID protein P55957 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 16151013 t "Nuclear p53" lperfetto "Bid is a p53 primary-response gene." SIGNOR-140248 MAPK7 protein Q13164 UNIPROT MAP2K5 protein Q13163 UNIPROT up-regulates phosphorylation Ser137 QHSSPAVsDSLPSNS 9606 BTO:0000671 12628002 t lperfetto "Phosphorylation and activation of extracellular-signal-regulated protein kinase 5 (erk5) by mitogen-activated protein kinase kinase 5 (mkk5)activated erk5 also phosphorylated mitogen-activated protein kinase kinase 5 (mkk5) extensively at ser(129), ser(137), ser(142) and ser(149)" SIGNOR-99131 Flesinoxan chemical CID:57347 PUBCHEM HTR1A protein P08908 UNIPROT "up-regulates activity" "chemical activation" 10029 BTO:0000246 9760039 t miannu "Several compounds proposed as ‘atypical’ antipsychoticagents were found to exhibit agonist activity at 5-HT1A EC values were greater than the respective Kvalues50i .21.8""5.8-fold difference,ns10 and a high degree of correlation was observed. All the compounds displayed high or marked bind-ing affinity at CHO-h5-HT1A receptors except for olanzapine, which exhibited a micromolar Kvalue at h5-HTi1A receptors (table3)." SIGNOR-258950 PRKACA protein P17612 UNIPROT MAPT protein P10636 UNIPROT down-regulates phosphorylation Ser579 NVKSKIGsTENLKHQ 9606 BTO:0000938 9771888 t "The effect has been demonstrated using P10636-8" gcesareni "Tau is phosphorylated by gsk-3 at several sites found in alzheimer disease and its biological activity markedly inhibited only after it is prephosphorylated by a-kinase." SIGNOR-60659 DPYD protein Q12882 UNIPROT 5-fluorouracil chemical CHEBI:46345 ChEBI "down-regulates quantity" "chemical modification" 9606 10499634 t miannu "Dihydropyrimidine dehydrogenase (DPD) is responsible for degradation of the pyrimidines uracil and thymine and the inactivation of the chemotherapeutic agent 5-fluorouracil. DPD activity is highly variable in cancer populations, and this variation may influence the antitumor efficacy of 5-fluorouracil." SIGNOR-253987 NUP43 protein Q8NFH3 UNIPROT NPC complex SIGNOR-C263 SIGNOR "form complex" binding 27016207 t lperfetto "The protein inventory of the NPC has been studied for a very diverse set of eukaryotes, including trypanosomes, fungi, plants, animals, and humans [4], [5], [6], [7], [8], [9]. In all cases, about 30 different Nups were found (Fig. 2)." SIGNOR-262087 UPF3B protein Q9BZI7 UNIPROT Upf-EJC complex SIGNOR-C367 SIGNOR "form complex" binding 9606 BTO:0000567 17803942 t miannu "The three Up-frameshift (Upf) proteins, Upf1, Upf2, and Upf3 that together form the Upf complex, constitute the conserved core of NMD from yeast to humans. hUpf3b Forms Multiple Contacts with the EJC and Depends on hUpf2 for Complex Formation with hUpf1" SIGNOR-265236 SH2B2 protein O14492 UNIPROT INSR protein P06213 UNIPROT down-regulates binding 9606 BTO:0000975 11498022 t lperfetto "APS couples c-Cbl to the insulin receptor, resulting in ubiquitination of the insulin receptor." SIGNOR-109694 PTGER3 protein P43115 UNIPROT GNA12 protein Q03113 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257203 AKT1 protein P31749 UNIPROT TWIST1 protein Q15672 UNIPROT up-regulates phosphorylation Ser42 GGRKRRSsRRSAGGG 9606 20400976 t llicata "Moreover, phosphorylation of twist-1 at ser42 was shown in vivo in various human cancer tissues, suggesting that this post-translational modification ensures functional activation of twist-1 after promotion of survival during carcinogenesis." SIGNOR-164884 RPS6KB1 protein P23443 UNIPROT PDCD4 protein Q53EL6 UNIPROT down-regulates phosphorylation Ser67 KRRLRKNsSRDSGRG 9606 BTO:0000007 BTO:0001253 18296647 t gcesareni "Both akt and p70(s6k) phosphorylate pdcd4, allowing for binding of the e3-ubiquitin ligase beta-trcp and consequently ubiquitylation." SIGNOR-160989 CTNNB1 protein P35222 UNIPROT LEF1 protein Q9UJU2 UNIPROT "up-regulates activity" binding 9606 21078818 t gcesareni "Phosphorylated lrp5/6 leads to inhibition of the so-called beta-catenin destruction complex (which includes axin, gsk3, dvl, ck1, and the tumor suppressor adenomatous polyposis coli), resulting in the stabilization and translocation of beta-catenin in the nucleus, where it activates target genes through binding to tcf/lef transcription factors." SIGNOR-169632 BMPR1B protein O00238 UNIPROT SMAD1 protein Q15797 UNIPROT up-regulates phosphorylation Ser465 HNPISSVs 9606 9335504 t llicata "The c terminus of smad1, which is phosphorylated directly by the bmp type i receptor at the ssvs sequence in contrast to the bmp-stimulated phosphorylation of smad1, which affects carboxy-terminal serines and induces nuclear accumulation of smad1, erk-mediated phosphorylation specifically inhibits the nuclear accumulation of smad1." SIGNOR-52670 RASSF1 protein Q9NS23 UNIPROT CCND1 protein P24385 UNIPROT "down-regulates quantity by repression" "post transcriptional regulation" 9606 BTO:0002552 12024041 f Luana "RASSF1A expression dramatically inhibits native cyclin D1 accumulation | Regulation of cyclin D1 accumulation by RASSF1A is independent of the cyclin D1 promoter and likely occurs through inhibition of mRNA translation." SIGNOR-259455 MAML1 protein Q92585 UNIPROT NOTCH proteinfamily SIGNOR-PF30 SIGNOR up-regulates binding 9606 11101851 t "inferred from 70% of family members" gcesareni "Maml1 binds to the ankyrin repeat domain of all four mammalian notch receptors, forms a dna-binding complex with icn and rbp-jkappa, and amplifies notch-induced transcription of hes4" SIGNOR-269934 sabcomeline chemical CHEBI:134846 ChEBI CHRM1 protein P11229 UNIPROT "up-regulates activity" "chemical activation" 10116 9399977 t miannu "SB 202026 (R-(Z)-(+)-alpha-(methoxyimino)-1-azabicyclo[2.2.2] octane-3-acetonitrile) displaced [3H]-oxotremorine-M from muscarinic receptors in the rat brain with high affinity (IC50 = 14 nM), a potency similar to that of oxotremorine-M itself (IC50 = 13 nM), but exhibited low affinity for cholinergic nicotinic receptors and other neuroreceptors. In studies using cloned human muscarinic receptors, SB 202026 possessed approximately equal affinity in displacing [3H]-quinuclidinyl benzilate from all muscarinic receptor subtypes" SIGNOR-258678 BTF3 protein P20290 UNIPROT MADCAM1 protein Q13477 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0000584 17312387 f "In contrast, BTF3 silencing resulted in down-regulation of several cancer-associated genes, including EPHB2, ABL2, HPSE2 and ATM, and up-regulation of KRAG, RRAS2, NFkappa-B, MRVI1, MADCAM1 and others. In conclusion, BTF3 is overexpressed in PDAC, where it acts as a transcriptional regulator rather than a direct modulator of apoptosis." SIGNOR-253945 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR THRB protein P10828 UNIPROT "down-regulates activity" phosphorylation 9606 12809513 t "inferred from 70% family members" llicata "We concluded that serine 142 of the tr dbd is the likely site of phosphorylation by t(4)-activated mapk and that the docking site on tr for activated mapk includes residues 128-133 (kgffrr), a basic amino acid-enriched motif novel for mapk substrates. Tr mutations in the proposed mapk docking domain and at residue 142 modulated t(4)-conditioned shedding of co-repressor and recruitment of co-activator proteins by the receptor, and they altered transcriptional activity of tr in a thyroid hormone response element-luciferase reporter assay." SIGNOR-270143 VCAM1 protein P19320 UNIPROT "A4/b1 integrin" complex SIGNOR-C162 SIGNOR "up-regulates activity" binding 9606 12123670 t lperfetto "We have developed a cell-free assay for binding of solubilized beta1 integrins to their physiologically relevant ligands using an electrochemiluminescent detection method|Binding was clearly optimal for the presumed physiological ligands, i.e., collagen IV for a1b1, collagen I for a2b1, VCAM-Ig for a4b1, fibronectin (the 120-kDa cell attachment fragment was used) for a5b1, and laminin for a6b1." SIGNOR-253241 MAPK7 protein Q13164 UNIPROT GJA1 protein P17302 UNIPROT "down-regulates activity" phosphorylation Ser255 HATSGALsPAKDCGS 9606 BTO:0000007 12637502 t miannu "Activated BMK1 selectively phosphorylates Cx43 on Ser-255 in vitro and in vivo. These data demonstrate that BMK1 kinase activity alone is both a necessary and sufficient component in the mediation of EGF-induced Cx43 Ser-255 phosphorylation and subsequent inhibition of GJC." SIGNOR-250115 PIAS4 protein Q8N2W9 UNIPROT RPA2 protein P15927 UNIPROT up-regulates phosphorylation Ser8 MWNSGFEsYGSSSYG 9606 20016603 t gcesareni "Pias1 and pias4 promote brca1 accumulation and sumoylation, rpa phosphorylation, and dsb repair furthermore, phosphorylation of the 34 kda subunit of rpa on ser-4 and ser-8 (ps4/ps8) in response to ir or camptothecin treatment was diminished by pias4 depletion, while pias1 depletion impaired ir-induced but not camptothecin-induced rpa phosphorylation" SIGNOR-162164 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR RANGAP1 protein P46060 UNIPROT up-regulates phosphorylation Thr409 GQGEKSAtPSRKILD 9606 15037602 t lperfetto "Here, we show that rangap1 is phosphorylated on residues t409, s428, and s442. Phosphorylation occurs before nuclear envelope breakdown and is maintained throughout mitosis. The m-phase kinase cyclin b/cdk1 phosphorylates rangap1 efficiently in vitro, and t409 phosphorylation correlates with nuclear accumulation of cyclin b1 in vivo." SIGNOR-216789 PIM3 protein Q86V86 UNIPROT BAD protein Q92934 UNIPROT "down-regulates activity" phosphorylation Ser99 PFRGRSRsAPPNLWA 9606 BTO:0000007 16403219 t miannu "Pim kinases phosphorylate multiple sites on Bad and promote 14-3-3 binding and dissociation from Bcl-XL. pim kinases are constitutively active when expressed in HEK-293 cells and are able to phosphorylate the Bcl-2 family member Bad on three residues, Ser112, Ser136 and Ser155 in vitro and in cells." SIGNOR-250399 RPS6K proteinfamily SIGNOR-PF26 SIGNOR BAD protein Q92934 UNIPROT "down-regulates activity" phosphorylation Ser75 EIRSRHSsYPAGTED 9606 BTO:0000848 18246127 t lperfetto "To understand the mechanisms underlying B-RAF effects on cell survival we initially analysed the Bcl-2 family protein, Bad, that is phosphorylated by RSK1 at the inhibitory serine-75 residue in a MEK-dependent manner in melanoma cells" SIGNOR-252784 CAMK2A protein Q9UQM7 UNIPROT ETS2 protein P15036 UNIPROT down-regulates phosphorylation Ser310 LDVQRVPsFESFEDD 9606 19182667 t lperfetto "Camkii caused ets-2 phosphorylation.Serine 246, 310, and 313 were the targets. Camkii to phosphorylates ets-2, thus altering ets-2 binding to its downstream promoters" SIGNOR-183600 CyclinD/CDK4 complex SIGNOR-C18 SIGNOR RB1 protein P06400 UNIPROT "down-regulates activity" phosphorylation Thr356 DSFETQRtPRKSNLD -1 9139732 t llicata "In summary, we have shown evidence that CDK4-cyclin D1 phosphorylates Thr5, Ser249, Thr252, Thr356, Thr373, Ser788, Ser795, Ser807, Ser811, and Thr826 of pRB." SIGNOR-250760 RIPK2 protein O43353 UNIPROT IRF5 protein Q13568 UNIPROT up-regulates phosphorylation Ser435 EMFSGELsWSADSIR 9606 22412986 t lperfetto "Activation of interferon regulatory factor 5 by site specific phosphorylation. Phosphorylation of carboxyl serines 451 and 462 appear the primary trigger of irf5 function in nuclear accumulation, transcription, and apoptosis. Rip2 activation of the irf5 aspartic acid substitutions showed a similar positive effect of s451d and s462d function in this assay" SIGNOR-196520 SSTR5 protein P35346 UNIPROT GNAI3 protein P08754 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-256833 "40S cytosolic small ribosomal subunit" complex SIGNOR-C286 SIGNOR 43S_pre_initiation_complex complex SIGNOR-C453 SIGNOR "form complex" binding 9606 35489072 t lperfetto "In eukaryotes, mRNA is recruited to the 43S pre-initiation complex (43S PIC), which consists of the 40S ribosomal subunit, translation initiation factors eIF1, eIF1A, eIF3, eIF5, and a ternary complex (TC) composed of eIF2, GTP and Met-tRNAiMet. 43S PIC binds to the 5′ end of the mRNA and scans along the 5′ untranslated region (5′UTR) in the 3′ direction to find the start codon (AUG) within the context of an optimal Kozak sequence. Start codon recognition stabilizes the 48S initiation complex (48S IC), initiates dissociation of eIF1, eIF1A, eIF2 and eIF5, and promotes recruitment of the 60S ribosomal subunit to form 80S IC ready to enter the elongation cycle of protein synthesis." SIGNOR-269160 MECP2 protein P51608 UNIPROT MGMT protein P16455 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0000567 15657354 f "Chromatin immunoprecipitation analysis of methyl-CpG binding domain containing proteins detected a greater amount of MeCP2, MBD1, and CAF-1 bound to the MGMT promoter in MGMT-silenced cells. Our findings implicate specific MBD proteins in methylation-mediated transcriptional silencing of MGMT." SIGNOR-254035 MFGE8 protein Q08431 UNIPROT p38 proteinfamily SIGNOR-PF16 SIGNOR "down-regulates activity" 10116 19020771 f Giorgia "In our current study, we have shown that after LPS-stimulation, MFG-E8-mediated apoptotic cell phagocytosis suppresses various ERK1/2, p38, JNK, and NFκB activation, resulting in a lower TNF-α release. We also explored whether MFG-E8 helps to suppress the proinflammatory pathway within RPMs. We hence incubated the macrophages with apoptotic cells and stimulated them with LPS and examined the activation of MAP kinase and NFkB pathways after the exogenous addition of recombinant MFG-E8 (rMFG-E8). While apoptotic cells alone had no effect on these pathways, the addition of rMFG-E8 to apoptotic cells prior to phagocytosis and LPS stimulation had a marked suppressive effect on all of the investigated pathways, particularly on the p38 and NFκB pathways that play a key role in the cytokine response of macrophages" SIGNOR-260651 TBK1 protein Q9UHD2 UNIPROT REL protein Q04864 UNIPROT up-regulates phosphorylation 9606 SIGNOR-C68 16888014 t miannu "The present results demonstrate that ikkepsilon- and tbk1-mediated phosphorylation of crel in the c-terminal td leads to cytoplasmic dissociation of a crel-ikb_ complex and nuclear accumulation of crel." SIGNOR-148623 SPRY4 protein Q9C004 UNIPROT CD82 protein P27701 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0002058 20501643 f miannu "When Spry4 was stably transfected into H157 and H2122 NSCLC cell lines, decreased migration and invasion were observed. Matrix metalloproteinase-9 activity was decreased, and the expression of matrix metalloproteinase inhibitors TIMP1 and CD82 were increased. Stable expression of Spry4 led to reduced cell growth and reduced anchorage-independent growth in NSCLC cell lines, along with upregulation of tumor suppressors p53 and p21." SIGNOR-253039 MAGEL2 protein Q9UJ55 UNIPROT TRIM27 protein P14373 UNIPROT "up-regulates activity" binding 9606 23452853 t miannu "MAGE proteins are a family of proteins that contain a conserved domain known as the MAGE homology domain. Recently, we showed that MAGE proteins function biochemically to bind to and enhance the activity of E3 RING ubiquitin ligases. The E3 RING ubiquitin ligase TRIM27 was identified as a major binding partner of MAGE-L2." SIGNOR-253513 CDK2 protein P24941 UNIPROT RBL2 protein Q08999 UNIPROT unknown phosphorylation Ser639 DEICIAGsPLTPRRV 9606 11157749 t llicata "We now identify 22 in vivo phosphorylation sites of p130, targeted by diverse kinases, and present evidence for three cyclin-dependent kinase 4(6) [cdk4(6)] specific phosphorylations, which appear critical for controlling the growth-restraining activity of p130." SIGNOR-104679 PRKCE protein Q02156 UNIPROT IQGAP1 protein P46940 UNIPROT up-regulates phosphorylation Ser1443 DKMKKSKsVKEDSNL 9606 21349850 t gcesareni "Using a mass spectrometry-based assay, we show that egf induces phosphorylation of iqgap1 ser(1443), a residue known to be phosphorylated by pkcthe nonphosphorylatable iqgap1 s1441a/s1443a had no effect. In contrast, the s1441e/s1443d mutation markedly enhanced the ability of iqgap1 to induce neurite outgrowth." SIGNOR-172239 FGFR1 protein P11362 UNIPROT FGFR1 protein P11362 UNIPROT up-regulates phosphorylation Tyr730 SNCTNELyMMMRDCW 10116 19224897 t lperfetto "Furthermore, under conditions in which wild-type or mutant FGFR1 are overexpressed, Y463, Y583, Y585, and Y730 are dispensable for tyrosine phosphorylation of Shc, the mitogen-activated protein kinase (MAPK) response, and stimulation of FGFR1-mediated cell proliferation and differentiation" SIGNOR-236191 CyclinA2/CDK2 complex SIGNOR-C83 SIGNOR CDK7 protein P50613 UNIPROT "up-regulates activity" phosphorylation Thr170 GSPNRAYtHQVVTRW -1 11113184 t lperfetto "Activating phosphorylation of CDK7 by CDC2 and CDK2. The ability of pure CDK2-cyclin A to activate CDK7 in T170-dependent fashion (Fig. ​(Fig.3C,3C, lane 2) strongly suggested a direct phosphorylation mechanism. Tryptic phosphopeptide mapping confirmed that both CDK2-cyclin A (Fig. ​(Fig.4A)4A) and CDC2-cyclin B (Fig. ​(Fig.4D)4D) phosphorylated CDK7 on both S164 and T170." SIGNOR-270806 BDKRB2 protein P30411 UNIPROT GNA13 protein Q14344 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257399 PRKCA protein P17252 UNIPROT KCNQ2 protein O43526 UNIPROT "up-regulates quantity" phosphorylation Ser558 SKRKFKEsLRPYDVM 10029 BTO:0000246 12754513 t lperfetto "Phosphorylation of KCNQ2 channels was increased by muscarinic stimulation; this was prevented either by coexpression with AKAP(DeltaA) or pretreatment with PKC inhibitors that compete with diacylglycerol. These inhibitors also reduced muscarinic inhibition of M-current. | These results suggest that Ser534 and 541 are key sites for PKC phosphorylation, although we have not ruled out the possibility that other PKC sites are involved in this process." SIGNOR-249210 HRAS protein P01112 UNIPROT PIK3CA protein P42336 UNIPROT "up-regulates activity" binding 9534 BTO:0004055 8052307 t lperfetto "In vivo, dominant negative ras mutant n17 inhibits growth factor induced production of 3' phosphorylated phosphoinositides in pc12 cells, and transfection of ras, but not raf, into cos cells results in a large elevation in the level of these lipids. Grb2 binds and activates sos, which then activates ras, and this activates p110 independently of p85. it was also described that ras interacts with pi3k in a direct manner. lysine residue 227 is essential for the interaction of ras with pi3k" SIGNOR-236443 RASSF1 protein Q9NS23 UNIPROT STK3 protein Q13188 UNIPROT up-regulates binding 9606 21808241 t "Mst1/2 are pro-apoptotic kinases that are activated by caspase cleavage" milica "Mst1/2 is also activated by binding to Ras association domain family (RASSF) proteins, possibly owing to alteration of Mst1/2 subcellular localization." SIGNOR-175790 GRM4 protein Q14833 UNIPROT Excitatory_synaptic_transmission phenotype SIGNOR-PH133 SIGNOR up-regulates 9606 BTO:0000938 24564659 f miannu "Excitatory synaptic transmission in the mammalian brain is mediated primarily by the amino acid glutamate, activating two different groups of glutamate receptors: ionotropic and metabotropic." SIGNOR-264352 WNT9B protein O14905 UNIPROT LRP6 protein O75581 UNIPROT up-regulates binding 9606 20093360 t gcesareni "We find that wnt9b binds to a different part of the lrp6 extracellular domain" SIGNOR-163552 PAFAH1B2 protein P68402 UNIPROT APP protein P05067 UNIPROT up-regulates 9606 23238734 f miannu "We provide evidence that the loss of pafah1b2 potently reduces a_ by promoting the degradation of its immediate precursor, the _ctf." SIGNOR-200188 DRD2 protein P14416 UNIPROT GNAZ protein P19086 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257096 AKT proteinfamily SIGNOR-PF24 SIGNOR BAD protein Q92934 UNIPROT "down-regulates activity" phosphorylation Ser99 PFRGRSRsAPPNLWA 9606 BTO:0000938 9346240 t lperfetto "Experiments in this study reveal that akt phosphorylates bad both in vitro and in vivo and that akt-mediated phosphorylation of bad effectively blocks bad induced cell death.[...] In addition, these findings implicate a particular phosphorylation site on bad, serine 136, in the suppression of bad-mediated death by akt.[...]The Phosphorylation of bad may lead to the prevention of cell death via a mechanism that involves the selective association of the phosphorylated forms of bad with 14-3-3 protein isoforms. Akt phosphorylates bad in vitro and in vivo we show that growth factor activation of the pi3'k/akt signaling pathway culminates in the phosphorylation of the bcl-2 family member bad, thereby suppressing apoptosis and promoting cell survival. Akt phosphorylates bad in vitro and in vivo erbb-mediated phosphorylation of bad by akt promotes survival by blocking the interaction of this pro-apoptotic molecule with bcl-2 and bcl-x proteins" SIGNOR-244144 SMARCE1 protein Q969G3 UNIPROT "Brain-specific SWI/SNF SMARCA4 variant" complex SIGNOR-C486 SIGNOR "form complex" binding 9606 BTO:0000142 11790558 t miannu " Whereas chromatin-remodeling complexes are generally thought to promote gene expression, recent genetic and biochemical studies suggest that the SWI/SNF complex may also be involved in transcriptional repression . The subunit composition of the different human complexes that belong to this family is listed in Table 1. Several of the subunits, including SNF5/INI1, are common to all complexes and may constitute its core." SIGNOR-270752 MAPK3 protein P27361 UNIPROT mTORC1 complex SIGNOR-C3 SIGNOR unknown phosphorylation 9606 21071439 t lperfetto "We found three proline-directed residues within raptor, ser(8), ser(696), and ser(863), which are directly phosphorylated by erk1/2. Expression of phosphorylation-deficient alleles of raptor revealed that phosphorylation of these sites by erk1/2 normally promotes mtorc1 activity and signaling to downstream substrates, such as 4e-bp1." SIGNOR-217577 DERA protein Q9Y315 UNIPROT acetaldehyde smallmolecule CHEBI:15343 ChEBI "up-regulates quantity" "chemical modification" 9606 25229427 t miannu "Deoxyribose-phosphate aldolase (EC 4.1.2.4), which converts 2-deoxy-d-ribose-5-phosphate into glyceraldehyde-3-phosphate and acetaldehyde, belongs to the core metabolism of living organisms. his study provides the first experimental evidence that DERA, which is mainly expressed in lung, liver and colon, is the human deoxyribose phosphate aldolase." SIGNOR-267099 GSK3B protein P49841 UNIPROT SPAG5 protein Q96R06 UNIPROT up-regulates phosphorylation Thr111 PIPQISStPKTSEEA 9606 18055457 t lperfetto "Astrin acts as a substrate for gsk3beta and is phosphorylated at thr-111, thr-937 ((s/t)p motif) and ser-974/thr-978 ((s/t)xxx(s/t)-p motif;p is a phosphorylatable residue). Inhibition of gsk3beta impairs spindle and kinetochore accumulation of astrin and spindle formation at mitosis, suggesting that astrin association with the spindle microtubule and kinetochore may be dependent on phosphorylation by gsk3beta" SIGNOR-159578 CSNK2A1 protein P68400 UNIPROT MDC1 protein Q14676 UNIPROT up-regulates phosphorylation Thr378 ESQAGSDtDVEEGKA 9606 18678890 t gcesareni "The mdc1-nbs1 interaction occurs through a specific region (residues 200-420) of mdc1, which contains multiple consensus casein kinase 2 (ck2) phosphorylation sites." SIGNOR-179887 DNMT3B protein Q9UBC3 UNIPROT BAG4 protein O95429 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0001109 18413740 f lperfetto "In contrast, an increase in BAG-1, BAG-3, and BAG-4 gene expression was observed in HCT116 cells overexpressing either DNMT1 (DNMT1+) or DNMT3B (DNMT3B+)" SIGNOR-254113 MLNR protein O43193 UNIPROT GNA14 protein O95837 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257132 UQCR10 protein Q9UDW1 UNIPROT "Mitochondrial respiratory chain complex III" complex SIGNOR-C279 SIGNOR "form complex" binding 30030361 t lperfetto "Complex III (EC 1.10.2.2) or quinol-cytochrome c reductase performs electron transfer coupled to proton pumping using the ‘Q-cycle’ mechanism [79,80]. Structurally, it is a tightly bound symmetrical dimer (cIII2), being each ‘monomer’ composed of three catalytic core (MT-CYB, CYC1 and UQCRFS1) and seven supernumerary subunits" SIGNOR-262199 CSNK2A1 protein P68400 UNIPROT CORO1C protein Q9ULV4 UNIPROT up-regulates phosphorylation Ser463 CNQDERIsKLEQQMA 9606 22355754 t lperfetto "We demonstrate that crn2 is a binding partner and substrate of protein kinase ck2, which phosphorylates crn2 at s463 in its c-terminal coiled coil domain" SIGNOR-196193 phenylalanine smallmolecule CHEBI:28044 ChEBI tyrosine smallmolecule CHEBI:18186 ChEBI "up-regulates quantity" "precursor of" 9606 NBK536726 t brain lperfetto "L-phenylalanine is converted into L-tyrosine in the liver, by the enzyme phenylalanine hydroxylase (PH) in the presence of oxygen, iron, and tetrahydrobiopterin as cofactors" SIGNOR-264172 EDNRA protein P25101 UNIPROT GNA14 protein O95837 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257427 ITGAL protein P20701 UNIPROT "AL/b2 integrin" complex SIGNOR-C169 SIGNOR "form complex" binding 16988024 t lperfetto "Integrins are one of the major families of cell adhesion receptors (Humphries, 2000; Hynes, 2002). All integrins are non-covalently-linked, heterodimeric molecules containing an α and a β subunit. Both subunits are type I transmembrane proteins, containing large extracellular domains and mostly short cytoplasmic domains (Springer and Wang, 2004; Arnaout et al., 2005). Mammalian genomes contain 18 α subunit and 8 β subunit genes, and to date 24 different α,β combinations have been identified at the protein level. Although some subunits only appear in a single heterodimer, twelve integrins contain the β1 subunit, and five contain αV." SIGNOR-253189 GLI3 protein P10071 UNIPROT GLI1 protein P08151 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 10090 BTO:0002572 16571352 f lperfetto "The basal expression of Gli1, Ptc1, and Hip1 was positively associated with the loss of Gli3 alleles.These findings implicate Gli3 as a repressor of Hh target gene expression." SIGNOR-209638 GSK3B protein P49841 UNIPROT PTEN protein P60484 UNIPROT "down-regulates activity" phosphorylation Thr366 ASSSTSVtPDVSDNE 9606 16107342 t lperfetto "Gsk3beta Phosphorylates pten at thr-366 in intact cells phosphorylation of pten at thr-366 reduces the activity of pten in cells" SIGNOR-236641 NEUROG3 protein Q9Y4Z2 UNIPROT INSM1 protein Q01101 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 BTO:0000944 17300785 f miannu "The ngn3/E47 heterodimer selectively binds and activates the E-box3 of the INSM1 promoter. The endogenous ngn3 and CREB-binding protein (CBP) co-activator occupy the INSM1 promoter, resulting in hyper-acetylation of histone H3/H4 chromatin in a human neuroblastoma cell line, IMR-32." SIGNOR-253814 CSDE1 protein O75534 UNIPROT FOS protein P01100 UNIPROT "down-regulates quantity" "post transcriptional regulation" 10090 BTO:0000944 15314026 t "By testing different classes of mammalian poly(A) nucleases, we identified CCR4 as a poly(A) nuclease involved in the mCRD-mediated rapid deadenylation in viv" SIGNOR-261145 GRK2 protein P25098 UNIPROT MC4R protein P32245 UNIPROT "down-regulates activity" phosphorylation Ser330 GGLCDLSsRY 9606 12639913 t gcesareni "Mutagenesis studies revealed that Thr312 and Ser329/330 in the C-terminal tail are potential sites for PKA and GRK phosphorylation and may play an essential role in the recruitment of beta-arrestin to the activated receptor." SIGNOR-249673 AURKB protein Q96GD4 UNIPROT HASPIN protein Q8TF76 UNIPROT "up-regulates activity" phosphorylation Ser93 RVPKDRPsLTVTPKR 9606 BTO:0000567 21658950 t miannu "Here, we show that Aurora B phosphorylates Haspin to promote generation of H3T3ph and that Aurora B kinase activity is required for normal chromosomal localization of the CPC, indicating an intimate linkage between Aurora B and Haspin functions in mitosis." SIGNOR-263139 PKN1 protein Q16512 UNIPROT MARCKS protein P29966 UNIPROT unknown phosphorylation Ser163 KRFSFKKsFKLSGFS 9534 BTO:0000298 8557118 t lperfetto "PRK1 phosphorylates MARCKS at the PKC sites: serine 152, serine 156 and serine 163." SIGNOR-248938 XRCC6 protein P12956 UNIPROT DNA-PK complex SIGNOR-C107 SIGNOR "form complex" binding 9606 BTO:0002419 17308091 t miannu "complexes formed by interactions between Ku70, Ku80, and DNA-PKcs were well-established" SIGNOR-226023 "Polycomb repressive complex 2" complex SIGNOR-C130 SIGNOR KDM5B protein Q9UGL1 UNIPROT "down-regulates activity" 9606 35217626 t SaraGualdi "Our transcriptomic profiling in AML further identified Kdm5b (also known as Jarid1b, Plu-1, or RBP2-H1), a multifunctional demethylase that can remove histone H3 lysine 4 tri/di-methylation (H3K4me3/2), to be a critical downstream target repressed by PRC2." SIGNOR-271577 CSNK2B protein P67870 UNIPROT CACNA1S protein Q13698 UNIPROT "up-regulates activity" phosphorylation Ser1575 PEICRTVsGDLAAEE -1 20937870 t miannu "To identify the regulatory sites of phosphorylation under physiologically relevant conditions, Ca(V)1.1 channels were purified from skeletal muscle and sites of phosphorylation on the α1 subunit were identified by mass spectrometry. Two phosphorylation sites were identified in the proximal C-terminal domain, serine 1575 (S1575) and threonine 1579 (T1579), which are conserved in cardiac Ca(V)1.2 channels (S1700 and T1704, respectively). In vitro phosphorylation revealed that Ca(V)1.1-S1575 is a substrate for both cAMP-dependent protein kinase and calcium/calmodulin-dependent protein kinase II, whereas Ca(V)1.1-T1579 is a substrate for casein kinase 2." SIGNOR-263115 BOC protein Q9BWV1 UNIPROT CDON/BOC/PTCH1 complex SIGNOR-C95 SIGNOR "form complex" binding 10090 21664576 t lperfetto "Secreted Hedgehog (HH) ligands signal through the canonical receptor Patched (PTCH1). However, recent studies implicate three additional HH-binding, cell-surface proteins, GAS1, CDO, and BOC, as putative coreceptors for HH ligands." SIGNOR-209599 SEPTIN2 protein Q15019 UNIPROT SEPT6/SEPT2 complex SIGNOR-C71 SIGNOR "form complex" binding 9606 16914550 t miannu "We have characterized the conformation of a complex of filamentous human septins, sept2, sept6, and sept7. / we now show that sept6 and sept7 interact through a parallel coiled-coil, and that sept2 interacts with sept6 through their c-terminal domains." SIGNOR-148889 "Cullin 1-RBX1-Skp1" complex SIGNOR-C529 SIGNOR CCNE1 protein P24864 UNIPROT "down-regulates quantity by destabilization" polyubiquitination 9606 BTO:0002524 17298674 t miannu "Cdk2 (S384) and GSK3 (T380) prime cyclin E for destruction. The hyper-phosphorylated T380/S384 degron has high affinity for monomeric Fbw7α, which engages the remainder of the SCF to initiate cyclin E's ubiquitination by an E2 enzyme" SIGNOR-271639 NfKb-p65/p50 complex SIGNOR-C13 SIGNOR SOCS3 protein O14543 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 19643666 t lperfetto "Expression of SOCS1 and SOCS3 is regulated primarily by activation of STAT1 and STAT3, respectively, although their expression can be mediated through other signaling cascades, including the mitogen activated protein kinase (MAPK) and nuclear factor-kappa B (NF-kappaB) pathways." SIGNOR-249566 MAPK14 protein Q16539 UNIPROT KHSRP protein Q92945 UNIPROT "down-regulates activity" phosphorylation Thr692 QAAYYGQtPGPGGPQ 10090 BTO:0000165 16364914 t lperfetto "KSRP, an important factor for AU-rich element (ARE)-directed mRNA decay, undergoes p38-dependent phosphorylation during muscle differentiation. KSRP phosphorylated by p38 displays compromised binding to ARE-containing transcripts and fails to promote their rapid decay, although it retains the ability to interact with the mRNA degradation machinery" SIGNOR-235856 ATR protein Q13535 UNIPROT WDHD1 protein O75717 UNIPROT "up-regulates activity" phosphorylation Thr826 KAAELTAtQVEEEEE 9606 BTO:0001109 26082189 t miannu "And-1 is phosphorylated at T826 by ATR following replication stress, and this phosphorylation is required for And-1 to accumulate at the damage sites, where And-1 promotes the interaction between Claspin and Chk1, thereby stimulating efficient Chk1 activation by ATR." SIGNOR-262664 acetylcholine smallmolecule CHEBI:15355 ChEBI CHRNB3 protein Q05901 UNIPROT "up-regulates activity" "chemical activation" 9606 BTO:0000227 28901280 t miannu "Neuronal nicotinic acetylcholine receptors (nAChRs) belong to a super-family of Cysloop ligand-gated ion channels that respond to endogenous acetylcholine (ACh) or other cholinergic ligands. These receptors are also the targets of drugs such as nicotine (the main addictive agent delivered by cigarette smoke) and are involved in a variety of physiological and pathophysiological processes." SIGNOR-264258 JAG2 protein Q9Y219 UNIPROT NOTCH2 protein Q04721 UNIPROT up-regulates binding 9606 10958687 t gcesareni "Binding of delta1, jagged1, and jagged2 to notch2 rapidly induces cleavage, nuclear translocation, and hyperphosphorylation of notch2" SIGNOR-81367 MAPK1 protein P28482 UNIPROT GAB1 protein Q13480 UNIPROT "up-regulates activity" phosphorylation Thr312 ISYDIPPtPGNTYQI 10029 BTO:0000246 15379552 t lperfetto "Our results demonstrate that ERK1/2 phosphorylate Gab1 at six serine/threonine residues (T312, S381, S454, T476, S581, S597) in consensus motifs for MAP kinase phosphorylation. |serine and threonine phosphorylation are capable of modulating the initial signal" SIGNOR-249399 GSK3B protein P49841 UNIPROT SPAG5 protein Q96R06 UNIPROT up-regulates phosphorylation Thr937 ADEEPEStPVPLLGS 9606 18055457 t lperfetto "Astrin acts as a substrate for gsk3beta and is phosphorylated at thr-111, thr-937 ((s/t)p motif) and ser-974/thr-978 ((s/t)xxx(s/t)-p motif;p is a phosphorylatable residue). Inhibition of gsk3beta impairs spindle and kinetochore accumulation of astrin and spindle formation at mitosis, suggesting that astrin association with the spindle microtubule and kinetochore may be dependent on phosphorylation by gsk3beta" SIGNOR-159582 PRKD1 protein Q15139 UNIPROT ATP7B protein P35670 UNIPROT "up-regulates activity" phosphorylation Ser481 ILAKSPQsTRAVAPQ 9606 BTO:0000599 21189263 t lperfetto "ATP7B trafficking was markedly reduced by the Ser-478/481/1121/1453 to Ala mutation. We conclude that PKD plays a key role in copper-dependent serine phosphorylation, permitting high levels of ATP7B protein expression and trafficking." SIGNOR-272293 PRKCI protein P41743 UNIPROT NOS3 protein P29474 UNIPROT "down-regulates activity" phosphorylation Thr495 TGITRKKtFKEVANA 9606 24379783 t lperfetto "The phosphorylation of both S617 and S635 have also been shown to promote increased eNOS-derived NO release (Michell et al., 2002). The phosphorylaiton of S617 can be induced by PKA or Akt activity, and may serve to sensitize eNOS to calmodulin binding and modulate the phosphorylation of other eNOS sites" SIGNOR-251635 SLC25A13 protein Q9UJS0 UNIPROT "aspartic acid" smallmolecule CHEBI:22660 ChEBI "up-regulates quantity" relocalization 9606 12084073 t miannu "Aralar1 and citrin are members of the subfamily of calcium-binding mitochondrial carriers and correspond to two isoforms of the mitochondrial aspartate/glutamate carrier (AGC). These proteins are activated by Ca2+ acting on the external side of the inner mitochondrial membrane." SIGNOR-265157 farnesol chemical CHEBI:28600 ChEBI UGT1A1 protein P22309 UNIPROT "down-regulates activity" "chemical inhibition" 9606 BTO:0000007 21030469 t Luana "Fourteen of the compounds studied inhibited both bilirubin and estradiol glucuronidation (Table 1). Among these 14 compounds, ritonavir, anthraflavic acid, levothyroxine, riluzole, baicalein, farnesol, 4′-OH-phenytoin, 4-methylumbelliferone, raltegravir, and 1-naphthol exhibited very similar IC50 values (differences less than 2-fold) on both bilirubin glucuronidation and estradiol-3-glucuronidation (Table 1). Ketoconazole, carvedilol, and niflumic acid exhibited more disparity with respect to inhibition of the two reactions in that these compounds exhibited at least a 2-fold higher IC50 value against bilirubin glucuronidation than against estradiol-3-glucuronidation. SN-38 only weakly inhibited bilirubin glucuronidation (IC50 = 356 μM) and seemed to be a partial inhibitor of estradiol-3-glucuronidation." SIGNOR-258159 DUSP7 protein Q16829 UNIPROT GHR protein P10912 UNIPROT down-regulates dephosphorylation 9606 12907755 t gcesareni "Identification of protein tyrosine phosphatases with specificity for the ligand-activated growth hormone receptor." SIGNOR-104545 NR3C1 protein P04150 UNIPROT FOXO3 protein O43524 UNIPROT "up-regulates quantity" "transcriptional regulation" 10090 22848740 t miannu "We show that FOXO3 is an immediate early glucocorticoid receptor (GR) target, whose transcription is even further enhanced by conditions that mimic metabolic stress." SIGNOR-255759 ZBTB16 protein Q05516 UNIPROT miR-146a mirna URS000075D8A0_9606 RNAcentral "down-regulates quantity by repression" "transcriptional regulation" 9606 22327366 t "In endothelial cells. KLF2 binds to the promoter and induces a signi cant upregulation of the miR-143/145 cluster" SIGNOR-255941 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR RPS6KA5 protein O75582 UNIPROT up-regulates phosphorylation Thr581 PDNQPLKtPCFTLHY 9606 18267068 t lperfetto "Together, our in vivo and in vitro studies indicate that the pkc/c-raf/mek/erk pathway plays a major role in the s6k1 activation in hypertrophic cardiac growth." SIGNOR-249573 GEMIN7 protein Q9H840 UNIPROT "SMN complex" complex SIGNOR-C158 SIGNOR "form complex" binding 12065586 t lperfetto "SMN is part of a large macromolecular complex that also contains Gemin2, Gemin3, Gemin4, Gemin5, and Gemin6. The SMN complex functions in the assembly of spliceosomal small nuclear ribonucleoproteins and probably other ribonucleoprotein particles. We have identified a novel protein component of the SMN complex termed Gemin7 using native purified SMN complexes and peptide sequencing by mass spectrometry." SIGNOR-253121 KIT protein P10721 UNIPROT PIK3R1 protein P27986 UNIPROT "up-regulates activity" binding 9534 7509796 t "Tyrosine residue 719 of the c-kit receptor is essential for binding of the P85 subunit of phosphatidylinositol (PI) 3-kinase and for c-kit-associated PI 3-kinase activity in COS-1 cells" SIGNOR-255948 MAPK1 protein P28482 UNIPROT TNFRSF1A protein P19438 UNIPROT "down-regulates activity" phosphorylation Thr280 FSPTPGFtPTLGFSP -1 11606045 t lperfetto "Phosphorylation of murine CD120a by p42(mapk/erk2) has been shown to inhibit its ability to initiate apoptosis while preserving signaling events such as NF-kappaB activation.|Additionally, we demonstrated that (i) the p42(mapk/erk2)-dependent phosphorylation of CD120a and DR3 occurred on Ser and Thr residues, (ii) p42(mapk/erk2) phosphorylated residues located in the membrane proximal regions but not the death domains of CD120a and DR3, (iii) Ser 253 is a preferred site of phosphorylation on CD120a" SIGNOR-249453 AFAP1L2 protein Q8N4X5 UNIPROT PIK3CA protein P42336 UNIPROT "up-regulates activity" binding 9606 BTO:0000007 19060924 t miannu "RET/PTC induced robust tyrosine phosphorylation of XB130, which promoted its subsequent association with the p85alpha subunit of phosphatidylinositol 3-kinase (PI 3-kinase). We identified tyrosine 54 of XB130 as the major target of RET/PTC-mediated phosphorylation and a critical binding site for the SH2 domains of p85alpha." SIGNOR-263193 CDK12 protein Q9NYV4 UNIPROT PAK2 protein Q13177 UNIPROT "up-regulates activity" phosphorylation Thr169 TEAPAVVtEEEDDDE 9606 BTO:0004828 32483448 t lperfetto "Mechanistically, CDK12 directly binds to and phosphorylates PAK2 at T134/T169 to activate MAPK signaling pathway" SIGNOR-273110 DHODH protein Q02127 UNIPROT orotate smallmolecule CHEBI:30839 ChEBI "up-regulates quantity" "chemical modification" 9606 30449682 t miannu "OXPHOS directly drives the respiration-coupled mitochondrial enzyme dihydroorotate dehydrogenase (DHODH) that converts dihydroorotate (DHO) to orotate in the de novo pyrimidine synthesis pathway" SIGNOR-267433 daunorubicin chemical CHEBI:41977 ChEBI ABCC1 protein P33527 UNIPROT "down-regulates activity" "chemical inhibition" 9606 BTO:0002206 9647783 t "Simone Vumbaca" "Unconjugated Dox and Dau failed to inhibit the transport of LTC4, whereas 30 microM GS-Dox or GS-Dau conjugates completely inhibited the transport." SIGNOR-261086 FAU protein P62861 UNIPROT "40S cytosolic small ribosomal subunit" complex SIGNOR-C286 SIGNOR "form complex" binding -1 25901680 t lperfetto "Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins." SIGNOR-262443 TRAF2 protein Q12933 UNIPROT MAP3K14 protein Q99558 UNIPROT "down-regulates quantity by destabilization" ubiquitination 9606 20651737 t lperfetto "Under resting conditions cellular inhibitor of apoptosis (ciap) proteins target nuclear factor-kb (nf-kb)-inducing kinase (nik) for ubiquitylation and proteasomal degradation." SIGNOR-167066 tRNA(Pro) smallmolecule CHEBI:29177 ChEBI Pro-tRNA(Pro) smallmolecule CHEBI:29154 ChEBI "up-regulates quantity" "precursor of" 9606 28271488 t miannu "Aminoacyl-tRNA synthetases (AARSs) are essential enzymes that specifically aminoacylate one tRNA molecule by the cognate amino acid. In mammals, nine synthetases, those specific for amino acids Arg, Asp, Gln, Glu, Ile, Leu, Lys, Met and Pro, associate into a multi-aminoacyl-tRNA synthetase complex, an association which is believed to play a key role in the cellular organization of translation, but also in the regulation of the translational and nontranslational functions of these enzymes." SIGNOR-270433 RET protein P07949 UNIPROT RET protein P07949 UNIPROT up-regulates phosphorylation Tyr905 DVYEEDSyVKRSQGR 9606 14711813 t llicata "Mass spectrometric analysis revealed that ret tyr(806), tyr(809), tyr(900), tyr(905), tyr(981), tyr(1062), tyr(1090), and tyr(1096) were autophosphorylation sites. taken together, the results suggest that phosphorylation of tyr981 is not obligatorily required for the catalytic activity but plays a supplementary role in initiating autophosphorylation of tyr905, which brings about the overall kinase activity." SIGNOR-121165 EFNB2 protein P52799 UNIPROT EPHB3 protein P54753 UNIPROT up-regulates binding 9606 8559144 t gcesareni "Lerk-5 is a ligand for both elk and hek and induces receptor phosphorylation" SIGNOR-39862 CDKN1B protein P46527 UNIPROT CDK1 protein P06493 UNIPROT down-regulates binding 9606 15340381 t gcesareni "P21 and p27 are key inhibitors of both cdk1 and cdk2." SIGNOR-128445 PRTN3 protein P24158 UNIPROT F2RL1 protein P55085 UNIPROT "down-regulates activity" cleavage Thr75 VLTGKLTtVFLPIVY -1 10978167 t lperfetto "PAR1E and PAR2E (10 microM) were incubated in the presence of the different proteases | The enzymes were used at the following concentrations: 0.5 unit/mL thrombin, 2.5 nM trypsin, 20 nM plasmin, 20 nM cathepsin G, 20 nM elastase, 20 nM proteinase 3, and 2 units/mL calpain I and II|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus.|Mass spectrometry studies of PAR2E predicted activation of PAR2 by trypsin through cleavage at the Arg36-Ser37 site, no effect of thrombin, and inactivation of the receptor by plasmin, calpain and leukocyte elastase, cathepsin G, and proteinase 3" SIGNOR-263597 SMARCC1 protein Q92922 UNIPROT "Muscle cell-specific SWI/SNF ARID1A variant" complex SIGNOR-C481 SIGNOR "form complex" binding 9606 BTO:0000887 11073988 t miannu "The SWI/SNF family of chromatin-remodeling complexes facilitates gene activation by assisting transcription machinery to gain access to targets in chromatin. Our data suggest that BAF250 confers specificity to the human BAF complex and may recruit the complex to its targets through either protein-DNA or protein-protein interactions." SIGNOR-270696 pizotifen chemical CHEBI:50212 ChEBI HTR1A protein P08908 UNIPROT "up-regulates activity" "chemical activation" 10029 BTO:0000246 9205951 t miannu "The actions of several serotonergic ligands in use or under development for the treatment of migraine headaches were examined at recombinant human 5-HT1A receptors stably expressed in Chinese Hamster Ovary cells. Of the prophylactic antimigraine drugs tested, methysergide and lisuride behaved as efficacious agonists (Emax > or = 90% relative to 5-HT) whereas pitozifen and (-)propranolol acted as a partial agonist (60%) and an antagonist, respectively." SIGNOR-258617 SETDB2 protein Q96T68 UNIPROT "Histone H3" proteinfamily SIGNOR-PF69 SIGNOR "up-regulates activity" methylation 9606 20404330 t miannu "Here, we have characterized a previously undescribed member of the histone H3K9 methyltransferase family named CLLD8 (or SETDB2 or KMT1F). This protein contributes to the trimethylation of both interspersed repetitive elements and centromere-associated repeats and participates in the recruitment of heterochromatin protein 1 to centromeres. Methylation of histone H3 at lysine 9 (H3K9) has emerged as an important player in the formation of heterochromatin, chromatin condensation, and transcriptional repression." SIGNOR-265351 Calcineurin complex SIGNOR-C155 SIGNOR NFATC2 protein Q13469 UNIPROT "up-regulates activity" dephosphorylation Ser276 PQRSRSPsPQPSSHV 9606 BTO:0000567 11030334 t "NFAT1 is phosphorylated on fourteen conserved phosphoserine residues in its regulatory domain, thirteen of which are dephosphorylated upon stimulation. Dephosphorylation of all thirteen residues is required to mask a nuclear export signal (NES), cause full exposure of a nuclear localization signal (NLS), and promote transcriptional activity" SIGNOR-252333 TNFRSF13C protein Q96RJ3 UNIPROT TRAF3 protein Q13114 UNIPROT "down-regulates quantity by destabilization" binding 9606 BTO:0000776;BTO:0000785 20889926 t lperfetto "Activation of br3 induces recruitment and degradation of traf3." SIGNOR-168199 CHKA protein P35790 UNIPROT PLIN3 protein O60664 UNIPROT "down-regulates quantity by destabilization" phosphorylation Tyr251 ERLRQHAyEHSLGKL 9606 BTO:0000527 34929314 t lperfetto "In addition, as a protein kinase, CHKα2 phosphorylates PLIN2 at Tyrosine 232 and PLIN3 at Tyrosine 251. Phosphorylated PLIN2 and PLIN3 are separated from lipid droplets and degraded by Hsc70-mediated autophagy, thereby promoting lipid droplet lipolysis, fatty acid oxidation and glioblastoma growth " SIGNOR-267650 PRKAA2 protein P54646 UNIPROT PFKFB2 protein O60825 UNIPROT "up-regulates activity" phosphorylation Ser466 PVRMRRNsFTPLSSS 9606 BTO:0000007 11069105 t miannu "AMPK phosphorylates and activates heart PFK-2 in vitro and in intact cells.  activation of PFK-2 was due to the phosphorylation of Ser466" SIGNOR-250323 PTPN2 protein P17706 UNIPROT KDR protein P35968 UNIPROT "down-regulates activity" dephosphorylation Tyr1054 FGLARDIyKDPDYVR 9606 BTO:0000007 18840653 t "We show that a TCPTP substrate-trapping mutant interacts with VEGFR2. Moreover, TCPTP dephosphorylates VEGFR2 in a phosphosite-specific manner, inhibits its kinase activity and prevents its internalization from the cell surface. |The autophosphorylation sites Tyr1054/1059 and Tyr1214 were dephosphorylated by TCPTP (Fig. 4B). Tyr996, the functional significance of which is currently uncertain (Olsson et al., 2006), was a TCPTP target as well." SIGNOR-248399 DUSP3 protein P51452 UNIPROT MAPK3 protein P27361 UNIPROT "down-regulates activity" dephosphorylation Tyr204 HTGFLTEyVATRWYR 9534 BTO:0004055 10224087 t "Extracellular regulated kinases (ERK) 1 and ERK2 are authentic substrates for the dual-specificity protein-tyrosine phosphatase VHR. A novel role in down-regulating the ERK pathway.|Catalysis by VHR requires the native structure of ERK and is specific for tyrosine 185 of ERK2" SIGNOR-248535 "TIP-LINK complex" complex SIGNOR-C291 SIGNOR LHFPL5 protein Q8TAF8 UNIPROT "up-regulates activity" binding 10090 BTO:0000630 23217710 t lperfetto "We conclude that the transmembrane and membrane proximal CR domain of PCDH15 mediate interaction with TMHS.|Based on the interdependence of PCDH15 and TMHS for their efficient localization to stereocilia, we reasoned that interaction between the two proteins might regulate their effective cell surface transport." SIGNOR-262580 SPOP protein O43791 UNIPROT MACROH2A1 protein O75367 UNIPROT "up-regulates activity" binding 9606 BTO:0000007 15897469 t miannu "Here, we describe an E3 ubiquitin ligase consisting of SPOP and CULLIN3 that is able to ubiquitinate the PcG protein BMI1 and the variant histone MACROH2A1. BMI1 and MACROH2A1 interact with and are ubiquitinated by the CULLIN3 and SPOP ligase complex." SIGNOR-272657 SLC9A7 protein Q96T83 UNIPROT hydron chemical CHEBI:15378 ChEBI "down-regulates quantity" relocalization 9606 BTO:0000938 31507243 t miannu "Na+/H+ exchangers play pivotal roles in the control of cell and tissue pH by mediating the electroneutral exchange of Na+ and H+ across cellular membranes. " SIGNOR-265597 Galanin smallmolecule CHEBI:80161 ChEBI GALR3 protein O60755 UNIPROT "up-regulates activity" "chemical activation" 9606 BTO:0002524 31160049 t "Ligand-GPCR dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257496 CCNA1 protein P78396 UNIPROT WT1 protein P19544 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 19082485 f irozzo "This study identified WT1 as a repressed target of cyclin A1 and suggests that the suppression of WT1 in cyclin A1-overexpressing leukemias might play a role in the growth and suppression of apoptosis in these leukemic cells." SIGNOR-255905 ITGB1BP1 protein O14713 UNIPROT "AIIB/b3 integrin" complex SIGNOR-C173 SIGNOR "down-regulates activity" binding 9606 19118207 t miannu "Integrins also bind to many PTBdomain-containing proteins (Calderwood et al., 2003) – including Dok1 and integrincytoplasmic-domain-associated protein 1 (ICAP1) – and these can compete with talin for binding to integrin and so can impair activation" SIGNOR-257655 RPS15A protein P62244 UNIPROT "40S cytosolic small ribosomal subunit" complex SIGNOR-C286 SIGNOR "form complex" binding -1 25901680 t lperfetto "Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins." SIGNOR-262436 AKT1 protein P31749 UNIPROT HSPB1 protein P04792 UNIPROT down-regulates phosphorylation Ser82 RALSRQLsSGVSEIR 9606 19593530 t "10383393: We demonstrate that both phosphorylated sHsps and the triple mutant Hsp27-S15D,S78D,S82D show significantly decreased abilities to act as molecular chaperones suppressing thermal denaturation and facilitating refolding of citrate synthase in vitro." lperfetto "First, the akt1, akt2, and akt3 isoforms can bind directly to hsp27 and can be found in a complex with p38 mapk, mk2, and hsp27 [98_100]. Second, rane and colleagues showed that akt could phosphorylate hsp27 at ser-82, but not ser-15 or ser-78, in vitro, while co-expression of an active akt mutant and hsp27 in hek cells resulted in hsp27 phosphorylation at the same residue." SIGNOR-252526 "Factor FVIIa:TF" complex SIGNOR-C319 SIGNOR F5 protein P12259 UNIPROT "down-regulates activity" cleavage Arg707 ESTVMATrKMHDRLE -1 10026263 t lperfetto "Thrombin is considered the physiological activator of factor V and is the most potent activator, catalyzing the cleavage of three peptide bonds at Arg709, Arg1018, and Arg1545" SIGNOR-263647 p38 proteinfamily SIGNOR-PF16 SIGNOR CDC25B protein P30305 UNIPROT "down-regulates activity" phosphorylation Ser375 ARVLRSKsLCHDEIE 9606 11333986 t lperfetto "P38 binds and phosphorylates cdc25-b and -c at serines 309 and 361 and at serine 216, respectively, and phosphorylation of these residues is required for binding to 14-3-3 proteins phosphorylation of cdc25 triggers cell-cycle arrest by the sequestration of cdc25 by 14-3-3" SIGNOR-107416 PPARGC1A protein Q9UBK2 UNIPROT Aldolase proteinfamily SIGNOR-PF75 SIGNOR "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000599 16891307 f "inferred from family member" miannu "Overexpression of SRC1 and PGC1alpha by recombinant adenoviruses led to a significant up-regulation of well characterized HNF4alpha-dependent genes (ApoCIII, ApoAV, PEPCK, AldoB, OTC, and CYP7A1) and forced HepG2 cells toward a more differentiated phenotype as demonstrated by increased ureogenic rate." SIGNOR-270226 TCF3 protein P15923 UNIPROT MYOD/E12E47 complex SIGNOR-C127 SIGNOR "form complex" binding 10090 BTO:0001103 18094043 t lperfetto "MyoD omodimers or heterodimers of MyoD plus E12 or E47 serve as transcription factor complexes that bind to CANNTG consensus sites in the promoter regions of genes, performing major functions in specification and differentiation of skeletl muscle precursor cells." SIGNOR-241551 CD27 protein P26842 UNIPROT BIK protein Q13323 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 12324477 f gcesareni "Bik expression was weakly but significantly down-regulated by cd27 but up-regulated by cd40." SIGNOR-93323 PLK1 protein P53350 UNIPROT NINL protein Q9Y2I6 UNIPROT "down-regulates activity" phosphorylation Thr161 SDEEAEStKEAQNEL -1 12852856 t lperfetto "Here, we identify a centrosomal plk1 substrate, termed nlp (ninein-like protein), whose properties suggest an important role in microtubule organization. Nlp interacts with two components of the gamma-tubulin ring complex and stimulates microtubule nucleation. Plk1 phosphorylates nlp and disrupts both its centrosome association and its gamma-tubulin interaction" SIGNOR-103364 NSMCE3 protein Q96MG7 UNIPROT SMC5/6 complex SIGNOR-C374 SIGNOR "form complex" binding -1 27427983 t miannu "The SMC5/6 complex, consisting of SMC5, SMC6, and non-SMC elements NSMCE1–6, has key roles in the maintenance of chromosome integrity during mitotic proliferation, meiosis, and DNA repair and is critical for genome stability. In particular, the SMC5/6 complex is involved in resolving intermediates during recombination (5, 6) and other complex DNA structures, such as stalled replication forks" SIGNOR-265485 ponatinib chemical CHEBI:78543 ChEBI STAT5A protein P42229 UNIPROT "down-regulates activity" "chemical inhibition" 9606 BTO:0000830 23539538 t miannu "Ponatinib was found to inhibit the kinase activity of KIT G560V and KIT D816V in the human mast cell leukemia cell line HMC-1. In addition, ponatinib was found to block Lyn- and STAT5 activity in neoplastic mast cells" SIGNOR-259274 MAPK3 protein P27361 UNIPROT EPS8 protein Q12929 UNIPROT "down-regulates activity" phosphorylation Ser625 ADTPPAPsPPPTPAP -1 19564905 t miannu "We further show that the actin barbed-end capping activity of Eps8 is inhibited by brain-derived neurotrophic factor (BDNF) treatment through MAPK-dependent phosphorylation of Eps8 residues S624 and T628. Additionally, an Eps8 mutant, impaired in the MAPK target sites (S624A/T628A), displays increased association to actin-rich structures, is resistant to BDNF-mediated release from microfilaments, and inhibits BDNF-induced filopodia. The opposite is observed for a phosphomimetic Eps8 (S624E/T628E) mutant. Thus, collectively, our data identify Eps8 as a critical capping protein in the regulation of axonal filopodia and delineate a molecular pathway by which BDNF, through MAPK-dependent phosphorylation of Eps8, stimulates axonal filopodia formation, a process with crucial impacts on neuronal development and synapse formation." SIGNOR-263058 COL4A2 protein P08572 UNIPROT ECM_synthesis phenotype SIGNOR-PH8 SIGNOR up-regulates 9606 12778132 t "Type IV collagen is the most abundant Type IV collagen is the most abundant constituent of the BM…All of the type IV collagen in mammals is derived from six genetically distinct alpha-chain polypeptides (alpha1-alpha6)" SIGNOR-254666 RPS6KB1 protein P23443 UNIPROT CAD protein P27708 UNIPROT up-regulates phosphorylation Ser1859 PPRIHRAsDPGLPAE 9606 23429703 t lperfetto "Mtorc1 signaling posttranslationally regulated this metabolic pathway via its downstream target ribosomal protein s6 kinase 1 (s6k1), which directly phosphorylates s1859 on cad, the enzyme that catalyzes the first three steps of de novo pyrimidine synthesis. Growth signaling through mtorc1 thus stimulates the production of new nucleotides to accommodate an increase in rna and dna synthesis." SIGNOR-201117 calcium(2+) smallmolecule CHEBI:29108 ChEBI CDH3 protein P22223 UNIPROT "up-regulates activity" "chemical activation" 9606 22535893 t miannu "Cadherins are Ca(2+)-dependent cell-cell adhesion molecules that play critical roles in animal morphogenesis." SIGNOR-265843 thioridazine chemical CHEBI:9566 ChEBI HTR1A protein P08908 UNIPROT "down-regulates activity" "chemical inhibition" 10029 9760039 t miannu "Marked differences were observed between the actions of ‘antagonists’ (Table 2; Fig. 2D ). methiothepin and butaclamol, as well asspiperone, exhibited negative efficacy by concentration-dependently inhibiting S GTPgS binding below basal levels, indicating that they act as inverse agonists in this system.WAY 100,135, yUH 301 and the 5-HTreceptor1A and b-adrenergic receptor antagonist ,ytertatolol, acted as ‘neutral’ antagonists, exhibiting antagonist activity without any detectable agonist or inverse agonist effects." SIGNOR-258839 SMAD2/STAT3/EP300 complex SIGNOR-C203 SIGNOR IL17A protein Q16552 UNIPROT up-regulates "transcriptional regulation" 9606 26194464 t "MARCO ROSINA" "Thus, pSmad2L (Ser255) forms complex with p300 and STAT3 to bind to the proximal promoter of the Rorc and Il17a genes." SIGNOR-255027 TAF3 protein Q5VWG9 UNIPROT TAF3/TRF3 complex SIGNOR-C23 SIGNOR "form complex" binding 9606 BTO:0000887;BTO:0001103;BTO:0001760 18851836 t lperfetto "We recently identified taf3 as a subunit specifically associated with trf3 to form a complex that is required for myogenic differentiation" SIGNOR-181611 STK3 protein Q13188 UNIPROT MOB1A protein Q9H8S9 UNIPROT up-regulates phosphorylation Thr35 LLKHAEAtLGSGNLR 9606 21808241 t "The regulation of MOB1 and LATS1/2 by MST1/2 may be organ and disease-specific." gcesareni "Mob1, which forms a complex with lats1/2, is also phosphorylated by mst1/2, resulting in an enhanced lats1/2 mob1 interaction." SIGNOR-175809 ATR protein Q13535 UNIPROT XPA protein P23025 UNIPROT up-regulates phosphorylation Ser196 RSLEVWGsQEALEEA 9606 16540648 t miannu "Atr was the major kinase responsible for the cellular phosphorylation of xpa following uv irradiation / we propose that the phosphorylation of xpa by atr checkpoint may positively regulate ner activity and thus may facilitate the cells to recover from ner-related dna damages." SIGNOR-145190 PRKDC protein P78527 UNIPROT PDX1 protein P52945 UNIPROT "down-regulates quantity by destabilization" phosphorylation Thr11 EEQYYAAtQLYKDPC 10090 16166097 t miannu "The interaction of PDX-1 with Ku subunits and its phosphorylation on threonine 11 by the DNA-PK appear to be implicated in its degradation by the proteosome." SIGNOR-225542 FUS protein P35637 UNIPROT DLG4 protein P78352 UNIPROT "up-regulates quantity" "post transcriptional regulation" 10090 BTO:0000142 32118033 t lperfetto "These results point toward a novel mechanism by which FUS targets neuronal mRNA and given that these PSD-95 and Shank1 3'-UTR G quadruplex structures are also targeted by the fragile X mental retardation protein (FMRP), they raise the possibility that FUS and FMRP might work together to regulate the translation of these neuronal mRNA targets.|As seen in Figure 7 (top panel), both PSD-95 Q1-Q2 and Shank1a GQ probes pulled down endogenous FUS, whereas their M2 mutants did not, indicating that the GQ structure is sufficient for recognition." SIGNOR-262103 Nalorphine chemical CHEBI:7458 ChEBI OPRK1 protein P41145 UNIPROT "up-regulates activity" "chemical activation" 10029 BTO:0000246 9686407 t miannu "Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors." SIGNOR-258814 PRKCH protein P24723 UNIPROT PRKD2 protein Q9BZL6 UNIPROT up-regulates phosphorylation Ser706 ARIIGEKsFRRSVVG 9606 12058027 t gcesareni "Thus, pkd2 is likely to be a novel downstream target of specific pkcs upon the stimulation of ags-b cells with gastrin. Our data suggest a two-step mechanism of activation of pkd2 via endogenously produced diacylglycerol and the activation of pkcs." SIGNOR-89423 MAPK3 protein P27361 UNIPROT RPS6K proteinfamily SIGNOR-PF26 SIGNOR "up-regulates activity" phosphorylation 9606 BTO:0000007 12832467 t lperfetto "Phosphorylation of p90 ribosomal S6 kinase (RSK) regulates extracellular signal-regulated kinase docking and RSK activity.Erk-activates the rsk family of serine/threonine kinases,rsk1, rsk2, and rsk3." SIGNOR-252760 BMPR1A protein P36894 UNIPROT SMAD1 protein Q15797 UNIPROT "up-regulates activity" phosphorylation 9606 19620713 t lperfetto "Two types of bmp-induced signaling pathways are known, the smad and p38 mapk pathways. In the former case, bmpr1 phosphorylates smad-1,-5,-8, which forms a complex with smad4 that translocates into the nucleus and regulates gene expression." SIGNOR-255263 KAT2B protein Q92831 UNIPROT H3-3A protein P84243 UNIPROT "down-regulates activity" acetylation Lys15 ARKSTGGkAPRKQLA 9606 SIGNOR-C465 34811519 t "Acetlyation of H3 causes transcriptional activation, thus has an inhibitory role on H3" lperfetto "The HAT module within the SAGA and ADA complexes acetylates histone H3, mainly on residues K9 and K14." SIGNOR-269620 BMPR1A protein P36894 UNIPROT SMAD8/SMAD4 complex SIGNOR-C206 SIGNOR "up-regulates activity" phosphorylation 10090 19620713 t ggiuliani "The expression of CA-BMPr1A and CA-BMPr1B mRNA was confirmed by RT-PCR using appropriate primers to distinguish expression of the constitutively active receptors from endogenous BMP receptors; specific antibodies for these receptors were not available. However, the functional effects of their expression, i.e., phosphorylation of Smad1/5/8 and p38 MAPK, verify overexpression of the constitutively active receptors (Fig. 3B). Thus, their overexpression provoked a substantial rise in the phosphorylation of Smad1/5/8 and p38 MAPK, known downstream phosphorylated intermediates in the BMP signaling pathway (Fig. 3B) (16, 17)." SIGNOR-255786 propranolol chemical CHEBI:8499 ChEBI HTR1A protein P08908 UNIPROT "down-regulates activity" "chemical inhibition" 10029 BTO:0000246 9205951 t miannu "The actions of several serotonergic ligands in use or under development for the treatment of migraine headaches were examined at recombinant human 5-HT1A receptors stably expressed in Chinese Hamster Ovary cells. Of the prophylactic antimigraine drugs tested, methysergide and lisuride behaved as efficacious agonists (Emax > or = 90% relative to 5-HT) whereas pitozifen and (-)propranolol acted as a partial agonist (60%) and an antagonist, respectively." SIGNOR-258614 SOS1 protein Q07889 UNIPROT HRAS protein P01112 UNIPROT "up-regulates activity" "guanine nucleotide exchange factor" 9606 23132018 t lperfetto "The enhancement of H-Ras GTP levels induced by oncogenic K-Ras was abrogated when the expression of endogenous Sos was suppressed, implicating Sos as an essential intermediate in the cross talk between oncogenic K-Ras and WT H-Ras." SIGNOR-39237 AKT proteinfamily SIGNOR-PF24 SIGNOR MAP3K11 protein Q16584 UNIPROT down-regulates phosphorylation Ser674 PGRERGEsPTTPPTP 9606 BTO:0000938 12458207 t lperfetto "Negative regulation of mixed lineage kinase 3 by protein kinase b/akt leads to cell survivalthe expression of activated akt1 inhibits mlk3-mediated cell death in a manner dependent on serine 674 phosphorylation." SIGNOR-96062 DROSHA protein Q9NRR4 UNIPROT "Microprocessor complex" complex SIGNOR-C356 SIGNOR "form complex" binding 9606 BTO:0000552 24581491 t lperfetto "Microprocessor minimally comprises the ribonuclease DROSHA and its double-stranded RNA-binding partner DGCR8 (Denli et al., 2004; Gregory et al., 2004). Microprocessor recognizes pri-miRNA through the stem-loop (Zeng et al., 2005) and the stem-loop-ssRNA junction (Han et al., 2006), and cleaves both the 5′ and 3′ flanking segments to generate pre-miRNA." SIGNOR-264848 Ub:E2 complex SIGNOR-C497 SIGNOR ZNF521 protein Q96K83 UNIPROT "up-regulates activity" ubiquitination 9606 34199813 t miannu "The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t" SIGNOR-271103 JAK2 protein O60674 UNIPROT SLC6A8 protein P48029 UNIPROT "down-regulates activity" relocalization 443947 BTO:0000964 22407360 t miannu "Janus-activated kinase-2 (JAK2) participates in the regulation of the Na⁺-coupled glucose transporter SGLT1 and the Na⁺-coupled amino acid transporter SLC6A19. JAK2 is a novel regulator of the creatine transporter SLC6A8, which downregulates the carrier, presumably by interference with carrier protein insertion into the cell membrane." SIGNOR-265781 NCBP1 protein Q09161 UNIPROT IRF8 protein Q02556 UNIPROT "up-regulates activity" binding 9606 BTO:0001413 11483597 t miannu "we found that tyrosine phosphorylated ICSBP activates CYBB and NCF2 transcription, during late myeloid differentiation, by interacting with PU.1, IRF1 and CBP." SIGNOR-222939 mTORC1 complex SIGNOR-C3 SIGNOR EIF4EBP1 protein Q13541 UNIPROT "down-regulates activity" phosphorylation Thr45 PGGTLFStTPGGTRI 9606 9465032 t lperfetto "Mtorc1 promotes protein synthesis by phosphorylating the eukaryotic initiation factor 4e (eif4e)- binding protein 1 (4e-bp1) and the p70 ribosomal s6 kinase 1 (s6k1). Raft1 phosphorylation of 4e-bp1 on thr-36 and thr-45 blocks its association with the cap-binding protein, eif-4e,in vitro. in response to insulin and nutrients, mtorc1, consisting of mtor, raptor (regulatory-associated protein of mtor), and mlst8, is activated and phosphorylates eukaryotic initiation factor 4e-binding protein (4ebp) and p70 s6 kinase to promote protein synthesis and cell size." SIGNOR-217090 ASNS protein P08243 UNIPROT L-aspartate(1-) smallmolecule CHEBI:29991 ChEBI "down-regulates quantity" "chemical modification" 9606 29084849 t miannu "Asparagine synthetase (ASNS) converts aspartate and glutamine to asparagine and glutamate in an ATP-dependent reaction. ASNS is present in most, if not all, mammalian organs, but varies widely in basal expression. Human ASNS activity is highly responsive to cellular stress, primarily by increased transcription from a single gene located on chromosome 7." SIGNOR-267531 NR2F2 protein P24468 UNIPROT NR3C1 protein P04150 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 14739255 f gcesareni "Gralpha, but not grbeta, enhanced coup-tfii-induced transactivation of the simple coup-tfii-responsive 7alpha-hydroxylase promoter through the transcriptional activity of its activation function-1 domain, whereas coup-tfii repressed gralpha-induced transactivation of the glucocorticoid-responsive promoter by attracting the silencing mediator for retinoid and thyroid hormone receptors." SIGNOR-121419 RXRB protein P28702 UNIPROT THR proteinfamily SIGNOR-PF84 SIGNOR up-regulates binding 9606 10976919 t "inferred from 70% of family members" gcesareni "Like many receptors belonging to the superfamily of steroid/thyroid nuclear receptors, thyroid hormone receptors (trs) bind to specific th-dna responsive elements (tre) upstream of target gene in heterodimeric complex with the 9-cis retinoid acid receptor (rxr" SIGNOR-269880 DLL3 protein Q9NYJ7 UNIPROT PP2B proteinfamily SIGNOR-PF18 SIGNOR "up-regulates activity" binding 9606 BTO:0000776 16140393 t lperfetto "Notch signaling is a highly conserved pathway involved in cell fate choice during development with Delta and Jagged constituting the two evolutionary conserved families of Notch ligands. These ligands are transmembrane proteins with conserved biochemical structure that share their receptors and signal through a common mechanism. Upon ligand binding Notch receptors are proteoliticaly cleaved, the intracellular domain of Notch (NICD) is released and translocated to the nucleus, where it activates target genes. In mammals, four receptors and five ligands have been described. Delta-1, Delta-3 and Delta-4 are homologues to Drosophila Delta and Jagged-1 and Jagged-2 to Drosophila Serrate." SIGNOR-209747 MAPK3 protein P27361 UNIPROT RPS6K proteinfamily SIGNOR-PF26 SIGNOR "up-regulates activity" phosphorylation Ser380 HQLFRGFsFVATGLM 9534 BTO:0001538 9430688 t lperfetto "Several lines of evidence indicate that the mapkap-k1 isoforms are also activated by mapks in vivo via the ras-dependent protein kinase cascade that is triggered by growth factors or tumor-promoting phorbol esters, such as phorbol 12-myristate 13-acetate (pma). here we identify six sites in mapkap-k1a that become phosphorylated in transfected cos-1 cells. The inactive form of mapkap-k1a in unstimulated cells is partially phosphorylated at ser222 and ser733. Stimulation with phorbol 12-myristate 13-acetate induces the phosphorylation of thr360, ser364, thr574, and ser381 and increases the phosphorylation of ser222 and ser733." SIGNOR-252756 ADORA2B protein P29275 UNIPROT GNA14 protein O95837 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257414 CDK1 protein P06493 UNIPROT CDC25C protein P30307 UNIPROT up-regulates phosphorylation Thr48 VCPDVPRtPVGKFLG 9606 SIGNOR-C17 10864927 t gcesareni "Activation of human cdc25c at the g2/m transition occurs concomitantly with phosphorylation of five serine/threonine-proline sites: thr48, thr67, ser122, thr130, and ser214, presumably by cdc2-cyclin b." SIGNOR-78428 SOS1 protein Q07889 UNIPROT HRAS protein P01112 UNIPROT "up-regulates activity" "guanine nucleotide exchange factor" 9606 23132018 t lperfetto "The enhancement of H-Ras GTP levels induced by oncogenic K-Ras was abrogated when the expression of endogenous Sos was suppressed, implicating Sos as an essential intermediate in the cross talk between oncogenic K-Ras and WT H-Ras." SIGNOR-59472 CHAF1B protein Q13112 UNIPROT MGMT protein P16455 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0000567 15657354 f miannu "Chromatin immunoprecipitation analysis of methyl-CpG binding domain containing proteins detected a greater amount of MeCP2, MBD1, and CAF-1 bound to the MGMT promoter in MGMT-silenced cells. Our findings implicate specific MBD proteins in methylation-mediated transcriptional silencing of MGMT." SIGNOR-254570 BMP7 protein P18075 UNIPROT PRDM16 protein Q9HAZ2 UNIPROT up-regulates "transcriptional regulation" 9606 18719589 f fspada "Bmp7 activates a full program of€š brown€š adipogenesis€š including induction of early regulators of€š brown€š fat fate prdm16 (pr-domain-containing 16; ref. 4) and pgc-1alpha (peroxisome proliferator-activated receptor-gamma (ppargamma) coactivator-1alpha; ref. 5), increased expression of the€š brown-fat-defining marker uncoupling protein 1 (ucp1) and adipogenic transcription factors ppargamma and ccaat/enhancer-binding proteins (c/ebps), and induction of mitochondrial biogenesis via p38 mitogen-activated protein (map) kinase-(also known as mapk14) and pgc-1-dependent pathways" SIGNOR-210053 LRRC4 protein Q9HBW1 UNIPROT DLG4 protein P78352 UNIPROT "up-regulates activity" binding 9606 BTO:0000938 19467332 t miannu "A possible function for the NGL–PSD-95 interaction is to couple trans-synaptic adhesion events to the recruitment of PSD-95 and other PSD-95-associated postsynaptic proteins. PSD-95 and liprin-α may be key synaptic scaffolding proteins that couple trans-synaptic adhesions to the assembly of synaptic proteins/vesicles" SIGNOR-264051 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR MASTL protein Q96GX5 UNIPROT "up-regulates activity" phosphorylation Thr207 PRQDYSRtPGQVLSL 8355 22354989 t gcesareni "We propose a model in which the initiating event for Gwl activation is phosphorylation by MPF of the proline-directed sites T193 and T206 in the presumptive activation loop" SIGNOR-249652 RUNX2 protein Q13950 UNIPROT VEGFA protein P15692 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0001610 22641097 f miannu "Effective silencing of Runx2 by short interfering RNA (siRNA) demonstrated downregulation of EMT-related molecules (SNAI2, SNAI3 and TWIST1), MMP2 and vasculogenic factors (VEGFA and VEGFC) in thyroid carcinoma cells." SIGNOR-255084 AKT1 protein P31749 UNIPROT CHUK protein O15111 UNIPROT up-regulates phosphorylation Thr23 EMRERLGtGGFGNVC 9606 SIGNOR-C14 19609947 t gcesareni "Although there are likely to be multiple levels of crosstalk between the pi3k-akt and nf-kb pathways, one mechanism has been attributed to direct phosphorylation of the amino acid residue t23 on ikb kinase alfa (ikkalfa) by akt, thereby leading to activation of this kinase upstream of nf-kb akt mediates ikkalpha phosphorylation at threonine 23 akt transiently associates in vivo with ikk and induces ikk activation. Akt mediates ikkalfa phosphorylation at threonine 23.Akt phosphorylates ikkalpha on t23, and this phosphorylation event is a prerequisite for the phosphorylation of p65 at s534 by ikkalpha and beta" SIGNOR-187006 MEF2C protein Q06413 UNIPROT MYF6 protein P23409 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 BTO:0000165;BTO:0000222 7739551 t lperfetto "Myogenin and MEF2 function synergistically to activate the MRF4 promoter during myogenesis." SIGNOR-238652 OPTN protein Q96CV9 UNIPROT BDNF protein P23560 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 22194658 f "same result in PC12 cell" miannu "SiRNA effectively downregulated optineurin expression in RGC-5 and PC12 stable transfected cells. Optineurin siRNA significantly inhibited cell growth and increased apoptosis in RGC-5 and PC12 cells. Microarray analysis identified 112 differentially expressed genes in optineurin siRNA transfected RGC-5 cells. Quantitative real-time PCR and western blot confirmed that the expression of brain-derived neurotrophic factor (Bdnf), neurotrophin-3(Ntf3), synaptosomal-associated protein 25(Snap25), and neurofilament, light polypeptide(Nefl) was significantly downregulated in RGC-5 and PC12 cells transfected with optineurin siRNA." SIGNOR-259878 chlorpromazine chemical CHEBI:3647 ChEBI HTR1A protein P08908 UNIPROT "down-regulates activity" "chemical inhibition" 10029 BTO:0000246 9760039 t miannu "Marked differences were observed between the actions of ‘antagonists’ (Table 2; Fig. 2D ). methiothepin and butaclamol, as well asspiperone, exhibited negative efficacy by concentration-dependently inhibiting S GTPgS binding below basal levels, indicating that they act as inverse agonists in this system.WAY 100,135, yUH 301 and the 5-HTreceptor1A and b-adrenergic receptor antagonist ,ytertatolol, acted as ‘neutral’ antagonists, exhibiting antagonist activity without any detectable agonist or inverse agonist effects." SIGNOR-258836 P2RY14 protein Q15391 UNIPROT GNA14 protein O95837 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257210 PTPRG protein P23470 UNIPROT ZAP70 protein P43403 UNIPROT "up-regulates activity" dephosphorylation Tyr315 MPMDTSVyESPYSDP -1 25624455 t miannu "PTPRG activation by the P1-WD peptide affected the tyrosine phosphorylation of several signaling molecules. Data analysis identified 31 molecules whose phosphorylation was modified in a statistically significant manner (Table I). inhibition of ABL1, BMX, BTK, DAB1, ITGB1, JAK2, KDR, KIT, LIMK1, MET, PDGFRB, SHC1, and VCL correlates with tyrosine dephosphorylation. In contrast, SRC inhibition correlates with hyperphosphorylation of the inhibitory Tyr530 residue and with dephosphorylation of the activatory Tyr419. Moreover, CDK2 and CTTN inhibition correlates with a hyperphosphorylation of the inhibitory Tyr15 and Tyr470, respectively. In contrast, a subgroup of 13 proteins, including BLNK, DOK2, ERBB2, GRIN2B, INSR, PDGFRA, PRKCD, PXN, STAT1, STAT2, STAT3, STAT5A, and ZAP70, appears to be activated by PTPRG activity." SIGNOR-254733 TAOK2 protein Q9UL54 UNIPROT ELK1 protein P19419 UNIPROT "up-regulates activity" phosphorylation Ser383 IHFWSTLsPIAPRSP 9606 BTO:0000007 12665513 t lperfetto "Transfection studies demonstrated that TAO2 stimulates phosphorylation of the TCF Elk1 on the major activating site, Ser383, and that TAO2 stimulates transactivation of Elk1 and the related TCF, Sap1." SIGNOR-246638 SRC protein P12931 UNIPROT YAP1 protein P46937-3 UNIPROT "up-regulates activity" phosphorylation Tyr341 PFLNSGTyHSRDEST 11090 BTO:0000667 27013234 t done miannu "We found that YAP1, the pivotal effector of the Hippo signaling pathway, is a direct SRC phosphorylation target, and YAP1 phosphorylation at three sites in its transcription activation domain is necessary for SRC-YAP1-mediated transformation. " SIGNOR-274024 TLN1 protein Q9Y490 UNIPROT "A1/b1 integrin" complex SIGNOR-C159 SIGNOR "up-regulates activity" binding 10090 BTO:0000132 19118207 t miannu "Over the past 10 years, the binding of talin to the cytoplasmic tail of integrin-β subunits has been established to have a key role in integrin activation. Binding of the phosphotyrosinebinding (PTB)-domain-like subdomain of the protein 4.1, ezrin, radixin, moesin (FERM) domain of talin to the conserved WxxxNP(I/L)Y motif of the β-integrin tail permits additional weaker interactions between talin and the membrane-proximal region of the tail that trigger integrin activation, probably through the disruption of inhibitory interactions between α- and β-subunit cytoplasmic tails." SIGNOR-257608 TERT protein O14746 UNIPROT Immortality phenotype SIGNOR-PH47 SIGNOR up-regulates 11327115 f lperfetto "Telomerase is tightly repressed in the vast majority of normal human somatic cells but becomes activated during cellular immortalization and in cancers" SIGNOR-252292 "vitamin K epoxide" smallmolecule CHEBI:28371 ChEBI VKORC1L1 protein Q8N0U8 UNIPROT "up-regulates activity" "chemical activation" 9606 31226734 t lperfetto "This series of oxidation-reduction reactions begins with conversion of vitamin K from a stable oxidized form (quinone form) to a hydroquinone form by vitamin K epoxide reductase (VKOR)" SIGNOR-265916 FZR1 protein Q9UM11 UNIPROT CDC25A protein P30304 UNIPROT "down-regulates quantity by destabilization" ubiquitination 9606 BTO:0000567 12234927 t miannu "We found that Cdc25 A degradation during mitotic exit and in early G(1) is mediated by the anaphase-promoting complex or cyclosome (APC/C)(Cdh1) ligase, and that a KEN-box motif in the N-terminus of the protein is required for its targeted degradation." SIGNOR-271388 PGK2 protein P07205 UNIPROT 3-phosphonato-D-glycerate(3-) smallmolecule CHEBI:58272 ChEBI "up-regulates quantity" "chemical modification" 9606 16051738 t miannu "Phosphoglycerate kinase generates one molecule of ATP by catalyzing the reversible conversion of 1,3-bisphosphoglycerate to 3-phosphoglycerate. Two isozymes of PGK exist: PGK-1, ubiquitously expressed in all somatic cells, and PGK-2, expressed only in spermatozoa." SIGNOR-266506 "VAPB-PTPIP51 complex" complex SIGNOR-C275 SIGNOR Excitatory_synaptic_transmission phenotype SIGNOR-PH133 SIGNOR up-regulates 10116 BTO:0000142 30841933 f lperfetto "Here, we demonstrate that the VAPB-PTPIP51 tethers regulate synaptic activity. VAPB and PTPIP51 localise and form contacts at synapses, and stimulating neuronal activity increases ER-mitochondria contacts and the VAPB-PTPIP51 interaction." SIGNOR-262120 PRKAA1 protein Q13131 UNIPROT PRKAA1 protein Q13131 UNIPROT "down-regulates activity" phosphorylation Ser486 DDEITEAKsGTATPQRS -1 17023420 t "We show that AMPK α-Ser485/491 can be a site for autophosphorylation, which may play a role in limiting AMPK activation in response to energy depletion or other regulators" SIGNOR-256114 E2F1 protein Q01094 UNIPROT PPARG protein P37231 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 12110166 f fspada "We show here that e2f1 induces ppar gamma transcription during clonal expansion, whereas e2f4 represses pparg amma expression during terminal adipocyte differentiation" SIGNOR-90459 NEDD4 protein P46934 UNIPROT AP1G2 protein O75843 UNIPROT "up-regulates activity" monoubiquitination 9606 BTO:0001950 18772139 t miannu "Gamma2-Adaptin is a putative member of the clathrin adaptor protein family with unknown physiological function. We previously reported that gamma2-adaptin acts as a ubiquitin receptor by virtue of its ubiquitin-interacting motif. Here we demonstrate that this motif mediates a specific physical interaction with the ubiquitin ligase Nedd4 and promotes ubiquitination of gamma2-adaptin. These antibodies clearly recognized the 96 kDa form, thus demonstrating that a fraction of γ2-adaptin is modified by monoubiquitination (Fig. 1C). Thus, binding of γ2-adaptin to Nedd4 is not necessary for its membrane association.Accordingly, one possible function of γ2-adaptin may be to act as an adaptor for Nedd4, recruiting it to membrane compartments for subsequent ubiquitination." SIGNOR-272634 UNC80 protein Q8N2C7 UNIPROT SRC protein P12931 UNIPROT "up-regulates activity" binding 9606 BTO:0000007 19535918 t miannu "UNC80 is a protein that is associated with the NALCN Na(+) leak cation channel, and is required for the activation of this channel by the neuropeptide substance P through GPCRs in a G-protein-independent fashion. Here, we show that UNC80 binds Src kinases and recruits Src into the channel complex. " SIGNOR-265179 GCC2 protein Q8IWJ2 UNIPROT IGF2R protein P11717 UNIPROT "up-regulates activity" relocalization 18195106 t lperfetto "Rab9-dependent transport from late endosomes to the Golgi requires the Rab9 effectors p40 (Diaz et al., 1997) and TIP47 (Diaz and Pfeffer, 1998), a protein that recognizes the cytoplasmic domains of the two types of MPRs and packages them into nascent transport vesicles (Carroll et al., 2001). MPR recycling also utilizes a TGN-localized coiled-coil protein named GCC185 that is also a Rab9 effector" SIGNOR-253085 PTPRG protein P23470 UNIPROT PXN protein P49023 UNIPROT "up-regulates activity" dephosphorylation -1 25624455 t miannu "a subgroup of 13 proteins, including BLNK, DOK2, ERBB2, GRIN2B, INSR, PDGFRA, PRKCD, PXN, STAT1, STAT2, STAT3, STAT5A, and ZAP70, appears to be activated by PTPRG activity." SIGNOR-254722 NEK7 protein Q8TDX7 UNIPROT KIF14 protein Q15058 UNIPROT "up-regulates activity" phosphorylation Ser1220 NLHSSHSsGLMDKSS 9606 BTO:0000565 28630147 t miannu "Nek7 direct phosphorylation is required for the anaphase localization of Kif14. we generated an EGFP-Kif14-5A construct in which Ser56, Ser607, Ser1217, Ser1219, and Ser1220 were all mutated to Ala. When transfected into HeLa cells, EGFP-Kif14-5A was expressed to similar levels as WT Kif14 (Fig. S3 C), but its localization to the central spindle in anaphase cells was completely abolished (Fig. 6 C)." SIGNOR-266418 NR0B2 protein Q15466 UNIPROT AR protein P10275 UNIPROT down-regulates binding 9606 11735420 t gcesareni "We demonstrated that shp inhibited both ar-lbd and ntd-dependent transactivation, which evidenced for the first time a protein capable of inhibiting a steroid receptor amino-terminal-dependent transactivation. We further characterized the shp mechanism of action by showing that shp reversed ar coactivator-mediated activation" SIGNOR-112589 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR PPARG protein P37231 UNIPROT "up-regulates activity" phosphorylation Ser112 AIKVEPAsPPYYSEK 9606 11733495 t gcesareni "Moreover, the inhibition of erks 1 and 2 with a mek inhibitor, u1026, lead to an inhibition in the decay of ppargamma proteins, indicating that serine phosphorylation influences the degradation of ppargamma in fat cells." SIGNOR-232236 belinostat chemical CHEBI:61076 ChEBI HDAC9 protein Q9UKV0 UNIPROT "down-regulates activity" "chemical inhibition" -1 17868033 t Luana "Our findings suggest that hydroxamic acid-derived compounds such as TSA, NVP-LAQ824, panobinostat, ITF2357, vorinostat and belinostat act as potent pan-HDAC isoform inhibitors. A notable observation was the similarity between belinostat and vorinostat in the biochemical isoform assays; both compounds exhibit similar EC50 values in all but the HDAC8 assay." SIGNOR-257748 FZD5 protein Q13467 UNIPROT CEBPA protein P49715 UNIPROT down-regulates 9606 10937998 f fspada "Wnt signaling maintains preadipocytes in an undifferentiated state through inhibition of the adipogenic transcription factors ccaat/enhancer binding protein alpha (c/ebpalpha) and peroxisome proliferator- activated receptor gamma (ppargamma)" SIGNOR-80607 STK3 protein Q13188 UNIPROT ABL1 protein P00519 UNIPROT down-regulates phosphorylation Thr735 DTEWRSVtLPRDLQS 9606 18794806 t lperfetto "Here, we identify clk1, clk4, mst1, mst2 and ttk (also known as mps1) as novel thr735 kinases in vitro / phosphorylation of thr735 in c-abl is critical for binding to 14-3-3" SIGNOR-181056 KDM6A protein O15550 UNIPROT "Histone H3" proteinfamily SIGNOR-PF69 SIGNOR "down-regulates activity" demethylation 9606 24561908 t "This tri-methylation is associated with the downregulation of nearby genes via the formation of heterochromatic regions." miannu "Ubiquitously Transcribed Tetratricopeptide Repeat on chromosome X (UTX) and Jumonji D3 (JMJD3) as novel histone demethylases that catalyze the removal of di- and trimethyl groups on histone H3 lysine 27, thereby promoting target gene activation." SIGNOR-265360 MAPK3 protein P27361 UNIPROT HNRNPK protein P61978 UNIPROT "down-regulates activity" phosphorylation Ser284 RRDYDDMsPRRGPPP 9606 11231586 t lperfetto "Erk phosphorylation drives cytoplasmic accumulation of hnrnp-k and inhibition of mrna translation mitogen-activated protein kinase/extracellular-signal-regulated kinase (mapk/erk) efficiently phosphorylates hnrnp-k both in vitro and in vivo at serines 284 and 353." SIGNOR-105238 RB1 protein P06400 UNIPROT Cell_cycle_block phenotype SIGNOR-PH10 SIGNOR up-regulates 9606 21524151 f lperfetto "Consistent with this, the magnitude of the response (i.e. the fraction of cells undergoing arrest) appears to diminish the closer the cells are to the time of S-phase entry. The existence of a time gap between full pRb phosphorylation and S-phase entry is also consistent with the notion that E2F, once released from pRb, transcriptionally activates factors needed for S-phase entry, a process which likely requires a significant amount of time." SIGNOR-245486 SP1 protein P08047 UNIPROT ATP2C1 protein P98194 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000667 15955096 f miannu "when Sp1 or YY1 was overexpressed in keratinocytes, an obvious increase in ATP2C1 promoter activity was observed, which was in contrast with the case where a mutant promoter lacking the binding sites for Sp1 and YY1 was used as the reporter." SIGNOR-255194 PRKCA protein P17252 UNIPROT CORO1B protein Q9BR76 UNIPROT down-regulates phosphorylation Ser2 sFRKVVRQ 9606 16027158 t lperfetto "We have identified serine 2 (ser-2) on coronin 1b as the major residue phosphorylated by pkc in vivo.In this work, we show that coronin 1b interacts in vivo with the arp2/3 complex and that this interaction is inhibited by pkc phosphorylation." SIGNOR-138733 MAPK1 protein P28482 UNIPROT NCF1 protein P14598 UNIPROT up-regulates phosphorylation Ser345 QARPGPQsPGSPLEE 9606 BTO:0000130 16778989 t gcesareni "Erk1/2 are the kinases involved in p47phox_ phosphorylation on ser345 in gm-csfprimed human neutrophils._ Phosphorylation of ser345 is required for the priming of nadph oxidase activity in neutrophil-like cells" SIGNOR-147170 CREB5 protein Q02930 UNIPROT LY96 protein Q9Y6Y9 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0002813 21132541 f miannu "Our result verified CREB5 biological regulation module in the upstream of frontal cortex of HIVE-control patients (MAPKAPK3 activation; DGKG, LY96, TNFRSF11B inhibition) and downstream (ATP6V0E1, CFB, DGKG, MX1, TGFBR3 activation; LGALS3BP, RASGRP3, RDX, STAT1 inhibition)," SIGNOR-253806 AURKB protein Q96GD4 UNIPROT NDC80 protein O14777 UNIPROT down-regulates phosphorylation Ser15 SGGAGRLsMQELRSQ 9606 20471944 t lperfetto "To determine whether the combinatorial regulation of the kmn network by aurora b observed in vitro is critical to controlling kinetochore-microtubule attachments in vivo, we next investigated the effect of the phosphomimetic (to aspartate) and nonphosphorylatable (to alanine) mutants of dsn1, knl1, and ndc80 in vertebrate cells. We predicted that both types of mutations in critical phosphorylation sites would affect chromosome segregation, since preventing the inactivation of inappropriately attached kinetochores by aurora b (in the nonphosphorylatable mutant) or constitutively inactivating this attachment (in the phosphomimetic mutant)." SIGNOR-165554 PCDHA10 protein Q9Y5I2 UNIPROT PCDHGA6 protein Q9Y5G7 UNIPROT "up-regulates activity" binding 9606 BTO:0000227 16697637 t miannu "The clustered protocadherins comprise the largest subfamily of the cadherin superfamily and are predominantly expressed in the nervous system. Pcdh-alpha proteins interact with beta1-integrin to promote cell adhesion. They also form oligomers with Pcdh-gamma proteins at the same membrane sites." SIGNOR-265716 NPTX1 protein Q15818 UNIPROT AMPA proteinfamily SIGNOR-PF58 SIGNOR "up-regulates activity" binding 10090 BTO:0000938 15115814 t "inferred from family member" lperfetto "We found that NP1 colocalizes and physically associates with the fast excitatory GluR1 AMPA receptors and that hypoxia induces a time-dependent increase in the NP1-GluR1 interactions. Thus hypoxia recruits NP1 protein to GluR1 subunits concurrent with the hypoxic excitotoxic cascade.|Rather we propose that through interactions with GluR1 clusters, NP1 modulates the function of AMPA receptors in a manner whereby increased NP1-GluR1 interactions sensitize neurons to hypoxia-induced excitotoxic death." SIGNOR-270235 GALR3 protein O60755 UNIPROT GNA14 protein O95837 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257206 GSK3B protein P49841 UNIPROT EIF2B5 protein Q13144 UNIPROT down-regulates binding 9606 21798082 t gcesareni "Akt also promotes protein synthesis by phosphorylating and inactivating gsk3b, thus releasing the gsk3b-dependent inhibition of the eukariotic translation initiation factor 2b (eif2b)." SIGNOR-175621 IKZF3 protein Q9UKT9 UNIPROT LNPEP protein Q9UIQ6 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0003420 15894523 f miannu "Activator protein-2 (AP-2) and Ikaros transcription factors play significant roles in exerting high promoter activity of P-LAP/OTase in the trophoblastic cells. Moreover, P-LAP/OTase is transcriptionally regulated in a trophoblast-differentiation-dependent fashion via up-regulation of AP-2, putatively AP-2alpha." SIGNOR-255405 3-[2,4-diamino-7-(3-hydroxyphenyl)-6-pteridinyl]phenol chemical CHEBI:94691 ChEBI PIK3CG protein P48736 UNIPROT "down-regulates activity" "chemical inhibition" -1 22037378 t Luana "Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here." SIGNOR-258300 PFDN5 protein Q99471 UNIPROT "Prefoldin co-chaperone" complex SIGNOR-C513 SIGNOR "form complex" binding 9606 32699605 t miannu "The correct folding is a key process for a protein to acquire its functional structure and conformation. Prefoldin is a well-known chaperone protein that regulates the correct folding of proteins.  Canonical prefoldin complex is a heterohexameric complex composed of two α subunits (PFDN3 and PFDN5) and four β subunits (PFDN1, PFDN2, PFDN4 and PFDN6)" SIGNOR-270934 CDK2 protein P24941 UNIPROT CDKN1B protein P46527 UNIPROT down-regulates phosphorylation Thr187 NAGSVEQtPKKPGLR 9606 17409098 t gcesareni "Ubiquitination and subsequent degradation play a critical role in regulating the levels of p27 during cell cycle progression. Here we provide evidence suggesting that both cdk2/e and phosphorylation of thr(187) on p27 are essential for the recognition of p27 by the scf(skp2/cks1) complex, the ubiquitin-protein isopeptide ligase (e3)." SIGNOR-154188 KRAS protein P01116 UNIPROT CARM1 protein Q86X55 UNIPROT "down-regulates activity" 9606 BTO:0000304 27840030 f lperfetto "Interestingly, overexpression of KRASG12V (an activating mutant) in BxPC-3 cells, a PDAC cell line carrying wild-type KRAS, led to a 40% decrease of CARM1 protein and consequent hypomethylation or activation of MDH1|These observations indicate that KRAS suppresses CARM1-mediated MDH1 methylation, contributing to Gln metabolism in pancreatic cancer." SIGNOR-267640 "Multiaminoacyl-tRNA synthetase" complex SIGNOR-C472 SIGNOR AMP smallmolecule CHEBI:456215 ChEBI "up-regulates quantity" "chemical modification" 9606 28271488 t miannu "Aminoacyl-tRNA synthetases (AARSs) are essential enzymes that specifically aminoacylate one tRNA molecule by the cognate amino acid. In mammals, nine synthetases, those specific for amino acids Arg, Asp, Gln, Glu, Ile, Leu, Lys, Met and Pro, associate into a multi-aminoacyl-tRNA synthetase complex, an association which is believed to play a key role in the cellular organization of translation, but also in the regulation of the translational and nontranslational functions of these enzymes." SIGNOR-270416 SRC protein P12931 UNIPROT GRK2 protein P25098 UNIPROT "up-regulates activity" phosphorylation Tyr13 AVLADVSyLMAMEKS 9606 BTO:0000007 16725308 t miannu "Here, we demonstrate that c-Src kinase activity increases the interaction between GRK2 and Galphaq. Tyrosine phosphorylation of GRK2 appears to be critically involved in the modulation of this interaction since the stimulatory effect of c-Src is not observed with a GRK2 mutant with impaired tyrosine phosphorylation (GRK2 Y13,86,92F), whereas a mutant that mimics GRK2 tyrosine phosphorylation in these residues displays an increased interaction with Galphaq. " SIGNOR-266307 EGLN3 protein Q9H6Z9 UNIPROT ADRB2 protein P07550 UNIPROT "up-regulates quantity by stabilization" hydroxylation Pro382 KLLCEDLpGTEDFVG 9606 BTO:0000007 19584355 t lperfetto "We further show that the interaction of pVHL with beta(2)AR is dependent on proline hydroxylation (proline-382 and -395) and that the dioxygenase EGLN3 interacts directly with the beta(2)AR to serve as an endogenous beta(2)AR prolyl hydroxylase. Under hypoxic conditions, receptor hydroxylation and subsequent ubiquitylation decrease dramatically, thus attenuating receptor degradation and down-regulation." SIGNOR-262006 miR-155 mirna URS000062749E_9606 RNAcentral JARID2 protein Q92833 UNIPROT "down-regulates quantity by repression" "post transcriptional regulation" 9606 31390932 t miannu " Mechanically, LINC01133 functioning as a ceRNA targeted miR-4784 to augment AHDC1 expression. Finally, LINCO1133/miR-4784 aggravated the malignant growth and aggressiveness and EMT of cervical cancer in an AHDC1-dependant way. In conclusion, we unveiled that LINC01133 may function as a ceRNA for miR-4784 to advance AHDC1 expression, intensifying CC cell malignant phenotypes and EMT process, which may demonstrate the implied value of LINC01133 as a therapeutic target for CC patients." SIGNOR-269188 GSK1292263 chemical CID:24996872 PUBCHEM GPR119 protein Q8TDV5 UNIPROT up-regulates "chemical activation" 9606 Other t Selleck gcesareni SIGNOR-192859 ZNF462 protein Q96JM2 UNIPROT PBX1 protein P40424 UNIPROT "down-regulates activity" binding 9534 BTO:0000298 17353115 t miannu "We demonstrated that ZFPIP is expressed in embryonic female genital tract but also in other PBX1 expression domains such as the developing head and the limb buds. We further showed that ZFPIP is able to bind physically and in vivo to PBX1 and moreover, that it prevents the binding of HOXA9/PBX complexes to their consensus DNA site. We suggest that ZFPIP is a new type of PBX1 partner that could participate in PBX1 function during several developmental pathways." SIGNOR-264477 CDK5 protein Q00535 UNIPROT SYN1 protein P17600 UNIPROT up-regulates phosphorylation Ser553 ARPPASPsPQRQAGP 9606 10880969 t lperfetto "Synapsin i (syni), a major sv phosphoprotein involved in the regulation of sv trafficking and neurotransmitter release, is one of the presynaptic substrates of cdk5, which phosphorylates it in its c-terminal region at ser(549) (site 6) and ser(551) (site 7). Phosphorylation of syni by cdk5 is physiologically regulated and enhances its binding to f-actin." SIGNOR-78887 RNF168 protein Q8IYW5 UNIPROT "Histone H2A" proteinfamily SIGNOR-PF70 SIGNOR "up-regulates quantity" ubiquitination 9606 31225475 t miannu "L3MBTL2 links RNF8 and RNF168 in the DNA double strand break response. The protein kinase ATM phosphorylates L3MBTL2, which recruits it to the DNA lesion by promoting the interaction between MDC1 and L3MBTL2. L3MBTL2 is subsequently ubiquitinated by RNF8, which acts as a docking site for RNF168, thereby recruiting the ubiquitin ligase to the damage site. RNF168, in turn, ubiquitinates H2A-type histones to amplify the DNA damage response and recruit downstream DNA repair proteins for proper DSB signaling." SIGNOR-266784 "Multiaminoacyl-tRNA synthetase" complex SIGNOR-C472 SIGNOR AMP smallmolecule CHEBI:456215 ChEBI "up-regulates quantity" "chemical modification" 9606 28271488 t miannu "Aminoacyl-tRNA synthetases (AARSs) are essential enzymes that specifically aminoacylate one tRNA molecule by the cognate amino acid. In mammals, nine synthetases, those specific for amino acids Arg, Asp, Gln, Glu, Ile, Leu, Lys, Met and Pro, associate into a multi-aminoacyl-tRNA synthetase complex, an association which is believed to play a key role in the cellular organization of translation, but also in the regulation of the translational and nontranslational functions of these enzymes." SIGNOR-270424 F2 protein P00734 UNIPROT F2R protein P25116 UNIPROT "up-regulates activity" cleavage Arg25 PLLSARTrARRPESK -1 10978167 t lperfetto "PAR1E and PAR2E (10 microM) were incubated in the presence of the different proteases | The enzymes were used at the following concentrations: 0.5 unit/mL thrombin, 2.5 nM trypsin, 20 nM plasmin, 20 nM cathepsin G, 20 nM elastase, 20 nM proteinase 3, and 2 units/mL calpain I and II|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus.|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus.|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus" SIGNOR-263568 BIRC3 protein Q13489 UNIPROT RIPK4 protein P57078 UNIPROT "up-regulates activity" polyubiquitination lys51 9606 BTO:0000007 21931591 t miannu "CIAP1/2 are direct E3 ligases conjugating diverse types of ubiquitin chains to receptor interacting proteins kinases 1 to 4 (RIP1-4).Together, our results demonstrate that depleting cIAP1/2 inhibits RIP1-4 mediated NF-kB activation without affecting RIP auto-phosphorylation.Lysine residues K51 and K145 of RIP4 are critical for cIAP1-mediated ubiquitination and NF-kB activation." SIGNOR-272707 CDON/SPAG9 complex SIGNOR-C21 SIGNOR MAPK14 protein Q16539 UNIPROT "up-regulates activity" binding 9606 BTO:0000222 17074887 t "p38 MAPK is activated by phosphorylation in response to CDO-BOC interactions. Activated p38 MAPK may translocate into the nucleus to further activate myogenic related transcription factors." gcesareni "One way this occurs is via the interaction of JLP with the Cdo cytoplasmic tail. JLP is, in turn, bound to p38α/β. This interaction facilitates p38 activation during differentiation and is important for Cdo's effects in myogenesis." SIGNOR-272542 MMP10 protein P09238 UNIPROT HAPLN1 protein P10915 UNIPROT "down-regulates quantity by destabilization" cleavage Leu40 QAENGPHlLVEAEQA -1 7694569 t miannu "Matrix metalloproteinases cleave at two distinct sites on human cartilage link protein. Sequencing studies of modified link protein components revealed that stromelysins-1 and -2, gelatinases A and B and collagenase cleaved specifically between His16 and Ile17, and matrilysin, stromelysin-2 and gelatinase A cleaved between Leu25 and Leu26. Based on previously determined in situ cleavage sites it is evident that matrix metalloproteinases are not solely responsible for the accumulation of link protein degradation products in adult human cartilage, indicating that additional proteolytic agents are involved in the normal catabolism of human cartilage matrix." SIGNOR-256332 STAT5A protein P42229 UNIPROT IGF1 protein P05019 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000972 10050749 t lperfetto "Growth hormone induces insulin-like growth factor-I gene transcription by a synergistic action of STAT5 and HNF-1α" SIGNOR-251743 MDH1 protein P40925 UNIPROT oxaloacetate(2-) smallmolecule CHEBI:16452 ChEBI "up-regulates quantity" "chemical modification" 9606 24068518 t miannu "Malate is dehydrogenated to produce oxaloacetate by the enzyme Malate Dehydrogenase. In this reaction NAD is converted to NADH2. Oxaloacetate formed in this reaction reacts with acetyl-CoA to form citrate in order to start another round of the citric acid cycle" SIGNOR-266285 PPP2R5B protein Q15173 UNIPROT AKT1 protein P31749 UNIPROT down-regulates dephosphorylation Thr308 KDGATMKtFCGTPEY 9606 16495456 t gcesareni "Activation of pp2a is the intermediate step between the abeta-ceramide cascade and the subsequent inactivation of akt." SIGNOR-252615 PRKACA protein P17612 UNIPROT GABRR1 protein P24046 UNIPROT unknown phosphorylation Ser443 PQRKSQRsSYVSMRI -1 12175859 t miannu "Here, we have identified phosphorylation sites on the human ρ1 GABA receptor for six protein kinases widely expressed in the brain: protein kinase C (PKC); cAMP‐dependent protein kinase (PKA); calmodulin‐dependent kinase (CaMKII); casein kinase (CKII); mitogen‐activated protein kinase (MAPK); and cGMP‐dependent protein kinase (PKG). These data, indicate that S422 and/or S423 are the major sites of PKA-mediated phosphorylation of the 1 GABA receptor.An extensive functional analysis comparing wild type 1 receptors and receptors with select or multiple phosphorylation sites removed as well as pharmacological manipulation of five kinase pathways failed to reveal any functional effects of phosphorylation" SIGNOR-262751 BIRC2 protein Q13490 UNIPROT RIPK4 protein P57078 UNIPROT "up-regulates activity" polyubiquitination lys145 9606 BTO:0000007 21931591 t miannu "CIAP1/2 are direct E3 ligases conjugating diverse types of ubiquitin chains to receptor interacting proteins kinases 1 to 4 (RIP1-4).Together, our results demonstrate that depleting cIAP1/2 inhibits RIP1-4 mediated NF-kB activation without affecting RIP auto-phosphorylation.Lysine residues K51 and K145 of RIP4 are critical for cIAP1-mediated ubiquitination and NF-kB activation." SIGNOR-272708 haloperidol chemical CHEBI:5613 ChEBI HTR1D protein P28221 UNIPROT "down-regulates activity" "chemical inhibition" 10116 8935801 t miannu "Risperidone and its active metabolite 9-OH-risperidone were compared to reference antipsychotic drugs (haloperidol, pipamperone, fluspirilene, clozapine, zotepine) and compounds under development (olanzapine, seroquel, sertindole, ORG-5222, ziprasidone) for in vitro binding to neurotransmitter receptors in brain tissue and on membranes of recombinant cells expressing cloned human receptors and for in vivo occupancy of neurotransmitter receptors in rat and guinea-pig brain following acute treatment (2 h., s.c.). The binding affinities of the compounds for various neurotransmitter receptors were measured using membrane preparations of animal brain regions and of recombinant cells expressing cloned, mostly human receptors. Receptors, tissues and cells are indicated in Table I; results are shown in Table 4A-B." SIGNOR-258522 HIF1A protein Q16665 UNIPROT NT5E protein P21589 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000414 12370277 f miannu "Examination of the CD73 gene promoter identified at least one binding site for hypoxia-inducible factor-1 (HIF-1) and inhibition of HIF-1alpha expression by antisense oligonucleotides resulted in significant inhibition of hypoxia-inducible CD73 expression" SIGNOR-254423 ATF2 protein P15336 UNIPROT FGF21 protein Q9NSA1 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0005787 25055037 f miannu "The increased production of reactive oxygen species, subsequent induction of p38 MAPK (mitogen-activated protein kinase) and activation of an ATF2 (activating transcription factor 2)-binding site at the proximal promoter region of the FGF21 gene was found to be a major mechanism linking mitochondrial dysfunction with enhanced FGF21 gene transcription in myogenic cells." SIGNOR-253743 BRD7 protein Q9NPI1 UNIPROT "SWI/SNF ACTL6B varian" complex SIGNOR-C476 SIGNOR "form complex" binding 9606 30397315 t miannu "Mammalian SWI/SNF (mSWI/SNF) complexes are ATP-dependent chromatin remodelers that modulate genomic architecture and DNA accessibility, enabling timely and appropriate control of gene expression. They are combinatorially assembled from the products of 29 total genes into three final-form complexes: canonical BAF, PBAF (polybromo-associated BAF complexes), and a newly-defined non-canonical BAF (ncBAF), with specific subunits specifying distinct complexes, such as PBRM1, ARID2, and BRD7 in PBAF complexes, ARID1A/ARID1B and DPF2 in canonical BAF (cBAF) complexes, and GLTSCR1/GLTSCR1L and BRD9 in ncBAF complexes" SIGNOR-270601 TGFBR2 protein P37173 UNIPROT TGFBR1 protein P36897 UNIPROT "up-regulates activity" phosphorylation Thr200 LPLLVQRtIARTIVL 452646 7774578 t lperfetto "The tgf-beta type ii receptor (t beta r-ii) is a transmembrane serine/threonine kinase that, upon ligand binding, recruits and phosphorylates a second transmembrane kinase, t beta r-i, as a requirement for signal transduction. In contrast to the relatively innocuous nature of single site mutations in the ttsgsgsg sequence, mutation of thr200 or 204 to valine causes marked losses in ligand-induced phosphorylation and signaling." SIGNOR-32744 SNARE_complex complex SIGNOR-C346 SIGNOR Synaptic_vesicle_exocytosis phenotype SIGNOR-PH160 SIGNOR up-regulates 9606 BTO:0000938 30267828 f miannu "The best-studied SNARE-complex is the one formed between three proteins, VAMP2/synaptobrevin-2, syntaxin-1, and SNAP-25, that mediate fast exocytosis in neuronal cells." SIGNOR-265065 P2RY4 protein P51582 UNIPROT GNAI1 protein P63096 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-256727 PRKCH protein P24723 UNIPROT ANXA1 protein P04083 UNIPROT up-regulates phosphorylation Ser27 EYVQTVKsSKGGPGS 9606 24103589 t lperfetto "The authors identified several phosphorylated residues by a combination of peptide mapping and sequence analysis and showed that recombinant pp60c-src phosphorylates annexin a1 near its amino terminus, at tyrosine 21 (tyr21). Also polyoma virus middle t/pp60c-src complex, recombinant pp50v-abl, and the egf receptor/kinase phosphorylated the same tyrosine residue. It was also shown that serine 27 residue of anxa1 is the primary site phosphorylated by protein kinase c (pkc). In the same study, the threonine 41 residue has been identified as a pkc substrate as well. The adenosine cyclic 3_,5_-phosphate dependent protein kinase a (pka) phosphorylates anxa1 in its carboxyl-terminal core at the threonine 216 residue (thr216) [2].The phosphorylation of serine 27 is essential for annexin a1 membrane localization." SIGNOR-202792 PRDM2 protein Q13029 UNIPROT HMOX1 protein P09601 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 8654390 f 2 miannu "We show that a portion of MTB-Zf, including an N-terminal zinc-finger domain, binds in vitro to MTE and that the transient coexpression of MTB-Zf cDNA leads to transativation of the heme-oxygenase-1 gene promoter." SIGNOR-241047 MET protein P08581 UNIPROT GAB1 protein Q13480 UNIPROT "up-regulates activity" phosphorylation Tyr659 VADERVDyVVVDQQK 9606 BTO:0000018 10734310 t miannu "Gab-1 is phosphorylated on the same residues by HGF and EGF receptors. Among 16 peptides only nine were phosphorylated by the EGF and HGF receptors, namely peptides containing the tyrosine residues 285, 307, 373, 407, 448, 473, 590, 628 and 660. we show that in the response to HGF or EGF, Gab1 is phosphorylated in vivo on the same residues. However, a sustained activation of signaling pathways downstream to Gab1 (as a result of its sustained phosphorylation) is achieved only in response to HGF." SIGNOR-250290 STK4 protein Q13043 UNIPROT STK4 protein Q13043 UNIPROT "up-regulates activity" phosphorylation Thr187 KRNTVIGtPFWMAPE 9534 BTO:0004055 12223493 t lperfetto "Mapping of MST1 kinase sites of phosphorylation. Activation and autophosphorylationWe define Thr(183) in subdomain VIII as a primary site of phosphoactivation. Thr(187) is also critical for kinase activity." SIGNOR-247581 BMPR1B protein O00238 UNIPROT SMAD1 protein Q15797 UNIPROT up-regulates 10090 10564272 f lperfetto "We found that both smad6 and smad7 inhibit the activation of smad1 and smad5 by bmpr-ia/alk-3 and bmpr-ib/alk-6, as well as that by alk-2" SIGNOR-235622 MAPK1 protein P28482 UNIPROT POLR2A protein P24928 UNIPROT down-regulates phosphorylation Ser1619 SPSYSPTsPSYSPTS 9606 14662762 t lperfetto "Erk1/2 are major ser-5 kinases after h2o2 treatment. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination." SIGNOR-120084 KIT protein P10721 UNIPROT KIT protein P10721 UNIPROT up-regulates phosphorylation Tyr936 SESTNHIySNLANCS 9606 10377264 t miannu "Identification of tyr-703 and tyr-936 as autophosphorylation sites in c-kit/scfr" SIGNOR-68647 "Cullin 3-RBX1-Skp1" complex SIGNOR-C526 SIGNOR PIK3C3 protein Q8NEB9 UNIPROT "down-regulates quantity by destabilization" polyubiquitination 9606 BTO:0000007 26687681 t miannu "Cul3-KLHL20 Ubiquitin Ligase Governs the Turnover of ULK1 and VPS34 Complexes to Control Autophagy Termination. KLHL20 promotes ubiquitination of phagophore-residing VPS34 and Beclin-1" SIGNOR-272418 STAT3 protein P40763 UNIPROT S100A9 protein P06702 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 18809714 f miannu "Accumulation of myeloid-derived suppressor cells (MDSCs) associated with inhibition of dendritic cell (DC) differentiation is one of the major immunological abnormalities in cancer and leads to suppression of antitumor immune responses. The molecular mechanism of this phenomenon remains unclear. We report here that STAT3-inducible up-regulation of the myeloid-related protein S100A9 enhances MDSC production in cancer." SIGNOR-261931 IL15RA protein Q13261 UNIPROT JAK3 protein P52333 UNIPROT up-regulates 9606 30029643 t "Since Jak-STAT pathway primarily activated in IL-15-me- diated cell proliferation, we tested whether it is also participates in IL-15-mediated proliferation of FAPs. Interestingly, we found the expression of phospho-Jak3 and phospho-Tyk2, as well as their downstream, phospho- STAT3 and phospho-STAT5, was significantly upregulated" SIGNOR-256226 Ub:E2 complex SIGNOR-C497 SIGNOR HERC1 protein Q15751 UNIPROT "up-regulates activity" ubiquitination 9606 34199813 t miannu "The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t" SIGNOR-271306 Scribble_complex_DLG4-LLGL2_variant complex SIGNOR-C505 SIGNOR Cell_polarity phenotype SIGNOR-PH213 SIGNOR up-regulates 9606 23397623 f miannu "The Scribble polarity complex or module is one of the three polarity modules that regulate cell polarity in multiple epithelia including blood-tissue barriers. This protein complex is composed of Scribble, Lethal giant larvae (Lgl) and Discs large (Dlg), which are well conserved across species from fruitflies and worms to mammals." SIGNOR-270890 PRKACA protein P17612 UNIPROT MBP protein P02686 UNIPROT unknown phosphorylation Ser190 RGAPKRGsGKDSHHP -1 2413024 t miannu "Ser-46 and Ser-151 were specifically phosphorylated by protein kinase C, whereas Thr-34 and Ser-115 were phosphorylated preferentially by protein kinase A. Both kinases reacted with Ser-8, Ser-11, Ser-55, Ser-110, Ser-132, and Ser-162" SIGNOR-250012 neratinib chemical CHEBI:61397 ChEBI EGFR protein P00533 UNIPROT "down-regulates activity" "chemical inhibition" -1 22037378 t Luana "Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here." SIGNOR-258254 CSNK2A1 protein P68400 UNIPROT HMGN1 protein P05114 UNIPROT down-regulates phosphorylation Ser89 KTEESPAsDEAGEKE 9606 10739259 t lperfetto "Protein kinases that phosphorylate hmg-14 17 at the major sites have been implicated from previous in vitro studies. Protein kinase c and a similar calcium phospholipid-dependent kinase have been reported to phosphorylate both proteins in vitro, where the phosphorylation of hmg-17 occurs predominantly at ser24 and to a lesser degree at ser28. Phosphorylation of hmg-14 at ser6 by camp- or cgmp-dependent kinases has also been reported. Thus, other kinases may contribute to phosphorylation at ser6 in response to oa. Ser88 and ser98 on hmg-14 are also phosphorylated by casein kinase ii in vitro. we conclude that the correlation we observe reflects a causal relationship, in which phosphorylation somehow facilitates the redistribution of hmg-14 and -17 toward non-nuclear pools." SIGNOR-76274 USP5 protein P45974 UNIPROT Ubiquitin proteinfamily SIGNOR-PF89 SIGNOR "up-regulates quantity" cleavage 9606 BTO:0000567 26235645 t miannu "Here we provide data suggesting that two of the four mammalian ubiquitin precursors, UBA52 and UBA80, are processed mostly post-translationally whereas the other two, UBB and UBC, probably undergo a combination of co- and post-translational processing. Using an unbiased biochemical approach we found that UCHL3, USP9X, USP7, USP5 and Otulin/Gumby/FAM105b are by far the most active DUBs acting on these precursors." SIGNOR-270830 F-actin_assembly phenotype SIGNOR-PH18 SIGNOR LATS2 protein Q9NRM7 UNIPROT down-regulates 9606 23450633 f gcesareni "Ga12/13 recruitment of rho-gefs causes rhoa activation and f-actin assembly, which promotes lats1/lat2 inactivation by an unknown, but myosin-independent mechanism." SIGNOR-192783 SRC protein P12931 UNIPROT YAP1 protein P46937-3 UNIPROT "up-regulates activity" phosphorylation Tyr357 SGLSMSSySVPRTPD 11090 27013234 t done miannu "We found that YAP1, the pivotal effector of the Hippo signaling pathway, is a direct SRC phosphorylation target, and YAP1 phosphorylation at three sites in its transcription activation domain is necessary for SRC-YAP1-mediated transformation. " SIGNOR-274025 TFIIH complex SIGNOR-C457 SIGNOR POLR2A protein P24928 UNIPROT "up-regulates activity" phosphorylation Ser1899 SPTYSPTsPVYTPTS 9606 24746699 t lperfetto "After PIC formation, Pol II initiates mRNA synthesis, but productive transcription requires Pol II to escape from the PIC and transit into transcription elongation. The transition between initiation and elongation is associated with phosphorylation at the serine 5 (Ser5) residues within the hepta-peptide repeats in the C-terminal domain (CTD) of the largest Pol II subunit. Ser5 phosphorylation is mediated primarily by Kin28, the kinase subunit of the general transcription factor TFIIH" SIGNOR-269378 NUF2 protein Q9BZD4 UNIPROT "Ndc80 complex" complex SIGNOR-C361 SIGNOR "form complex" binding 27881301 t lperfetto "Kinetochores, multisubunit protein assemblies, connect chromosomes to spindle microtubules to promote chromosome segregation. The 10-subunit KMN assembly (comprising KNL1, MIS12, and NDC80 complexes, designated KNL1C, MIS12C, and NDC80C) binds microtubules and regulates mitotic checkpoint function through NDC80C and KNL1C, respectively. |NDC80C contains the NDC80, NUF2, SPC24, and SPC25 subunits" SIGNOR-265187 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR KMT5A protein Q9NQR1 UNIPROT "up-regulates quantity by stabilization" phosphorylation Ser100 SKIYSYMsPNKCSGM 9606 20966048 t lperfetto "First, we found that pr-set7 is phosphorylated at ser 29 (s29) specifically by the cyclin-dependent kinase 1 (cdk1)/cyclinb complex, s29 phosphorylation also functions to stabilize pr-set7 by directly inhibiting its interaction with the anaphase-promoting complex (apc), an e3 ubiquitin ligase." SIGNOR-216856 ITGA6 protein P23229 UNIPROT "A6/b1 integrin" complex SIGNOR-C164 SIGNOR "form complex" binding 16988024 t lperfetto "Integrins are one of the major families of cell adhesion receptors (Humphries, 2000; Hynes, 2002). All integrins are non-covalently-linked, heterodimeric molecules containing an α and a β subunit. Both subunits are type I transmembrane proteins, containing large extracellular domains and mostly short cytoplasmic domains (Springer and Wang, 2004; Arnaout et al., 2005). Mammalian genomes contain 18 α subunit and 8 β subunit genes, and to date 24 different α,β combinations have been identified at the protein level. Although some subunits only appear in a single heterodimer, twelve integrins contain the β1 subunit, and five contain αV." SIGNOR-253179 CSK protein P41240 UNIPROT ITCH protein Q96J02 UNIPROT "down-regulates activity" phosphorylation 9606 BTO:0000007 16888620 t gcesareni "CISK strongly interacts and colocalizes with the E3 ubiquitin ligase AIP4, which is important for the ubiquitin-dependent lysosomal degradation of CXCR4. Moreover, the observed inhibition is both dependent on the interaction between CISK and AIP4 and on the activation status of CISK. Consistent with this, an activated form of CISK but not of the related kinase SGK1 phosphorylates specific sites of AIP4 in vitro." SIGNOR-245327 ARHGDIA protein P52565 UNIPROT RAC1 protein P63000 UNIPROT "down-regulates activity" "guanine nucleotide exchange factor" 10116 BTO:0000526 20696765 t miannu "Here, we report the expression of plexin-B3 in glioma cells, which upon stimulation by its ligand Sema5A results in significant inhibition of cell migration and invasion. A search for the underlying mechanism revealed direct interaction of plexin-B3 with RhoGDP dissociation inhibitor α (RhoGDIα), a negative regulator of RhoGTPases that blocks guanine nucleotide exchange and sequesters them away from the plasma membrane. direct interaction of RhoGDIα and the cytoplasmic domain of plexin-B3 (plexin-B3CD) was confirmed by GST pulldown assays.RhoGDIα is required for Sema5A-induced Rac1 inactivation and inhibition of cell invasion in C6 glioma." SIGNOR-268436 PRKCD protein Q05655 UNIPROT PRKCD protein Q05655 UNIPROT up-regulates phosphorylation Thr507 FGESRAStFCGTPDY 9606 19366211 t llicata "This study identifies novel in vitro pkcdelta autophosphorylation sites at thr(141) adjacent to the pseudosubstrate domain, thr(218) in the c1a-c1b interdomain, ser(295), ser(302), and ser(304) in the hinge region, and ser(503) adjacent to thr(505) in the activation loop. studies reported herein show that a t505a substitution reduces pkcdelta-thr(295) autophosphorylation" SIGNOR-185287 ARHGAP44 protein Q17R89 UNIPROT RAC1 protein P63000 UNIPROT "down-regulates activity" "gtpase-activating protein" 9606 BTO:0000007 32203420 t Luana "We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2)." SIGNOR-260498 MAP3K6 protein O95382 UNIPROT MAPK14 protein Q16539 UNIPROT "up-regulates activity" phosphorylation Tyr182 RHTDDEMtGYVATRW 9534 8622669 t Manara "These data indicate that MKK6 phosphorylates p38 MAP kinase on Thr-180 and Tyr-182, the sites of phosphorylation that activate p38 MAP kinase" SIGNOR-260916 CHEK2 protein O96017 UNIPROT CDC25A protein P30304 UNIPROT "down-regulates quantity" phosphorylation Ser279 VLKRPERsQEESPPG 9606 12676583 t Manara "Chk2 phosphorylates a subset of the Chk1-targeted sites of Cdc25A | Phosphorylation of serines 123, 178, 278, and 292 regulates both basal and IR-induced accelerated proteolysis of Cdc25A" SIGNOR-260834 HNF1A protein P20823 UNIPROT AKR1C4 protein P17516 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 2044952 f 2 miannu "Hepatocyte nuclear factor (HNF)-4_/_, HNF-1_, and vHNF-1 regulate the cell-specific expression of the human dihydrodiol dehydrogenase (DD)4/AKR1C4 gene. HNF-1_ binds to the target element in the rat DBP gene in the liver, while vHNF-1 recognizes a target element in extrahepatic tissues. The ability of vHNF-1-A to activate the rat DBP gene is much higher than that of vHNF-1-C." SIGNOR-239964 CDK9 protein P50750 UNIPROT HES1 protein Q14469 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 15546612 f gcesareni "Cycc:cdk8 and cyct1:cdk9/p-tefb are recruited with notch and associated coactivators (mam, skip) to the hes1 promoter in signaling cells." SIGNOR-130703 SOX6 protein P35712 UNIPROT HBG1 protein P69891 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0004911 20395365 f Regulation miannu "BCL11A and SOX6 co-occupy the human beta-globin cluster along with GATA1, and cooperate in silencing gamma-globin transcription in adult human erythroid progenitors." SIGNOR-251810 EGFR protein P00533 UNIPROT NCK1 protein P16333 UNIPROT up-regulates 9606 9362449 f "Nck interacts witn ErbB1 through SH2 and SH3 domains" gcesareni "We found that nck does not directly bind to egf receptor, instead it binds via its sh2 domain to a 62 kda phosphotyrosine protein" SIGNOR-52954 TLN1 protein Q9Y490 UNIPROT "Av/b2 integrin" complex SIGNOR-C176 SIGNOR "up-regulates activity" binding 10090 BTO:0000132 19118207 t miannu "Over the past 10 years, the binding of talin to the cytoplasmic tail of integrin-β subunits has been established to have a key role in integrin activation. Binding of the phosphotyrosinebinding (PTB)-domain-like subdomain of the protein 4.1, ezrin, radixin, moesin (FERM) domain of talin to the conserved WxxxNP(I/L)Y motif of the β-integrin tail permits additional weaker interactions between talin and the membrane-proximal region of the tail that trigger integrin activation, probably through the disruption of inhibitory interactions between α- and β-subunit cytoplasmic tails." SIGNOR-257622 TFIIH complex SIGNOR-C457 SIGNOR POLR2A protein P24928 UNIPROT "up-regulates activity" phosphorylation Ser1951 SPGYSPTsPTYSLTS 9606 24746699 t lperfetto "After PIC formation, Pol II initiates mRNA synthesis, but productive transcription requires Pol II to escape from the PIC and transit into transcription elongation. The transition between initiation and elongation is associated with phosphorylation at the serine 5 (Ser5) residues within the hepta-peptide repeats in the C-terminal domain (CTD) of the largest Pol II subunit. Ser5 phosphorylation is mediated primarily by Kin28, the kinase subunit of the general transcription factor TFIIH" SIGNOR-269372 CyclinK/CDK12 complex SIGNOR-C37 SIGNOR POLR2A protein P24928 UNIPROT "up-regulates activity" phosphorylation Ser1721 SPTSPSYsPTSPSYS 9606 BTO:0006413 32917631 t "Ser2 in CTD of PolII" lperfetto "Together, these studies demonstrate the important, yet largely redundant, role for CDK12 and CDK13 for the regulation of POLII CTD phosphorylation at multiple residues, as well as the global role for both of these kinases in regulating POLII occupancy across the genome.|CDK12 and CDK13 are thus evolutionarily related and structurally similar kinases, and biochemical assays have demonstrated that both have POLII C-terminal domain (CTD) kinase activity and the ability to phosphorylate the Ser2 residue of the repetitive CTD heptad sequence" SIGNOR-273098 MET protein P08581 UNIPROT Metastasis phenotype SIGNOR-PH107 SIGNOR up-regulates 9606 BTO:0001033 22035268 f miannu "C-Met expression and activation appears to be one of the common mechanisms of resistance to other targeted therapies. Given these multiple roles of c-Met in prostate cancer, several c-Met inhibitors have been developed. Evidence to date suggests that aberrant activation of the HGF/c-Met axis in prostate cancer epithelial cells appears to be a relatively late event in tumor progression. C-Met expression increases in advanced stages of the disease, with the highest expression observed in bone metastases." SIGNOR-263658 "Factor FVIIa:TF" complex SIGNOR-C319 SIGNOR F5 protein P12259 UNIPROT "down-regulates activity" cleavage Arg737 LAAALGIrSFRNSSL -1 10026263 t lperfetto "Thrombin is considered the physiological activator of factor V and is the most potent activator, catalyzing the cleavage of three peptide bonds at Arg709, Arg1018, and Arg1545" SIGNOR-263646 PRKDC protein P78527 UNIPROT RPA2 protein P15927 UNIPROT unknown phosphorylation Thr21 YGGAGGYtQSPGGFG -1 9139719 t lperfetto "In this study, we show that efficient phosphorylation of HSSB-p34 by DNA-PK requires Ku as well as DNA. The DNA-PK phosphorylation sites in HSSB-p34 have been mapped at Thr-21 and Ser-33. Kinetic studies demonstrated that a phosphate residue is first incorporated at Thr-21 followed by the incorporation of a second phosphate residue at Ser-33." SIGNOR-248972 "WRC complex" complex SIGNOR-C191 SIGNOR ARP2/3 complex SIGNOR-C146 SIGNOR "up-regulates activity" binding 9606 20332100 t miannu "The activated WAVE complex at the leading edge of lamellipodia promotes actin polymerization at the plasma membrane by activating the Arp2/3 complex" SIGNOR-253573 reserpine chemical CHEBI:28487 ChEBI SLC18A1 protein P54219 UNIPROT "down-regulates activity" "chemical inhibition" 9606 8643547 t miannu "Reserpine and ketanserin are slightly more potent inhibitors of VMAT2-mediated transport than of VMAT1-mediated transport, whereas tetrabenazine binds to and inhibits only VMAT2." SIGNOR-258492 MAPK3 protein P27361 UNIPROT HIF1A protein Q16665 UNIPROT up-regulates phosphorylation Ser641 DIKILIAsPSPTHIH 9606 BTO:0000567 18519666 t lperfetto "We show that at least two different nuclear protein kinases, one of them identified as p42/p44 mapk, can modify hif-1_. Analysis of in vitro phosphorylated hif-1_ by mass spectroscopy revealed residues ser-641 and ser-643 as possible mapk phosphorylation sites these data suggest that phosphorylation of ser-641/643 by mapk promotes the nuclear accumulation and transcriptional activity of hif-1_" SIGNOR-178731 TP53 protein P04637 UNIPROT HR protein O43593 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 15489903 f miannu "P53 may downregulate HR through multiple mechanisms including the reported associations with the Rad51 and Rad54 recombinases, and the BLM and WRN helicases." SIGNOR-255436 PIM2 protein Q9P1W9 UNIPROT PK proteinfamily SIGNOR-PF80 SIGNOR "up-regulates quantity by stabilization" phosphorylation 9606 24142698 t Manara "Importantly, we found that PIM2 could directly phosphorylate PKM2 on the Thr-454 residue, resulting in an increase of PKM2 protein levels." SIGNOR-268151 MAP3K7 protein O43318 UNIPROT IKBKB protein O14920 UNIPROT "up-regulates activity" phosphorylation 9606 SIGNOR-C14 19632174 t lperfetto "Tak1 become activated and then phosphorylates and activates ikk2 which in turn now phosphorylates ikba, marking it for k48-ubiquitination and proteasomal degradation. tak1 kinase complex phosphorylates and activates ikk in a manner that depends on traf6 and ubc13-uev1a our studies suggests that tak1_ acts as an upstream activating kinase for ikkbeta." SIGNOR-187242 CyclinK/CDK12 complex SIGNOR-C37 SIGNOR POLR2A protein P24928 UNIPROT "up-regulates activity" phosphorylation Ser1896 SPTSPTYsPTSPVYT 9606 BTO:0006413 32917631 t "Ser2 in CTD of PolII" lperfetto "Together, these studies demonstrate the important, yet largely redundant, role for CDK12 and CDK13 for the regulation of POLII CTD phosphorylation at multiple residues, as well as the global role for both of these kinases in regulating POLII occupancy across the genome.|CDK12 and CDK13 are thus evolutionarily related and structurally similar kinases, and biochemical assays have demonstrated that both have POLII C-terminal domain (CTD) kinase activity and the ability to phosphorylate the Ser2 residue of the repetitive CTD heptad sequence" SIGNOR-273101 IGF1R protein P08069 UNIPROT PIK3R3 protein Q92569 UNIPROT up-regulates binding 9606 phosphorylation:Tyr1346 SFDERQPyAHMNGGR 9415396 t gcesareni "Moreover, we found that the insulin-like growth factor-1 receptor (igf-ir) bound to p55pik;the interaction occurred at the receptor tyrosine 1316 and involved both p55pik sh2 domains." SIGNOR-52683 PTPN9 protein P43378 UNIPROT INSR protein P06213 UNIPROT down-regulates dephosphorylation Tyr999 YASSNPEyLSASDVF 9606 16679294 t gcesareni "Ectopic expression of ptp-meg2 in cells inhibited insulin-induced phosphorylation of the insulin receptor, while rnai-mediated reduction of ptp-meg2 transcript levels enhanced insulin action" SIGNOR-146680 CSNK1D protein P48730 UNIPROT KIR3DL1 protein P43629 UNIPROT up-regulates phosphorylation Ser385 AGNRTANsEDSDEQD 9606 17911614 t gcesareni "In this study, we have mapped constitutive phosphorylation sites for casein kinases, protein kinase c, and an unidentified kinase on the kir cytoplasmic domain. Three of these phosphorylation sites are highly conserved in human inhibitory kir. Functional studies of the wild-type receptor and serine/threonine mutants indicated that phosphorylation of ser(394) by protein kinase c slightly suppresses kir3dl1 inhibitory function, and reduces receptor internalization and turnover." SIGNOR-158121 LY294002 chemical CHEBI:65329 ChEBI PIK3C3 protein Q8NEB9 UNIPROT down-regulates "chemical inhibition" 9534 BTO:0001444 22253445 t lperfetto "From these results, we conclude that LY294002 and wortmannin inhibit SARS pseudovirus entry by targeting PI4KB and that PI4KB is involved in SARS-CoV S-mediated entry into VeroE6 cells." SIGNOR-260731 RAB4A protein P20338 UNIPROT RUFY1 protein Q96T51 UNIPROT "up-regulates activity" binding 9606 20534812 t Giulio "Here, we have demonstrated that Rab14 interacts with RUFY1, previously identified as a Rab4 effector, and is required for RUFY1 recruitment onto endosomes and efficient recycling of Tfn.|We also found that enlargement of early endosomes mediated by RUFY1 requires its interaction with Rab4" SIGNOR-261280 SERPINE1 protein P05121 UNIPROT Cell_adhesion phenotype SIGNOR-PH7 SIGNOR up-regulates 9606 10368279 f gcesareni "Pai-1 is now being identified as a key player in the link between coagulation and the cell adhesion pathways involved in tissue remodeling and metastasis. Active pai-1 (but not its latent or cleaved forms) binds tightly to the adhesive glycoprotein vitronectin in the extracellular matrix." SIGNOR-68478 ATM protein Q13315 UNIPROT TP53BP1 protein Q12888 UNIPROT unknown phosphorylation Ser784 GVEKCSDsQSWEDIA 9606 12697768 t llicata "To examine whether the respective sq sites become phosphorylated in vivo, we raised polyclonal antibodies against phosphorylated ser-6 (anti-s6p), phosphorylated ser-25 and ser-29 (anti-s25p/29p), and phosphorylated ser-784 (anti-s784p). All affinity-purified antisera recognized 53bp1" SIGNOR-100653 MTOR protein P42345 UNIPROT AKT1S1 protein Q96B36 UNIPROT "down-regulates activity" phosphorylation Ser183 PTQQYAKsLPVSVPV -1 SIGNOR-C3 SIGNOR-C3 18372248 t lperfetto "Pras40 functions as a negative regulator when bound to mtorc1, and it dissociates from mtorc1 in response to insulin. Pras40 has been demonstrated to be a substrate of mtorc1, and one phosphorylation site, ser-183, has been identified." SIGNOR-178120 APC-c complex SIGNOR-C150 SIGNOR REV1 protein Q9UBZ9 UNIPROT "down-regulates quantity by destabilization" polyubiquitination 9606 BTO:0000007 23287467 t miannu " Here, we show that human REV1 undergoes proteosomal degradation mediated by the E3 ubiquitin ligase known as anaphase-promoting complex (APC). REV1 associates with APC. Overexpression of APC coactivator CDH1 or CDC20 promotes polyubiquitination and proteosomal degradation of REV1." SIGNOR-272894 CAPN3 protein P20807 UNIPROT CDK5/CDK5R1 complex SIGNOR-C144 SIGNOR "up-regulates activity" cleavage 9606 25969760 t lperfetto "Calpains also modulate the activity of CDK5. Physiologically, CDK 5 is activated by p35 and its cleaved product p25. The latter has a longer half life than p35 and therefore it is a more potent activator of CDK5. The cleavage of p35 to p25 is mediated by calpain" SIGNOR-251602 metyrapone chemical CHEBI:44241 ChEBI CYP11B2 protein P19099 UNIPROT "down-regulates activity" "chemical inhibition" -1 21129965 t Luana "In an effort to develop and evaluate new classes of compounds as CYP inhibitors, we based our investigations on the structure of the well-known CYP inhibitor Metyrapone 2, which has been used for the treatment of hypercortisolism and Cushing’ssyndrome for several decades." SIGNOR-257885 MAOB protein P27338 UNIPROT (R)-adrenaline smallmolecule CHEBI:28918 ChEBI "up-regulates quantity" "chemical modification" 9606 BTO:0000142 20493079 t Luana "The selective monoamine oxidase inhibitors clorgyline and (−)-deprenyl were used to study the distribution of monoamine oxidase-A and -B (MAO-A, MAO-B) activities towards (−)-noradrenaline and (+),(−)-adrenaline in homogenates from seven different regions of human brain. Noradreanline and adrenaline were substrates for both forms of the enzyme in all regions studied." SIGNOR-269746 MAPK8 protein P45983 UNIPROT IRS1 protein P35568 UNIPROT "down-regulates activity" phosphorylation Ser616 DDGYMPMsPGVAPVP 9606 12510059 t gcesareni "Insulin also activates jnk, erk, pkc and mtor, which induce the phosphorylation of irs1 on serine residues 307, 612 and 632 and inhibit its functions. Our results indicate that the insulin-stimulated degradation of irs-1 via the phosphatidylinositol 3-kinase pathway is in part dependent upon the ser(312) phosphorylation of irs-1." SIGNOR-96944 KDM4C protein Q9H3R0 UNIPROT H3-3A protein P84243 UNIPROT "down-regulates activity" demethylation Lys37 APSTGGVkKPHRYRP 9606 29207681 t miannu "As one member of the Jumonji-C histone demethylase family, JMJD2C has the ability to demethylate tri- or di-methylated histone 3 and 2 in either K9 (lysine residue 9) or K36 (lysine residue 36) sites by an oxidative reaction, thereby affecting heterochromatin formation, genomic imprinting, X-chromosome inactivation, and transcriptional regulation of genes.JMJD2C has been proved to be a demethylase for H3K9 methylation, in the manner of catalyzing the demethylation of H3K9me3/me2 (the known repressive markers of gene regulation), a histone mark found in heterochromatin associated with euchromatic transcriptional silencing and heterochromatin formation" SIGNOR-263868 SGK3 protein Q96BR1 UNIPROT FLII protein Q13045 UNIPROT up-regulates phosphorylation Ser436 RLRRRKDsAQDDQAK 9606 19293151 t lperfetto "Here we show that flii is an in vivo substrate of cisk that functions downstream of pi 3-kinase. Cisk can associate with flii and phosphorylate flii at residues ser(436) and thr(818).We demonstrate here that cisk can enhance er transcription, which is dependent on its kinase activity, and mutation of cisk phosphorylation sites on flii attenuates its activity as an er co-activator." SIGNOR-184688 PRKDC protein P78527 UNIPROT JUN protein P05412 UNIPROT unknown phosphorylation Ser249 LSPIDMEsQERIKAE -1 8464713 t lperfetto "Here, we show that the DNA-PK modifies c-Jun in vitro and that serine residue 249 (Ser-249) is required for phosphorylation to occur. This residue corresponds to one of three sites of c-Jun that are phosphorylated in vivo and which negatively regulate c-Jun DNA binding in vitro. However, we find that phosphorylation of c-Jun by the DNA-PK does not interfere with DNA binding, indicating that phosphorylation at other sites is required for this effect." SIGNOR-248934 AKT1 protein P31749 UNIPROT TSC complex SIGNOR-C101 SIGNOR "down-regulates activity" phosphorylation 10090 BTO:0000944 12150915 t lperfetto "We have shown thataktregulates the tsc1-tsc2 complex by directly phosphorylating tsc2. Tsc2 is inactivated by akt-dependent phosphorylation, which destabilizes tsc2 and disrupts its interaction with tsc1. Tsc2 is inactivated by akt-dependent phosphorylation, which destabilizes tsc2 and disrupts its interaction with tsc1akt has been shown to directly phosphorylate two sites on tsc2 (s939 and t1462 on the full-length human protein), which are conserved and phosphorylated in drosophila tsc2, and is likely to phosphorylate two or three additional sites (s981 and s1130/s1132)." SIGNOR-235628 CDC14A protein Q9UNH5 UNIPROT KMT5A protein Q9NQR1 UNIPROT "down-regulates quantity by destabilization" dephosphorylation Ser100 SKIYSYMsPNKCSGM 9606 20966048 t "The dephosphorylation of S29 during late mitosis by the Cdc14 phosphatases was required for APC(cdh1)-mediated ubiquitination of PR-Set7 and subsequent proteolysis." SIGNOR-248835 "Cullin 3-RBX1-Skp1" complex SIGNOR-C526 SIGNOR MACROH2A1 protein O75367 UNIPROT "up-regulates activity" monoubiquitination 9606 BTO:0000007 15897469 t miannu "BMI1 and MACROH2A1 interact with and are ubiquitinated by the CULLIN3 and SPOP ligase complex. t present, we cannot discriminate the main role in vivo of the polyubiquitinated or monoubiquitinated MACROH2A1, because both modifications can be detected (Fig. 2 d and e and ref. 34).Importantly, RNAi-mediated knock-down of CULLIN3 or SPOP results in loss of MACROH2A1 from the inactivated X chromosome (Xi), leading to reactivation of the Xi in the presence of inhibitors of DNA methylation and histone deacetylation. No significant changes in protein stability were observed, suggesting that ubiquitination serves regulatory functions other than protein degradation of BMI1 and MACROH2A1" SIGNOR-272660 RNF7 protein Q9UBF6 UNIPROT ROS stimulus SIGNOR-ST2 SIGNOR down-regulates 9606 23136067 f miannu "We examined potential role of SAG in conferring cellular radioresistance, based upon two pieces of evidence. First, SAG is an antioxidant protein that scavenges ROS. R" SIGNOR-271445 CBL protein P22681 UNIPROT ERBB2 protein P04626 UNIPROT "down-regulates quantity by destabilization" ubiquitination 9606 20332299 t lperfetto "Ligand binding to EGFR also leads to rapid internalization and proteosomal/lysosomal degradation of the receptors. This process results in a dramatic downregulation of both total and cell surface receptors. EGF-induced degradation of EGFR is thought to be initiated by phosphorylation of tyrosine 1045 of the receptor followed by binding of Cbl adaptor proteins and ubiquitination of the receptor. Internalized EGFR is transported to early endosomes where receptor-ligand complexes are sorted for either degradation or recycling to the cell surface." SIGNOR-30794 MAPKAPK2 protein P49137 UNIPROT CREB1 protein P16220 UNIPROT up-regulates phosphorylation Ser119 EILSRRPsYRKILND 9606 17389598 t lperfetto "Neverthless, some transcription factors, such as e47, er81, srf and creb are also phosphorylated by mk2." SIGNOR-153944 PSMB4 protein P28070 UNIPROT "26S Proteasome" complex SIGNOR-C307 SIGNOR "form complex" binding 9606 29636472 t lperfetto "Here, we report near-atomic resolution cryo-EM structures of the activated human proteasome|The proteasome is composed of a 28-subunit barrel-shaped core particle (CP) and two 19- subunit regulatory particles (RP)5–8 capped at both sides of the CP|Human proteasomes were purified through affinity chromatography on a large scale from a stable HEK293 cell line" SIGNOR-263355 EGFR protein P00533 UNIPROT SHC2 protein P98077 UNIPROT up-regulates binding 9606 11350724 t miannu "Shc exists in three different isoforms, p46shc, p52shc and p66shc which are tyrosine phosphorylated upon egf stimulation and bind to the activated egfr and grb2. Interestingly, while the 46 and 52 kda isoforms increase mitogenic signalling after egf stimulation and are able to transform nih3t3 cells (pelicci et al. 1992), p66shc has no transforming potential and negatively influences egf-induced c-fos transcription" SIGNOR-107750 PIK3R1 protein P27986 UNIPROT PIK3CB protein P42338 UNIPROT "up-regulates activity" binding 9534 BTO:0004055 14665640 t lperfetto "Signal transduction pathways triggered by Tie2 have been extensively examined. Tyr-1101of Tie2 directly associates in a phosphotyrosine (pTyr)-dependent manner with the p85 regulatory subunit of phosphatidylinositol (PI) 3-kinase, which in turn activate PI 3-kinase, leading to cell motility and survival" SIGNOR-242640 CRKL protein P46109 UNIPROT PIK3CB protein P42338 UNIPROT "up-regulates activity" binding 9606 BTO:0005029 28723560 t irozzo "Here, we identify CRKL as a member of the class of PI3Kβ-interacting proteins. Silencing CRKL expression in PTEN-null human cancer cells leads to a decrease in p110β-dependent PI3K signaling and cell proliferation.In conclusion, our study identified CRKL as an important regulator of PI3K activity in PTEN-deficient tumor cells through its association with p110β/p85." SIGNOR-255821 PKN1 protein Q16512 UNIPROT PGAM1 protein P18669 UNIPROT down-regulates phosphorylation Ser118 QVKIWRRsYDVPPPP 9606 BTO:0000130 12189148 t llicata "Activated pak1 inhibits glycolysis by association of its catalytic domain with pgam-b and subsequent phosphorylation of the enzyme on serine residues 23 and 118, thereby abolishing pgam activity." SIGNOR-91602 KPNB1 protein Q14974 UNIPROT SMAD3 protein P84022 UNIPROT up-regulates relocalization 9606 10846168 t gcesareni "Here we show that the isolated smad 3 mh1 domain displays significant specific binding to importin beta. we propose that activation of all of the pathway-specific smad proteins (smads 1, 2, 3, 5, 8, and 9) exposes the conserved nls motif, which then binds directly to importin beta and triggers nuclear translocation." SIGNOR-78191 tRNA(Leu) smallmolecule CHEBI:29169 ChEBI Leu-tRNA(Leu) smallmolecule CHEBI:16624 ChEBI "up-regulates quantity" "precursor of" 9606 28271488 t miannu "Aminoacyl-tRNA synthetases (AARSs) are essential enzymes that specifically aminoacylate one tRNA molecule by the cognate amino acid. In mammals, nine synthetases, those specific for amino acids Arg, Asp, Gln, Glu, Ile, Leu, Lys, Met and Pro, associate into a multi-aminoacyl-tRNA synthetase complex, an association which is believed to play a key role in the cellular organization of translation, but also in the regulation of the translational and nontranslational functions of these enzymes." SIGNOR-270417 TNF protein P01375 UNIPROT SCN2A protein Q99250 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 26112872 f miannu "TNF-α increases Na(+) currents by accelerating the channel activation as well as increasing the expression of VGSCs in a mechanism dependent upon NF-κB and p38 MAPK signal pathways in CNS neurons. TNF-α increased Na(+) currents by accelerating the activation of VGSCs. The threshold for action potential (AP) was decreased and firing rate were increased. VGSCs were up-regulated at both the mRNA and protein levels." SIGNOR-253480 CNR1 protein P21554 UNIPROT GNAO1 protein P09471 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257003 RPS6KA5 protein O75582 UNIPROT TH protein P07101 UNIPROT up-regulates phosphorylation Ser40 GQGAPGPsLTGSPWP 9606 12421349 t "The effect has been demonstrated using P07101-3" gcesareni "Recombinant human tyrosine hydroxylase (hth1) was found to be phosphorylated by mitogen and stress-activated protein kinase 1 (msk1) at ser40 and by p38 regulated/activated kinase (prak) on ser19. Phosphorylation by msk1 induced an increase in vmax. studies on th from several species suggest that ser40 is the main site involved in direct activation of th" SIGNOR-95491 STK11 protein Q15831 UNIPROT MARK1 protein Q9P0L2 UNIPROT up-regulates phosphorylation Thr215 TVGNKLDtFCGSPPY 9606 14976552 t lperfetto "Lkb1 is a master kinase that activates 13 kinases of the ampk subfamily, including mark/par-1we recently demonstrated that the lkb1 tumour suppressor kinase, in complex with the pseudokinase strad and the scaffolding protein mo25, phosphorylates and activates amp-activated protein kinase (ampk). A total of 12 human kinases (nuak1, nuak2, brsk1, brsk2, qik, qsk, sik, mark1, mark2, mark3, mark4 and melk) are related to ampk. Here we demonstrate that lkb1 can phosphorylate the t-loop of all the members of this subfamily, apart from melk, increasing their activity >50-fold" SIGNOR-122545 "ISGF3 complex" complex SIGNOR-C124 SIGNOR EIF2AK2 protein P19525 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 27712625 f miannu "The activated kinases then phosphorylate the signal transducers and transcription factors STAT1 and STAT2, which form a complex with IRF9 (ISGF3) that enters the nucleus to transactivate promoters of an antiviral gene expression program. Genes that are specifically upregulated by IFNs are collectively called ISGs (IFN-stimulated genes). The kinase PKR is an ISG product acting as a signaling PRR on one hand (see earlier), but its main function in antiviral defense is the inhibition of protein synthesis.PKR has a broad antiviral spectrum." SIGNOR-260158 PTPN22 protein Q9Y2R2 UNIPROT CBL protein P22681 UNIPROT down-regulates dephosphorylation Ser798 SDISNASsSFGWLSL 9606 BTO:0000782 10068674 t amattioni "The tyrosine phosphatase lyp1 was found to be constitutively associated with the proto-oncogene c-cbl in thymocytes and t cells. Overexpression of lyp1 reduces cbl tyrosine phosphorylation. It is known that cbl is heavily tyrosine phosphorylated after tcr stimulation and can associate with the syk and zap tyrosine kinases, negatively regulating their activities. Tyrosine phosphatases keep cbl in a basally dephosphorylated state." SIGNOR-65405 ZAP70 protein P43403 UNIPROT SHC1 protein P29353 UNIPROT up-regulates phosphorylation Tyr350 EPPDHQYyNDFPGKE 9606 BTO:0000782 9710204 t gcesareni "The syk-family kinases (syk and zap-70) were able to phosphorylate the y239 and y240 sites, and less efficiently the y317 site on shc1 (iso2)." SIGNOR-59651 POFUT1 protein Q9H488 UNIPROT NOTCH proteinfamily SIGNOR-PF30 SIGNOR up-regulates binding 9606 12909620 t Fucosylation gcesareni "Notch_ is modified in its epidermal growth factor-like domains by the addition of_ fucose_ to serine or threonine residues. O-fucosylation is mediated by protein o-fucosyltransferase 1 and down-regulation of this enzyme by rna interference or mutation of the ofut1 gene in drosophila or by mutation of the pofut1 gene in mouse prevents notch signaling." SIGNOR-254326 "RING E3 ligase" proteinfamily SIGNOR-PF106 SIGNOR Ub:RING_E3 complex SIGNOR-C519 SIGNOR "form complex" binding 9606 34199813 t miannu "The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5′-triphosphate (ATP)-dependent manner to form a thioester-linked E1‒Ub conjugate. The activated Ub is then delivered to an E2 enzyme via a transthiolation reaction. Finally, an E3 enzyme, which can bind both a substrate and an E2‒Ub conjugate, mediates the covalent linkage of Ub to the target protein as a tag." SIGNOR-271377 tRNA(Thr) smallmolecule CHEBI:29180 ChEBI Thr-tRNA(Thr) smallmolecule CHEBI:29163 ChEBI "up-regulates quantity" "precursor of" 9606 25824639 t miannu "Here we show, using X-ray crystal structures and functional analyses, that a single molecule of borrelidin simultaneously occupies four distinct subsites within the catalytic domain of bacterial and human ThrRSs. These include the three substrate-binding sites for amino acid, ATP and tRNA associated with aminoacylation, and a fourth 'orthogonal' subsite created as a consequence of binding." SIGNOR-270507 MET protein P08581 UNIPROT GAB1 protein Q13480 UNIPROT "up-regulates activity" phosphorylation Tyr627 KGDKQVEyLDLDLDS 9606 BTO:0000018 10734310 t miannu "Gab-1 is phosphorylated on the same residues by HGF and EGF receptors. Among 16 peptides only nine were phosphorylated by the EGF and HGF receptors, namely peptides containing the tyrosine residues 285, 307, 373, 407, 448, 473, 590, 628 and 660. we show that in the response to HGF or EGF, Gab1 is phosphorylated in vivo on the same residues. However, a sustained activation of signaling pathways downstream to Gab1 (as a result of its sustained phosphorylation) is achieved only in response to HGF." SIGNOR-250289 CASP3 protein P42574 UNIPROT "Caspase 3 complex" complex SIGNOR-C221 SIGNOR "form complex" binding cleavage:Asp28 IHGSESMdSGISLDN 15115390 t lperfetto "Caspases are expressed as inactive proenzymes of 30−50 kDa that include an amino-terminal domain of variable length and sequence that is followed by two domains of conserved sequences:  a large subunit (approximately 20 kDa, designated p17 in caspase-3) and a small carboxy-terminal subunit (approximately 10 kDa, designated p12 in caspase-3). Activation is accomplished by proteolytic cleavage between these domains and subsequent assembly of heterotetramers that contain two copies each of the large and small subunits but lack the amino-terminal domains." SIGNOR-256387 PPP2CB protein P62714 UNIPROT PRKCD protein Q05655 UNIPROT "down-regulates activity" dephosphorylation Thr507 FGESRAStFCGTPDY 10090 BTO:0000944 11959144 t "PP2A(c) displayed the highest specific activity towards PKCdelta. The role of PP2A(c) in the dephosphorylation of PKCdelta in cells was supported by the demonstration that these proteins could be co-immunoprecipitated from NIH3T3 cells.|In conclusion, the evidence here indicates that PKCdelta de-phosphorylation and hence inactivation is effected by PP2A with which it forms a complex" SIGNOR-248594 MAPK1 protein P28482 UNIPROT RPTOR protein Q8N122 UNIPROT "up-regulates activity" phosphorylation Ser863 LTQSAPAsPTNKGVH 9606 SIGNOR-C3 21071439 t lperfetto "We found three proline-directed residues within raptor, ser(8), ser(696), and ser(863), which are directly phosphorylated by erk1/2. Expression of phosphorylation-deficient alleles of raptor revealed that phosphorylation of these sites by erk1/2 normally promotes mtorc1 activity and signaling to downstream substrates, such as 4e-bp1." SIGNOR-188916 MAPK1 protein P28482 UNIPROT HNRNPH1 protein P31943 UNIPROT unknown phosphorylation Ser104 LKHTGPNsPDTANDG 10090 BTO:0000944 22028470 t miannu "We have optimized a chemical genetic system using analog-sensitive ERK2, a form of ERK2 engineered to use an analog of adenosine 5'-triphosphate (ATP), to tag and isolate ERK2 substrates in vitro. This approach identified 80 proteins phosphorylated by ERK2, 13 of which are known ERK2 substrates. With this improved methodology, we detected 98 sites directly phosphorylated by ERK2 on 80 proteins from NIH 3T3-L1 fibroblasts. Thirteen of these proteins are known substrates and the rest represent previously unknown kinase/substrate interactions. (table1)" SIGNOR-262776 GRK2 protein P25098 UNIPROT BDKRB2 protein P30411 UNIPROT "down-regulates activity" phosphorylation Ser375 GTLRTSIsVERQIHK 9606 BTO:0000007 11517230 t "Ligand-induced phosphorylation is found at Ser339 and Ser346/Ser348 that could be executed by several G protein-coupled receptor kinases. 32P labeling of peptide 3 containing pS346/pS348 was enhanced 1.5–3-fold as compared with mock-transfected cells in the order GRK6 < GRK5 < GRK2 < GRK4α < GRK3. several endogenous GRKs may phosphorylate the B2R and that the various GRKs, even without apparent effect on total GPCR phosphorylation levels, may induce distinct phosphorylation patterns with possible functional consequences for receptor desensitization and sequestration." SIGNOR-251446 CyclinK/CDK12 complex SIGNOR-C37 SIGNOR POLR2A protein P24928 UNIPROT "up-regulates activity" phosphorylation Ser1889 SPTTPKYsPTSPTYS 9606 BTO:0006413 32917631 t "Ser2 in CTD of PolII" lperfetto "Together, these studies demonstrate the important, yet largely redundant, role for CDK12 and CDK13 for the regulation of POLII CTD phosphorylation at multiple residues, as well as the global role for both of these kinases in regulating POLII occupancy across the genome.|CDK12 and CDK13 are thus evolutionarily related and structurally similar kinases, and biochemical assays have demonstrated that both have POLII C-terminal domain (CTD) kinase activity and the ability to phosphorylate the Ser2 residue of the repetitive CTD heptad sequence" SIGNOR-273103 BRSK1 protein Q8TDC3 UNIPROT CDC25B protein P30305 UNIPROT "down-regulates activity" phosphorylation Ser375 ARVLRSKsLCHDEIE 9606 BTO:0000567 15150265 t lperfetto "Hssad1 specifically phosphorylated wee1a, cdc25-c, and -b on ser-642, ser-216, and ser-361 in vitro, respectively phosphorylation of cdc25 triggers cell-cycle arrest by the sequestration of cdc25 by 14-3-3" SIGNOR-107404 TAF1B protein Q53T94 UNIPROT "SL1 complex" complex SIGNOR-C464 SIGNOR "form complex" binding 9606 30693017 t lperfetto "SL1 comprises TBP, TAF1A (also known as TAFI48), TAF1B (also known as TAFI63), TAF1C (also known as TAFI110), and TAF1D (also known as TAFI41) and recruits the RNAP1 complex to induce PIC formation." SIGNOR-269565 PCDH15 protein Q96QU1 UNIPROT "TIP-LINK complex" complex SIGNOR-C291 SIGNOR "form complex" binding 10090 BTO:0000630 23217710 t lperfetto "The adaptor proteins harmonin and SANS, and the motor protein myosin 7a (Myo7a) bind in vitro to each other and to CDH23 (Adato et al., 2005; Bahloul et al., 2010; Boeda et al., 2002; Siemens et al., 2002) and co-localize at the upper insertion site of tip links (Grati and Kachar, 2011; Grillet et al., 2009b), suggesting that they form a protein complex important for transduction." SIGNOR-262575 GSK3B protein P49841 UNIPROT EIF4EBP1 protein Q13541 UNIPROT "down-regulates activity" phosphorylation Thr37 PPGDYSTtPGGTLFS 9606 BTO:0000671 18701453 t lperfetto "We found that gsk-3Beta phosphorylates and inactivates 4e-bp1, thereby increasing eif4e-dependent protein synthesis. upon stimulation, 4e-bp1 is phosphorylated on several threonine and serine residues, including thr-37/46 (36). This results in dissolution of the complex, freeing eif4e to bind with mrna cap to promote translation initiation." SIGNOR-236026 HPN protein P05981 UNIPROT F7 protein P08709 UNIPROT "up-regulates activity" cleavage Arg212 NASKPQGrIVGGKVC -1 7814421 t lperfetto "Hepsin, a putative membrane-associated serine protease, activates human factor VII and initiates a pathway of blood coagulation on the cell surface leading to thrombin formation|In contrast, an activation cleavage site factor VII mutant, R152E factor VII, was not cleaved by hepsin-transfected cells, suggesting that factor VII and S344A factor VII were activated on these cells by cleavage of the Arg152-Ile153 peptide bond. I" SIGNOR-263638 CyclinK/CDK12 complex SIGNOR-C37 SIGNOR POLR2A protein P24928 UNIPROT "up-regulates activity" phosphorylation Ser1616 TPQSPSYsPTSPSYS 9606 BTO:0006413 32917631 t "Ser2 in CTD of PolII" lperfetto "Together, these studies demonstrate the important, yet largely redundant, role for CDK12 and CDK13 for the regulation of POLII CTD phosphorylation at multiple residues, as well as the global role for both of these kinases in regulating POLII occupancy across the genome.|CDK12 and CDK13 are thus evolutionarily related and structurally similar kinases, and biochemical assays have demonstrated that both have POLII C-terminal domain (CTD) kinase activity and the ability to phosphorylate the Ser2 residue of the repetitive CTD heptad sequence" SIGNOR-273104 ACP1 protein P24666 UNIPROT AKT3 protein Q9Y243 UNIPROT "down-regulates activity" dephosphorylation Ser472 RPHFPQFsYSASGRE 10090 17353188 t "Reduction in the levels of both LMW-PTP isoforms in vitro and in vivo increased tyrosine phosphorylation of IR and AktSer473 and increased IRS-1- and IRS-2-associated PI3-K activities in both liver and fat.|Activated PI3-K stimulates Akt (or protein kinase B) that in turn phosphorylates and inactivates glycogen synthase kinase-3" SIGNOR-248457 JAK2 protein O60674 UNIPROT STAT6 protein P42226 UNIPROT "up-regulates activity" phosphorylation 9606 9852261 t gcesareni "Stat6 activation is mediated through jak1 and jak2 tyrosine kinases." SIGNOR-62585 "EBV gH:gL:gp42" complex SIGNOR-C403 SIGNOR HLA-DRA protein P01903 UNIPROT "up-regulates activity" binding 9606 BTO:0000776 11864610 t scontino "The EBV gp42 glycoprotein binds MHC class II molecules, playing a critical role in infection of B lymphocytes. The gp42 binds HLA-DR1 using a surface site" SIGNOR-266628 SMO protein Q99835 UNIPROT GNB3 protein P16520 UNIPROT up-regulates binding 9606 23074268 t gcesareni "Consistent with its predicted topology, smo couples to a specific family of inhibitory g protein (gis) to regulate hh signaling as pka suppresses the activity of gli, smo might use the stimulation of pi3k by galfai and gbetagamma subu- nits to block pka in cells that have high levels of camp" SIGNOR-199180 NR0B2 protein Q15466 UNIPROT G6PC1 protein P35575 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 17909097 f gcesareni "As shown in fig. 3a, metformin (0.5 to 2 mmol/l) induced shp gene expression and repressed the camp/dex-induced expression of pepck and g6pase in a dose-dependent manner in h4iie cells" SIGNOR-158065 PPP1R9A protein Q9ULJ8 UNIPROT F-actin_assembly phenotype SIGNOR-PH18 SIGNOR up-regulates 10090 BTO:0001976 15996550 f miannu "Neurabin and spinophilin are preferentially expressed in neurons, where they are highly localized to dendritic spines via an interaction with F-actin. The results obtained in the present study suggest a mechanism by which neurabin or spinophilin contributes to the organization of the F-actin cytoskeleton in dendritic spines, and in turn to the regulation of spine morphology, via the activity-dependent recruitment of the Rho-specific GEF Lfc" SIGNOR-269180 PGM2 protein Q96G03 UNIPROT "2-deoxy-D-ribose 5-phosphate" smallmolecule CHEBI:16132 ChEBI "up-regulates quantity" "chemical modification" 9606 17804405 t miannu "Biochemical characterization of phosphoglucomutase (PGM) isozymes indicated that one of them, designated PGM2 in man (PGM1 in mouse) was more active as a phosphopentomutase than as a phosphoglucomutase, whereas mammalian PGM1 (equivalent to PGM2 in mouse) has a phosphopentomutase activity representing only about 0.2% of its phosphoglucomutase activity. Phosphopentomutase catalyzes the conversion of the nucleoside breakdown products ribose 1-phosphate and deoxyribose 1-phosphate to the corresponding 5-phosphopentoses." SIGNOR-267095 2-[[2-[[1-[2-(dimethylamino)-1-oxoethyl]-5-methoxy-2,3-dihydroindol-6-yl]amino]-7H-pyrrolo[2,3-d]pyrimidin-4-yl]amino]-6-fluoro-N-methylbenzamide chemical CHEBI:93768 ChEBI ALK protein Q9UM73 UNIPROT "down-regulates activity" "chemical inhibition" -1 22037378 t Luana "Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here." SIGNOR-258219 "AP-2 complex" complex SIGNOR-C245 SIGNOR AAK1 protein Q2M2I8 UNIPROT "up-regulates activity" binding 10116 BTO:0000142 15496985 t Giorgia "We therefore characterised protein ligands using liquid chromatography tandem mass spectrometry (LC‐MS/MS) and confirmed this using Western blotting to recognise both major and minor bands. Some of the more minor interactors are very strongly enriched (AAK, auxilin, Dab2, eps15, epsin1 and synaptojanin170). All these enriched proteins have multiple copies of short alpha‐appendage interaction motifs" SIGNOR-260393 MTMR3 protein Q13615 UNIPROT 1-phosphatidyl-1D-myo-inositol(1-) smallmolecule CHEBI:57880 ChEBI "up-regulates quantity" "chemical modification" 9606 18429927 t miannu "PtdIns(3,5)P2 can be dephosphorylated by the 3-phosphatase myotubularins (MTMs), leading to the production of PtdIns5P. Myotubularins also dephosphorylate PtdIns3P into PtdIns" SIGNOR-269811 CCDC102B protein Q68D86 UNIPROT CROCC protein Q5TZA2 UNIPROT "up-regulates activity" binding 30404835 t lperfetto "CCDC102B is recruited to the centrosome by C-Nap1 (also known as CEP250) and interacts with the centrosome linker components rootletin and LRRC45. CCDC102B decorates and facilitates the formation of rootletin filaments. Furthermore, CCDC102B is phosphorylated by Nek2A (an isoform encoded by NEK2) and is disassociated from the centrosome at the onset of mitosis." SIGNOR-275628 LCK protein P06239 UNIPROT PIK3R1 protein P27986 UNIPROT "down-regulates activity" phosphorylation Tyr688 FAEPYNLySSLKELV 9534 BTO:0004055 9461588 t "the regulatory p85 subunit of phosphatidylinositol 3-kinase is phosphorylated on tyrosine residues. We report that this phosphorylation event is readily catalyzed by the Abl and Lck protein-tyrosine kinases in vitro, by Bcr-Abl or a catalytically activated Lck-Y505F in co-transfected COS cells. we have mapped a major phosphorylation site to Tyr-688 in the C-terminal SH2 domain of p85. Tyrosine phosphorylation of p85 in vitro or in vivo was not associated with detectable change in the enzymatic activity of the phosphatidylinositol 3-kinase heterodimer, but correlated with a strong reduction in the binding of some, but not all, phosphoproteins to the SH2 domains of p85." SIGNOR-251383 KREMEN1 protein Q96MU8 UNIPROT LRP6 protein O75581 UNIPROT up-regulates 9606 12050670 f gcesareni "Dkk1 has been shown to inhibit wnt signalling by binding to and antagonizing lrp5/6. Here we show that the transmembrane proteins kremen1 and kremen2 are high-affinity dkk1 receptors that functionally cooperate with dkk1 to block wnt/beta-catenin signalling." SIGNOR-88891 TNFRSF21 protein O75509 UNIPROT TRADD protein Q15628 UNIPROT up-regulates binding 9606 14585074 t amattioni "Dr6 interacts with tradd" SIGNOR-100184 PRKCD protein Q05655 UNIPROT MGluR proteinfamily SIGNOR-PF55 SIGNOR "up-regulates activity" phosphorylation -1 15894802 t "inferred from family member" lperfetto "Thus, we showed that it is phosphorylation of Ser-839, not Thr-840, that is absolutely required for the unique Ca2+ oscillations produced by mGluR5 activation. The Thr-840 residue is important only in that it is permissive for the PKC-dependent phosphorylation of Ser-839." SIGNOR-270275 UTS2R protein Q9UKP6 UNIPROT GNAL protein P38405 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-256922 ILK protein Q13418 UNIPROT ILK protein Q13418 UNIPROT "up-regulates activity" phosphorylation Ser343 SMADVKFsFQCPGRM 9606 11313365 t lperfetto "Although ilk has been shown to autophosphorylate serine 343 (s343) is in the hydrophobic motif fsf within the activation loop of the kinase domain and has previously been suggested to be the target of autophosphorylation (9). Mutation of serine 343 to alanine (s343a) resulted in the inability of ilk to stimulate phosphorylation of pkb/akt in cos cells (9)." SIGNOR-106838 PPARGC1A protein Q9UBK2 UNIPROT CAV3 protein P56539 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9534 BTO:0001538 15199055 f "Furthermore, we show that the muscle carnitine palmitoyltransferase-1 and caveolin-3 promoters are directly regulated by ROR and coactivated by p300 and PGC-1. This study implicates RORs in the control of lipid homeostasis in skeletal muscle." SIGNOR-254261 CDK2 protein P24941 UNIPROT NR3C1 protein P04150 UNIPROT "up-regulates activity" phosphorylation Ser203 DLEFSSGsPGKETNE -1 9199329 t lperfetto "Cyclin-dependent kinase (CDK) and mitogen-activated protein kinase (MAPK) phosphorylate the rat glucocorticoid receptor in vitro at distinct sites that together correspond to the major phosphorylated receptor residues observed in vivo; MAPK phosphorylates receptor residues threonine 171 and serine 246, whereas multiple CDK complexes modify serines 224 and 232.|MAPKs and CDKs exert opposite effects on receptor transcriptional enhancement. From our results, we speculate that activators of the MAPK pathway, such as growth factors, insulin, and certain oncoproteins, or inhibitors of CDK function, such as tumor growth factor beta (TGF_), p21, and p27, might attenuate receptor-induced transcrip- tional responses. In contrast, negative regulators of MAPK, such as pKA, as well as activators of CDK, such as the cyclins or CAKs, should potentiate receptor action." SIGNOR-249426 CCP110 protein O43303 UNIPROT CALM1 protein P0DP23 UNIPROT "up-regulates activity" binding 9606 16760425 t miannu "We report that CP110 interacts with two different Ca2+-binding proteins, calmodulin (CaM) and centrin, in vivo. our data demonstrate a functional role for CaM binding to CP110 and suggest that CP110 cooperates with CaM and centrin to regulate progression through cytokinesis." SIGNOR-265965 DAMPS stimulus SIGNOR-ST18 SIGNOR MEFV protein O15553 UNIPROT "up-regulates activity" 16037825 f lperfetto "Among these sensors, members of the evolutionary conserved NLRs, together with AIM2 and pyrin, can assemble into a multimeric protein complex that is called the inflammasome (see poster).| An inflammasome assembles in response to a diverse range of pathogen-associated or danger-associated molecular patterns (PAMPs or DAMPs). The inflammasome platform leads to activation of caspase-1 through proximity-induced self-cleavage" SIGNOR-256422 RPL18 protein Q07020 UNIPROT "60S cytosolic large ribosomal subunit" complex SIGNOR-C287 SIGNOR "form complex" binding -1 25901680 t lperfetto "Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins." SIGNOR-262481 LAMTOR4 protein Q0VGL1 UNIPROT LAMTOR complex SIGNOR-C26 SIGNOR "form complex" binding 9606 20381137 t lperfetto "Mammals express four rag proteinsRaga, ragb, ragc, and ragdthat form heterodimers consisting of raga or ragb with ragc or ragd. Raga and ragb, like ragc and ragd, are highly similar to each other and are functionally redundant" SIGNOR-164778 "all-trans-retinoic acid" smallmolecule CHEBI:15367 ChEBI RARA protein P10276 UNIPROT "up-regulates activity" "chemical activation" 9606 17132853 t miannu "The physiological effects of retinoic acids (RAs) are mediated by members of two families of nuclear receptors, the retinoic acid receptors (RARs) and the retinoid X receptors (RXRs), which are encoded by three distinct human genes, RXRalpha, RXRbeta, and RXRgamma." SIGNOR-256194 FZD2 protein Q14332 UNIPROT DVL3 protein Q92997 UNIPROT "up-regulates activity" binding 9606 23151663 t areggio "Upon ligand binding, DVL proteins are recruited to Frizzled receptors at the plasma membrane and co-recruit cytoplasmic transducers, such as Axin, CK1 and GSK3 binding protein (GBP), presumably along with their partners, to promote ?-catenin-dependent signalling. " SIGNOR-258962 "β-D-fructose 6-phosphate" smallmolecule CHEBI:57634 ChEBI "beta-D-fructofuranose 1,6-bisphosphate(4-)" smallmolecule CHEBI:32966 ChEBI "up-regulates quantity" "precursor of" 9606 16051738 t miannu "Phosphofructokinase catalyzes the rate-limiting, ATP-mediated phosphorylation of F6P to FBP. PFK is a homo- or heterotetramer with a molecular mass of approximately 380 kDa, and the enzyme is allosterically regulated, among other metabolites, by 2,3-DPG.35 Three different subunits have been identified in humans: PFK-M (muscle), PFK-L (liver), and PFK-P (platelet).The subunits are expressed in a tissue-specific manner and, in erythrocytes, 5 isoenzymes of varying subunit composition (M4, M3L1, M2L2, ML3, and L4) can be identified." SIGNOR-266463 FBXL7 protein Q9UJT9 UNIPROT BIRC5 protein O15392 UNIPROT "down-regulates quantity by destabilization" binding 10090 BTO:0002268 25778398 t miannu "Fbxl7 targets survivin for polyubiquitylation and proteasomal degradation.these data suggest that the Skp1·Cul1·F-box protein complex subunit Fbxl7 modulates mitochondrial function by controlling the cellular abundance of survivin. These results suggest that both Lys-90 and Lys-91 are critical for Fbxl7-mediated polyubiquitylation." SIGNOR-272436 CDK1 protein P06493 UNIPROT NFAT5 protein O94916 UNIPROT up-regulates phosphorylation Thr135 TVQQHPStPKRHTVL 9606 BTO:0000007 21209322 t lperfetto "High nacl-induced activation of cdk5 increases phosphorylation of the osmoprotective transcription factor tonebp/orebp at threonine 135, which contributes to its rapid nuclear localization. we performed in vitro kinase assays using the tonebp/orebp peptide containing t135 as substrate (figure 3b, right panel) and various recombinant kinases. The peptide is strongly phosphorylated by cdk5, less by cdk1." SIGNOR-170882 Ub:E2 complex SIGNOR-C497 SIGNOR RNF157 protein Q96PX1 UNIPROT "up-regulates activity" ubiquitination 9606 34199813 t miannu "The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t" SIGNOR-270959 GGCX protein P38435 UNIPROT F9 protein P00740 UNIPROT "up-regulates activity" carboxylation 9606 31226734 t lperfetto "Thus, vitamin K acts as a cofactor for GGCX via the vitamin K cycle and exerts physiological effects through its regulation of VKDPs [29]. More than 20 VKDPs have been found. Osteocalcin promotes bone formation, and blood coagulation factors II, VII, IX, and X activate blood coagulation. Matrix Gla protein suppresses cardiovascular calcification, and brain-expressed Gas 6 promotes neural differentiation [29]. GGCX is an enzyme that converts glutamic acid (Glu) residues to Gla residues, so that the Gla-containing proteins can exert various physiological actions such as blood coagulation and bone formation." SIGNOR-265920 WASF2 protein Q9Y6W5 UNIPROT "WAVE complex" complex SIGNOR-C271 SIGNOR "form complex" binding 9606 BTO:0000567 15070726 t lperfetto "Here we purify Wave-2 from HeLa cells. Five proteins, Sra, Nap, Wave-2, Abi, and Hspc, are copurified, indicating that they form a tight complex. " SIGNOR-261871 mTORC2 complex SIGNOR-C2 SIGNOR MYC protein P01106 UNIPROT up-regulates 9606 24856037 f miannu "MTORC1 and mTORC2 converge on c-Myc to control metabolic reprogramming in cancer. mTORC1 and mTORC2 conspire to link growth factor receptor–PI3K signaling with c-Myc-dependent metabolic reprogramming by controlling both c-Myc levels and activity" SIGNOR-256171 ETV4 protein P43268 UNIPROT POU5F1 protein Q01860 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 24983502 f miannu "Transcriptional activation of oct4 by the ets transcription factor pea3 in nccit human embryonic carcinoma cells" SIGNOR-205173 CDK8 protein P49336 UNIPROT H3C1 protein P68431 UNIPROT "down-regulates activity" phosphorylation Ser11 TKQTARKsTGGKAPR 18418385 t "Ser 11 phosphorylation of H3 is either activatory and inhibitory as promotes DNA condensation (activatory) and induce transcription (inhibitory)." lperfetto "However, within T/G-Mediator, cdk8 phosphorylates serine-10 on histone H3, which in turn stimulates H3K14 acetylation by GCN5L within the complex. Tandem phosphoacetylation of H3 correlates with transcriptional activation, and ChIP assays demonstrate co-occupancy of T/G-Mediator components at several activated genes in vivo." SIGNOR-273171 PPP2R5C protein Q13362 UNIPROT Gbeta proteinfamily SIGNOR-PF4 SIGNOR down-regulates binding 9606 16456541 t "inferred from 70% of family members" gcesareni "B56-containing pp2a dephosphorylate erk and their activity is controlled by the early gene iex-1 and erk" SIGNOR-269900 "Sumanirole maleate" chemical CID:9818478 PUBCHEM DRD2 protein P14416 UNIPROT up-regulates "chemical activation" 9606 Other t Selleck gcesareni SIGNOR-207594 HDAC2 protein Q92769 UNIPROT "MBD3/NuRD complex" complex SIGNOR-C338 SIGNOR "form complex" binding 9606 27098840 t miannu "The NuRD complex is a multi-protein transcriptional corepressor that couples histone deacetylase and ATP-dependent chromatin remodelling activities.In humans, an assembly of proteins called the NuRD complex makes chromatin more compact by removing acetyl groups from nucleosomes. This complex is important for early development and for the stability and repair of our genes. Three proteins make up its core: HDAC1, which removes the acetyl group from the nucleosome; MTA1, which acts as a scaffold to hold the complex together; and RBBP4, which enables the complex to interact with nucleosomes. MBD2 and MBD3 are members of the methyl cytosine-guanosine (CpG)-binding domain (MBD) family of proteins42; 43. Of the five MBD members, only MBD2 and MBD3 associate with NuRD and are required for the complex formation and gene repression." SIGNOR-263850 SCF-SKP2 complex SIGNOR-C136 SIGNOR E2F1 protein Q01094 UNIPROT "down-regulates quantity by destabilization" polyubiquitination 9606 BTO:0001938 10559858 t miannu "P45 SKP2 binds to a specific domain of E2F-1. We propose a model in which an SCFSKP2-dependent ubiquitination pathway contributes to the timely ubiquitination and degradation of E2F-1 in the S/G2 phases of the cell cycle." SIGNOR-272557 SRC protein P12931 UNIPROT GRIN2A protein Q12879 UNIPROT "up-regulates activity" phosphorylation Tyr1267 PATGEQVyQQDWAQN -1 10195142 t lperfetto "To gain further insight into the roles of Src and Fyn in the phosphorylation and regulation of the NMDA receptor, we have characterized the tyrosine phosphorylation of NR2A and NR2B by exogenous Src and FynIn the case of NR2A, three potential tyrosine phosphorylation sites have been proposed: Tyr1105, Tyr1267 and Tyr1387 (Zheng et al. 1998; Bi et al. 2000), all of which are similarly located in the C-terminal, cytoplasmic domain." SIGNOR-247167 ETS1 protein P14921 UNIPROT BAX protein Q07812 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0002181 17213822 f miannu "Our results suggest that the interaction between ETS1 and GFI1 facilitates their binding to specific sites on the Bax promoter and represses Bax expression in vivo." SIGNOR-254204 G6PC2 protein Q9NQR9 UNIPROT "alpha-D-glucose 6-phosphate(2-)" smallmolecule CHEBI:58225 ChEBI "down-regulates quantity" "chemical modification" 9606 12093795 t miannu "Glucose-6-phosphatase (G6Pase), a key enzyme in glucose homeostasis, is anchored to the endoplasmic reticulum by nine transmembrane helices. The amino acids comprising the catalytic center of G6Pase include Lys(76), Arg(83), His(119), Arg(170), and His(176). During catalysis, a His residue in G6Pase becomes phosphorylated generating an enzyme-phosphate intermediate. Glucose-6-phosphatase (G6Pase,1 EC 3.1.3.9), a key enzyme in glucose homeostasis, catalyzes the hydrolysis of glucose 6-phosphate (G6P) to glucose and phosphate, the terminal steps in gluconeogenesis and glycogenolysis" SIGNOR-266583 hexestrol chemical CHEBI:31669 ChEBI ESR1 protein P03372 UNIPROT "down-regulates activity" "chemical inhibition" -1 9048584 t miannu "In total 37 substances were tested for both ER subtypes (Fig. 3 and Table 1). In Fig. 3 several examples of typical competitor curves obtained are shown. In all cases monophasic curves were obtained for compounds with significant affinity. . The present study is the first in which the ligand binding properties of both ER subtypes are measured separately, and caution is needed when comparing RBAs from this study with the previous studies involving mixtures of ER subtypes." SIGNOR-258593 CyclinD3/CDK11B complex SIGNOR-C543 SIGNOR EIF3F protein O00303 UNIPROT "up-regulates activity" phosphorylation Thr119 GAARVIGtLLGTVDK 19245811 t lperfetto "Here, we identified a second eIF3f phosphorylation site (Thr119) by CDK11(p46) during apoptosis. We demonstrated that eIF3f is directly phosphorylated by CDK11(p46) in vivo. Phosphorylation of eIF3f plays an important role in regulating its function in translation and apoptosis. Phosphorylation of eIF3f enhances the association of eIF3f with the core eIF3 subunits during apoptosis. " SIGNOR-273132 CyclinK/CDK12 complex SIGNOR-C37 SIGNOR POLR2A protein P24928 UNIPROT "up-regulates activity" phosphorylation Ser1861 TPTSPKYsPTSPKYS 9606 BTO:0006413 32917631 t "Ser2 in CTD of PolII" lperfetto "Together, these studies demonstrate the important, yet largely redundant, role for CDK12 and CDK13 for the regulation of POLII CTD phosphorylation at multiple residues, as well as the global role for both of these kinases in regulating POLII occupancy across the genome.|CDK12 and CDK13 are thus evolutionarily related and structurally similar kinases, and biochemical assays have demonstrated that both have POLII C-terminal domain (CTD) kinase activity and the ability to phosphorylate the Ser2 residue of the repetitive CTD heptad sequence" SIGNOR-273105 14-3-3 proteinfamily SIGNOR-PF7 SIGNOR GRB10 protein Q13322 UNIPROT up-regulates binding 9606 15722337 t miannu "The interaction of phosphorylated grb10 with 14-3-3 may lead to the translocation of grb10 back to the cytosol" SIGNOR-134198 BLOC-3 complex SIGNOR-C253 SIGNOR RAB38 protein P57729 UNIPROT "up-regulates activity" "guanine nucleotide exchange factor" 9606 23174301 t lperfetto "HPS1/HPS4 was active exclusively for RAB32 and RAB38. Moreover, when overexpressed with HPS1 in HeLa cells, a mitochondrially restricted form of HPS4 preferentially recruited GFP-tagged RAB32 or RAB38 – but not the related RAB7 or RAB9 – to mitochondria. Activity in both assays required both HPS1 and HPS4. Finally, depletion of HPS1 or HPS4 by siRNA in a pigmented human melanoma cell line, MNT-1, resulted in the mislocalization of RAB32. These data provide strong evidence that BLOC-3 is a selective GEF for RAB32 and RAB38 " SIGNOR-260694 MAPK1 protein P28482 UNIPROT GTF2I protein P78347 UNIPROT up-regulates phosphorylation Ser668 INTKALQsPKRPRSP 9606 10648599 t lperfetto "Tfii-i can be phosphorylated in vitro by erk and mutation of consensus map kinase substrate sites at serines 627 and 633 impairs the phosphorylation of tfii-i by erk and its activity on the c-fos promoter. These results suggest that erk regulates the activity of tfii-i by direct phosphorylation." SIGNOR-74296 BMP7 protein P18075 UNIPROT Brown_adipogenesis phenotype SIGNOR-PH27 SIGNOR up-regulates 9606 18719589 f fspada "Here we demonstrate that whereas some members of the family of bone morphogenetic proteins (bmps) support white adipocyte differentiation, bmp7 singularly promotes differentiation of brown preadipocytes even in the absence of the normally required hormonal induction cocktail." SIGNOR-180305 MAPK1 protein P28482 UNIPROT BCL2 protein P10415 UNIPROT "up-regulates quantity by stabilization" phosphorylation Thr74 ARTSPLQtPAAPGAA 9606 BTO:0000567 10669763 t lperfetto "In endothelial cells, tumor necrosis factor alpha (tnf-alpha) induces dephosphorylation and subsequent ubiquitin-dependent degradation of the antiapoptotic protein bcl-2. Here, we investigate the role of different putative phosphorylation sites to facilitate bcl-2 degradation" SIGNOR-74927 GMIP protein Q9P107 UNIPROT CDC42 protein P60953 UNIPROT "down-regulates activity" "gtpase-activating protein" 9606 BTO:0000007 32203420 t Luana "We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2)." SIGNOR-260507 U0126 chemical CHEBI:90693 ChEBI MAP2K1 protein Q02750 UNIPROT down-regulates "chemical inhibition" 9606 9873633 t gcesareni "The mek1/2 inhibitors pd98059, sl327, and u0126 have been extensively used to implicate erk1/2 in neuroplasticity. u0126 was found to functionally antagonize ap-1 transcriptional activity via noncompetitive the dual specificity kinase mek with an ic50 of 0.07 microm for mek 1 and 0.06 microm for mek 2." SIGNOR-62892 ARHGAP20 protein Q9P2F6 UNIPROT CDC42 protein P60953 UNIPROT "down-regulates activity" "gtpase-activating protein" 9606 BTO:0000007 32203420 t Luana "We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2)." SIGNOR-260474 FOXP2 protein O15409 UNIPROT FOXP2 protein O15409 UNIPROT "up-regulates activity" binding -1 16407075 t miannu "Our studies also reveal that the FOXP2 forkhead domain can form a domain-swapped dimer. The most surprising finding from these studies is that the FOXP2 forkhead domain can form a domain-swapped dimer. Disease-related mutations, sequence comparison, and biochemical analyses argue strongly that this domain swapping is a physiologically relevant function evolved in the P branch of FOX proteins." SIGNOR-225738 PFKP protein Q01813 UNIPROT "β-D-fructose 6-phosphate" smallmolecule CHEBI:57634 ChEBI "down-regulates quantity" "chemical modification" 9606 16051738 t miannu "Phosphofructokinase catalyzes the rate-limiting, ATP-mediated phosphorylation of F6P to FBP. PFK is a homo- or heterotetramer with a molecular mass of approximately 380 kDa, and the enzyme is allosterically regulated, among other metabolites, by 2,3-DPG.35." SIGNOR-266469 "diarsenic trioxide" chemical CHEBI:30621 ChEBI PML-RARalpha "fusion protein" SIGNOR-FP2 SIGNOR "down-regulates quantity by destabilization" "chemical inhibition" 9606 24344243 t "ATO was shown to degrade PML-RARa via its PML moiety further reinforcing the idea that APL is addicted to the PML-RARa oncoprotein" SIGNOR-259924 R547 chemical CID:6918852 PUBCHEM CDK1 protein P06493 UNIPROT "down-regulates activity" "chemical inhibition" -1 22037378 t miannu "Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here." SIGNOR-259792 PHF12 protein Q96QT6 UNIPROT TLE2 protein Q04725 UNIPROT "up-regulates activity" binding 9606 BTO:0000007 11390640 t miannu "We have cloned and characterized a new member of the PHD zinc finger family called Pf1 that interacts with two global transcription corepressors: mSin3A and TLE. Pf1 interacts with TLE. The Groucho/TLE proteins are members of an abundant corepressor family, and we hypothesized that Pf1 might interact with TLE family members. Together, these data suggest that in the absence of interactions with mSin3A, Gal4-Pf1 (102–273 L212P/A216P)-dependent repression can be attributed to interaction with endogenous TLE." SIGNOR-266992 TPH1 protein P17752 UNIPROT tryptophan smallmolecule CHEBI:27897 ChEBI "down-regulates quantity" "chemical modification" 9606 31024440 t brain lperfetto "In serotonergic neurons Trp serves as the precursor for 5-HT. The 5-HT metabolic pathway is initiated by Trp being hydroxylated to the intermediate 5-hydroxytryptophan (5-HTP), which is subsequently decarboxylated to become 5-HT|Thus, the rate limiting step in the biosynthesis of 5-HT is the hydroxylation of Trp which is catalyzed by the enzyme tryptophan hydroxylase (TPH) (Figure 1). This enzyme is specific for 5-HT producing cells, however, it is present in two different isoforms, TPH1 and TPH2 [reviewed in (22, 23)]." SIGNOR-264009 HCK protein P08631 UNIPROT HCK protein P08631 UNIPROT "up-regulates activity" phosphorylation Tyr51 ASPHCPVyVPDPTST 9606 BTO:0000007 10934191 t "Hck transiently expressed in human embryonic kidney 293T cells was found to be phosphorylated at Tyr-29 and Tyr-388, proving that Hck can also undergo autophosphorylation at both sites in vivo. autophosphorylation of Tyr-29 contributes significantly to the activation of Hck." SIGNOR-251265 CyclinK/CDK12 complex SIGNOR-C37 SIGNOR POLR2A protein P24928 UNIPROT "up-regulates activity" phosphorylation Ser1910 TPTSPKYsPTSPTYS 9606 BTO:0006413 32917631 t "Ser2 in CTD of PolII" lperfetto "Together, these studies demonstrate the important, yet largely redundant, role for CDK12 and CDK13 for the regulation of POLII CTD phosphorylation at multiple residues, as well as the global role for both of these kinases in regulating POLII occupancy across the genome.|CDK12 and CDK13 are thus evolutionarily related and structurally similar kinases, and biochemical assays have demonstrated that both have POLII C-terminal domain (CTD) kinase activity and the ability to phosphorylate the Ser2 residue of the repetitive CTD heptad sequence" SIGNOR-273106 PKN1 protein Q16512 UNIPROT CDC25C protein P30307 UNIPROT unknown phosphorylation Ser216 SGLYRSPsMPENLNR 9606 BTO:0000567 15791647 t lperfetto "A role for PKN1 in mediating arsenite-induced G(2)/M delay was supported by the finding that expression of a constitutively active form of PKN1 (PKN1AF3) in HeLa cells delayed the mitotic entry of cell cycle. Further experiments indicate that PKN1 directly phosphorylated serine 216 (Ser216) in Cdc25C, which then facilitated association between Cdc25C and 14-3-3." SIGNOR-249277 AREL1 protein O15033 UNIPROT DIABLO protein Q9NR28 UNIPROT "down-regulates quantity by destabilization" ubiquitination 9606 BTO:0002552 23479728 t lperfetto "Furthermore, the ubiquitination and degradation of SMAC, HtrA2, and ARTS were significantly enhanced in AREL1-expressing cells following apoptotic stimulation, indicating that AREL1 binds to and ubiquitinates cytosolic but not mitochondria-associated forms of IAP antagonists|" SIGNOR-267668 CNTFR protein P26992 UNIPROT STAT3 protein P40763 UNIPROT up-regulates 9606 10582086 f gcesareni "Clc/clf activates stat1 and stat3." SIGNOR-72774 SRC protein P12931 UNIPROT BCAR1 protein P56945 UNIPROT "up-regulates activity" phosphorylation Tyr287 RDPLLEVyDVPPSVE 10090 12972425 t lperfetto "Cas is a member of the focal adhesion complex. Phosphorylation of Cas by Src is an important event leading to cell transformation. Using mass spectrometry, we have mapped 11 sites in Cas that are phosphorylated by Src. These sites are all located between residues 132 and 414 of CasBased on these data, 11 tyrosine residues (132, 169, 183, 196, 238, 253, 271, 291, 301, 391, and 414) were phosphorylated by Src|the biological activity of Cas depends on its phosphorylation by Src (16–18). After phosphorylation, Cas associates with a number of proteins, including Crk, Src, phosphatidylinositol 3-kinase, Nck, and phospholipase Cgamma, via SH2 binding motifs" SIGNOR-246405 SREBF1 protein P36956 UNIPROT FASN protein P49327 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 20373869 t lperfetto "Ultimately, both the AKT and MAPK transduction pathways regulate FASN expression through the modulation of expression of sterol regulatory element-binding protein (SREBP)-1c, which binds to regulatory elements in the FASN promoter. Proto-oncogene FBI-1 (Pokemon), a transcription factor of the bric--brac tramtrack broad complex/pox viruses and zinc fingers (BTB/POZ) domain family, interacts directly with SREBP-1c through its DNA-binding domain to synergistically activate the transcription of FASN" SIGNOR-242884 FBXO3 protein Q9UK99 UNIPROT SQSTM1 protein Q13501 UNIPROT "down-regulates quantity by destabilization" binding 9606 BTO:0000007 25721664 t miannu "F-box protein Fbxo3 targets Smurf1 ubiquitin ligase for ubiquitination and degradation. Here we show that another F-box protein Fbxo3, belonging to the FBXO type protein family, also interacts with and targets Smurf1 for poly-ubiquitination and proteasomal degradation. The SCF complex is composed of F-box protein, Skp1, Cullin1 (Cul1) and ROC1. Fbxo3, whose substrates are few, forms SCF Fbxo3 ubiquitin ligase and regulates the degradations of Fbxl2, p62, HIPK2 and p300 through the ubiquitin-proteasome pathway." SIGNOR-272444 GRK3 protein P35626 UNIPROT TBXA2R protein P21731-2 UNIPROT "down-regulates activity" phosphorylation Ser239 AQQRPRDsEVEMMAQ 9606 16956790 t done miannu " These data suggest a model whereby agonist-induced PKC phosphorylation of Ser(145) partially impairs TPbeta signalling while GRK2/3 phosphorylation at both Ser(239) and Ser(357) within its IC(3) and C-tail domains, respectively, sterically inhibits G-protein coupling, profoundly desensitizing signalling, and promotes beta-arrestin association and, in turn, facilitates TPbeta internalization." SIGNOR-274090 DNM1L protein O00429 UNIPROT ARP2/3 complex SIGNOR-C146 SIGNOR "up-regulates activity" binding 10090 BTO:0002295 31063459 t lperfetto "Importantly, we found that crosstalk between phosphorylated Drp1S600 (p-Drp1S600) and the actin-binding protein com- plex Arp2/3 is a required step in mitochondrial Drp1 recruitment and mitochondrial fission under HG conditions." SIGNOR-262550 INPP4B protein O15327 UNIPROT "phosphatidylinositol bisphosphate" smallmolecule CHEBI:37328 ChEBI "down-regulates quantity" "chemical modification" 9606 21127264 t gcesareni "Collectively this data indicates INPP4B is the only PtdIns(3,4)P2 4-phosphatase expressed in breast cancer cells and suggests a correlation between INPP4B and hormone receptor status in human breast cancer" SIGNOR-252433 Cell-Cell_contact stimulus SIGNOR-ST13 SIGNOR CDH1 protein P12830 UNIPROT up-regulates 9606 24532814 f milica "Adherens junctions and the cadheriBeta-catenin complex have been found to activate the Hippo signaling pathway and inhibit cell growth. Cadherin-mediated stimulation of the Hippo signaling pathway requires cadherin ligation and the formation of a homophilic bond – consistent with a role in cell-cell contact – and works owing to phosphorylation of YAP by Lats and nuclear exclusion of YAP." SIGNOR-230707 CDK5/CDK5R1 complex SIGNOR-C144 SIGNOR MAPT protein P10636 UNIPROT "down-regulates activity" phosphorylation Thr529 TPGSRSRtPSLPTPP 9606 BTO:0000590 12387894 t lperfetto "We found that cdk5 phosphorylated tau(441) at Thr-181, Ser-199, Ser-202, Thr-205, Thr-212, Ser-214, Thr-217, Thr-231, Ser-235, Ser-396, and Ser-404, but not at Ser-262, Ser-400, Thr-403, Ser-409, Ser-413, or Ser-422. GSK-3beta phosphorylated all the cdk5-catalyzed sites above except Ser-235." SIGNOR-251594 NYYJKMXNVNFOFQ-MHZLTWQESA-N chemical CID:9829836 PUBCHEM ADRB3 protein P13945 UNIPROT "up-regulates activity" "chemical activation" 10030 BTO:0000457 20590599 t Luana "There were several β3-selective compounds (e.g. AZ 40140d, L 755507, L 748337 and TAK 677)" SIGNOR-257856 IRS1 protein P35568 UNIPROT PI3K complex SIGNOR-C156 SIGNOR "up-regulates activity" binding 9606 BTO:0000551 20966354 t lperfetto "Irs proteins are capable of both regulating and activating pi3k, depending on the cell of origin." SIGNOR-256170 ROS stimulus SIGNOR-ST2 SIGNOR NLRP3 protein Q96P20 UNIPROT "up-regulates activity" 28531279 f lperfetto "Different mechanisms have been proposed for NLRP3 activation, including potassium efflux, calcium influx, reactive oxygen species (ROS), oxidized mitochondrial DNA, translocation of cardiolipin from the inner mitochondrial membrane, phagosome destabilization, perturbation in cell volume and pore-formation mechanisms driven by the host or bacteria" SIGNOR-256427 CTTNBP2NL protein Q9P2B4 UNIPROT STRN protein O43815 UNIPROT "up-regulates activity" binding 9606 23015759 t miannu "Although CTTNBP2 and CTTNBP2NL are different in terms of tissue and subcellular distribution, our data indicate that, similar to CTTNBP2NL, CTTNBP2 associates with members of the striatin family, namely striatin and zinedin. Moreover, CTTNBP2 is critical for the distribution of striatin and zinedin in dendritic spines. The role of CTTNBP2 in the regulation of the synaptic distribution of striatin and zinedin suggests that CTTNBP2 regulates synaptic signaling through PP2A." SIGNOR-261702 oxaprozin chemical CHEBI:7822 ChEBI PTGS1 protein P23219 UNIPROT "down-regulates activity" "chemical inhibition" 9606 BTO:0000132;BTO:0003652 9650852 t miannu "We used human platelets cyclooxygenase-1 and interleukin-1beta-stimulated human synovial cell cyclooxygenase-2 for measuring cyclooxygenase selectivity. The presence of the enzymes was confirmed by immunoblotting and immunoprecipitation analysis, and by the reverse transcriptase-polymerase chain reaction. Mean IC50 values (microM) for human platelet cyclooxygenase-1 and interleukin-1beta-stimulated human synovial cell cyclooxygenase-2 and cyclooxygenase-1/-2 IC50 ratio of various NSAIDs were as follows: aspirin, 3.2, 26, 0.12; diclofenac, 0.037, 0.00097, 38; etodolac, 122, 0.68, 179; ibuprofen, 3.0, 3.5, 0.86; indomethacin, 0.013, 0.044, 0.30; loxoprofen (active metabolite), 0.38, 0.12, 3.2; NS-398, 12, 0.0095, 1263; oxaprozin, 2.2, 36, 0.061; zaltoprofen, 1.3, 0.34, 3.8; respectively." SIGNOR-258929 RBBP7 protein Q16576 UNIPROT "MBD3/NuRD complex" complex SIGNOR-C338 SIGNOR "form complex" binding 9606 27098840 t miannu "The NuRD complex is a multi-protein transcriptional corepressor that couples histone deacetylase and ATP-dependent chromatin remodelling activities.In humans, an assembly of proteins called the NuRD complex makes chromatin more compact by removing acetyl groups from nucleosomes. This complex is important for early development and for the stability and repair of our genes. Three proteins make up its core: HDAC1, which removes the acetyl group from the nucleosome; MTA1, which acts as a scaffold to hold the complex together; and RBBP4, which enables the complex to interact with nucleosomes. MBD2 and MBD3 are members of the methyl cytosine-guanosine (CpG)-binding domain (MBD) family of proteins42; 43. Of the five MBD members, only MBD2 and MBD3 associate with NuRD and are required for the complex formation and gene repression." SIGNOR-263848 PRKCD protein Q05655 UNIPROT FLI1 protein Q01543 UNIPROT down-regulates phosphorylation Thr312 TNGEFKMtDPDEVAR 9606 24058639 t miannu "After tgf-_ stimulation, fli1 phosphorylation by protein kinase c-_ induces disassembly of this transcription repressor complex and the acetylation of fli1 by pcaf, leading to the loss of fli1 dna binding. / phosphorylation of fli1 at threonine 312 decreases its interactions with p300 and hdac1" SIGNOR-202693 KDM2A protein Q9Y2K7 UNIPROT RELA protein Q04206 UNIPROT down-regulates demethylation Lys218 EIFLLCDkVQKEDIE 9606 SIGNOR-C13 20080798 t miannu "Fbxl11 and nsd1 have opposite effects on nf-kb; both bind to p65 subunit after activation of nf-kb. / nsd1 activates nf-kb and reverses the inhibitory effect of fbxl11 / these data confirm that fbxl11 and nsd1 constitute an enzyme pair that methylates and demethylates p65 on k218 and 221 in response to cytokine stimulation." SIGNOR-163384 TNKS2 protein Q9H2K2 UNIPROT BLZF1 protein Q9H2G9 UNIPROT "down-regulates quantity by destabilization" ADP-ribosylation 9606 BTO:0000007 21478859 t lperfetto "Here, we identify RNF146, a RING-domain E3 ubiquitin ligase, as a positive regulator of Wnt signalling. RNF146 promotes Wnt signalling by mediating tankyrase-dependent degradation of axin. Mechanistically, RNF146 directly interacts with poly(ADP-ribose) through its WWE domain, and promotes degradation of PARsylated proteins. Using proteomics approaches, we have identified BLZF1 and CASC3 as further substrates targeted by tankyrase and RNF146 for degradation." SIGNOR-263384 TTBK2 protein Q6IQ55 UNIPROT KIF2A protein O00139 UNIPROT "down-regulates activity" phosphorylation Ser135 SSAQQNGsVSDISPV 9534 26323690 t Manara "TTBK2 phosphorylates KIF2A primarily at growing MT ends and counteracts the depolymerization activity of KIF2A" SIGNOR-260926 PPARGC1A protein Q9UBK2 UNIPROT SOD2 protein P04179 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 20089851 f Regulation miannu "PGC-1α has been reported to induce Mn-SOD expression" SIGNOR-251762 serotonin(1+) smallmolecule CHEBI:350546 ChEBI HTR1D protein P28221 UNIPROT "up-regulates activity" "chemical activation" 9606 BTO:0002524 31160049 t "Ligand-GPCR dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257518 CDK4 protein P11802 UNIPROT MYOD1 protein P15172 UNIPROT down-regulates binding 9606 SIGNOR-C18 21902831 t gcesareni "In contrast to cdk2, cyclin d/cdk4 blocks myod activity through an as yet unclear mechanism that may involve direct binding. Cyclin d/cdk4 can also block the activity of myogenin and all mef2 isoforms." SIGNOR-176527 BRD4 protein O60885 UNIPROT EP300 protein Q09472 UNIPROT "up-regulates activity" binding 9606 32544088 t lperfetto "In this study, we explored the role of Brd4 and its interaction with the p300 acetyltransferase in the regulation of Nox4 and the in vivo efficacy of a BET inhibitor to reverse established age-associated lung fibrosis. |Together, these studies suggest that Brd4 enhances p300-mediated histone acetylation." SIGNOR-262064 NFATC2 protein Q13469 UNIPROT MEF2D protein Q14814 UNIPROT up-regulates binding 9606 11796223 t lperfetto "Upon dephosphorylation by calcineurin, nfatc2, also referred to as nfatp/nfat1, translocates to the nucleus where it directly associates with mef2a and -d. Nfatc2 stimulates mef2-dependent transcription by facilitating recruitment of the p300 coactivator to mef2-response elements." SIGNOR-117589 PPP2CB protein P62714 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR down-regulates dephosphorylation 9606 8650155 t gcesareni "These results confirm that the activity changes observed are achieved by a reversible phosphorylation mechanism, and also argue that pp2a may negatively regulate rac-pk activity in vivo. Dephosphorylation of the activated rac-pk in itro by pp2ac resulted in an 87% reduction of kinase activity" SIGNOR-42050 MYOD1 protein P15172 UNIPROT SP1 protein P08047 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 10090 9148896 t lperfetto "These data suggest a regulatory model in which MyoD activation during myogenesis causes the down-regulation of Sp1, which contributes to the repression of GLUT1 gene transcription and, therefore, leads to the reduction in GLUT1 expression and glucose transport." SIGNOR-241765 SETD1A protein O15047 UNIPROT "Set1-Ash2 HMT complex" complex SIGNOR-C352 SIGNOR "form complex" binding 9606 BTO:0000567 12670868 t miannu "Our analysis of HCF-1-associated proteins suggests that a K4 histone H3 HMT complex has been conserved from yeast to humans in both structure and activity: the Set1/Ash2 HMT. The results presented here show that this Set1/Ash2 HMT complex, in mutually exclusive interactions, can associate with HCF-1 bound to the repressive Sin3 HDAC or the transcriptional activator VP16, indicating a diversity of transcriptional regulatory roles." SIGNOR-264478 "MSL acetyltransferase" complex SIGNOR-C344 SIGNOR H2BC20P protein Q6DN03 UNIPROT "down-regulates activity" monoubiquitination Lys35 KKRKRSRkESYSIYV 9606 21726816 t miannu "MSL1/2 ubiquitylates histone H2B on K 34. Importantly, only mono-ubiquitylation of H2B by MSL1/2 was detected in cells (data not shown), suggesting that MSL1/2, like RNF20/RNF40, was mainly a mono-ubiquitylase under physiological conditions.the MOF-MSL complex functions to promote both H4 K16ac and H2B K34ub. H2B K34ub, in turn, promotes H2B K120ub, H3 K4me3 and K79me2 to facilitate transcription elongation." SIGNOR-271988 SOCS3 protein O14543 UNIPROT IRS1 protein P35568 UNIPROT down-regulates binding 9606 23115649 t gcesareni "Irs-1 is the major signaling protein that socs3 targets to inhibit insulin signaling" SIGNOR-199361 MAPKAPK5 protein Q8IW41 UNIPROT KALRN protein O60229 UNIPROT "up-regulates activity" phosphorylation Ser487 DVLQRPLsPGNSESL -1 22508986 t miannu "The brain-specific nucleotide exchange factor kalirin-7 (Kal7) was identified as an MK5 interaction partner and substrate protein. The MK5 substrate Kal7, a Rho GEF and known activator of Rac GTPases, further contributes to PAK activation and actin filament reorganization. Thus, the coordinated phosphorylation of Borg proteins and Kal7 by ERK3 and MK5 constitute a novel signaling cascade involving feed-forward circuits, multiple GTPases, and cytoskeletal elements. The fragment SR3-6, but not the mutated fragment SR3-6-S487A, is phosphorylated by MK5." SIGNOR-263093 UBE2J1 protein Q9Y385 UNIPROT DIO2 protein Q92813 UNIPROT "down-regulates quantity by destabilization" ubiquitination Lys244 KIAYLGGkGPFSYNL 9606 BTO:0001379 29892818 t scontino "ER residency places D2 physically close to an array of proteins that interact and modify the D2 molecule via ubiquitination and targeting to the proteasomal system, explaining its relatively short half-life. Both ubiquitin conjugases UBC6 and or UBC7 interact with D2 and support D2 ubiquitination. Two Lys residues in D2 are involved in this process, K237 and K244." SIGNOR-267482 CSNK2B protein P67870 UNIPROT IKZF1 protein Q13422 UNIPROT down-regulates phosphorylation Ser295 LSDTPYDsSASYEKE 9606 21750978 t miannu "We identified four novelikarosphosphorylation sites that are phosphorylated by ck2 kinase. / ck2-mediated phosphorylation inhibits ikaros' localization to pc-hc / hyperphosphorylation of ikaros promotes its degradation by the ubiquitin/proteasome pathway / these results suggest that ck2 kinase directly phosphorylates amino acids 13, 23, 63, 101 and 294 in vivo" SIGNOR-174848 PTPRS protein Q13332 UNIPROT Synaptic_plasticity phenotype SIGNOR-PH158 SIGNOR up-regulates 9606 BTO:0000938 27225731 f miannu "LAR (for leukocyte common antigen-related) is a family of receptor protein tyrosine phosphatases (LAR-RPTPs) with three known members: LAR/PTPRF, PTPδ/PTPRD, and PTPσ/PTPRS. In mammals, LAR-RPTPs have been shown to regulate dendrite and excitatory synapse development and maintenance" SIGNOR-264091 MTOR protein P42345 UNIPROT IRS1 protein P35568 UNIPROT "down-regulates activity" phosphorylation Ser307 TRRSRTEsITATSPA 9606 BTO:0000671 9335553 t lperfetto "These results indicate that activation of protein kinase c stimulates a kinase which can phosphorylate insulin receptor substrate-1 at serine 612, resulting in an inhibition of insulin signaling in the cell these data suggest that: 1) activation of pkctheta contributes to ikk and jnk activation by ffas;2) ikk and jnk mediate pkctheta signals for irs-1 serine phosphorylation and degradation; ser-302 phosphorylation is dependent on pi 3-kinase/mtor, whereas ser-307 depends on c-jun nh2-terminal kinase to inhibit irs1 tyrosine phosphorylation. Ser-636 is located around the pi 3-kinase binding site and, therefore, thought to inhibit pi 3-kinase signaling." SIGNOR-52700 NCAPH2 protein Q6IBW4 UNIPROT "Condensin II" complex SIGNOR-C342 SIGNOR "form complex" binding 9606 32445620 t miannu "The majority of higher eukaryotes, including humans, have two condensins, condensin I (CI) and II (CII) Although sharing the same SMC subunits (SMC2 and SMC4), condensin I and II have distinct non-SMC regulatory subunits, including the kleisin subunit (CAP-H and CAP-H2, respectively) and a pair of HEAT repeat subunits (CAP-D2/G and CAP-D3/G2, respectively; Figure 1B). the combined actions of both condensins contribute to formation of a nested-loop architecture necessary to achieve the highest level of chromosome compaction." SIGNOR-263910 POLR2D protein O15514 UNIPROT "RNA Polymerase II" complex SIGNOR-C391 SIGNOR "form complex" binding 9606 BTO:0000567 9852112 t lperfetto "Pol II is composed of 10–12 polypeptides ranging in size from 220 to 7 kDa, depending on the source of purification (11, 12, 13). The subunits of human pol II (or RNA polymerase B) have been defined as RPB1 (220 kDa), RPB2 (140 kDa), RPB3 (33 kDa), RPB4 (18 kDa), RPB5 (28 kDa), RPB6 (19 kDa), RPB7 (27 kDa), RPB8 (17 kDa), RPB9 (14.5 kDa), RPB10alpha (or RPB12, 7.0 kDa), RPB10beta (or RPB10, 7.6 kDa), and RPB11 (14 kDa) (3,11, 12, 13). RPB5, RPB6, RPB8, RPB10alpha, and RPB10beta are shared by all three eukaryotic RNA polymerases, whereas the rest of the RPB components are unique to pol II" SIGNOR-266164 MAPK3 protein P27361 UNIPROT METTL3 protein Q86U44 UNIPROT "up-regulates quantity by stabilization" phosphorylation Ser50 SPTFRSDsPVPTAPT 9606 BTO:0000007 33217317 t miannu "Mass spectrometry analysis showed that ERK phosphorylates METTL3 at three highly conserved residues: S43, S50, and S525 (Figures 2D and 2E). Mutational analysis further confirmed these three sites as main ERK phosphorylation sites (Figure 2F). Phosphorylation of METTL3 increases interaction with USP5, decreasing ubiquitination to stabilize the m6 A methyltransferase complex." SIGNOR-265945 CEP43 protein O95684 UNIPROT FGFR1OP/CEP350 complex SIGNOR-C52 SIGNOR "form complex" binding 9606 16314388 t miannu "Here we show that cap350 and fop (fgfr1 oncogene partner) form a centrosomal complex required for mt anchoring." SIGNOR-142358 RPA2 protein P15927 UNIPROT ATRIP protein Q8WXE1 UNIPROT up-regulates binding 9606 20068082 t gcesareni "Ssdna lesions are then coated by replication protein a (rpa), recruiting atr/atrip (atr-interacting protein) complexes via recognition and association of rpa-ssdna by atrip." SIGNOR-163176 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR FOXO proteinfamily SIGNOR-PF27 SIGNOR "down-regulates quantity by destabilization" phosphorylation 9606 19282669 t "inferred from 70% family members" lperfetto "Phosphorylation of foxo3a by erk1/2 at residues ser 294, ser 344 and ser 425 increases foxo3amdm2 interaction and enhances foxo3a degradation via an mdm2-dependent ubiquitin-proteasome pathway" SIGNOR-270146 FOXP3 protein Q9BZS1 UNIPROT IL10 protein P22301 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000782 24315995 f alessandro "FoxP3, a lineage-specification factor, executes its multiple activities mostly through transcriptional regulation of target genes. We identified an interleukin-10 (IL-10)-producing FoxP3(+) T regulatory cell population that contributes to IL-10-dependent type 2 cytokine bias in breast-cancer patients. Although genetic ablation of FOXP3 inhibited IL10 transcription, genome-wide analysis ruled out its role as a transcription factor for IL10" SIGNOR-254525 STAT5A protein P42229 UNIPROT RAD51 protein Q06609 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 15626738 t "FLT3-ITD-TKD dual mutants induce hyperactivation of STAT5 and up-regulation of its downstream targets Bcl-x(L) and RAD51 in Ba/F3 cells" SIGNOR-261552 FGF6 protein P10767 UNIPROT FGFR2 protein P21802 UNIPROT up-regulates binding 9606 8663044 t gcesareni "The nine known fgf ligands and the four signaling fgf receptors (and their alternatively spliced variants) are expressed in specific spatial and temporal patterns. The activity of this signaling pathway is regulated by ligand binding specificity, heparan sulfate proteoglycans, and the differential signaling capacity of individual fgf receptors." SIGNOR-42380 HMGA2 protein P52926 UNIPROT E4F1 protein Q66K89 UNIPROT down-regulates binding 9606 14645522 t miannu "Here we show that hmga2 associates with the e1a-regulated transcriptional repressor p120(e4f), interfering with p120(e4f) binding to the cyclin a promoter" SIGNOR-119537 AXL protein P30530 UNIPROT AXL protein P30530 UNIPROT "up-regulates activity" phosphorylation Tyr866 EVHPAGRyVLCPSTT -1 9178760 t llicata "Our data showed that various receptor substrates are at least associated with the C-terminal tyrosine pY821. Two additional potential autophosphorylation sites (pY866 and pY779) may play a minor role in binding of e€ector proteins" SIGNOR-250593 "CHIR 99021" chemical CHEBI:91091 ChEBI GSK3A protein P49840 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-190997 p38 proteinfamily SIGNOR-PF16 SIGNOR DROSHA protein Q9NRR4 UNIPROT "down-regulates activity" phosphorylation Ser300 RHRDNRRsPSLERSY 9606 BTO:0000007 25699712 t lperfetto "Our findings suggest that phosphorylation of Drosha at multiple sites including S300 promotes its translocation to the cytoplasm. Interestingly, GSK3beta can phosphorylate Drosha at S300 and S302 in vitro. This has been reported to promote the nuclear localization of Drosha under basal condition (Tang et al., 2011). Thus, it appears that phosphorylation of S300 by GSK3beta and p38 MAPK is involved in opposing processes. " SIGNOR-264847 TJP1 protein Q07157 UNIPROT ARVCF protein O00192 UNIPROT "up-regulates activity" binding 9615 BTO:0000837 15456900 t "Regulation of binding" miannu "We identified ARVCF as a binding partner of ZO-1 and ZO-2 and characterized the role of PDZ-domain proteins in plasma membrane and nuclear localization of ARVCF. E-cadherin, ZO-1, and ARVCF are recruited to sites of initial cell-cell contact. Binding of the ZO-1 PDZ domains per se does not facilitate membrane recruitment of ARVCF, indicating a requirement for the intact ZO-1 and possibly its association with membrane proteins and/or the cytoskeleton for this process." SIGNOR-252121 RFX1 protein P22670 UNIPROT HLA-DOB protein P13765 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000776 11823510 f "Class II transactivator is required for maximal expression of HLA-DOB in B cells|HLA-DO, encoded by the HLA-DOA and HLA-DOB genes, has been shown to function as a modulator of Ag presentation. DNA microarray comparisons between B cells wild-type and mutant for the master regulator of MHC class II transcription, class II transactivator (CIITA), identified HLA-DOA and HLA-DOB as being up-regulated by CIITA." SIGNOR-254022 sorafenib chemical CHEBI:50924 ChEBI RAF1 protein P04049 UNIPROT down-regulates "chemical inhibition" 9606 21654832 t gcesareni "Inhibition of map kinases mek, jnk, p38, and multikinases (braf, craf, vegfp by sorafenib) in wm-115 and m14 human melanoma cell lines led to either significant reduction or complete inhibition of the plk-1 protein expression." SIGNOR-174039 PTH1R protein Q03431 UNIPROT GNAQ protein P50148 UNIPROT "up-regulates activity" binding 28363951 t lperfetto "This calciotropic hormone exerts its actions via binding to the PTH/PTH-related peptide receptor (PTH1R), which couples to multiple heterotrimeric G proteins, including Gs and Gq/11." SIGNOR-270550 CDK2 protein P24941 UNIPROT RBL2 protein Q08999 UNIPROT unknown phosphorylation Ser1080 IFYYFSNsPSKRLRE 9606 11157749 t llicata "We now identify 22 in vivo phosphorylation sites of p130, targeted by diverse kinases, and present evidence for three cyclin-dependent kinase 4(6) [cdk4(6)] specific phosphorylations, which appear critical for controlling the growth-restraining activity of p130." SIGNOR-104671 threonine smallmolecule CHEBI:26986 ChEBI Thr-tRNA(Thr) smallmolecule CHEBI:29163 ChEBI "up-regulates quantity" "precursor of" 9606 25824639 t miannu "Here we show, using X-ray crystal structures and functional analyses, that a single molecule of borrelidin simultaneously occupies four distinct subsites within the catalytic domain of bacterial and human ThrRSs. These include the three substrate-binding sites for amino acid, ATP and tRNA associated with aminoacylation, and a fourth 'orthogonal' subsite created as a consequence of binding." SIGNOR-270508 CyclinK/CDK12 complex SIGNOR-C37 SIGNOR POLR2A protein P24928 UNIPROT "up-regulates activity" phosphorylation Ser1763 TPTSPSYsPTSPSYS 9606 BTO:0006413 32917631 t "Ser2 in CTD of PolII" lperfetto "Together, these studies demonstrate the important, yet largely redundant, role for CDK12 and CDK13 for the regulation of POLII CTD phosphorylation at multiple residues, as well as the global role for both of these kinases in regulating POLII occupancy across the genome.|CDK12 and CDK13 are thus evolutionarily related and structurally similar kinases, and biochemical assays have demonstrated that both have POLII C-terminal domain (CTD) kinase activity and the ability to phosphorylate the Ser2 residue of the repetitive CTD heptad sequence" SIGNOR-273108 ASB2 protein Q96Q27 UNIPROT FLNA protein P21333 UNIPROT "down-regulates quantity by destabilization" polyubiquitination 9606 BTO:0000567 18799729 t miannu "ASB2 is the specificity subunit of an E3 ubiquitin ligase complex and is proposed to exert its effects by regulating the turnover of specific proteins; however, no ASB2 substrates had been identified. Here, we report that ASB2 targets the actin-binding proteins filamin A and B for proteasomal degradation. " SIGNOR-271740 PRKCD protein Q05655 UNIPROT ADRB2 protein P07550 UNIPROT "down-regulates activity" phosphorylation Ser261 TGHGLRRsSKFCLKE -1 1848190 t lperfetto "We investigate the role of the beta 2-adrenergic receptor phosphorylation by protein kinase C in this regulatory process. Mutation of the serine-261, -262, -344 and -345 of the beta 2-adrenergic receptor prevented the phorbol-ester-induced phosphorylation of the receptor. This mutation also abolished the phorbol-ester-induced decrease in high-affinity agonist binding and potency of the beta 2-adrenergic receptor. We suggest that protein kinase C mediated phosphorylation of the receptor promotes its functional uncoupling." SIGNOR-248854 AGPAT4 protein Q9NRZ5 UNIPROT "phosphatidic acid" smallmolecule CHEBI:16337 ChEBI up-regulates "chemical modification" 9606 21173190 t lperfetto "The enzyme 1-acylglycerol-3-phosphate-O-acyltransferase (AGPAT) converts lysophosphatidic acid (LPA) to phosphatidic acid (PA).¬†" SIGNOR-267014 ACOT8 protein O14734 UNIPROT succinyl-CoA(5-) smallmolecule CHEBI:57292 ChEBI "down-regulates quantity" "chemical modification" 33148467 t lperfetto "The acyl-CoA thioesterase (ACOT) family catalyses the hydrolysis of acyl-CoA thioesters to their corresponding non-esterified fatty acid and coenzyme A (CoA)." SIGNOR-271810 CDK1 protein P06493 UNIPROT PLK1 protein P53350 UNIPROT "up-regulates activity" binding 9606 26259146 t miannu "Moreover, CDK1 phosphorylates RSF1 at Ser1375, and this phosphorylation is necessary for PLK1 recruitment. Subsequently, PLK1 phosphorylates RSF1 at Ser1359, stabilizing PLK1 deposition." SIGNOR-273589 AKT proteinfamily SIGNOR-PF24 SIGNOR YWHAZ protein P63104 UNIPROT unknown phosphorylation Ser58 VVGARRSsWRVVSSI 9606 BTO:0000007 11956222 t lperfetto "Ese data indicate that pkb/akt phosphorylates ser-58 on 14-3-3zeta both in vitro and in intact cells. The functional relevance of this phosphorylation remains to be determined." SIGNOR-244381 ACSL5 protein Q9ULC5 UNIPROT "long-chain fatty acid anion" smallmolecule CHEBI:57560 ChEBI "down-regulates quantity" "chemical modification" 9606 24269233 t "ACSs catalyze the conversion of FAs to their active form acyl-CoAs. The human genome codes for 26 ACS isozymes, which are classified into six subfamilies based on their substrate specificities toward the chain length of FAs and on sequence similarity" SIGNOR-267713 MAP2K2 protein P36507 UNIPROT ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR "up-regulates activity" phosphorylation 10090 11730323 t "Raf proteins have been shown to phosphorylate and activate MAPKKs (MAP kinase kinases) called MEKs (MAPK or ERK kinases) which in turn phosphorylate and activate MAPKs (MAP kinases) called ERKs" SIGNOR-258995 CREB5 protein Q02930 UNIPROT STAT1 protein P42224 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0002817 21132541 f miannu "Our result verified CREB5 biological regulation module in the upstream of frontal cortex of HIVE-control patients (MAPKAPK3 activation; DGKG, LY96, TNFRSF11B inhibition) and downstream (ATP6V0E1, CFB, DGKG, MX1, TGFBR3 activation; LGALS3BP, RASGRP3, RDX, STAT1 inhibition)," SIGNOR-253810 PRKCA protein P17252 UNIPROT DGKD protein Q16760 UNIPROT "down-regulates activity" phosphorylation Ser66 MLTKQNNsFQRSKRR 9534 15228384 t lperfetto "The plasma membrane translocation of diacylglycerol kinase delta1 is negatively regulated by conventional protein kinase C-dependent phosphorylation at Ser-22 and Ser-26 within the pleckstrin homology domain." SIGNOR-249265 NLGN4Y protein Q8NFZ3 UNIPROT NRXN1 protein Q9ULB1 UNIPROT "up-regulates activity" binding 9606 BTO:0000938 18923512 t brain lperfetto "Pre- and postsynaptic plasma membranes are always precisely aligned, and are separated by a synaptic cleft of ~20 nm. The cleft contains an undefined proteinaceous material in the middle, and is presumably bridged by synaptic cell-adhesion molecules such as Nrxns and Nlgns that align the pre- and postsynaptic elements and mediate trans-synaptic signaling.|Nlgns bind to both alpha- and beta-Nrxns with nanomolar affinities; binding involves the sixth LNS-domain of alpha-Nrxns which corresponds to the only LNS-domain of beta-Nrxns52. The binding affinities differ characteristically between various pairs of Nlgns and Nrxns, and are controlled by alternative splicing of both Nrxns and Nlgns (Figure 1c)" SIGNOR-264143 FBXW11 protein Q9UKB1 UNIPROT CLSPN protein Q9HAW4 UNIPROT down-regulates ubiquitination 9606 16885021 t gcesareni "Claspin degradation was triggered by its interaction with, and ubiquitylation by, the scfbetatrcp ubiquitin ligase." SIGNOR-148438 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR MKNK1 protein Q9BUB5 UNIPROT "up-regulates activity" phosphorylation -1 9155018 t "These results indicate that MNK1 is a novel class of protein kinase that is activated through both the ERK and p38 MAP kinase signaling pathways" SIGNOR-253013 cabozantinib chemical CHEBI:72317 ChEBI AXL protein P30530 UNIPROT "down-regulates activity" "chemical inhibition" 9606 BTO:0000184 26536165 t miannu "Cabozantinib (XL184) is a small-molecule kinase inhibitor with potent activity toward MET and VEGF receptor 2 (VEGFR2), as well as a number of other receptor tyrosine kinases that have also been implicated in tumor pathobiology, including RET, KIT, AXL, and FLT3." SIGNOR-262241 afatinib chemical CHEBI:61390 ChEBI EGFR protein P00533 UNIPROT "down-regulates activity" "chemical inhibition" -1 22037378 t Luana "Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here." SIGNOR-258169 CSNK2A1 protein P68400 UNIPROT XRCC1 protein P18887 UNIPROT up-regulates phosphorylation Thr523 AGSTDENtDSEEHQE 9606 20471329 t lperfetto "Xrcc1 phosphorylation by ck2 is required for its stability and efficient dna repair. Rcc1 is phosphorylated in vivo and in vitro by ck2, and ck2 phosphorylation of xrcc1 on s518, t519, and t523" SIGNOR-165435 NEK2 protein P51955 UNIPROT CEP250 protein Q9BV73 UNIPROT down-regulates phosphorylation Ser2394 LHHSLSHsLLAVAQA 9606 24695856 t lperfetto "C-nap1 hyperphosphorylation triggers the loss of both oligomerization and, crucially, interaction with the core centriole proximal-end protein, cep135. All three of these sites were identified in our in vivo analysis but only two (s2234 and s2394) were identified as nek2 phosphorylation sites in vitro." SIGNOR-204837 AKT1 protein P31749 UNIPROT TTC3 protein P53804 UNIPROT up-regulates phosphorylation Ser378 AYTPRSLsAPIFTTS 9606 20059950 t llicata "Phosphorylation of ttc3 at ser378 is required for efficient biological function together, these observations support that ttc3 is a phosphorylation target of akt both in an in vitro and in a cellular context" SIGNOR-252508 GSK3B protein P49841 UNIPROT CRMP1 protein Q14194 UNIPROT up-regulates phosphorylation Thr509 PVYEVPAtPKYATPA 9606 BTO:0000938 16611631 t lperfetto "In summary, phosphorylation of thr509 of human crmp1 appears to be regulated by two mechanisms; direct phosphorylation by cdk5, or by priming of ser522 by cdk5 followed by sequential phosphorylation of ser518, thr514, and thr509 by gsk3." SIGNOR-145995 IKBKB protein O14920 UNIPROT HES1 protein Q14469 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 22056382 f "Tnf-α enhanced the transcriptional activity of a classical Notch target gene via Ikk2 by inducing histone H3 phosphorylation" SIGNOR-253585 PRKCZ protein Q05513 UNIPROT IRS1 protein P35568 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser1101 GCRRRHSsETFSSTP 9606 BTO:0000975 17360977 t lperfetto "Tyrosine phosphorylation of IRS-1 initiates insulin signaling, whereas serine/threonine phosphorylation alters the ability of IRS-1 to transduce the insulin signalInsulin increased the phosphorylation of Ser312, Ser616, Ser636, Ser892, Ser1101, and Ser1223" SIGNOR-236022 PLG protein P00747 UNIPROT APOH protein P02749 UNIPROT "down-regulates activity" cleavage Lys336 HSSLAFWKTDASDVK 9606 BTO:0000131 9596664 t lperfetto "Plasmin can reduce the function of human beta2 glycoprotein I by cleaving domain V into a nicked form| The cleavage site of r-Domain V and beta2GPI by plasmin was proved to be Lys 317-Thr 318 by amino acid sequence analysis of the digest and of the C-terminal peptide isolated by high-performance liquid chromatography. The cleavage was completely inhibited by plasmin inhibitor (alpha2PI). The nicked form was demonstrated to show reduced affinity for CL with a dissociation constant of one order of magnitude larger than that of the intact beta2GPI." SIGNOR-266996 P2RY12 protein Q9H244 UNIPROT GNAI1 protein P63096 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-256712 EGFR protein P00533 UNIPROT STAT1 protein P42224 UNIPROT up-regulates phosphorylation 9606 22693070 t lperfetto "The transcription factors stat1, stat3, and stat5 are directly phosphorylated by erbb-1, subsequent to which they dimerize through phosphotyrosine-sh2 domain interactions and translocate to the nucleus to activate gene trascription critical for proliferation" SIGNOR-235689 KIRREL3 protein Q8IZU9 UNIPROT DLG4 protein P78352 UNIPROT "up-regulates activity" binding 10090 BTO:0004032 28381988 t miannu "We here report that, through its C-terminal PDZ domain-binding motif, Neph2 directly interacts with postsynaptic density (PSD)-95, an abundant excitatory postsynaptic scaffolding protein. Moreover, Neph2 protein is detected in the brain PSD fraction and interacts with PSD-95 in synaptosomal lysates. Functionally, loss of Neph2 in mice leads to age-specific defects in the synaptic connectivity of DG neurons." SIGNOR-269079 "Factor FVIIa:TF" complex SIGNOR-C319 SIGNOR F7 protein P08709 UNIPROT "up-regulates activity" cleavage Arg212 NASKPQGrIVGGKVC 9606 BTO:0000131 12524220 t lperfetto "The factor VII zymogen is cleaved at arginine 152 by a variety of proteases, including thrombin, factor IXa, factor Xa, and factor VIIa–tissue factor to produce the serine protease factor VIIa." SIGNOR-263521 ARHGAP33 protein O14559 UNIPROT RAC1 protein P63000 UNIPROT "down-regulates activity" "gtpase-activating protein" 9606 BTO:0000007 32203420 t Luana "We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2)." SIGNOR-260491 CSNK1D protein P48730 UNIPROT MDM2 protein Q00987 UNIPROT down-regulates phosphorylation 9606 20708156 t gcesareni "Phosphorylation by casein kinase i promotes the turnover of the mdm2 oncoprotein via the scf(beta-trcp) ubiquitin ligase." SIGNOR-167520 (4R,4aS,7aR,12bS)-3-(cyclopropylmethyl)-4a,9-dihydroxy-6-(phenylmethylene)-1,2,4,5,7a,13-hexahydro-4,12-methanobenzofuro[3,2-e]isoquinoline-7-one chemical CHEBI:125500 ChEBI OPRD1 protein P41143 UNIPROT "down-regulates activity" "chemical inhibition" 10029 BTO:0000246 9686407 t miannu "Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors." SIGNOR-258775 WNT7B protein P56706 UNIPROT FZD3 protein Q9NPG1 UNIPROT up-regulates binding 9606 15578921 t gcesareni "Wnt proteins bind to the frizzled receptors and lrp5/6 co-receptors, and through stabilizing the critical mediator betBeta-catenin, initiate a complex signaling cascade that plays an important role in regulating cell proliferation and differentiation." SIGNOR-131978 VPS11 protein Q9H270 UNIPROT EZR protein P15311 UNIPROT "up-regulates activity" binding 9606 BTO:0000567 21148287 t Sara "The interaction between the full-length Vps11 and ezrin was confirmed by immunoprecipitation and GST-pull down. ERM proteins and the HOPS complex are required for the transition from early to late endosomes" SIGNOR-261311 "Parathyroid hormone-related peptide (1-36)" smallmolecule CHEBI:80274 ChEBI PTH1R protein Q03431 UNIPROT "up-regulates activity" "chemical activation" 9606 BTO:0002524 31160049 t "Ligand-GPCR dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257575 CHRM2 protein P08172 UNIPROT GNAO1 protein P09471 UNIPROT "up-regulates activity" binding 9606 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-256964 UNG protein P13051 UNIPROT 5-fluorouracil chemical CHEBI:46345 ChEBI "down-regulates quantity by destabilization" "chemical modification" 9606 27875297 t lperfetto "Uracil N-glycosylase 2 (UNG2), the nuclear isoform of UNG, catalyzes the removal of uracil or 5-fluorouracil lesions that accumulate in DNA following treatment with the anticancer agents 5-fluorouracil and 5-fluorodeoxyuridine (floxuridine), a 5-fluorouracil metabolite. By repairing these DNA lesions before they can cause cell death, UNG2 promotes cancer cell survival and is therefore critically involved in tumor resistance to these agents. " SIGNOR-264888 TNPO1 protein Q92973 UNIPROT PER1 protein O15534 UNIPROT "up-regulates activity" relocalization 9606 29377895 t lperfetto "The non-classical nuclear import carrier Transportin 1 modulates circadian rhythms through its effect on PER1 nuclear localization" SIGNOR-262102 PRKACG protein P22612 UNIPROT BAD protein Q92934 UNIPROT down-regulates phosphorylation Ser118 GRELRRMsDEFVDSF 9606 10949026 t gcesareni "Ser-155 is the major phosphoacceptor site for pka on bad, but that pka also phosphorylates ser-112 and ser-136. Phosphorylated bad appears to be the inactive moiety. These results implicate pkac as the candidate kinase for s112 phosphorylation in vivo." SIGNOR-81153 nafamostat chemical CHEBI:135466 ChEBI TMPRSS2 protein O15393 UNIPROT "down-regulates activity" "chemical inhibition" 9606 BTO:0002750 27550352 t Monia "Nafamostat also blocked MERS-CoV infection in vitro. This inhibition was most likely a result of inhibition of TMPRSS2 on the plasma membrane. Because MERS-CoV may infect cells via a TMPRSS2-independent endocytotic pathway, we evaluated the effects of nafamostat on MERS-CoV infection using an in vitro virus infection assay" SIGNOR-261065 PPP1CC protein P36873 UNIPROT TP53 protein P04637 UNIPROT "down-regulates activity" dephosphorylation Ser37 NVLSPLPsQAMDDLM 9606 16501611 t "Protein serine/threonine phosphatase-1 dephosphorylates p53 at Ser-15 and Ser-37 to modulate its transcriptional and apoptotic activities|In addition, our results reveal that one of the molecular mechanisms by which PP-1 promotes cell survival is to dephosphorylate p53, and thus negatively regulate p53-dependent death pathway." SIGNOR-248500 BTK protein Q06187 UNIPROT PLCG2 protein P16885 UNIPROT "up-regulates activity" phosphorylation Tyr759 LYDVSRMyVDPSEIN 9606 BTO:0000776 11507089 t lperfetto "These findings indicate that the phosphorylations of the tyrosine residues 753, 759, 1197, and 1217, which have been identified as btk-dependent phosphorylation sites in vitro, coordinately contribute to bcr-induced activation of plcgamma2." SIGNOR-109758 PTK6 protein Q13882 UNIPROT EPS8 protein Q12929 UNIPROT "up-regulates activity" phosphorylation Tyr498 YAFSSNIyTRGSHLD 9606 BTO:0000007 27738316 t miannu "Eps8 which was identified by this method is phosphorylated by Myr-PTK6 in HEK293 cells. Mouse Eps8 expressed in HEK293 cells is phosphorylated by Myr-PTK6 at residues Tyr497, Tyr524, and Tyr534. These results indicate that plasma-membrane-associated PTK6 phosphorylates Eps8, which promotes cell proliferation, adhesion, and migration and, thus, tumorigenesis." SIGNOR-263189 GSK3B protein P49841 UNIPROT EIF2B5 protein Q13144 UNIPROT "down-regulates activity" phosphorylation Ser540 MDSEEPDsRGGSPQM 9606 BTO:0000007 11500362 t "We identify multiple phosphorylation sites in the largest, catalytic, subunit (epsilon) of mammalian eIF2B. Glycogen synthase kinase 3 (GSK3) is responsible for phosphorylating Ser535. This regulatory phosphorylation event requires both the fourth site (Ser539) and a distal region, which acts to recruit GSK3 to eIF2Bepsilon in vivo. eIF2Bϵ from mammals or insects is a substrate for glycogen synthase kinase 3 (GSK3), and this inhibits the activity of eIF2B" SIGNOR-251237 STAT5A protein P42229 UNIPROT M1_polarization phenotype SIGNOR-PH54 SIGNOR up-regulates 9606 22025054 f lperfetto "The activation of receptors for both GM-CSF and IFN-g stimulates the Jak kinaseSTAT transcription factor pathway, and an ISRE in the Irf5 promoter can bind STAT1 and STAT2, which suggests a possible mechanism for IRF5 expression induced by GM-CSF and IFN-g. Consequently, high expression of IRF5 results in polarization of the macrophage phenotype toward M1." SIGNOR-249510 Ub:E2 complex SIGNOR-C497 SIGNOR LONRF2 protein Q1L5Z9 UNIPROT "up-regulates activity" ubiquitination 9606 34199813 t miannu "The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t" SIGNOR-271157 Ub:E2 complex SIGNOR-C497 SIGNOR TRIM41 protein Q8WV44 UNIPROT "up-regulates activity" ubiquitination 9606 34199813 t miannu "The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t" SIGNOR-270954 CyclinA2/CDK2 complex SIGNOR-C83 SIGNOR AKT1 protein P31749 UNIPROT "up-regulates activity" phosphorylation Ser477 PQFSYSAsGTA 9606 BTO:0000093 24670654 t gcesareni "Phosphorylation of S477 and T479 at the Akt extreme carboxy terminus by cyclin-dependent kinase 2 (Cdk2)/cyclin A or mTORC2, under distinct physiological conditions, promotes Akt activation through facilitating, or functionally compensating for, S473 phosphorylation" SIGNOR-252440 MEF2A protein Q02078 UNIPROT MYF6 protein P23409 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 7739551 t lperfetto "Myogenin and MEF2 function synergistically to activate the MRF4 promoter during myogenesis." SIGNOR-238709 pazopanib chemical CHEBI:71219 ChEBI FLT1 protein P17948 UNIPROT "down-regulates activity" "chemical inhibition" 9606 BTO:0001949 18620382 t Luana "Pyrimidine 13 showed good potency against all the human VEGFR receptors with an IC50 of 10, 30, and 47 nM for VEGFR-1, -2, and -3, respectively. Significant activity was also seen against the closely related tyrosine receptor kinases PDGFRβ, c-Kit, FGF-R1, and c-fms with IC50’s of 84, 74, 140, and 146 nM, respectively." SIGNOR-257734 EPHB1 protein P54762 UNIPROT EPHB1 protein P54762 UNIPROT "up-regulates activity" phosphorylation Tyr594 GSPGMKIyIDPFTYE 10029 BTO:0000246 12223469 t " Co-immunoprecipitation was used to confirm the interaction of Grb7 with the cytoplasmic domain of EphB1 as well as the full-length receptor in intact cells. This interaction is mediated by the SH2 domain of Grb7 and requires tyrosine autophosphorylation of EphB1. We also found that EphB1 could phosphorylate Grb7 and mutation of either Tyr-928 or Tyr-594 to Phe decreased this activity." SIGNOR-251122 NLGN2 protein Q8NFZ4 UNIPROT NRXN1 protein Q9ULB1 UNIPROT "up-regulates activity" binding 9606 BTO:0000938 18923512 t brain lperfetto "Pre- and postsynaptic plasma membranes are always precisely aligned, and are separated by a synaptic cleft of ~20 nm. The cleft contains an undefined proteinaceous material in the middle, and is presumably bridged by synaptic cell-adhesion molecules such as Nrxns and Nlgns that align the pre- and postsynaptic elements and mediate trans-synaptic signaling.|Nlgns bind to both alpha- and beta-Nrxns with nanomolar affinities; binding involves the sixth LNS-domain of alpha-Nrxns which corresponds to the only LNS-domain of beta-Nrxns52. The binding affinities differ characteristically between various pairs of Nlgns and Nrxns, and are controlled by alternative splicing of both Nrxns and Nlgns (Figure 1c)" SIGNOR-264146 RAB32 protein Q13637 UNIPROT "AP-3 complex" complex SIGNOR-C247 SIGNOR "up-regulates activity" relocalization 9606 23247405 t lperfetto "Rab32 and Rab38 interact physically and colocalize with BLOC-2, AP-1 and AP-3|These results indicate that Rab32 and Rab38 operate in the same pathways previously defined for AP-1, AP-3 and BLOC-2 and suggest they are the specific proteins that divert AP-1, AP-3 and BLOC-2-dependent cargoes to maturing melanosomes and away from lysosomes." SIGNOR-260698 AP1G1 protein O43747 UNIPROT "AP-1 complex" complex SIGNOR-C248 SIGNOR "form complex" binding 9606 21097499 t lperfetto "Key components of this system are the heterotetrameric adaptor protein (AP)4 complexes, AP-1 (gamma-beta1-mi1-sigma1), AP-2 (α-beta2-mi2-sigma2), AP-3 (delta-beta3-mi3-sigma3), and AP-4 (epsilon-beta4-mi4-sigma4) (subunit composition shown in parentheses)" SIGNOR-260687 PIMREG protein Q9BSJ6 UNIPROT PICALM protein Q13492 UNIPROT down-regulates relocalization 9606 16491119 t miannu "The cats interaction domain of calm was mapped to aa 221-335 of calm. This domain is contained in the calm/af10 fusion protein. Cats localizes to the nucleus and shows a preference for nucleoli. Expression of cats was able to markedly increase the nuclear localization of calm and of the leukemogenic fusion protein calm/af10." SIGNOR-144680 pirenzepine chemical CHEBI:8247 ChEBI CHRM1 protein P11229 UNIPROT "down-regulates activity" "chemical inhibition" 10029 BTO:0000246 2704370 t miannu "In order to investigate the pharmacological properties of the individual muscarinic receptors, we have transfected each of these genes into Chinese hamster ovary cells (CHO-K1) and have established stable cell lines expressing each receptor. In the present study we have examined the antagonist binding properties of each muscarinic receptor. Antagonists were chosen that had previously been proposed to be selective for muscarinic receptor subtypes and included pirenzepine, AF-DX 116, methoctramine, dicyclomine, hexohydrodifenidol, hexahydrosiladifenidol, hexocyclium, and silahexocyclium." SIGNOR-258394 Hypoxia stimulus SIGNOR-ST25 SIGNOR KDM4B protein O94953 UNIPROT up-regulates 9606 30759871 f miannu "The KDM4 family of Jumonj domain histone demethylases specifically target di- and tri-methylated lysine 9 on histone H3 (H3K9me3), removing a modification central to defining heterochromatin and gene repression. KDM4 enzymes are generally over-expressed in cancers, making them compelling targets for study and therapeutic inhibition. One of these family members, KDM4B, is especially interesting due to its regulation by multiple cellular stimuli, including DNA damage, steroid hormones, and hypoxia." SIGNOR-263735 ARTN protein Q5T4W7 UNIPROT GFRA3 protein O60609 UNIPROT up-regulates binding 9606 BTO:0000938 9883723 t gcesareni "Here, we report the identification of artemin, a novel member of the gdnf family, and demonstrate that it is the ligand for the former orphan receptor gfralpha3-ret. Artemin can also activate the gfralpha1-ret complex." SIGNOR-63009 SOX17/POU5F1 complex SIGNOR-C451 SIGNOR PRDM14 protein Q9GZV8 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 31583686 t SimoneGraziosi "Both SOX2 and SOX17 are able to partner with OCT4 and, as a consequence, recognize and bind specific binding motifs.6, 7 In human and mouse ESCs, SOX2/OCT4 bind to canonical motifs (CTTTGTCATGCAAAT-like), which are composite SOX (CATTGTC-like) and OCT (ATGCAAAT-like) motifs|This way SOX17 and SOX2 regulate a common set of pluripotency and GC-related genes (PRDM14, DPPA4, TDGF1, NANOG, LIN28A, TRIM71, OTX2, PIM2) (Fig. 6). Additionally, in TCam-2 cells SOX17 binds to compressed motifs or SOX motifs (not bound by SOX2 in ECs), thereby regulating the PGC specifiers PRDM1 and TFAP2C, the GC-related genes NANOS3 and BMP7 and the cancer-related genes MYC and IGF1 (Fig. 6). In 2102EP cells, SOX2 further binds canonical elements or SOX motifs (not bound by SOX17 in TCam-2), regulating additional pluripotency genes (GDF3, LEFTY2, SALL4, SOX2 and POU5F1) (Fig. 6)." SIGNOR-269242 VARS1 protein P26640 UNIPROT valine smallmolecule CHEBI:27266 ChEBI "down-regulates quantity" "chemical modification" 9606 30755602 t miannu "Aminoacyl-tRNA synthetases (ARSs) function to transfer amino acids to cognate tRNA molecules, which are required for protein translation. VARS encodes the only known valine cytoplasmic-localized aminoacyl-tRNA synthetase." SIGNOR-270526 LRRK2 protein Q5S007 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates phosphorylation Ser473 RPHFPQFsYSASGTA 9606 BTO:0000938 24916379 t lperfetto "Expression of wild-type LRRK2 promoted neuronal survival against apoptosis through activation of the downstream effector, Akt by phosphorylation of Ser473. Phosphorylated Akt in turn inhibited FOXO 1 signaling" SIGNOR-205115 JUN protein P05412 UNIPROT LORICRIN protein P23490 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000667 12200429 f miannu "Mutation and DNA-protein analyses show that Sp1, c-Jun, an unidentified regulator, and the co-activator p300/CREB-binding protein up-regulate whereas Sp3, CREB-1/CREMalpha/ATF-1, Jun B, and an AP2-like protein (termed the keratinocyte-specific repressor-1 (KSR-1)) suppress loricrin promoter activity." SIGNOR-254536 tiotropium chemical CHEBI:90960 ChEBI CHRM1 protein P11229 UNIPROT "down-regulates activity" "chemical inhibition" -1 8441333 t miannu "A newly developed compound, Ba 679 BR (abbreviated Ba 679) proved to be a highly potent muscarinic antagonist in guinea pig tracheal rings. Its binding to human receptors (Hm1, Hm2, Hm3) was characterized by KD-values in the 10(-10) M concentration range.he drug showed ""kinetic receptor subtype selectivity"" by having a more rapid dissociation from Hm2 than from Hm1 and Hm3 receptors." SIGNOR-258485 MAPK3 protein P27361 UNIPROT RXRA protein P19793 UNIPROT "down-regulates activity" phosphorylation Thr82 HSMSVPTtPTLGFST 9606 17604322 t lperfetto "In colon cancer cells, the Ras/mitogen‐activated protein kinase (MAPK) pathway phosphorylates RXRalpha, which impairs its function as a heterodimeric partner for PPARgamma|A point‐mutated RXRalpha T82A/S260A, which mimics the unphosphorylated form of RXRalpha, can form a heterodimer with PPARgamma and thereby activate target gene expression by binding to the PPRE" SIGNOR-262959 JQ1 chemical CHEBI:137113 ChEBI BRD4 protein O60885 UNIPROT "down-regulates activity" "chemical inhibition" -1 20871596 t lperfetto "Enantiomerically pure (+)-JQ1 bound with a Kd of about 50 nM and 90 nM to the first and second bromodomains of BRD4, respectively (Fig. 1c, Supplementary Table 3). Comparable binding to both domains of BRD3 was observed, whereas the first bromodomains of BRDT and BRD2 revealed about 3-fold weaker binding.|Here, we present a first, thoroughly characterized inhibitor of the BET-family of bromodomains." SIGNOR-261989 EPHB2 protein P29323 UNIPROT ARHGEF15 protein O94989 UNIPROT "down-regulates quantity by destabilization" phosphorylation Tyr353 PLQDEPLyQTYRAAV 9606 BTO:0000007 21029865 t miannu "We have identified a RhoA guanine nucleotide exchange factor, Ephexin5, which negatively regulates excitatory synapse development until EphrinB binding to the EphB receptor tyrosine kinase triggers Ephexin5 phosphorylation, ubiquitination, and degradation. EphB2 mediates phosphorylation of Ephexin5 at tyrosine-361" SIGNOR-262864 SMAD1/5/8/SMAD4 complex SIGNOR-C215 SIGNOR FBXO30 protein Q8TB52 UNIPROT down-regulates 10090 BTO:0000887 24076600 f "BMP-Smad1/5/8 signaling negatively regulates a gene (Fbxo30) that encodes a ubiquitin ligase required for muscle loss, which we named muscle ubiquitin ligase of the SCF complex in atrophy-1 (MUSA1)" SIGNOR-256488 CTTNBP2NL protein Q9P2B4 UNIPROT Actin_cytoskeleton_reorganization phenotype SIGNOR-PH84 SIGNOR up-regulates 10116 23015759 f miannu "Through alternative splicing, a single CTTNBP2 gene encodes three different transcripts, namely short (S), long (L), and intron forms. The interaction with cortactin is required for the function of CTTNBP2-S in dendritic spine formation because the CTTNBP2-S mutant, which no longer interacts with cortactin, is unable to rescue the spine defects resulting from CTTNBP2 knockdown. Thus CTTNBP2-S may control cortactin–F-actin cytoskeletons and regulate the formation and maintenance of dendritic spines in neurons." SIGNOR-261694 MAPK1 protein P28482 UNIPROT SMAD3 protein P84022 UNIPROT down-regulates phosphorylation Ser213 NLSPNPMsPAHNNLD 9606 19914161 t lpetrilli "Phosphorylation of the linker region of smads mediated by erk2, gsk3?, And cdk2/4 negatively regulates smad activity by preventing their relocation to the nucleus, by inhibiting their interactions with coactivators, or by accelerating their degradation;in contrast, erk2 phosphorylated all four smad1 residues almost evenly, while showing a preference for s204 over s208 and s213 in smad3" SIGNOR-161617 MAPK3 protein P27361 UNIPROT IRX2 protein Q9BZI1 UNIPROT "up-regulates activity" phosphorylation Ser317 TPQGSRTsPGAPPPA -1 15133517 t miannu "To identify the phosphorylated residue, we introduced a serine-to-alanine substitution at residues 294 and 326 and a threonine-to-alanine substitution at residue 331 in Irx2(291–356). Erk1 phosphorylated S294A and T331A, but not S326A (Fig. 4b), indicating that Ser326 is the bona fide MAP kinase target." SIGNOR-263060 CIITA protein P33076 UNIPROT HLA-A protein P04439 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000776 10329350 f "Transfection of CIITA in JEG-3 cells also upregulated functional HLA-B and HLA-C expression." SIGNOR-254020 citrate(3-) smallmolecule CHEBI:16947 ChEBI D-threo-isocitrate(3-) smallmolecule CHEBI:15562 ChEBI "up-regulates quantity" "precursor of" 9606 24068518 t miannu "Citrate is converted to cis-aconitate. This is catalyzed by aconitase. Cis-aconitate is an intermediate and is further converted to isocitrate by aconitase. Aconitase is involved in both reactions. In which first dehydration and then rehydration occur and as a result final product isocitrate is obtained." SIGNOR-266243 AFF1 protein P51825 UNIPROT "AEP complex" complex SIGNOR-C117 SIGNOR "form complex" binding 9606 BTO:0000664 20153263 t 1 miannu "These data demonstrate that AF4, AF5q31 and ENL associate in an endogenous higher-order complex (hereafter referred to as AEP for the AF4 family/ENL family/P-TEFb complex) containing P-TEFb in hematopoietic lineage cells." SIGNOR-239231 MAPK14 protein Q16539 UNIPROT GSK3B protein P49841 UNIPROT down-regulates phosphorylation Ser389 ARIQAAAsTPTNATA 9606 BTO:0000142 18451303 t gcesareni "Here, we show that p38 mitogen-activated protein kinase (mapk) also inactivates gsk3beta by direct phosphorylation at its c terminus, and this inactivation can lead to an accumulation of beta-catenin." SIGNOR-178603 BUB1 protein O43683 UNIPROT CDC20 protein Q12834 UNIPROT "down-regulates activity" phosphorylation Ser92 AAQMEVAsFLLSKEN 9606 BTO:0000567 15525512 t llicata "Bub1 directly phosphorylates Cdc20 in vitro and inhibits the ubiquitin ligase activity of APC/C(Cdc20) catalytically. A Cdc20 mutant with all six Bub1 phosphorylation sites removed is refractory to Bub1-mediated phosphorylation and inhibition in vitro. " SIGNOR-250608 PIM2 protein Q9P1W9 UNIPROT CDKN1A protein P38936 UNIPROT "up-regulates quantity by stabilization" phosphorylation Thr145 QGRKRRQtSMTDFYH 9606 20307683 t lperfetto "Pim-2 phosphorylation of p21(cip1/waf1) enhances its stability and inhibits cell proliferation in hct116 cellsere we demonstrate that like pim-1, pim-2 also phosphorylates the cell cycle inhibitor p21(cip1/waf1) (p21) on thr145 in vitro and in vivo" SIGNOR-164646 4-oxobutanoate smallmolecule CHEBI:57706 ChEBI succinate(2-) smallmolecule CHEBI:30031 ChEBI "up-regulates quantity" "precursor of" 9606 19300440 t miannu "Succinic semialdehyde dehydrogenase (SSADH) is involved in the final degradation step of the inhibitory neurotransmitter gamma-aminobutyric acid by converting succinic semialdehyde to succinic acid in the mitochondrial matrix." SIGNOR-266615 SMARCB1 protein Q12824 UNIPROT "Muscle cell-specific SWI/SNF SMARCA4 variant" complex SIGNOR-C483 SIGNOR "form complex" binding 9606 BTO:0000887 11073988 t miannu "We have also found that, of the two human SWI/2/SNF2 family-related ATPases, the PBAF complex contains only BRG1 but not hbrm (Xue et al., submitted). In contrast, the BAF complex isolated by BAF250 can include either BRG1 or hbrm (Fig. ​(Fig.4b).4b). These data underscore the distinctness of the two human complexes and suggest that BAF250 is a signature subunit that may confer specificity to the BAF complex." SIGNOR-270737 CADPS protein Q9ULU8 UNIPROT VAMP2 protein P63027 UNIPROT "up-regulates activity" binding 9606 BTO:0000938 SIGNOR-C346 24363652 t miannu "CAPS interactions with N-terminal regions of the SNARE motif of VAMP2 were also detected, which suggests that CAPS might recruit VAMP2 into syntaxin-1/SNAP-25 heterodimers for RQaQbc-SNARE complex assembly." SIGNOR-264340 FBXW7 protein Q969H0 UNIPROT MED13 protein Q9UHV7 UNIPROT "down-regulates quantity by destabilization" ubiquitination 9606 BTO:0000007 SIGNOR-C135 SIGNOR-C406 23322298 t miannu "The SCF-Fbw7 ubiquitin ligase degrades MED13 and MED13L and regulates CDK8 module association with Mediator. We show that Fbw7, a tumor suppressor and ubiquitin ligase, binds to CDK8-Mediator and targets MED13/13L for degradation. MED13/13L physically link the CDK8 module to Mediator, and Fbw7 loss increases CDK8 module-Mediator association." SIGNOR-266690 MC4R protein P32245 UNIPROT GNAL protein P38405 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-256940 TET2 protein Q6N021 UNIPROT OGT protein O15294 UNIPROT up-regulates binding 9606 23353889 t miannu "Tet2 and tet3 associate with the o_glcnac transferase ogt / tet2 and tet3 promote ogt_mediated glcnacylation" SIGNOR-200695 MAPK1 protein P28482 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR "down-regulates quantity by destabilization" phosphorylation Ser425 TKGSGLGsPTSSFNS 9606 BTO:0000007 18204439 t lperfetto "Here, we show that erk downregulates forkhead box o 3a (foxo3a) by directly interacting with and phosphorylating foxo3a at ser 294, ser 344 and ser 425, which consequently promotes cell proliferation and tumorigenesisMDM2 is required for ERk-mediated FOXO3a degradation." SIGNOR-252959 AURKB protein Q96GD4 UNIPROT CHMP4C protein Q96CF2 UNIPROT up-regulates phosphorylation Ser210 MSSTARRsRAASSQR 9606 22724069 t lperfetto "Moreover, we find that the cpc's catalytic subunit, aurora b kinase, phosphorylates one of the three human snf7 paralogues-chmp4c-in its c-terminal tail, a region known to regulate its ability to form polymers and associate with membranes. Phosphorylation at these sites appears essential for chmp4c function because their mutation leads to cytokinesis defects. The introduction of the s214a and s215a mutations together with s210a almost completely abolished aurora b phosphorylation" SIGNOR-197967 Ub:E2 complex SIGNOR-C497 SIGNOR RNF152 protein Q8N8N0 UNIPROT "up-regulates activity" ubiquitination 9606 34199813 t miannu "The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t" SIGNOR-271199 CSNK1D protein P48730 UNIPROT YAP1 protein P46937 UNIPROT down-regulates phosphorylation Ser403 ESTDSGLsMSSYSVP 9606 phosphorylation:Ser127 PQHVRAHsSPASLQL 24715453 t milica "LATS1/2-mediated phosphorylation of a conserved serine in this region (Ser311 in human TAZ; Ser397 in human YAP) primes for further phosphorylation by CK1_/_ kinases (Ser314 on human TAZ; Ser400/403 in human YAP)" SIGNOR-230743 UBN2 protein Q6ZU65 UNIPROT "HIRA complex 2" complex SIGNOR-C462 SIGNOR "form complex" binding 9606 30285846 t miannu "H3.3 is an ancient and conserved H3 variant and plays essential roles in transcriptional regulation. HIRA complex, which is composed of HIRA, UBN1 or UBN2, and Cabin1, is a H3.3 specific chaperone complex. In this study, we demonstrate that the UBN1 or UBN2 subunit is mainly responsible for specific recognition and direct binding of H3.3 by the HIRA complex." SIGNOR-269436 "Elongator complex" complex SIGNOR-C466 SIGNOR TUBA3C protein P0DPH7 UNIPROT "up-regulates activity" acetylation 9606 BTO:0000007 19185337 t miannu "Elongator Subunits Interact with the Microtubules and Are Required for Proper Acetylation of α-Tubulin. α-Tubulin Acetylation Promotes Radial Migration and Branching of Cortical Projection Neurons" SIGNOR-269716 AMPK complex SIGNOR-C15 SIGNOR EPM2A protein O95278 UNIPROT "up-regulates activity" phosphorylation -1 18029386 t miannu "Here, we provide evidence indicating that the formation of the laforin–malin complex is positively regulated by AMPK. We show that laforin, but not malin, can interact physically with the catalytic subunit of AMPK and that purified AMPK phosphorylates GST::laforin in vitro." SIGNOR-271730 ROCK1 protein Q13464 UNIPROT MYL12A protein P19105 UNIPROT "up-regulates activity" phosphorylation Ser19 KRPQRATsNVFAMFD 9606 BTO:0000567 12185584 t miannu "Phosphorylation of myosin II regulatory light chain (MRLC) is important for cell motility and cytokinesis in nonmuscle cells. Although the regulation of monophosphorylated MRLC at serine 19 throughout the cell cycle was examined in detail, MRLC diphosphorylation at both threonine 18 and serine 19 is still unclear. Here we found that Rho-kinase has an activity for MRLC diphosphorylation in nonmuscle cells using sequential column chromatographies. we showed that the inhibition of Rho-kinase reduced diphosphorylated MRLC in the center of cells even in the presence of phosphatase inhibitor, suggesting that Rho-kinase directly diphosphorylates MRLC (red arrow in Figure 6). Taken together, we propose a model of diphosphorylation of MRLC through dual pathways of both the direct phosphorylation and the inhibition of myosin phosphatase by Rho-kinase (Figure 6)." SIGNOR-263073 VEPH1 protein Q14D04 UNIPROT YAP1 protein P46937 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000938 23989952 f "or inhibits the Hippo pathway to activate Yki" lperfetto "A double positive-feedback loop between melt and yki, wherein yki acti- vates melt expression, and melt promotes yki" SIGNOR-202540 TRIM63 protein Q969Q1 UNIPROT PSMD4 protein P55036 UNIPROT "down-regulates quantity by destabilization" polyubiquitination Lys262 DSDDALLkMTISQQE -1 19240029 t miannu "S5a/Rpn10 is a ubiquitin (Ub)-binding protein that is a subunit of the 26S proteasome but also exists free in the cytosol. It binds poly-Ub chains through its two Ub-interacting motifs (UIMs). We discovered that, unlike typical substrates of Ub ligases (E3s), S5a can be ubiquitinated by all E3s tested including multimeric and monomeric Ring finger E3s (MuRF1, Siah2, Parkin, APC, and SCF(betaTRCP1)), the U-box E3, CHIP, and HECT domain E3s (E6AP and Nedd4) when assayed with UbcH5 or related Ub-conjugating enzymes.The short half-life of S5a presumably is because of the presence of the UIM domain and reflects the ubiquitination of free S5a by many E3s. Surprisingly, the same four Lys residues on S5a, Lys-74, Lys-122, Lys-262, and Lys-365 were ubiquitinated by MuRF1 and E6AP (Fig. 10)." SIGNOR-272740 CAMK4 protein Q16566 UNIPROT HDAC4 protein P56524 UNIPROT "down-regulates activity" phosphorylation Ser632 RPLSRAQsSPASATF 11470791 t llicata "CaMKIV phosphorylates HDAC4 in vitro and promotes its nuclear-cytoplasmic shuttling in vivo. | Thus, CaMKIV can phosphorylate HDAC4 at Ser-467 and/or Ser-632 in vitro. | Collectively, our results suggest that CaMKIV reverses the transcriptional repression activity of HDAC4 by stimulating the mobilization of HDAC4 out of the nucleus." SIGNOR-250712 "SAGA complex" complex SIGNOR-C465 SIGNOR H3Y2 protein P0DPK5 UNIPROT "down-regulates activity" acetylation Lys10 RTKQTARkATAWQAP 9606 34811519 t "Acetlyation of H3 causes transcriptional activation, thus has an inhibitory role on H3" lperfetto "The HAT module within the SAGA and ADA complexes acetylates histone H3, mainly on residues K9 and K14." SIGNOR-269632 YAP1 protein P46937 UNIPROT TEAD3 protein Q99594 UNIPROT up-regulates binding 9606 23431053 t "Crystallographic data revealed that the N-terminal TEAD-binding domain of YAP wraps around a globular structure formed by the C-terminal domains of TEAD1, 2 and 4" gcesareni "When dephosphorylated, yap/taz enter nuclei and induce gene transcription by interacting with transcription factors tead14." SIGNOR-201471 PAMPs stimulus SIGNOR-ST11 SIGNOR TLR4 protein O00206 UNIPROT "up-regulates activity" 9606 BTO:0000801 19946286 f lperfetto "The lipopolysaccharide (LPS) of Gram negative bacteria is a wellknown inducer of the innate immune response1. Toll-like receptor (TLR) 4 and myeloid differentiation factor 2 (MD-2) form a heterodimer that recognizes a common pattern in structurally diverse LPS molecules." SIGNOR-249516 GSK3A protein P49840 UNIPROT NBR1 protein Q14596 UNIPROT "down-regulates activity" phosphorylation Thr586 HNTPVDVtPCMSPLP -1 24879152 t lperfetto "The autophagy receptor NBR1 (neighbor of BRCA1 gene 1) binds UB/ubiquitin and the autophagosome-conjugated MAP1LC3/LC3 (microtubule-associated protein 1 light chain 3) proteins, thereby ensuring ubiquitinated protein degradation|Here we show that NBR1 is a substrate of GSK3. NBR1 phosphorylation by GSK3 at Thr586 prevents the aggregation of ubiquitinated proteins and their selective autophagic degradation." SIGNOR-261794 HES5 protein Q5TA89 UNIPROT NEUROG1 protein Q92886 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 10090 BTO:0000938 30030829 f lperfetto "The basic-helixloop-helix factors HES1 and HES5 repress the expression of the proneural genes (Ascl1, Atoh1, Neurog1 and Neurog2) and thereby inhibit NSCs differentiation and neuron production" SIGNOR-265141 CTSD protein P07339 UNIPROT APP protein P05067 UNIPROT "up-regulates activity" cleavage Thr663 IATVIVItLVMLKKK -1 10605825 t lperfetto "In this work, we used a sensitive in vitro method of detection to investigate the role of cathepasin D in the proteolytic processing of a 100-amino acid C-terminal fragment (C100) inclusive of βA4 and cytoplasmic domain of APP. Digestion of C100 with cathepsin D resulted in cleavage at the amyloidogenic γ-cleavage sites. This occurred preferentially at Thr43–Val44 and at Ala42–Thr43, generating full length βA4 43 and βA4 42 amyloid peptides, respectively. Cathepsin D was also found to cleave the substrate at the following nonamyloidogenic sites; Leu34–Met35, Thr48–Leu49 and Leu49–Val50. A high concentration of cathepsin D resulted in cleavage also occurring at Phe19–Phe20, Phe20–Ala21 and Phe93–Phe94 of the C100, suggesting that these sites are somewhat less sensitive to the action of cathepsin D." SIGNOR-261793 SRC protein P12931 UNIPROT HSP90AB1 protein P08238 UNIPROT up-regulates phosphorylation Tyr301 DDITQEEyGEFYKSL 9606 17855507 t lperfetto "C-src directly phosphorylates hsp90 on tyrosine 300 residue and that this event is essential for vegf-stimulated enos association to hsp90 and thus no release from endothelial cells." SIGNOR-157781 CDKN2A protein P42771 UNIPROT CyclinD1/CDK6 complex SIGNOR-C143 SIGNOR down-regulates binding 9606 8891723 t luana "The first group, including p16ink4a, p15ink4b,p18ink4cand p19ink4d, is specific for the g1 cdks,cdk4and cdk6, inhibiting the kinase activity of cyclin d/cdk4-cdk6 complexes on prb." SIGNOR-259810 "WASH complex" complex SIGNOR-C258 SIGNOR ARP2/3 complex SIGNOR-C146 SIGNOR "up-regulates activity" binding 9606 BTO:0000567 20498093 t lperfetto "Members of the Wiskott-Aldrich syndrome protein (WASP) family, which includes WASP, N-WASP, WAVE (1–3), WHAMM, JMY, and WASH, control actin cytoskeletal dynamics throughout biology. They act in large part by regulating the actin nucleating activity of the ubiquitous Arp2/3 complex. WASP proteins stimulate Arp2/3 complex using a conserved C-terminal VCA (Verprolin homologous, central hydrophobic, and acidic) region. They contain distinct N-terminal elements, which facilitate integration into unique macromolecular complexes." SIGNOR-261006 MAPK3 protein P27361 UNIPROT STMN1 protein P16949 UNIPROT "down-regulates activity" phosphorylation Ser38 SVPEFPLsPPKKKDL 9606 9731215 t lperfetto "Stress-induced stathmin phosphorylation is not de- pendent on ERK. Stathmin is also known to be phos- phorylated by ERK on Ser-25 and Ser-38 (17). Thus, it is possible that ERK phosphorylates stathmin in 293 cells|In subsequent reports (28, 29) it was shown that phosphorylation of stathmin blocks its ability to destabilize MTs." SIGNOR-249483 GNAO1 protein P09471 UNIPROT Tubulin proteinfamily SIGNOR-PF46 SIGNOR "up-regulates activity" binding -1 10224115 t "G protein alpha subunits Gi1alpha, Gsalpha, and Goalpha are shown to activate the GTPase activity of tubulin, inhibit microtubule assembly, and accelerate microtubule dynamics." SIGNOR-256540 SHMT1 protein P34896 UNIPROT 3-hydroxy-N(6),N(6),N(6)-trimethyl-L-lysine smallmolecule CHEBI:15786 ChEBI "down-regulates quantity" "chemical modification" 9606 11802770 t miannu "HTMLA might be identical to serine hydroxymethyltransferase (SHMT; EC 2.1.2.1), since it has been shown that SHMT purified from rabbit liver acts upon HTML, yielding TMABA and glycine." SIGNOR-269687 CDK1 protein P06493 UNIPROT BAD protein Q92934 UNIPROT "up-regulates activity" phosphorylation Ser91 EGMGEEPsPFRGRSR 24677263 t lperfetto "CDK1-mediated Bcl-2 serine 70 phosphorylation enhances its pro-apoptotic function, whereas CDK1-mediated Bad serine 128 phosphorylation promotes apoptosis. " SIGNOR-267921 "AEP complex" complex SIGNOR-C117 SIGNOR MEIS1 protein O00470 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 20854876 f irozzo "Inhibition of EAP components pTEFb and Dot1l show that both contribute significantly to activation of Hoxa9 and Meis1 expression. EAP is dynamically associated with the Hoxa9 and Meis1 loci in hematopoietic cells and rapidly dissociates during induction of differentiation. In the presence of MLL fusion proteins, its dissociation is prevented." SIGNOR-256144 AKT proteinfamily SIGNOR-PF24 SIGNOR IKK-complex complex SIGNOR-C14 SIGNOR up-regulates phosphorylation 9606 BTO:0001454 19609947 t lperfetto "Although there are likely to be multiple levels of crosstalk between the pi3k-akt and nf-kb pathways, one mechanism has been attributed to direct phosphorylation of the amino acid residue t23 on ikb kinase alfa (ikkalfa) by akt, thereby leading to activation of this kinase upstream of nf-kb akt mediates ikkalpha phosphorylation at threonine 23 akt transiently associates in vivo with ikk and induces ikk activation. Akt mediates ikkalfa phosphorylation at threonine 23.Akt phosphorylates ikkalpha on t23, and this phosphorylation event is a prerequisite for the phosphorylation of p65 at s534 by ikkalpha and beta" SIGNOR-244281 HNRNPH1 protein P31943 UNIPROT TERF2 protein Q15554 UNIPROT "down-regulates quantity" "post transcriptional regulation" 10116 BTO:0001009 27117401 t miannu "During neuronal differentiation, use of an alternative splice site on the rat telomere repeat-binding factor 2 (TRF2) mRNA generates a short TRF2 protein isoform (TRF2-S) capable of derepressing neuronal genes. However, the RNA-binding proteins (RBPs) controlling this splicing event are unknown. Here, using affinity pull-down analysis, we identified heterogeneous nuclear ribonucleoproteins H1 and H2(HNRNPH) as RBPs specifically capable of interacting with the spliced RNA segment (exon 7) of Trf2 pre-mRNA. HNRNPH proteins prevent the production of the short isoform of Trf2 mRNA, as HNRNPH silencing selectively elevates TRF2-S levels." SIGNOR-266807 REN protein P00797 UNIPROT Angiotensin-1 protein P01019-PRO_0000032457 UNIPROT "up-regulates quantity" cleavage 9606 32201502 t miannu "Renin is an aspartic protease that enzymatically cleaves its substrate angiotensinogen, which is produced by the liver, to form an inactive peptide: angiotensin (Ang)I or Ang (1–10)." SIGNOR-260225 "trichostatin A" chemical CHEBI:46024 ChEBI HDAC4 protein P56524 UNIPROT "down-regulates activity" "chemical inhibition" -1 17868033 t Luana "Our findings suggest that hydroxamic acid-derived compounds such as TSA, NVP-LAQ824, panobinostat, ITF2357, vorinostat and belinostat act as potent pan-HDAC isoform inhibitors. A notable observation was the similarity between belinostat and vorinostat in the biochemical isoform assays; both compounds exhibit similar EC50 values in all but the HDAC8 assay." SIGNOR-257941 TNFRSF10A protein O00220 UNIPROT FADD protein Q13158 UNIPROT up-regulates binding 9606 14585074 t amattioni "Fadd binds to ligated trailr1 or trail-r2" SIGNOR-97869 EGR1 protein P18146 UNIPROT PDGFC protein Q9NRA1 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10116 BTO:0001685 15247255 f "The PDGF family of ligands is comprised of A, B, C, and D chains. Here, we provide the first functional characterization of the PDGF-C promoter. We examined 797 bp of the human PDGF-C promoter and identified several putative recognition elements for Sp1, Ets Egr-1, and Smad.|These findings thus demonstrate that PDGF-C transcription, activated by FGF-2, is mediated by Egr-1 and its upstream kinase ERK.|Egr-1 and Sp1 specifically bind the PDGF-C promoter" SIGNOR-254268 TP63 protein Q9H3D4 UNIPROT PLEC protein Q15149 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 28595999 t lperfetto "Here we show that in the developing skin, epidermal progenitor cells of mice lacking p63 transcription factor display alterations in the nuclear shape accompanied by a marked decrease in expression of several nuclear envelope-associated components (Lamin B1, Lamin A/C, Sun1, Nesprin-3, Plectin) compared with controls. Furthermore, chromatin immunoprecipitation-quantitative PCR assay showed enrichment of p63 on Sun1, Syne3, and Plec promoters, suggesting them as p63 targets." SIGNOR-263279 ETF1 protein P62495 UNIPROT "Translation release factor ERF1-ERF3" complex SIGNOR-C494 SIGNOR "form complex" binding 9606 29735640 t miannu "Termination of mRNA translation occurs when a stop codon enters the A site of the ribosome, and in eukaryotes is mediated by release factors eRF1 and eRF3, which form a ternary eRF1/eRF3-guanosine triphosphate (GTP) complex." SIGNOR-270813 MRPS26 protein Q9BYN8 UNIPROT "28S mitochondrial small ribosomal subunit" complex SIGNOR-C266 SIGNOR "form complex" binding 9606 25838379 t miannu "The mammalian mitochondrial ribosome (mitoribosome) has a highly protein-rich composition with a small sedimentation coefficient of 55 S, consisting of 39 S large and 28 S small subunits. . We report here the identification of 28 S small subunit proteins." SIGNOR-261447 denopamine chemical CHEBI:135359 ChEBI ADRB1 protein P08588 UNIPROT "up-regulates activity" "chemical activation" 10030 BTO:0000457 20590599 t Luana "Denopamine is the most selective ligand for β1-receptors, with regard to intrinsic activity and efficacy, and clenbuterol, procaterol, zinterol, AZ 40140d and salbutamol are more selective for the β2-adrenoceptor than the β1-adrenoceptor based on intrinsic activity and efficacy. " SIGNOR-257860 PCSK2 protein P16519 UNIPROT OXT protein P01178 UNIPROT "down-regulates quantity" cleavage 9606 BTO:0001073 11690596 t miannu "Oxytocin-extended form is further cleaved by enzymatic activity to yield the nine-amino-acid active peptide, OT. The proteolysis may involve several pro-hormone convertases, convertase 2 (PC2) (20p11-1-11.2) and convertase 5 (PC5) (9q21.3) (Gabreels et al 1998). Both enzymes are found in OT neurosecretory vesicles and are a part of a family of subtilisen/kexinlike convertases (Seidah et al 1994). It is a product of the OT gene located at human gene locus 20p13 (Rao et al 1992). The processing cascade results in the production of neurophysin I and OT extended form (OT-X), which is OT with a C-terminal, three-amino-acid extension." SIGNOR-270328 WNK1 protein Q9H4A3 UNIPROT OXSR1 protein O95747 UNIPROT up-regulates phosphorylation Thr185 TRNKVRKtFVGTPCW 9606 17190791 t gcesareni "Activation of wnk1 coincides with the phosphorylation and activation of two wnk1 substrates, namely, the protein kinases ste20/sps1-related proline alanine-rich kinase (spak) and oxidative stress response kinase-1 (osr1)" SIGNOR-151663 AKT proteinfamily SIGNOR-PF24 SIGNOR SP7 protein Q8TDD2 UNIPROT up-regulates phosphorylation 9606 21777568 t gcesareni "We found that Akt phosphorylates Osterix and that Akt activation increases protein stability, osteogenic activity and transcriptional activity of Osterix. We also found that BMP-2 increases the protein level of Osterix in an Akt activity-dependent manner." SIGNOR-174017 CDC14B protein O60729 UNIPROT GSK3B/Axin/APC complex SIGNOR-C110 SIGNOR up-regulates dephosphorylation 9606 18662541 t lperfetto "The phosphatase cdc14b translocates from the nucleolus to the nucleoplasm and induces the activation of the ubiquitin ligase apc/ccdh1" SIGNOR-227927 PRKACA protein P17612 UNIPROT RAF1 protein P04049 UNIPROT "down-regulates activity" phosphorylation Ser621 PKINRSAsEPSLHRA 9606 11971957 t gcesareni "We have mapped all camp-induced phosphorylation sites in raf-1, showing that serines 43, 259, and 621 are phosphorylated by pka in vitro and induced by camp in vivo" SIGNOR-86137 PER1 protein O15534 UNIPROT CLOCK/BMAL1 complex SIGNOR-C195 SIGNOR "down-regulates activity" binding 9606 20817722 t miannu "The mammalian clock is regulated at the cellular level by a transcriptional/translational feedback loop. BMAL1/clock (or NPAS2) heterodimers activate the expression of the period (PER) and cryptochrome (CRY) genes acting as transcription factors directed to the PER and CRY promoters via E-box elements. PER and CRY proteins form heterodimers and suppress the activity of the BMAL1/clock (or NPAS2) completing the feedback loop." SIGNOR-267978 LMX1A protein Q8TE12 UNIPROT CUX2 protein O14529 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 30770393 t miannu "Lmx1a drives Cux2 expression in the cortical hem through activation of a conserved intronic enhancer. Lmx1a knockdown abolishes activation of the Cux2 enhancer in the cortical hem" SIGNOR-263961 IL10 protein P22301 UNIPROT IL10RA protein Q13651 UNIPROT up-regulates binding 9606 BTO:0000801;BTO:0000776 10347215 t milica "Functionally active il-10 receptors are composed of two distinct subunits. The il-10 receptor ? Chain is a 110-kda polypeptide that plays the dominant role in mediating high affinity ligand binding and signal transduction. The il-10 receptor ? Subunit (also known as crf2_4) is predicted to be a 40-kda polypeptide that is largely required only for signaling" SIGNOR-67964 AKT1 protein P31749 UNIPROT H3-3A protein P84243 UNIPROT "down-regulates activity" phosphorylation Ser11 TKQTARKsTGGKAPR 9606 12588998 t "Ser 11 phosphorylation of H3 is either activatory and inhibitory as promotes DNA condensation (activatory) and induce transcription (inhibitory)." gcesareni "Additionally, active akt1 kinase strongly phosphorylates histone h3 at serine 10 in vitro" SIGNOR-98285 PDPK1 protein O15530 UNIPROT MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR "up-regulates activity" phosphorylation 9606 BTO:0000007 15175348 t lperfetto "In vitro kinase assay revealed that the direct targets of pdk1 in the mapk pathway were the upstream mapk kinases mek1 and mek2. The identified pdk1 phosphorylation sites in mek1 and mek2 are ser222 and ser226, respectively, and are known to be essential for full activation" SIGNOR-244934 TRIP12 protein Q14669 UNIPROT CDKN2A protein Q8N726 UNIPROT "down-regulates quantity by destabilization" ubiquitination 9606 BTO:0000007 20208519 t miannu "ULF interacts with ARF both in vitro and in vivo and promotes the lysine-independent ubiquitylation and degradation of ARF." SIGNOR-266781 SCF-betaTRCP complex SIGNOR-C5 SIGNOR CD4 protein P01730 UNIPROT "down-regulates quantity by destabilization" polyubiquitination 9606 11893391 t miannu "Degradation of the HIV receptor CD4 by the proteasome, mediated by the HIV-1 protein Vpu, is crucial for the release of fully infectious virions. To promote CD4 degradation Vpu has to be phosphorylated on a motif DSGXXS, which is conserved in several signalling proteins known to be degraded by the proteasome upon phosphorylation. Such phosphorylation is required for the interaction of Vpu with the ubiquitin ligase SCF-beta-TrCP that triggers CD4 degradation by the proteasome." SIGNOR-272615 MAPK14 protein Q16539 UNIPROT EIF4EBP1 protein Q13541 UNIPROT "down-regulates activity" phosphorylation Thr46 GGTLFSTtPGGTRII 9606 BTO:0003316 11777913 t miannu "4E-BP1 Is Phosphorylated in Vitro by Active p38 Kinase. In the present study we demonstrated that UVB induced 4E-BP1 phosphorylation at multiple sites, Thr-36, Thr-45, Ser-64, and Thr-69, leading to dissociation of 4E-BP1 from eIF-4E." SIGNOR-250099 FYN protein P06241 UNIPROT CHN2 protein P52757 UNIPROT down-regulates phosphorylation Tyr21 VSSDAEEyQPPIWKS 9606 17560670 t llicata "Ere we report that beta2-chimaerin is tyrosine-phosphorylated by src-family kinases (sfks) upon cell stimulation with epidermal growth factor (egf). these results suggest tyr-21 phosphorylation as a novel, sfk-dependent mechanism that negatively regulates beta2-chimaerin rac-gap activity." SIGNOR-155709 ZNRF3 protein Q9ULT6 UNIPROT LRP6 protein O75581 UNIPROT "down-regulates quantity" ubiquitination 9606 BTO:0000007 22575959 t "Here we show that the cell-surface transmembrane E3 ubiquitin ligase zinc and ring finger 3 (ZNRF3) and its homologue ring finger 43 (RNF43) are negative feedback regulators of Wnt signalling. ZNRF3 is associated with the Wnt receptor complex, and inhibits Wnt signalling by promoting the turnover of frizzled and LRP6." SIGNOR-260112 amitriptyline chemical CHEBI:2666 ChEBI CHRM4 protein P08173 UNIPROT "down-regulates activity" "chemical inhibition" 10029 8100134 t miannu "Antagonism of the five cloned human muscarinic cholinergic receptors expressed in CHO-K1 cells by antidepressants and antihistaminics. Competition between [‘H]QNB and the antidepressant compounds (Table 1) showed that at the ml subtype the most potent drugs were amitriptyline > dothiepin > doxepin = nortriptyline; at the m2 receptor, amitriptyline > imipramine > nortriptyline = dothiepin; at the m3 recep- tor, amitriptyline > dothiepin > nortriptyline; at the m4 receptor, amitriptyline > dothiepin > doxepin = nortrip- tyline; and at the m5 receptor, amitriptyline > doxepin > imipramine." SIGNOR-258704 RAB22A protein Q9UL26 UNIPROT BLOC-2 complex SIGNOR-C252 SIGNOR "up-regulates activity" relocalization 9606 30404817 t lperfetto "Recycling endosomes (REs) are transient endosomal tubular intermediates of early/sorting endosomes (E/SEs) that function in cargo recycling to the cell surface and deliver the cell type-specific cargo to lysosome-related organelles such as melanosomes in melanocytes.|Taken together, these findings suggest that Rab22A promotes the assembly of a BLOC-1-BLOC-2-KIF13A complex on E/SEs to generate REs that maintain cellular and organelle homeostasis." SIGNOR-260696 IKBKB protein O14920 UNIPROT IKBKG protein Q9Y6K9 UNIPROT unknown phosphorylation Ser43 PAMLHLPsEQGAPET 9606 SIGNOR-C14 12657630 t "IKKbeta phosphorylates human IKKgamma at Ser-31, Ser-43, and Ser-376|Thus far, we have no compelling evidence that inducible phosphorylation of these IKKgamma domains is important for their assigned functions." SIGNOR-251287 FBXO22 protein Q8NEZ5 UNIPROT BSG protein P35613 UNIPROT "down-regulates quantity by destabilization" ubiquitination 9606 BTO:0000007;BTO:0003227;BTO:0005816 28117675 t lperfetto "F-Box Protein FBXO22 Mediates Polyubiquitination and Degradation of CD147 to Reverse Cisplatin Resistance of Tumor Cells" SIGNOR-273452 "Cullin 1-RBX1-Skp1" complex SIGNOR-C529 SIGNOR BSG protein P35613 UNIPROT "down-regulates quantity by destabilization" ubiquitination 9606 BTO:0000007;BTO:0003227;BTO:0005816 28117675 t lperfetto "F-Box Protein FBXO22 Mediates Polyubiquitination and Degradation of CD147 to Reverse Cisplatin Resistance of Tumor Cells" SIGNOR-273453 PRKAA2 protein P54646 UNIPROT CDC27 protein P30260 UNIPROT unknown phosphorylation Ser379 NALPRRSsRLFTSDS 9606 SIGNOR-C15 22137581 t lperfetto "Using this approach for ppp1r12c, baiap2, and cdc27, we found that mutation of a single serine to alanine (s452, s366, and s379, respectively) resulted in an almost complete loss of ampk phosphorylation in these proteins" SIGNOR-195106 SMURF2 protein Q9HAU4 UNIPROT TGFBR1 protein P36897 UNIPROT "down-regulates activity" ubiquitination 9606 11163210 t lperfetto "Smurf2 is nuclear, but binding to Smad7 induces export and recruitment to the activated TGF beta receptor, where it causes degradation of receptors and Smad7 via proteasomal and lysosomal pathways." SIGNOR-104999 MAPK3 protein P27361 UNIPROT RPS6KB1 protein P23443 UNIPROT "up-regulates activity" phosphorylation 9606 BTO:0000176 14967450 t lperfetto "Erk phosphorylates multiple cytoplasmatic and cytoskeletal proteins, including mapk-activated protein kinases and the ribosomal p70-s6 kinase" SIGNOR-121997 TP53 protein P04637 UNIPROT BBC3 protein Q9BXH1 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0001109 16151013 f amattioni "Nuclear p53 caused expression of puma, which then displaced p53 from bcl-xl, allowing p53 to induce mitochondrial permeabilization." SIGNOR-140245 F2RL2 protein O00254 UNIPROT GNAL protein P38405 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-256904 PRKCZ protein Q05513 UNIPROT ADD1 protein P35611 UNIPROT up-regulates phosphorylation Ser726 KKKFRTPsFLKKSKK 9606 8810272 t gcesareni "These data demonstrate that adducin is a significant in vivo substrate for pkc or other pma-activated kinases in a variety of cells, and that phosphorylation of adducin occurs in dendritic spines that are believed to respond to external signals by changes in morphology and reorganization of cytoskeletal structures. Ser-726 and ser-713 in the c-terminal marcks-related domains of alpha- and beta-adducin, respectively, were identified as the major phosphorylation sites common for pka and pkc." SIGNOR-43834 RPS5 protein P46782 UNIPROT "40S cytosolic small ribosomal subunit" complex SIGNOR-C286 SIGNOR "form complex" binding -1 25901680 t lperfetto "Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins." SIGNOR-262419 N-[(2S)-2,3-dihydroxypropyl]-3-(2-fluoro-4-iodoanilino)-4-pyridinecarboxamide chemical CHEBI:94793 ChEBI MAP2K1 protein Q02750 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-189930 wortmannin chemical CHEBI:52289 ChEBI PIK3C3 protein Q8NEB9 UNIPROT down-regulates "chemical inhibition" 9534 BTO:0001444 22253445 t lperfetto "From these results, we conclude that LY294002 and wortmannin inhibit SARS pseudovirus entry by targeting PI4KB and that PI4KB is involved in SARS-CoV S-mediated entry into VeroE6 cells." SIGNOR-260730 BCR-ABL "fusion protein" SIGNOR-FP6 SIGNOR GRB2 protein P62993 UNIPROT "down-regulates activity" phosphorylation Tyr209 TGMFPRNyVTPVNRN 9606 BTO:0000007 20554525 t lperfetto "More recently, however, tyrosine phosphorylation of Grb2 in BCR-ABL-transformed cells on residues Tyr7, Tyr37, Tyr52, and Tyr209 in the SH3 domains has been reported and shown to negatively regulate the Ras/MAPK pathway." SIGNOR-246281 PEX14 protein O75381 UNIPROT PEX13 protein Q92968 UNIPROT "up-regulates activity" binding -1 15798189 t miannu "Pex14 interacts via its proline-rich motif with the SH3 domain of Pex13. We conclude that the association of Pex13 with Pex14 is an essential step in peroxisomal protein import" SIGNOR-253029 STK4 protein Q13043 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR up-regulates phosphorylation Ser209 SSAGWKNsIRHNLSL 9606 18394876 t gcesareni "Bonni and coworkers demonstrated that mst1 can phosphorylate foxo3 (and subsequently, foxo1) principally ser207 (ser212 in foxo1), a conserved site in the forkhead domain. This phosphorylation interdicts 14-3-3 binding, promotes foxo nuclear residence and transcriptional activity." SIGNOR-253001 VAV1 protein P15498 UNIPROT RAC1 protein P63000 UNIPROT "up-regulates activity" "guanine nucleotide exchange factor" 7227 23525006 t "We identify the GTP exchange factor (GEF) Vav as a key regulator of Rac activity downstream of RTKs in a developmentally regulated cell migration event" SIGNOR-259081 mTORC1 complex SIGNOR-C3 SIGNOR EIF4EBP1 protein Q13541 UNIPROT "down-regulates activity" phosphorylation Thr70 RNSPVTKtPPRDLPT 9606 23486913 t lperfetto "These results indicate that arg, leu, and gln act coordinately to stimulate proliferation of ptr cells through activation of the mtor-rps6k-rps6-eif4ebp1 signal transduction pathway. Specifically as part of mtorc1, mtor directly phosphorylates the ribosomal protein s6 kinases (s6k1 and s6k2) and the eukaryotic initiation factor 4e (eif4e)-binding proteins (4e-bp1 and 4e-bp2), both of which control specific steps in the initiation of cap-dependent translation" SIGNOR-217141 AKT3 protein Q9Y243 UNIPROT GSK3B protein P49841 UNIPROT "down-regulates activity" phosphorylation Ser9 SGRPRTTsFAESCKP 9606 23552696 t lperfetto "Active AKT, a common mediator of cell survival signals induced by radiation through multiple intracellular signaling pathways,11, 12 suppresses apoptosis. AKT positively regulates cyclin D1 expression through inactivation of glycogen synthase kinase 3_ (GSK3_). The AKT-mediated phosphorylation of glycogen synthase kinase 3_ on serine9 decreases its kinase activity for Thr286 of cyclin D1, which inhibits the nuclear export and the cytoplasmic proteasomal degradation of cyclin D1" SIGNOR-245424 BRCA2 protein P51587 UNIPROT POLH protein Q9Y253 UNIPROT up-regulates binding 9606 24485656 t miannu "Palb2 and brca2 interact with pol_ and are required to sustain the recruitment of pol_ at blocked replication forks. Palb2 and brca2 stimulate pol_-dependent dna synthesis on d loop substrates" SIGNOR-204538 CyclinA2/CDK2 complex SIGNOR-C83 SIGNOR RB1 protein P06400 UNIPROT down-regulates phosphorylation Thr821 KISEGLPtPTKMTPR 9606 9139732 t lperfetto "We demonstrate that phosphorylation by either cdk2-cyclin a, which phosphorylates t821, or cdk4-cyclin d1, which phosphorylates threonine 826, can disable prb for subsequent binding of an lxcxe protein." SIGNOR-217324 OPRK1 protein P41145 UNIPROT GNAO1 protein P09471 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-256989 KIRREL3 protein Q8IZU9 UNIPROT Synaptic_plasticity phenotype SIGNOR-PH158 SIGNOR up-regulates 9606 BTO:0000142 32503885 f miannu "We demonstrate that ectopic Kirrel3 expression in CA1 neurons specifically induces ectopic DG synapse formation, providing direct evidence that Kirrel3 plays an instructive role in synapse development." SIGNOR-269077 HIPK2 protein Q9H2X6 UNIPROT ZBTB4 protein Q9P1Z0 UNIPROT "down-regulates activity" phosphorylation Thr983 AAPPAPPtPPPPTLP -1 19448668 t miannu "The human protein kinase HIPK2 phosphorylates and downregulates the methyl-binding transcription factor ZBTB4." SIGNOR-262882 sirolimus chemical CHEBI:9168 ChEBI CD80 protein P33681 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 18652845 f miannu "Although RAPA downregulated ILT2, ILT3 and ILT4 expression in DC, the inhibition of T cell proliferation by RAPA-treated DC is predominantly due to the reduction of CD40, CD80 and CD86 expression rather than the propensity to generate FoxP3 expressing regulatory cells." SIGNOR-255475 PRKCA protein P17252 UNIPROT CALD1 protein Q05682 UNIPROT down-regulates phosphorylation Ser677 AIVSKIDsRLEQYTS 9606 BTO:0000887;BTO:0001260 8182108 t gcesareni "Phosphorylation of both intact caldesmon and of its c-terminal fragment (658c), containing residues 658-756, significantly decreased their ability to inhibit acto-heavy meromyosin atpase." SIGNOR-36796 CDK1 protein P06493 UNIPROT MYOD1 protein P15172 UNIPROT down-regulates phosphorylation Ser5 sPPLRDVD 9606 SIGNOR-C17 14749395 t lperfetto "Myod is phosphorylated on ser5 and ser200 by cyclin b-cdc2, resulting in a decrease of its stability and down-regulation of both myod and p21." SIGNOR-121605 ATM protein Q13315 UNIPROT RAD17 protein O75943 UNIPROT unknown phosphorylation Ser656 SASELPAsQPQPFSA 9606 10608806 t lperfetto "We determined a general phosphorylation consensus sequence for atm and identified putative in vitro targets by using glutathione s-transferase peptides as substrates. Putative atm in vitro targets include p95/nibrin, mre11, brca1, rad17, pts, wrn, and atm (s440) itself." SIGNOR-73524 UQCRC2 protein P22695 UNIPROT "Mitochondrial respiratory chain complex III" complex SIGNOR-C279 SIGNOR "form complex" binding 30030361 t lperfetto "Complex III (EC 1.10.2.2) or quinol-cytochrome c reductase performs electron transfer coupled to proton pumping using the ‘Q-cycle’ mechanism [79,80]. Structurally, it is a tightly bound symmetrical dimer (cIII2), being each ‘monomer’ composed of three catalytic core (MT-CYB, CYC1 and UQCRFS1) and seven supernumerary subunits" SIGNOR-262191 FYN protein P06241 UNIPROT CAV1 protein Q03135 UNIPROT "down-regulates activity" phosphorylation Tyr14 VDSEGHLyTVPIREQ 9606 12921535 t lperfetto "Caveolin-1 is phosphorylated on tyr(14) in response to both oxidative and hyperosmotic stress. In the present paper, we show that this phosphorylation requires activation of the src family kinase fyn.Therefore," SIGNOR-118003 GSK3B protein P49841 UNIPROT CEBPB protein P17676 UNIPROT up-regulates phosphorylation Ser231 LSTSSSSsPPGTPSP 9606 phosphorylation:Thr235 IFGATDYtSSIDVWS 17601773 t fspada "Mass spectrometric analysis revealed that cdk2/cyclinA phosphorylates C/EBPbeta on Thr(188) and is required for phosphorylation (on Ser(184) or Thr(179)) of C/EBPbeta by GSK3beta and maintenance of DNA binding activity. However, the acquisition of dna binding and transactivation capacity of c/ebpbeta is delayed until further phosphorylation (on ser(184) or thr(179)) by gsk3beta occurs." SIGNOR-156514 NEFM protein P07197 UNIPROT "Neurofilament L/M" complex SIGNOR-C207 SIGNOR "form complex" binding 9606 19468066 t miannu "Neurofilaments are obligate heteropolymers that are minimally comprised of the low molecular neurofilament protein L (NFL) plus the medium and/or high molecular weight proteins neurofilament protein M (NFM) and neurofilament protein H" SIGNOR-255271 MAPK1 protein P28482 UNIPROT MKNK1 protein Q9BUB5 UNIPROT up-regulates phosphorylation 9606 9155017 t gcesareni "We have identified a new subfamily of murine serine/threonine kinases, whose members, map kinase-interacting kinase 1 (mnk1) and mnk2, bind tightly to the growth factor-regulated map kinases, erk1 and erk2erk and p38 phosphorylate mnk1 and mnk2, which stimulates their in vitro kinase activity toward a substrate, eukaryotic initiation factor-4e (eif-4e)." SIGNOR-48298 NELFB protein Q8WX92 UNIPROT NELF complex SIGNOR-C521 SIGNOR "form complex" binding 9606 18628398 t miannu "The Negative Elongation Factor (NELF) is a transcription regulatory complex that induces stalling of RNA polymerase II (Pol II) during early transcription elongation and represses expression of several genes studied to date, including Drosophila Hsp70, mammalian proto-oncogene junB, and HIV RNA. It is composed of four subunits, NELF-A, NELF-B, NELF-C/D, and NELF-E." SIGNOR-271402 SF3B1 protein O75533 UNIPROT "B-WICH complex" complex SIGNOR-C447 SIGNOR "form complex" binding 9606 21559432 t miannu "The B-WICH complex is an extended form of WICH [26], and is involved in both RNA pol I and RNA pol III transcription [20], [21]. In addition to the three core proteins, WSTF, SNF2h, and nuclear myosin (NM1); the myb binding protein 1b, RNA helicase II/DXX21, and SAP155 all also associate via RNA species [21]. The subunit SNF2h is an ISWI ATPase, which slides nucleosomes in an ATP-dependent manner [27]. WSTF is a component of several complexes: two SNF2h complexes, B-WICH [21] and WICH [26], and one SWI/SNF type of chromatin remodelling complex, the WINAC complex, which is involved in vitamin D-mediated RNA pol II transcription" SIGNOR-268819 TRAF2 protein Q12933 UNIPROT RIPK1 protein Q13546 UNIPROT "up-regulates activity" ubiquitination Lys377 NEPSLQSkLQDEANY 9606 BTO:0000007 8702708 t lperfetto "Following binding to tradd, traf2 was thought to mediate non-degradative lys-63-linked polyubiquitination of rip1 via its ring e3 ligase domain. Rip1 is known to directly interact with traf2." SIGNOR-42984 RET protein P07949 UNIPROT RET protein P07949 UNIPROT unknown phosphorylation Tyr826 SRKVGPGyLGSGGSR 9534 BTO:0004055 8621380 t lperfetto "Based on the phosphopeptide maps, we can identify six tyrosine phosphorylation sites in RET: Tyr-687, Tyr-826, Tyr-1062, Tyr-1096, Tyr-1015, and Tyr-1029. By comparing the peptide map of each mutant to the wild-type receptor, we can tentatively assign each tryptic peptide containing phosphorylation sites to individual P-labeled spots on the two-dimensional map " SIGNOR-248942 ATF4 protein P18848 UNIPROT "NLRP1 inflammasome" complex SIGNOR-C224 SIGNOR "up-regulates quantity by expression" "transcriptional regulation" 9606 26086088 t miannu "Transcription Factor ATF4 Induces NLRP1 Inflammasome Expression During Endoplasmic Reticulum Stress. Here we report that expression of NLRP1, a core inflammasome component, is specifically up-regulated during severe ER stress conditions in human cell lines. Both IRE1α and PERK, but not the ATF6 pathway, modulate NLRP1 gene expression. Furthermore, using mutagenesis, chromatin immunoprecipitation and CRISPR-Cas9-mediated genome editing technology, we demonstrate that ATF4 transcription factor directly binds to NLRP1 promoter during ER stress." SIGNOR-260354 masitinib chemical CHEBI:63450 ChEBI PDGFRB protein P09619 UNIPROT "down-regulates activity" "chemical inhibition" -1 22037378 t Luana "Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here." SIGNOR-258246 COL4A6 protein Q14031 UNIPROT "A1/b1 integrin" complex SIGNOR-C159 SIGNOR "up-regulates activity" binding 35267698 t lperfetto "Integrins constitute a major group of receptors for extracellular matrix components, including collagens.|Among the four types, the signaling mechanism of α1β1 and α2β1 integrins has especially been reported. These integrins bind to both collagen types I and IV; however, their affinities differ: α1β1 has a higher affinity for collagen type IV, while α2β1 preferentially binds to collagen type I [13,23]." SIGNOR-272352 SNRPD2 protein P62316 UNIPROT "U2 snRNP complex" complex SIGNOR-C479 SIGNOR "form complex" binding 9606 30765414 t lperfetto "The major spliceosomal building blocks are the U1, U2, U4/U6, and U5 small nuclear ribonucleoproteins (snRNPs). Each consists of a small nuclear RNA (snRNA) (or two, in the case of U4/U6), seven Sm proteins that form a ring (or seven Lsm proteins in the case of U6), and a variable number of snRNP-specific proteins (Fig. 1F) (Will and Lührmann 2011). Under splicing conditions, the U4/U6 and U5 snRNPs form a 25S U4/U6.U5 tri-snRNP, in which the U4 and U6 snRNAs are base-paired, forming a three-way junction." SIGNOR-270661 retinol smallmolecule CHEBI:50211 ChEBI retinal smallmolecule CHEBI:15035 ChEBI "up-regulates quantity" "precursor of" 9606 21621639 t lperfetto "Currently, at least three RDH seem physiologically involved in converting all-trans-retinol into all-trans-retinal: RDH1, RDH10 and DHRS9" SIGNOR-265112 MAPK9 protein P45984 UNIPROT ATF2 protein P15336 UNIPROT up-regulates phosphorylation Thr69 SVIVADQtPTPTRFL 9606 7737130 t gcesareni "Stimulation of atf-2-dependent transactivation by genotoxic agents requires the presence of threonines 69 and 71 located in the n-terminal transactivation domain. These sites are the target of p54 and p46 stress-activated protein kinases (sapks) which bind to, and phosphorylate atf-2 in vitro." SIGNOR-32429 TLX1 protein P31314 UNIPROT RB1 protein P06400 UNIPROT "down-regulates activity" binding 9606 BTO:0000661 15897879 t 2 miannu "ectopic HOX11 expression resulted in hyperphosphorylation of the retinoblastoma protein (Rb), which correlated with inhibition of the major Rb serine/threonine phosphatase PP1." SIGNOR-240725 UBE2L3 protein P68036 UNIPROT RNF19B protein Q6ZMZ0 UNIPROT "up-regulates activity" binding 9606 BTO:0000914 16709802 t miannu "We demonstrated that both UbcH7 and UbcH8 bind to full-length NKLAM.  We demonstrated decreased protein expression and enhanced ubiquitination of URKL-1 in the presence of NKLAM. These data indicate that NKLAM is a RING finger protein that binds Ubcs and" SIGNOR-271591 GSK3B protein P49841 UNIPROT CyclinD/CDK4 complex SIGNOR-C18 SIGNOR "down-regulates quantity by destabilization" phosphorylation 9606 phosphorylation:Ser9 SGRPRTTsFAESCKP 23552696 t lperfetto "Active AKT, a common mediator of cell survival signals induced by radiation through multiple intracellular signaling pathways,11, 12 suppresses apoptosis. AKT positively regulates cyclin D1 expression through inactivation of glycogen synthase kinase 3_ (GSK3_). The AKT-mediated phosphorylation of glycogen synthase kinase 3_ on serine9 decreases its kinase activity for Thr286 of cyclin D1, which inhibits the nuclear export and the cytoplasmic proteasomal degradation of cyclin D1" SIGNOR-245432 MAPK9 protein P45984 UNIPROT H2AX protein P16104 UNIPROT up-regulates phosphorylation Ser140 GKKATQAsQEY 9606 18158901 t gcesareni "H2ax interacts with numerous proteins required for dna damage signaling and repair when phosphorylated on ser-140. Phosphorylation of ser-140 (h2ax139ph) in response to ionizing radiation is mediated by both atm and prkdc. Our data showed that h2ax is phosphorylated by uva-activated jnk." SIGNOR-160210 CASP3 protein P42574 UNIPROT PTCH1 protein Q13635 UNIPROT down-regulates cleavage Asp1405 CPGYPETdHGLFEDP 9606 23074268 t gcesareni "Like other dependence receptors, ptc1 contains a dependence-as-associated receptor c-terminal motif that is cleaved by caspases at a conserved aspartic acid (asp 1392) in the absence of shh, to expose a proapoptotic domain." SIGNOR-199111 CSNK2A1 protein P68400 UNIPROT PPP1R1B protein Q9UD71 UNIPROT "up-regulates activity" phosphorylation Ser102 NLNENQAsEEEDELG -1 2557337 t llicata "Study of [Plphosphate release during manual Edman degradation confirmed that the phosphorylated residues in rat DARPP-32 were Ser45 and Ser102. | Phosphorylation by casein kinase II did not affect the potency of DARPP-32 as an inhibitor of protein phosphatase-1, which depended only on phosphorylation of Thr34 by cAMP-dependent protein kinase. However, phosphorylation of DARPP-32 by casein kinase II facilitated phosphorylation of Thr34 by cAMP-dependent protein kinase" SIGNOR-250927 CHEK2 protein O96017 UNIPROT TP53 protein P04637 UNIPROT "up-regulates quantity by stabilization" phosphorylation Ser15 PSVEPPLsQETFSDL 9606 BTO:0000567 10673501 t gcesareni "Chk1/chk2 and atm/atr also phosphorylate the effector p53, increasing its stability.We Have demonstrated that the human homologs of the checkpoint kinases, chk1 and chk2/hcds1, phosphorylate at least three dna damage-inducible phosphorylation sites in p53." SIGNOR-75009 PLK1 protein P53350 UNIPROT KAT7 protein O95251 UNIPROT up-regulates phosphorylation Ser57 SQSSQDSsPVRNLQS 9606 18250300 t lperfetto "Here, we show that the interaction between plk1 and hbo1 is mitosis-specific and that plk1 phosphorylates hbo1 on ser-57 in vitro and in vivo. During mitosis, cdk1 phosphorylates hbo1 on thr-85/88, creating a docking site for plk1 to be recruited. Significantly, the overexpression of hbo1 mutated at the plk1 phosphorylation site (s57a) leads to cell-cycle arrest in the g1/s phase, inhibition of chromatin loading of the minichromosome maintenance (mcm) complex, and a reduced dna replication rate." SIGNOR-160751 RPAP2 protein Q8IXW5 UNIPROT POLR2A protein P24928 UNIPROT "up-regulates activity" dephosphorylation Ser1619 SPSYSPTsPSYSPTS 9606 BTO:0000567 22137580 t "In addition, we show that RPAP2 is a CTD Ser5 phosphatase. Taken together, our results indicate that during transcription of snRNA genes, Ser7 phosphorylation facilitates recruitment of RPAP2, which in turn both recruits Integrator and dephosphorylates Ser5.|The Pol II CTD is first phosphorylated on Ser5 and then on Ser7 by CDK7. RPAP2 associates with the Pol II CTD after Ser7 phosphorylation and tethers a subcomplex of Integrator to snRNA genes. RPAP2 dephosphorylates Ser5P of the CTD, facilitating transcription and the subsequent recruitment of the Int11 catalytic subunit of Integrator" SIGNOR-248735 sirolimus chemical CHEBI:9168 ChEBI mTORC1 complex SIGNOR-C3 SIGNOR down-regulates "chemical inhibition" -1 17350953 t lperfetto "Rapamycin is an immunosuppressive drug that binds simultaneously to the 12-kDa FK506- and rapamycin-binding protein (FKBP12, or FKBP) and the FKBP-rapamycin binding (FRB) domain of the mammalian target of rapamycin (mTOR) kinase. The resulting ternary complex has been used to conditionally perturb protein function, and one such method involves perturbation of a protein of interest through its mislocalization." SIGNOR-219385 PRKCA protein P17252 UNIPROT PLCG1 protein P19174 UNIPROT down-regulates phosphorylation Ser1248 HGRAREGsFESRYQQ 9606 BTO:0000782;BTO:0000661 1370476 t llicata "The observation that pka also phosphorylates plc-yl on serine 1248 suggests that phosphorylation of this residue may be a common mechanism by which pkc and pka inhibit plc-yl." SIGNOR-17905 "oxotremorine M" chemical CHEBI:38322 ChEBI CHRM1 protein P11229 UNIPROT "up-regulates activity" "chemical activation" 10029 BTO:0000246 9224827 t miannu "We investigated whether the allosteric modulators can also increase the affinity of receptors for their agonists. Twelve agonists and five allosteric modulators were tested in experiments on membranes of CHO cells that had been stably transfected with genes for the M1-M4 receptor subtypes. Affinities of agonists for the M1–M4 receptor subtypes were determined according to the ability of the agonist to inhibit [3H]NMS binding in the presence of 0.5 mM GTP; in this way, the low affinity binding of agonists was measured.The computed pKi and nH values are summarized in Table 2." SIGNOR-258656 SP1 protein P08047 UNIPROT CDKN2B protein P42772 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 11013220 f irozzo "In this system, the basal transcription level from the p15Ink4B promoter was increased with increasing levels of Sp1, and Sp1 was required for transcriptional induction by Smads. Finally, inactivation of the Sp1 binding sites in the p15Ink4B promoter decreased the basal transcription level and TGF-β responsiveness." SIGNOR-256289 PRKCA protein P17252 UNIPROT EWSR1 protein Q01844 UNIPROT "down-regulates activity" phosphorylation Ser266 SSYGQQSsFRQDHPS 9606 9341188 t miannu "Here we report thatews, a nuclearrna-bindingprooncoprotein, contains an iq domain, is phosphorylated byproteinkinase c, and interacts with calmodulin. Interestingly, pkc phosphorylation of ews inhibits its binding to rna homopolymers, and conversely,rna binding to ews interferes with pkc phosphorylation./ these data indicate that ews contains an iq domain with ser266 acting as the primary site for pkc phosphorylation." SIGNOR-52850 "Dynorphin B" chemical CHEBI:80347 ChEBI OPRD1 protein P41143 UNIPROT "up-regulates activity" "chemical activation" 10029 BTO:0000246 9686407 t miannu "Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors." SIGNOR-258797 MAPK3 protein P27361 UNIPROT RUNX2 protein Q13950 UNIPROT up-regulates phosphorylation Ser294 DPRQAQSsPPWSYDQ 9606 19801668 t llicata "In this study, we identified two phosphorylation sites in runx2 at ser301 and ser319 that are required for mapk-dependent activation of runx2 transcriptional activity and osteoblast differentiation." SIGNOR-188343 HIPK2 protein Q9H2X6 UNIPROT CTBP1 protein Q13363 UNIPROT down-regulates phosphorylation Ser422 AHPPHAPsPGQTVKP 9606 BTO:0002552 15708980 t lperfetto "Homeodomain-interacting protein kinase-2 mediates ctbp phosphorylation and degradation in uv-triggered apoptosishipk2 phosphorylates ctbp at ser-422" SIGNOR-134040 TACR3 protein P29371 UNIPROT GNAS protein Q5JWF2 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-256794 RORA protein P35398 UNIPROT ARNTL protein O00327 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 24737872 t miannu "As RORs function as transcriptional activators and their expression correlates with histone acetylation and chromatin accessibility, RORs are thought to function as positive regulators of Bmal1 expression at its peak levels, whereas REV-ERBs block ROR and negatively regulate Bmal1 at the trough of its expression." SIGNOR-268002 MAPK8 protein P45983 UNIPROT SFN protein P31947 UNIPROT down-regulates phosphorylation Ser186 FHYEIANsPEEAISL 9606 15071501 t "JNK1 and JNK2 are required for apoptosis of thymocites,Ser residues in the reagion between alpha-helices 7 and 8" gcesareni "Jnk phosphorylates 14-3-3zeta_ at ser-184 and 14-3-3sigma_ at ser-187." SIGNOR-124016 MAPK14 protein Q16539 UNIPROT TWIST1 protein Q15672 UNIPROT up-regulates phosphorylation Ser68 GGGDEPGsPAQGKRG 9606 BTO:0000150 21502402 t llicata "Phosphorylation of serine 68 of twist1 by mapks stabilizes twist1 protein and promotes breast cancer cell invasiveness. this ser 68 is phosphorylated by p38, c-jun n-terminal kinases (jnk), and extracellular signal-regulated kinases1/2 in vitro" SIGNOR-173409 MECP2 protein P51608 UNIPROT BDNF protein P23560 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 10116 14593183 t Luana "We find that MeCP2 binds selectively to BDNF promoter III and functions to repress expression of the BDNF gene." SIGNOR-264540 SCN8A protein Q9UQD0 UNIPROT Action_potential phenotype SIGNOR-PH82 SIGNOR up-regulates 9606 26043074 f miannu "The expression of voltage-gated sodium channels (NaVs) is a key feature for initiation and conduction of action potentials in excitable tissues and cells such as cardiac and skeletal muscle and neurons." SIGNOR-253452 Adenylate_cyclase proteinfamily SIGNOR-PF92 SIGNOR ATP smallmolecule CHEBI:15422 ChEBI "down-regulates quantity" "chemical modification" 9606 11376933 t miannu "To date, ten different mammalian isoforms of adenylyl cyclase (AC) have been cloned and characterized. Each isoform has its own distinct tissue distribution and regulatory properties, providing possibilities for different cells to respond diversely to similar stimuli. The product of the enzymatic reaction catalyzed by ACs, cyclic AMP (cAMP) has been shown to play a crucial role for a variety of fundamental physiological cell functions ranging from cell growth and differentiation, to transcriptional regulation and apoptosis." SIGNOR-267843 procaterol chemical CHEBI:135209 ChEBI ADRB2 protein P07550 UNIPROT "up-regulates activity" "chemical activation" 10030 BTO:0000457 20590599 t Luana "Denopamine is the most selective ligand for β1-receptors, with regard to intrinsic activity and efficacy, and clenbuterol, procaterol, zinterol, AZ 40140d and salbutamol are more selective for the β2-adrenoceptor than the β1-adrenoceptor based on intrinsic activity and efficacy. " SIGNOR-257863 PAF1C complex SIGNOR-C471 SIGNOR TCEA1 protein P23193 UNIPROT "up-regulates activity" binding 9606 BTO:0000567 20178742 t miannu "HPAF1C Independently and Cooperatively (with SII) Stimulates Transcription Elongation. Direct Interactions of hPAF1C with Pol II and SII Are Required for Its Intrinsic and Synergistic Effects on Chromatin Transcription." SIGNOR-269838 regorafenib chemical CHEBI:68647 ChEBI NTRK1 protein P04629 UNIPROT "down-regulates activity" "chemical inhibition" 9606 24756792 t miannu "In biochemical in vitro or cell-based assays, Regorafenib or its major human active metabolites M-2 and M-5 inhibited the activity of RET,VEGFR 1-3, KIT, PDGFR-alpha, PDGFR-beta, FGFR1, FGFR2, TIE2, DDR2, TrkA, Eph2A, RAF-1, BRAF, BRAFV600E, SAPK2, PTK5, and Abl at concentrations that can be achieved clinically." SIGNOR-259212 SNAPIN protein O95295 UNIPROT BLOC-1 complex SIGNOR-C381 SIGNOR "form complex" binding 9606 22203680 t lperfetto "We show that BLOC-1 is an elongated complex that contains one copy each of the eight subunits pallidin, Cappuccino, dysbindin, Snapin, Muted, BLOS1, BLOS2, and BLOS3. The complex appears as a linear chain of eight globular domains, ∼300 A long and ∼30 A in diameter." SIGNOR-265935 GH1 protein P01241 UNIPROT PRLR protein P16471 UNIPROT up-regulates binding 9606 7984244 t gcesareni "Hprl does not bind to the hgh receptor, but hgh binds to both the hghr and hprlr, and mutagenesis studies have shown that the receptor-binding sites on hgh overlap." SIGNOR-35575 PTH1R protein Q03431 UNIPROT SOST protein Q9BQB4 UNIPROT "down-regulates quantity" 28363951 f lperfetto "Furthermore, PTH acts on osteocytes to suppress the expression of sclerostin, an inhibitor of canonical Wnt signaling (Li, et al. 2005; Semenov, et al. 2005)). PTH action on sclerostin is primarily through cAMP signaling (Keller and Kneissel 2005) and mediated by Myocyte enhancer factor-2 (MEF2) transcriptional regulators (Leupin, et al. 2007). Using the cAMP signaling pathway in osteoblasts, PTH also inhibits the expression of Dickkopf 1 (Dkk1) (Guo et al. 2010a), which is another Wnt pathway inhibitor " SIGNOR-270552 levomethadone chemical CHEBI:136003 ChEBI OPRK1 protein P41145 UNIPROT "up-regulates activity" "chemical activation" 10029 BTO:0000246 9686407 t miannu "Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors." SIGNOR-258807 "pazopanib hydrochloride" chemical CHEBI:71217 ChEBI FGFR3 protein P22607 UNIPROT "down-regulates activity" "chemical inhibition" -1 17620431 t miannu "Pazopanib inhibition of a number of kinases outside of the VEGFR family was also determined. These included Abl1; Akt3; activin-like kinase 6; cyclin-dependent kinase 1/cyclin A; cyclin-dependent kinase 2/cyclin A; c-fms; c-Kit; epidermal growth factor receptor; ErbB2; ErbB4; EphB4; focal adhesion kinase; FGF receptors (FGFR) 1, 2, and 3; Flt-3; glycogen synthase kinase 3; insulin-like growth factor type I receptor; insulin receptor; interleukin-2–inducible T-cell kinase; c-jun NH2-terminal kinases 1, 2, and 3; lymphocyte-specific protein tyrosine kinase (murine); Met; p38α; PDGFRα and PDGFRβ; protein kinase C-β1 and -β2; polo-like kinases 1 and 3; Ret; Src; Syk; Tie-2; and Wee1. All assays were conducted using purified, recombinantly expressed catalytic domains of the kinases. " SIGNOR-259165 N-formyl-L-methionyl-L-leucyl-L-phenylalanine smallmolecule CHEBI:53490 ChEBI FPR1 protein P21462 UNIPROT "up-regulates activity" "chemical activation" 9606 BTO:0002524 31160049 t "Ligand-GPCR dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257492 PLK1 protein P53350 UNIPROT RACGAP1 protein Q9H0H5 UNIPROT up-regulates phosphorylation Ser214 AVDQGNEsIVAKTTV 9606 19468302 t llicata "Tandem mass spectrometry analysis of a purified hscyk-4 fragment (hscyk-4n) phosphorylated by plk1 in vitro identified four major sites (s157, s170, s214, and s260 plk1 phosphorylation of hscyk-4 localizes ect2 at the midzone and stimulates rhoa-dependent contractile ring assembly at the equatorial cortex." SIGNOR-185754 NCBP1 protein Q09161 UNIPROT "Cap-binding complex" complex SIGNOR-C440 SIGNOR "form complex" binding 9606 26382858 t lperfetto "The cap-binding complex (CBC), consisting of the nuclear cap-binding protein (NCBP) 2 and its adaptor NCBP1, is believed to bind all capped RNA and to be necessary for its processing and intracellular localization." SIGNOR-268359 "Mitochondrial respiratory chain complex II" complex SIGNOR-C278 SIGNOR "Respiratory electron transport chain" phenotype SIGNOR-PH141 SIGNOR up-regulates 30030361 f lperfetto "The oxidative phosphorylation system (OXPHOS) of the mitochondrial inner membrane is composed of five enzymes (complexes I–V; cI–V). In mammals, they are all multimeric and, except for cII, have subunits encoded both in the mitochondrial genome (mtDNA) and the nuclear genome (nDNA)." SIGNOR-262138 MAPK9 protein P45984 UNIPROT IRS1 protein P35568 UNIPROT down-regulates phosphorylation Ser315 ITATSPAsMVGGKPG 9606 9335553 t gcesareni "These results indicate that activation of protein kinase c stimulates a kinase which can phosphorylate insulin receptor substrate-1 at serine 612, resulting in an inhibition of insulin signaling in the cell these data suggest that: 1) activation of pkctheta contributes to ikk and jnk activation by ffas;2) ikk and jnk mediate pkctheta signals for irs-1 serine phosphorylation and degradation; ser-302 phosphorylation is dependent on pi 3-kinase/mtor, whereas ser-307 depends on c-jun nh2-terminal kinase to inhibit irs1 tyrosine phosphorylation. Ser-636 is located around the pi 3-kinase binding site and, therefore, thought to inhibit pi 3-kinase signaling." SIGNOR-52696 HOXC13 protein P31276 UNIPROT LAMB2 protein P55268 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9534 BTO:0000298 10835276 t Luana "The specificity of binding of these two proteins to the Lamin B2 origin is confirmed by both band-shift and in vitro footprinting assays. In addition, the ability of HOXC10 and HOXC13 to increase the activity of a promoter containing the 74 bp sequence, as assayed by CAT-assay experiments, demonstrates a direct interaction of these homeoproteins with the origin sequence in mammalian cells." SIGNOR-261644 PTTG1 protein O95997 UNIPROT LGALS1 protein P09382 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0002428 19351864 f miannu "PTTG induced S100A4 and galectin-1 mRNA and protein expression as assessed by Western blot and reverse transcription-PCR." SIGNOR-255068 EIF2AK2 protein P19525 UNIPROT EIF2AK2 protein P19525 UNIPROT "up-regulates activity" phosphorylation Tyr101 EGLSMGNyIGLINRI 9606 BTO:0001282 16373505 t "PKR autophosphorylates on Y101, Y162, and Y293. unctional characterization of Y101F and Y162F mutants revealed that phosphorylation at these sites is needed for efficient dsRNA binding and kinase dimerization and activation." SIGNOR-251112 lurasidone chemical CHEBI:70735 ChEBI DRD2 protein P14416 UNIPROT "down-regulates activity" "chemical inhibition" 10030 20404009 t Luana "In vitro functional assays demonstrated that lurasidone acts as an antagonist at D2 and 5-HT7 receptors and as a partial agonist at the 5-HT1A receptor subtype." SIGNOR-257838 CDK1 protein P06493 UNIPROT MPLKIP protein Q8TAP9 UNIPROT up-regulates phosphorylation Ser93 YPGSYSRsPAGSQQQ 9606 17310276 t lperfetto "Ttdn1 is phosphorylated by cdk1 in vitro and in vivo. Ttdn1 is phosphorylated at multiple residues, including ser93 and ser104. Mutation of thr120 of ttdn1 abolishes its interaction with plk1, suggesting phosphorylation of thr120 in the consensus plk1-binding motif is required for its interaction with plk1" SIGNOR-153304 CDK5 protein Q00535 UNIPROT HTT protein P42858 UNIPROT up-regulates phosphorylation Ser1179 LTNPPSLsPIRRKGK 9606 BTO:0000938 17611284 t lperfetto "Huntingtin is an antiapoptotic proteinwe show here that huntingtin is phosphorylated by the cyclin-dependent kinase 5 (cdk5) at serines 1181 and 1201. Phosphorylation can be induced by dna damage in vitro and in vivo. The state of huntingtin phosphorylation is a crucial regulator of neuronal cell death. Absence of phosphorylation of huntingtin at serines 1181 and 1201 confers toxic properties to wild-type huntingtin in a p53-dependent manner in striatal neurons and accelerates neuronal death induced by dna damage." SIGNOR-156836 IKBKE protein Q14164 UNIPROT IRF3 protein Q14653 UNIPROT "up-regulates activity" phosphorylation Ser386 ARVGGASsLENTVDL -1 18440553 t lperfetto "Virus-induced phosphoactivation of irf-3, thought to be mediated directly or indirectly by ikk? And/or tbk1 occurs in the c-terminal region of irf-3 at seven ser/thr residues, 385sslentvdlhisnshplslts405 (fig. 1a).Within This region, irf-3 has two phosphorylation sites: site 1 includes ser385 and ser386, whereas site 2 includes ser396, ser398, ser402, ser405, and thr404." SIGNOR-178367 CS protein O75390 UNIPROT oxaloacetate(2-) smallmolecule CHEBI:16452 ChEBI "down-regulates quantity" "chemical modification" 9606 3013232 t miannu "Citrate synthase catalyzes an important step within the cycle, the Claisen condensation of acetyl-Coenzyme A with oxaloacetate to form citrate; and it is the only enzyme in the cycle that can catalyze the formation of a carbon-carbon bond." SIGNOR-266549 prednisone chemical CHEBI:8382 ChEBI NR3C1 protein P04150 UNIPROT up-regulates "chemical activation" 9606 4188963 t dermatitis gcesareni SIGNOR-251705 C1QB protein P02746 UNIPROT "Complement C1q" complex SIGNOR-C308 SIGNOR "form complex" binding -1 29449492 t lperfetto "C1q comprises 18 polypeptide chains; three chains of C1q-A, -B, and -C trimerize to form six collagen-like triple helices connected to six globular (trimeric) ligand-recognition (gC1q) modules (fig. S1B) (1)." SIGNOR-263388 PRKCD protein Q05655 UNIPROT PRKCD protein Q05655 UNIPROT up-regulates phosphorylation Ser645 LNEKARLsYSDKNLI 9606 9305920 t gcesareni "Taken together, our results demonstrate that serine 643 of pkc-delta is a major autophosphorylation site, and phosphorylation of this site plays an important role in controlling its enzymatic activity and biological function. The enzymatic activity of pkc-deltas643a mutant as measured by phosphorylating the pkc-delta pseudosubstrate region-derived substrate was also reduced more than 70% in comparison to that of pkc-deltawt." SIGNOR-51000 CHMP2A protein O43633 UNIPROT Viral_budding phenotype SIGNOR-PH125 SIGNOR up-regulates -1 30989108 f miannu "ESCRT-III has been proposed to assemble inside the membrane neck formed at a late stage of a budding vesicle or an enveloped virus. The membrane neck needs to be constricted to proceed to membrane fission, thereby splitting the vesicle or virus from the cellular membrane. CHMP2A and CHMP3 are engaged late in ESCRT-III assembly, recruit VPS4 (31, 42), and block Snf7 (CHMP4) polymerization" SIGNOR-260844 EEF1A2 protein Q05639 UNIPROT Glu-tRNA(Glu) smallmolecule CHEBI:29157 ChEBI up-regulates relocalization 9606 23699257 t lperfetto "During protein synthesis, eEF1A binds to and delivers aminoacylated tRNAs (aa-tRNAs) to the elongating ribosome (Fig. 1). GTP bound to eEF1A is hydrolyzed upon codon-anticodon match between an aa-tRNA in the A site of the ribosome and mRNA bound to the ribosome." SIGNOR-269529 RAB32 protein Q13637 UNIPROT BLOC-2 complex SIGNOR-C252 SIGNOR "up-regulates activity" relocalization 9606 23247405 t lperfetto "Rab32 and Rab38 interact physically and colocalize with BLOC-2, AP-1 and AP-3|These results indicate that Rab32 and Rab38 operate in the same pathways previously defined for AP-1, AP-3 and BLOC-2 and suggest they are the specific proteins that divert AP-1, AP-3 and BLOC-2-dependent cargoes to maturing melanosomes and away from lysosomes." SIGNOR-260695 "GABA-A (a2-b1-g2) receptor" complex SIGNOR-C331 SIGNOR Excitatory_synaptic_transmission phenotype SIGNOR-PH133 SIGNOR down-regulates 9606 BTO:0000227 18790874 f brain lperfetto "GABAA receptors (GABAA-Rs) are the major inhibitory receptors in the central nervous system (CNS). |Mammalian GABAA-Rs are all anion-selective channels. Increased chloride permeability generally reduces neuronal excitability (inhibition)" SIGNOR-263777 "Av/b1 integrin" complex SIGNOR-C175 SIGNOR Cell_adhesion phenotype SIGNOR-PH7 SIGNOR up-regulates 9606 25388208 f miannu "Integrin-mediated cell adhesion is important for development, immune responses, hemostasis and wound healing." SIGNOR-269024 SMO protein Q99835 UNIPROT GNB3 protein P16520 UNIPROT up-regulates binding 9606 17251915 t gcesareni "Consistent with its predicted topology, smo couples to a specific family of inhibitory g protein (gis) to regulate hh signaling as pka suppresses the activity of gli, smo might use the stimulation of pi3k by galfai and gbetagamma subu- nits to block pka in cells that have high levels of camp" SIGNOR-152814 EIF2AK2 protein P19525 UNIPROT "NLRP1 inflammasome" complex SIGNOR-C224 SIGNOR "up-regulates activity" binding 9606 BTO:0000007 22801494 t miannu "Here we identify a role for double-stranded RNA-dependent protein kinase (PKR, also known as EIF2AK2) in inflammasome activation. PKR physically interacts with several inflammasome components, including NOD-like receptor (NLR) family pyrin domain-containing 3 (NLRP3), NLRP1, NLR family CARD domain-containing protein 4 (NLRC4), absent in melanoma 2 (AIM2), and broadly regulates inflammasome activation." SIGNOR-263118 HOXB7 protein P09629 UNIPROT PRKDC protein P78527 UNIPROT "up-regulates activity" binding 9606 BTO:0002419 SIGNOR-C106 17308091 t miannu "Ku70 and Ku80 associated with HOXB7 in vivo. Ku70/Ku80 heterodimer formation is a prerequisite for HOXB7 binding. interaction between Ku70/80 and HOXB7 may affect the catalytic activity of DNA-PK. HOXB7 stimulates DNA-PK activity" SIGNOR-226063 AKT proteinfamily SIGNOR-PF24 SIGNOR ESR1 protein P03372 UNIPROT up-regulates phosphorylation Ser104 FPPLNSVsPSPLMLL 9606 11108261 t lperfetto "Studies using mutants of er-alpha demonstrated that akt increased estrogen receptor activity through the amino-terminal activation function-1 (af-1). Serines s104 s106, s118, and s167 appear to play a role in the activation of er-alpha by akt." SIGNOR-244243 FURIN protein P09958 UNIPROT VWF protein P04275 UNIPROT "up-regulates activity" cleavage BTO:0001538 8218226 t Giorgia "Like PACE,PACE4 was able to process pro-vWF to its mature form, and efficient cleavage required both the P4 arginine and the P2 lysine" SIGNOR-260368 SNAI2 protein O43623 UNIPROT VDR protein P11473 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0000356 18485278 f miannu "We have shown here that the transcriptional repressor protein SLUG inhibits the expression of VDR in human breast cancer cells." SIGNOR-255177 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR PML protein P29590 UNIPROT up-regulates phosphorylation 9606 BTO:0001271 15093545 t "The effect has been demonstrated using P29590-4" gcesareni "Phosphorylation of pml by mitogen-activated protein kinases plays a key role in arsenic trioxide-mediated apoptosis." SIGNOR-270153 CDK5 protein Q00535 UNIPROT NR3C1 protein P04150 UNIPROT "down-regulates activity" phosphorylation Ser203 DLEFSSGsPGKETNE 9606 17440046 t llicata "Cdk5 phosphorylated gr at multiple serines, including ser203 and ser211 of its n-terminal domain, and suppressed the transcriptional activity of this receptor on glucocorticoid-responsive promoters by attenuating attraction of transcriptional cofactors to dna.| the effect of CDK5 on GR-induced transcriptional activity is specific to gene promoter, and possibly, to tissue" SIGNOR-154401 CyclinD3/CDK11A complex SIGNOR-C542 SIGNOR SPDEF protein O95238 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser242 WTDSEVDsSCSGQPI 9606 BTO:0000007 26885618 t lperfetto "In this study we provide evidence that the cell cycle kinase CDK11p58, a protein involved in G2/M transition and degradation of several transcription factors, directly interacts with and phosphorylates SPDEF on serine residues|Western blot analysis demonstrated that only one of the mutant constructs, consisting of mutations of serine 238, 242 and 243, resulted in increased levels of SPDEF protein expression as compared to wild type SPDEF, leading to subsequent ubiquitination and degradation of SPDEF through the proteasome pathway.|" SIGNOR-273122 FOXO1 protein Q12778 UNIPROT BCL2L11 protein O43521 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 12913110 f lperfetto "FOXO transcription factors directly activate bim gene expression and promote apoptosis in sympathetic neurons." SIGNOR-209654 ITGB8 protein P26012 UNIPROT TGFB1 protein P01137 UNIPROT up-regulates 9606 BTO:0000142 11970960 f lperfetto "Integrin _v_8-mediated tgf_ activation is also required to regulate neurovascular homeostasis in the adult brain" SIGNOR-117386 NFATC2 protein Q13469 UNIPROT Differentiation phenotype SIGNOR-PH37 SIGNOR up-regulates 9606 BTO:0000776 11163226 f scontino "In this study, the roles of NFATc1 and NFATc2 in T and B cells were examined. These results further characterize NFAT as a transcription factor family that plays a critical role in the regulation of lymphocyte effector differentiation." SIGNOR-270538 ABL1 protein P00519 UNIPROT STK3 protein Q13188 UNIPROT up-regulates phosphorylation Tyr81 MQQCDSPyVVKYYGS 9606 BTO:0000938 22590567 t llicata "We demonstrate that c-abl kinase phosphorylates mst2 at an evolutionarily conserved site, y81, within the kinase domain. We further show that the phosphorylation of mst2 by c-abl leads to the disruption of the interaction with raf-1 proteins and the enhancement of homodimerization of mst2 proteins. It thereby enhances the mst2 activation and induces neuronal cell death." SIGNOR-197538 NFIX protein Q14938 UNIPROT FOXO6 protein A8MYZ6 UNIPROT "down-regulates quantity" "transcriptional regulation" 10090 31838646 t Gianni "By integrating transcriptomic profiling (RNA-seq) of Nfia- and Nfix-deficient GNPs with epigenomic profiling (ChIP-seq against NFIA, NFIB and NFIX, and DNase I hypersensitivity assays), we reveal that these transcription factors share a large set of potential transcriptional targets, suggestive of complementary roles for these NFI family members in promoting neural development" SIGNOR-268887 17beta-estradiol smallmolecule CHEBI:16469 ChEBI estrone smallmolecule CHEBI:17263 ChEBI "up-regulates quantity" "precursor of" -1 8994190 t Luana "Human 17 beta-hydroxysteroid dehydrogenase (17-HSD) type 1 catalyzes the conversion of the low activity estrogen, estrone, into highly active estradiol, both in the gonads and in target tissues. " SIGNOR-269757 WT1 protein P19544 UNIPROT NPHS1 protein O60500 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 15504938 t "The Wilms tumor suppressor gene (WT1) is a zinc-finger-containing transcription factor that is coexpressed with NPHS1 in differentiated podocytes; gel shift binding assays demonstrate that a recombinant WT1 protein can bind and activate the 186-bp NPHS1 fragment in a sequence-specific manner" SIGNOR-252299 ATM protein Q13315 UNIPROT SMC3 protein Q9UQE7 UNIPROT unknown phosphorylation Ser1083 ESERGSGsQSSVPSV 9606 18442975 t llicata "Ser-1083 phosphorylation is ir-inducible, depends on atm and nijmegen breakage syndrome 1 (nbs1), and is required for intra-s phase checkpoint." SIGNOR-178479 [4-[2-(1H-indazol-3-yl)ethenyl]phenyl]-(1-piperazinyl)methanone chemical CHEBI:91441 ChEBI AURKA protein O14965 UNIPROT "down-regulates activity" "chemical inhibition" -1 22037378 t Luana "Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here." SIGNOR-258232 CAMK4 protein Q16566 UNIPROT HDAC5 protein Q9UQL6 UNIPROT down-regulates phosphorylation Ser259 FPLRKTAsEPNLKVR 9606 BTO:0000887 11114197 t gcesareni "Camk phosphorylates serines -259 and -498 in hdac5, which subsequently serve as docking sites for 14-3-3. Our studies suggest that 14-3-3 binding to hdac5 is required for camk-dependent disruption of mef2hdac complexes and nuclear export of hdac5, and implicate 14-3-3 as a signal-dependent regulator of muscle cell differentiation.Recently, camkiv, a calcium-calmodulindependent protein kinase, was also shown to activate mef2s by dissociating class ii histone deacetylases (e.g., Hdac5) from mef2s, thus relieving the transcriptional repressive effect of hdacs." SIGNOR-85106 CSNK2A1 protein P68400 UNIPROT HOXB7 protein P09629 UNIPROT "down-regulates activity" phosphorylation Ser133 IYPWMRSsGTDRKRG 10090 BTO:0002882 11290787 t llicata "Thus, we concluded that CKII can phosphorylate HOXB7 in vitro and that this phosphorylation occurs at both of the CKII target sites, S133 and T204. | Wild-type HOXB7 inhibited the differentiation of 32D cells, whereas mutations in the Pbx-binding pentapeptide motif or the DNA-binding homeodomain, as well as internal deletions of the N-terminal unique region, blocked this effect. Interestingly, mutations eliminating two target sites for casein kinase II, the glutamate-rich C terminus, or the first 14 amino acids of HOXB7, led to enhanced 32D differentiation." SIGNOR-250896 SL-327 chemical CHEBI:92211 ChEBI MAPK7 protein Q13164 UNIPROT down-regulates "chemical inhibition" 9606 BTO:0000938 BTO:0000142 11160424 t gcesareni "Pd98059, sl327, and u0126 have been extensively used to implicate erk1/2 in neuroplasticity (impey et al., 1999) and neuronal survival (villalba and journot, 1997;meyerfranke et al., 1998;skaper et al., 1998;anderson and tolkovsky, 1999;singer et al., 1999;bi et al., 2000). Interestingly, erk5 activation by egf in cos7 cells is also blocked by these inhibitors, (kamakura et al., 1999), suggesting that the erk5 pathway may also regulate cellular processes credited previously to erk1/2." SIGNOR-104936 C1QBP protein Q07021 UNIPROT C1QB protein P02746 UNIPROT "down-regulates activity" binding SIGNOR-C308 28018340 t lperfetto "Previous studies have shown that gC1qR inhibits aggregated IgG-mediated complement activation by binding to the gC1q site on C1q, thereby preventing IgG from binding to the gh’s (28), suggesting that the binding sites for gC1qR and IgG on C1q may be identical or at least overlapping." SIGNOR-263403 SCF-betaTRCP complex SIGNOR-C5 SIGNOR NFKB2 protein Q00653 UNIPROT "up-regulates activity" ubiquitination 9606 BTO:0000567 14676825 t lperfetto "Mechanism of processing of the nf-kappa b2 p100 precursor: identification of the specific polyubiquitin chain-anchoring lysine residue and analysis of the role of nedd8-modification on the scf(beta-trcp) ubiquitin ligase." SIGNOR-217175 RNF216 protein Q9NWF9 UNIPROT TIRAP protein P58753 UNIPROT "down-regulates quantity by destabilization" ubiquitination 9606 BTO:0000007 16968706 t miannu "Triad3A promotes proteolytic degradation of adapter proteins. A, Triad3A promotes down-regulation of TIRAP, TRIF, and RIP1 proteins." SIGNOR-271607 PIK3IP1 protein Q96FE7 UNIPROT PI3K complex SIGNOR-C156 SIGNOR "down-regulates activity" binding 9606 24316979 t miannu "We demonstrate that CUX1 deficiency activates phosphoinositide 3-kinase (PI3K) signaling through direct transcriptional downregulation of the PI3K inhibitor PIK3IP1 (phosphoinositide-3-kinase interacting protein 1), leading to increased tumor growth and susceptibility to PI3K-AKT inhibition." SIGNOR-260073 EEF1A1P5 protein Q5VTE0 UNIPROT Gln-tRNA(Gln) smallmolecule CHEBI:29166 ChEBI up-regulates relocalization 9606 23699257 t lperfetto "During protein synthesis, eEF1A binds to and delivers aminoacylated tRNAs (aa-tRNAs) to the elongating ribosome (Fig. 1). GTP bound to eEF1A is hydrolyzed upon codon-anticodon match between an aa-tRNA in the A site of the ribosome and mRNA bound to the ribosome." SIGNOR-269550 ACACB protein O00763 UNIPROT malonyl-CoA smallmolecule CHEBI:15531 ChEBI "up-regulates quantity" "chemical modification" 9606 20952656 t miannu "ACC catalyzes the carboxylation of acetyl-CoA to malonyl-CoA, the rate-limiting and first committed step in de novo fatty acid biosynthesis. Two isoforms of ACC exist in mammals, ACC1 and ACC2, and both enzymes function to carboxylate acetyl-CoA to form malonyl-CoA" SIGNOR-267110 ABL1 protein P00519 UNIPROT WASF3 protein Q9UPY6 UNIPROT "up-regulates activity" phosphorylation Tyr337 LPAQIIEyYNPSGPP 9606 BTO:0000815 17623672 t "WAVE3-Abl interaction promotes the tyrosine phosphorylation of WAVE3 by Abl, and STI-571, a specific inhibitor of Abl kinase activity, abrogates the Abl-mediated phosphorylation of WAVE3." SIGNOR-262301 PRKCZ protein Q05513 UNIPROT GRM5 protein P41594 UNIPROT "up-regulates activity" phosphorylation Ser840 VRSAFTTsTVVRMHV -1 15894802 t lperfetto "Thus, we showed that it is phosphorylation of Ser-839, not Thr-840, that is absolutely required for the unique Ca2+ oscillations produced by mGluR5 activation. The Thr-840 residue is important only in that it is permissive for the PKC-dependent phosphorylation of Ser-839." SIGNOR-249284 CDK2 protein P24941 UNIPROT CCNA2 protein P20248 UNIPROT up-regulates phosphorylation Ser154 PMDGSFEsPHTMDMS 9606 10652300 t lperfetto "Here we present evidence from in vitro and in vivo assay systems that the degradation of human cyclin a can be inhibited by kinase-inactive mutants of cdk2 and cdc2cdk2 can phosphorylate cyclin a on ser-154" SIGNOR-74466 GSK3B protein P49841 UNIPROT AXIN1 protein O15169 UNIPROT "up-regulates activity" phosphorylation Ser486 LRTPGRQsPGPGHRS 9606 10581160 t "Axin residues T609 and S614 are physiological GSK3beta targets. Axin phosphorylation in the regulation of b-catenin stability. When active (left), GSK3b phosphorylates Axin as well as APC and b-catenin. The phosphorylated form of Axin binds strongly to b-catenin and promotes the phosphorylation of b-catenin by GSK3b, leading to strong interaction with b-TrCP" SIGNOR-251221 embelin chemical CHEBI:4778 ChEBI XIAP protein P98170 UNIPROT "down-regulates activity" "chemical inhibition" 9606 BTO:0001271 28704451 t lperfetto "Targeting of X-linked inhibitor of apoptosis protein and PI3-kinase/AKT signaling by embelin suppresses growth of leukemic cells." SIGNOR-262013 "Yellow AB" chemical CHEBI:82554 ChEBI PTCH1 protein Q13635 UNIPROT down-regulates "chemical inhibition" 9606 17970037 t gcesareni "Anti-patched-1 antibodies suppress hedgehog signaling pathway and pancreatic cancer proliferation." SIGNOR-158650 CDK5 protein Q00535 UNIPROT PIP5K1C protein O60331 UNIPROT down-regulates phosphorylation Ser650 DERSWVYsPLHYSAQ 9606 15738269 t lperfetto "The interaction of talin with phosphatidylinositol(4) phosphate 5 kinase type i gamma (pipki gamma) regulates pi(4,5)p2 synthesis at synapses and at focal adhesions. Here, we show that phosphorylation of serine 650 (s650) within the talin-binding sequence of human pipki gamma blocks this interaction. At synapses, s650 is phosphorylated by p35/cdk5 and mitogen-activated protein kinase at rest, and dephosphorylated by calcineurin upon stimulation." SIGNOR-134455 AIP protein O00170 UNIPROT ESR1 protein P03372 UNIPROT "down-regulates activity" "transcriptional regulation" 9606 BTO:0000093 21984905 t "The immunophilin-like protein XAP2 is a negative regulator of estrogen signaling through interaction with estrogen receptor α." SIGNOR-253644 CUL4A protein Q13619 UNIPROT ARIH1 protein Q9Y4X5 UNIPROT "up-regulates activity" binding 9606 BTO:0000007 24076655 t miannu "Here, we provide evidence that Ariadne RBR E3 ubiquitin ligases such as TRIAD1 and HHARI can bind and be activated by CRL complexes. Whereas TRIAD1 specifically associates with CUL5–RBX2, HHARI is more promiscuous towards cullin types and associates with RBX1-associated cullins 1, 2, 3, and 4A. Interestingly, both TRIAD1 and HHARI show a strong preference for binding the neddylated form of the cullin. Our data suggest a novel function of NEDD8 in directing specific CRLs to Ariadne RBR ligases, which in turn exert influence on the levels of their cognate neddylated cullin." SIGNOR-268847 SGK1 protein O00141 UNIPROT FOXO3 protein O43524 UNIPROT "down-regulates activity" phosphorylation Ser253 APRRRAVsMDNSNKY 9606 11154281 t lperfetto "Protein kinase SGK mediates survival signals by phosphorylating the forkhead transcription factor FKHRL1 (FOXO3a)|However, SGK and Akt display differences with respect to the efficacy with which they phosphorylate the three regulatory sites on FKHRL1. While both kinases can phosphorylate Thr-32, SGK displays a marked preference for Ser-315 whereas Akt favors Ser-253. These findings suggest that SGK and Akt may coordinately regulate the function of FKHRL1 by phosphorylating this transcription factor at distinct sites. The efficient phosphorylation of these three sites on FKHRL1 by SGK and Akt appears to be critical to the ability of growth factors to suppress FKHRL1-dependent transcription, thereby preventing FKHRL1 from inducing cell cycle arrest and apoptosis." SIGNOR-249133 HCRTR1 protein O43613 UNIPROT GNA15 protein P30679 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257354 SMURF proteinfamily SIGNOR-PF29 SIGNOR BMPR2 protein Q13873 UNIPROT down-regulates ubiquitination 9606 22298955 t "inferred from 70% family members" gcesareni "Smurf1 and smurf2 are e3 ubiquitin ligases known to suppress tgf-beta signaling through degra-dation of smads and receptors for tgf-beta and bmps." SIGNOR-270215 "Multiaminoacyl-tRNA synthetase" complex SIGNOR-C472 SIGNOR Asp-tRNA(Asp) smallmolecule CHEBI:29158 ChEBI "up-regulates quantity" "chemical modification" 9606 28271488 t miannu "Aminoacyl-tRNA synthetases (AARSs) are essential enzymes that specifically aminoacylate one tRNA molecule by the cognate amino acid. In mammals, nine synthetases, those specific for amino acids Arg, Asp, Gln, Glu, Ile, Leu, Lys, Met and Pro, associate into a multi-aminoacyl-tRNA synthetase complex, an association which is believed to play a key role in the cellular organization of translation, but also in the regulation of the translational and nontranslational functions of these enzymes." SIGNOR-270374 3-[(dimethylamino)methyl]-N-[2-[4-[(hydroxyamino)-oxomethyl]phenoxy]ethyl]-2-benzofurancarboxamide chemical CHEBI:92223 ChEBI HDAC3 protein O15379 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-203476 CSNK2A1 protein P68400 UNIPROT TWIST1 protein Q15672 UNIPROT up-regulates phosphorylation Ser20 ADDSLSNsEEEPDRQ 9606 21559372 t llicata "Further investigation revealed that il-6 stabilizes twist in scchn cell lines through casein kinase 2 (ck2) phosphorylation of twist residues s18 and s20, and that this phosphorylation inhibits degradation of twist." SIGNOR-173672 INSR protein P06213 UNIPROT GYS1 protein P13807 UNIPROT "up-regulates activity" 9606 BTO:0000887;BTO:0001103 10909964 f lperfetto "In skeletal muscle, insulin activates glycogen synthase by reducing phosphorylation at both NH2- and COOH-terminal sites of the enzyme and by elevating the levels of glucose-6-phosphate, an allosteric activator of glycogen synthase." SIGNOR-236803 GLS2 protein Q9UI32 UNIPROT glutamine smallmolecule CHEBI:28300 ChEBI "down-regulates quantity" "chemical modification" 9606 22049910 t "Glutaminase (GLS1/2) catalyzes the conversion of L-glutamine to L-glutamate and ammonia." SIGNOR-266909 PTPRG protein P23470 UNIPROT SHC1 protein P29353 UNIPROT "down-regulates activity" dephosphorylation Tyr349 EEPPDHQyYNDFPGK -1 25624455 t miannu "PTPRG activation by the P1-WD peptide affected the tyrosine phosphorylation of several signaling molecules. Data analysis identified 31 molecules whose phosphorylation was modified in a statistically significant manner (Table I). inhibition of ABL1, BMX, BTK, DAB1, ITGB1, JAK2, KDR, KIT, LIMK1, MET, PDGFRB, SHC1, and VCL correlates with tyrosine dephosphorylation. In contrast, SRC inhibition correlates with hyperphosphorylation of the inhibitory Tyr530 residue and with dephosphorylation of the activatory Tyr419. Moreover, CDK2 and CTTN inhibition correlates with a hyperphosphorylation of the inhibitory Tyr15 and Tyr470, respectively. In contrast, a subgroup of 13 proteins, including BLNK, DOK2, ERBB2, GRIN2B, INSR, PDGFRA, PRKCD, PXN, STAT1, STAT2, STAT3, STAT5A, and ZAP70, appears to be activated by PTPRG activity." SIGNOR-254723 POT1 protein Q9NUX5 UNIPROT RPA2 protein P15927 UNIPROT "down-regulates activity" binding SIGNOR-C306 18680434 t lperfetto "The current model for how telomeres repress ATR signaling proposes that POT1/TPP1 prevents the binding of RPA to the single-stranded telomeric DNA" SIGNOR-263324 ANKRD6 protein Q9Y2G4 UNIPROT DVL2 protein O14641 UNIPROT up-regulates binding 9606 20006983 t gcesareni "Our data thus demonstrate that diversin and dishevelled function together in a mutually dependent fashion in zebrafish gastrulation and organ formation" SIGNOR-162142 ELOC protein Q15369 UNIPROT H1-1 protein Q02539 UNIPROT up-regulates phosphorylation Ser183 KPKKVAKsPAKAKAV 9606 BTO:0000567 20551309 t lperfetto "Our results also show the potential function of p-tefb phosphorylation of h1, namely, to increase h1 dissociation from actively transcribed dna. P-tefb preferentially phosphorylates the ser-183 phosphorylation site of histone h1.1" SIGNOR-166120 MAPK1 protein P28482 UNIPROT ABI1 protein Q8IZP0 UNIPROT up-regulates phosphorylation Ser183 PPTQKPPsPPMSGRG 9606 21419341 t lperfetto "Our mass spectrometry also identified abi1 s183 and s225 on abi1 (numbering corresponds to abi1 isoform 1) as sites phosphorylated on endogenous protein and in the wildtype erk-dependent in vitro phosphorylated sample. these data indicate erk phosphorylation of abi1 is required for basal and egf-induced wrc interaction with the wrp2/3 complex." SIGNOR-172869 RFC3 protein P40938 UNIPROT "RF-C complex" complex SIGNOR-C375 SIGNOR "form complex" binding 12930972 t lperfetto "RF‐C, a complex of five subunits, is conserved in all eukaryotes (reviewed in 5). In yeast, all subunits of RF‐C are essential for viability. The genes encoding all five subunits of mammalian RF‐C (145, 40, 38, 37 and 36 kDa) have been cloned" SIGNOR-265507 LNX1 protein Q8TBB1 UNIPROT CLDN17 protein P56750 UNIPROT "down-regulates quantity by destabilization" ubiquitination -1 22889411 t miannu "We used the Ligand of Numb protein X (LNX) family of E3s, a group of PDZ domain-containing RING-type E3 ubiquitin ligases, to demonstrate the feasibility of this strategy. Many potential substrates of LNX E3s were identified. Eight of the nine selected candidates were ubiquitinated in vitro, and two novel endogenous substrates, PDZ-binding kinase (PBK) and breakpoint cluster region protein (BCR), were confirmed in vivo." SIGNOR-272900 midostaurin chemical CHEBI:63452 ChEBI FGR protein P09769 UNIPROT "down-regulates activity" "chemical inhibition" -1 30069632 t Gianni "Midostaurin (PKC412, Rydapt®) is an oral multiple tyrosine kinase inhibitor. Main targets are the kinase domain receptor, vascular endothelial-, platelet derived-, and fibroblast growth factor receptor, stem cell factor receptor c-KIT, as well as mutated and wild-type FLT3 kinase" SIGNOR-261976 GSK3B protein P49841 UNIPROT EIF2B3 protein Q9NR50 UNIPROT down-regulates binding 9606 21798082 t gcesareni "Akt also promotes protein synthesis by phosphorylating and inactivating gsk3b, thus releasing the gsk3b-dependent inhibition of the eukariotic translation initiation factor 2b (eif2b)." SIGNOR-175520 CSNK2A1 protein P68400 UNIPROT TELO2 protein Q9Y4R8 UNIPROT down-regulates phosphorylation Ser491 GSDSDLDsDDEFVPY 9606 20864032 t lperfetto "Here we report that tel2 and tti1 are targeted for degradation within mtorc1 by the scffbxo9 ubiquitin ligase to adjust mtor signalling to growth factor availability. This process is primed by ck2, which translocates to the cytoplasm to mediate mtorc1-specific phosphorylation of tel2/tti1. Here, we show that tel2 is constitutively phosphorylated on conserved serines 487 and 491 by casein kinase 2 (ck2)" SIGNOR-168040 SLC5A5 protein Q92911 UNIPROT sodium(1+) chemical CHEBI:29101 ChEBI "up-regulates quantity" relocalization 10116 28192058 t scontino "Active iodide (I-) transport in both the thyroid and some extrathyroidal tissues is mediated by the Na+/I- symporter (NIS). In the thyroid, NIS-mediated I- uptake plays a pivotal role in thyroid hormone (TH) biosynthesis. " SIGNOR-266961 PLK1 protein P53350 UNIPROT CENPQ protein Q7L2Z9 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser255 SSQMKSMsTFIEEAY 9606 BTO:0000567 25670858 t lperfetto "Notably, although Plk1 did not alter the level of PBIP1 and CENP-Q ubiquitination, Plk1-dependent phosphorylation and delocalization of these proteins from kinetochores appeared to indirectly lead to their degradation in the cytosol. From these analyses, we identified nine CENP-Q residues (Thr-123, Thr-135, Ser-138, Ser-139, Ser-248, Ser-249, Ser-253, Ser-255, and Thr-256) that were phosphorylated in both in vitro and in vivo samples (Fig. 4B), suggesting that Plk1 phosphorylates these sites." SIGNOR-265226 PDK2 protein Q15119 UNIPROT PDHA1 protein P08559 UNIPROT down-regulates phosphorylation Ser232 NRYGMGTsVERAAAS -1 7782287 t gcesareni "Sites 1, 2, and 3 in the E1 mutants were phosphorylated either individually or in the presence of the other sites by the dihydrolipoamide acetyltransferase-protein X-E1 kinase indicating a site-independent mechanism of phosphorylation." SIGNOR-33040 "sorafenib tosylate" chemical CHEBI:50928 ChEBI FLT1 protein P17948 UNIPROT "down-regulates activity" "chemical inhibition" -1 16757355 t miannu "Further characterization of sorafenib revealed that this molecule was a multikinase inhibitor that targeted the vascular endothelial growth factor receptor family (VEGFR-2 and VEGFR-3) and platelet-derived growth factor receptor family (PDGFR-beta and Kit), which play key roles in tumor progression and angiogenesis. The in vitro and cellular profile of sorafenib is summarized in Table I." SIGNOR-259222 HTR4 protein Q13639 UNIPROT GNAS protein Q5JWF2 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-256769 PRKAA2 protein P54646 UNIPROT IKK-complex complex SIGNOR-C14 SIGNOR up-regulates phosphorylation 9606 BTO:0000876 21673972 t lperfetto "These results demonstrate that the ikk is a direct substrate of ampk_2 and that its phosphorylation on ser177 and ser181no initiates the activation of the ampk_2 in endothelial cells which in turn phosphorylates and activates the _-subunit of the ikk. The latter also induces a higher rate of ikk auto-inactivation and thus attenuates the activation of nf_b and the expression of inflammatory genes" SIGNOR-217457 HES1 protein Q14469 UNIPROT NR3C1 protein P04150 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 19129776 t gcesareni "HES1 binding to the promoter of the NC3C1 gene inhibits its expression and results in insufficient production of the encoded glucocorticoid receptor- rendering these cells resistant to treatment with dexamethasone" SIGNOR-251674 PTPRE protein P23469 UNIPROT SRC protein P12931 UNIPROT "up-regulates activity" dephosphorylation Tyr530 FTSTEPQyQPGENL 9534 15522235 t llicata "PTPepsilonM activated c-Src kinase probably by directly dephosphorylating phospho-Tyr527, a negative regulatory site of c-Src." SIGNOR-238074 NOTCH3 protein Q9UM47 UNIPROT HEYL protein Q9NQ87 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000887;BTO:0001260 11044625 f gcesareni "In the latter, heyl is coexpressed with notch3, so far the only notch pathway gene detected in vascular smooth muscles (fig. 2h,i;joutel et al., 2000). Both genes are also coexpressed during late thymus development and our own promoter studies further suggest a potential regulation of heyl transcription by notch3." SIGNOR-83402 PP2B proteinfamily SIGNOR-PF18 SIGNOR BAD protein Q92934 UNIPROT "up-regulates activity" dephosphorylation 9606 BTO:0000007 10195903 t "inferred from 70% family members" "Ca2+-induced apoptosis through calcineurin dephosphorylation of BAD|Calcineurin was found to dephosphorylate BAD, a pro-apoptotic member of the Bcl-2 family, thus enhancing BAD heterodimerization with Bcl-xL and promoting apoptosis." SIGNOR-269992 PHGDH protein O43175 UNIPROT (R)-2-hydroxyglutarate(2-) smallmolecule CHEBI:15801 ChEBI "up-regulates activity" "chemical modification" 25406093 t lperfetto "Here we show that, in addition to catalyzing oxidation of 3-phosphoglycerate, PHGDH catalyzes NADH-dependent reduction of alpha-ketoglutarate (AKG) to the oncometabolite d-2-hydroxyglutarate (d-2HG)." SIGNOR-268572 ATR protein Q13535 UNIPROT POLH protein Q9Y253 UNIPROT up-regulates phosphorylation Ser601 EMDLAHNsQSMHASS 9606 21242293 t lperfetto "Atr-mediated phosphorylation of dna polymerase _ is needed for efficient recovery from uv damage. We show that, after uv irradiation, pol_ becomes phosphorylated at ser601 by the ataxia-telangiectasia mutated and rad3-related (atr) kinase. Atr-dependent phosphorylation of pol_ is necessary to restore normal survival and postreplication repair" SIGNOR-171290 ELF2 protein Q15723 UNIPROT VCP protein P55072 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000093 18544453 f "These findings indicate that ELF2 transactivates VCP promoter through binding to two motifs, with a predominant contribution of the upstream one." SIGNOR-254283 ERG protein P11308 UNIPROT TDRD1 protein Q9BXT4 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0001033 23555854 f miannu "we report that ERG and TDRD1 are co-expressed in human prostate cancers and we provide a mechanistic explanation for the observed co-expression. We demonstrate that ERG activates TDRD1 transcription by inducing loss of DNA methylation at the TDRD1 promoter-associated CpG island." SIGNOR-254068 PREX1 protein Q8TCU6 UNIPROT RAC1 protein P63000 UNIPROT "up-regulates activity" "guanine nucleotide exchange factor" 9606 BTO:0000007 32203420 t Luana "We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2)." SIGNOR-260569 CSNK2A1 protein P68400 UNIPROT IGF2R protein P11717 UNIPROT unknown phosphorylation Ser2409 LHGDDQDsEDEVLTI 9606 8318012 t lperfetto "The two sites phosphorylated by ck ii in vivo and in vitro are ser82 and ser157." SIGNOR-37831 PRKACA protein P17612 UNIPROT CBX3 protein Q13185 UNIPROT up-regulates phosphorylation Ser93 KDGTKRKsLSDSESD 9606 16531993 t gcesareni "We demonstrate that p-ser 83-hp1gamma has an exclusively euchromatic localization, interacts with ku70 (a regulatory protein involved in multiple nuclear procesess), has impaired silencing activity and serves as a marker for transcription elongation." SIGNOR-145109 CXCL11 protein O14625 UNIPROT CXCR3 protein P49682 UNIPROT "up-regulates activity" binding 9606 BTO:0000782 12750173 t miannu "The chemokines CXCL9, 10, and 11 exert their action via CXC chemokine receptor-3 (CXCR3), a receptor highly expressed on activated T cells." SIGNOR-260971 AKT2 protein P31751 UNIPROT CDKN1A protein P38936 UNIPROT "down-regulates activity" binding 9606 BTO:0000222 16982699 t gcesareni "Whereas akt1 phosphorylates p21, inducing its release from cdk2 and cytoplasmic localization as previously described for akt, akt2 binds p21 in the region spanning the t145 site of p21, thus competing with phosphorylation by akt1 and inducing its accumulation in the nucleus. These distinct roles of akt/pkb isoforms in modulating proliferation and p21 have important implications for the development of drugs aimed at inhibiting cancer cell proliferation." SIGNOR-149705 H2BC11 protein P06899 UNIPROT "Nucleosome_H2A.Z.1 variant" complex SIGNOR-C322 SIGNOR "form complex" binding -1 24311584 t miannu "In the nucleosome, two of each of the histones H2A, H2B, H3 and H4 form the histone octamer and about 145–147 base pairs of DNA are wrapped around it . The histone H2A.Z variant is widely conserved among eukaryotes. Two isoforms, H2A.Z.1 and H2A.Z.2, have been identified in vertebrates and may have distinct functions in cell growth and gene expression. However, no structural differences between H2A.Z.1 and H2A.Z.2 have been reported. In the present study, the crystal structures of nucleosomes containing human H2A.Z.1 and H2A.Z.2 were determined." SIGNOR-263716 CHRM1 protein P11229 UNIPROT GNAI1 protein P63096 UNIPROT "up-regulates activity" binding 9606 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-256735 AKT proteinfamily SIGNOR-PF24 SIGNOR ALYREF protein Q86V81 UNIPROT up-regulates phosphorylation Thr219 GGGTRRGtRGGARGR 9606 18562279 t llicata "Nuclear akt directly binds aly and phosphorylates it on the t219 residue. gfp-aly t219d displayed comparable activity to gfp control and wild-type aly, indicating that aly phosphorylation by akt is sufficient to enhance mrna export." SIGNOR-179054 CDC14B protein O60729 UNIPROT KMT5A protein Q9NQR1 UNIPROT "down-regulates quantity by destabilization" dephosphorylation Ser100 SKIYSYMsPNKCSGM 9606 20966048 t "The dephosphorylation of S29 during late mitosis by the Cdc14 phosphatases was required for APC(cdh1)-mediated ubiquitination of PR-Set7 and subsequent proteolysis." SIGNOR-248339 SETDB1/NLK/CHD7 complex SIGNOR-C189 SIGNOR PPARG protein P37231 UNIPROT "down-regulates activity" "transcriptional regulation" 10090 21952300 f FFerrentino "The non-canonical WNT ligand WNT5A activates the histone methyltransferase SET domain bifurcated 1 (SETDB1). SETDB1 forms a complex with chromodomain helicase DNA-binding 7 (CHD7) and NEMO-like kinase (NLK) to inhibit the ability of PPARγ to transcriptionally activate its downstream metabolic target genes in the MSC cell line ST2 and in 3T3-L1 cells" SIGNOR-253524 Ub:E2 complex SIGNOR-C497 SIGNOR NFXL1 protein Q6ZNB6 UNIPROT "up-regulates activity" ubiquitination 9606 34199813 t miannu "The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t" SIGNOR-271175 14-3-3 proteinfamily SIGNOR-PF7 SIGNOR BAD protein Q92934 UNIPROT down-regulates binding 9606 8929531 t gcesareni "14-3-3 blocks bad activity by promoting ser-155 phosphorylation, which induces the dissociation of bad and bcl-xl. in the presence of survival factor il-3, cells phosphorylated bad on two serine residues embedded in 14-3-3 consensus binding sites. Only the nonphosphorylated bad heterodimerized with bcl-x(l) at membrane sites to promote cell death." SIGNOR-44855 TUBB protein P07437 UNIPROT SMAD2 protein Q15796 UNIPROT down-regulates binding 9606 17429065 t lpetrilli "Smad2/3 also binds to _-tubulin, which provides a negative regulatory mechanism controlling tgf-_ activity. the results showed that the mh2 domain of smad2 binds to _-tubulin with almost the same efficiency as the full-length (wild-type) smad2. Similar results were obtained for the smad3 binding to _-tubulin." SIGNOR-154316 PPARA protein Q07869 UNIPROT Fatty_acid_oxidation phenotype SIGNOR-PH129 SIGNOR up-regulates 9606 BTO:0001103;BTO:0000671 18836859 f miannu "PPAR-α is predominantly expressed in the liver and skeletal muscles, participating in fatty-acids catabolism. PPAR-α also activates fatty-acid oxidation in the kidney, skeletal muscles, and heart" SIGNOR-268027 CyclinD3/CDK11B complex SIGNOR-C543 SIGNOR SPDEF protein O95238 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser242 WTDSEVDsSCSGQPI 9606 BTO:0000007 26885618 t lperfetto "In this study we provide evidence that the cell cycle kinase CDK11p58, a protein involved in G2/M transition and degradation of several transcription factors, directly interacts with and phosphorylates SPDEF on serine residues|Western blot analysis demonstrated that only one of the mutant constructs, consisting of mutations of serine 238, 242 and 243, resulted in increased levels of SPDEF protein expression as compared to wild type SPDEF, leading to subsequent ubiquitination and degradation of SPDEF through the proteasome pathway.|" SIGNOR-273127 Ub:E2 complex SIGNOR-C497 SIGNOR UBE4A protein Q14139 UNIPROT "up-regulates activity" ubiquitination 9606 34199813 t miannu "The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t" SIGNOR-271274 NFE2 protein Q16621 UNIPROT HBE1 protein P02100 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 BTO:0000426 16287851 f "Regulation of expression" miannu "NF-E2 is a transcription activator for the regulation of a number of erythroid- and megakaryocytic lineage-specific genes. Here we present evidence that the large subunit of mammalian NF-E2, p45, is sumoylated in vivo in human erythroid K562 cells. we demonstrated by stable transfection assay that only the wild-type p45, but not its mutant form p45 (K368R), could efficiently rescue β-globin gene expression in the p45-null, erythroid cell line CB3. These data together point to a model of mammalian β-like globin gene activation by sumoylated p45/NF-E2 in erythroid cells." SIGNOR-251842 EIF2AK2 protein P19525 UNIPROT EIF2AK2 protein P19525 UNIPROT up-regulates phosphorylation Thr255 DLPDMKEtKYTVDKR 9606 11152499 t tpavlidou "We previously identified four autophosphorylated amino acids and elucidated their participation in pkr activation.Replacement Of all four of these residues in pkr with alanines did not dramatically affect kinase activity in vitro or in yeast saccharomyces cerevisiae.However, when coupled with mutations of serine 242 and threonines 255 and 258 in the central region, these mutations increased pkr protein expression in mammalian cells, consistent with diminished kinase activity." SIGNOR-85773 CARD11 protein Q9BXL7 UNIPROT BCL10 protein O95999 UNIPROT up-regulates binding 9606 12356734 t gcesareni "Card11 cooperates with bcl10 in a card domain-dependent manner.;These results implicate card11 in factor- specific activation of nf-kappab" SIGNOR-93869 RLN2 protein P04090 UNIPROT RXFP2 protein Q8WXD0 UNIPROT up-regulates binding 9606 BTO:0000142 11809971 t gcesareni "Lgr7 and lgr8, are capable of mediating the action of relaxin through an adenosine 3',5'-monophosphate (camp)-dependent pathway." SIGNOR-114585 TLN1 protein Q9Y490 UNIPROT "Av/b5 integrin" complex SIGNOR-C178 SIGNOR "up-regulates activity" binding 10090 BTO:0000132 19118207 t miannu "Over the past 10 years, the binding of talin to the cytoplasmic tail of integrin-β subunits has been established to have a key role in integrin activation. Binding of the phosphotyrosinebinding (PTB)-domain-like subdomain of the protein 4.1, ezrin, radixin, moesin (FERM) domain of talin to the conserved WxxxNP(I/L)Y motif of the β-integrin tail permits additional weaker interactions between talin and the membrane-proximal region of the tail that trigger integrin activation, probably through the disruption of inhibitory interactions between α- and β-subunit cytoplasmic tails." SIGNOR-257630 DUSP5 protein Q16690 UNIPROT Gbeta proteinfamily SIGNOR-PF4 SIGNOR down-regulates dephosphorylation 9606 10224087 t "inferred from 70% of family members" gcesareni "Extracellular regulated kinases (erk) 1 and erk2 are authentic substrates for the dual-specificity protein-tyrosine phosphatase vhr. A novel role in down-regulating the erk pathway" SIGNOR-269912 CYP11B2 protein P19099 UNIPROT corticosterone smallmolecule CHEBI:16827 ChEBI "up-regulates quantity" "chemical modification" 9606 BTO:0000048 33117906 t lperfetto "The zona glomerulosa lacks the 17alpha-hydroxylase enzyme, committing pregnenolone to the exclusive production of aldosterone.|In the adrenal steroidogenic pathway, 21-hydroxylase (P450c21) catalyzes the conversion of 17-hydroxyprogesterone (17OHP) to 11-deoxycortisol to form cortisol and the conversion of progesterone to 11-deoxycorticosterone to form aldosterone" SIGNOR-268680 IGF1 protein P05019 UNIPROT PPP3CA protein Q08209 UNIPROT up-regulates 10090 BTO:0000165;BTO:0002314 BTO:0000887;BTO:0001103;BTO:0001760 10448861 f lperfetto "Treatment with igf-1 or insulin and dexamethasone mobilizes intracellular calcium, activates the ca2+/calmodulin-dependent phosphatase calcineurin, and induces the nuclear translocation of the transcription factor nf-atc1." SIGNOR-235645 CSNK2A1 protein P68400 UNIPROT EGR1 protein P18146 UNIPROT "down-regulates activity" phosphorylation Thr526 TNSFSAStGLSDMTA 10090 BTO:0000944 8662759 t llicata "Casein kinase II associates with Egr-1 and acts as a negative modulator of its DNA binding and transcription activities in NIH 3T3 cells. | There are three CKII recognition sites (S376XXD, T389XE, and T516XXXD) in fragment 10." SIGNOR-250858 INSR protein P06213 UNIPROT IRS1 protein P35568 UNIPROT "up-regulates activity" phosphorylation Tyr612 TLHTDDGyMPMSPGV 10116 11416002 t lperfetto "All known IRS proteins contain multiple YXXM motifs that upon phosphorylation by activated insulin re- ceptors Tyr(612) and Tyr(632) in human insulin receptor substrate-1 are important for full activation of insulin-stimulated phosphatidylinositol 3-kinase activity and translocation of GLUT4 in adipose cells" SIGNOR-235971 HDAC2 protein Q92769 UNIPROT CCND1 protein P24385 UNIPROT up-regulates binding 9606 15713663 t gcesareni "Cyclin d1 bound hdac in vivo and preferentially physically associated with hdac1, hdac2, hdac3, and hdac5." SIGNOR-134062 "2-Hydroxy-3-[N-[4-[methyl-[2-(4-methylpiperazin-1-yl)acetyl]amino]phenyl]-C-phenylcarbonimidoyl]-1H-indole-6-carboxylic acid" chemical CID:135461425 PUBCHEM FGFR2 protein P21802 UNIPROT "down-regulates activity" "chemical inhibition" -1 22037378 t miannu "Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here." SIGNOR-259704 OXSR1 protein O95747 UNIPROT SLC12A2 protein P55011 UNIPROT up-regulates phosphorylation Thr203 HQHYYYDtHTNTYYL 9606 12145304 t gcesareni "The secretory na-k-cl cotransporter nkcc1 is activated by secretagogues through a phosphorylation-dependent mechanism. three phosphoacceptor sites were identified in the n-terminal domain of the protein (at thr184, thr189, and thr202) none of these residues occurs in the context of strong consensus sites for known ser/thr kinases." SIGNOR-90927 CSNK1A1 protein P48729 UNIPROT YWHAQ protein P27348 UNIPROT "down-regulates activity" phosphorylation Ser232 LTLWTSDsAGEECDA -1 9360956 t llicata "This protein kinase has been identified as casein kinase Ialpha (CKIalpha) by peptide mapping analysis and sequencing. Among mammalian 14-3-3, only 14-3-3 tau possesses a phosphorylatable residue at the same position (Ser-233), and we show that this residue is also phosphorylated by CKI. In addition, we show that 14-3-3 zeta is exclusively phosphorylated on Thr-233 in human embryonic kidney 293 cells. The residue 233 is located within a region shown to be important for the association of 14-3-3 to target proteins. " SIGNOR-250795 ATM protein Q13315 UNIPROT DBF4 protein Q9UBU7 UNIPROT down-regulates phosphorylation Thr449 DDIRQNFtQLPLHKN 9606 22123827 t lperfetto "Dbf4/cdc7 (dbf4-dependent kinase (ddk)) is activated at the onset of s-phase, and its kinase activity is required for dna replication initiation from each origin. We identified novel atm/atr phosphorylation sites on dbf4 and showed that atm/atr-mediated phosphorylation of dbf4 is critical for the intra-s-phase checkpoint to inhibit dna replication." SIGNOR-177801 PRLHR protein P49683 UNIPROT GNAQ protein P50148 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257089 sorafenib chemical CHEBI:50924 ChEBI BRAF protein P15056 UNIPROT down-regulates "chemical inhibition" 9606 BTO:0000848 21654832 t gcesareni "Inhibition of map kinases mek, jnk, p38, and multikinases (braf, craf, vegfp by sorafenib) in wm-115 and m14 human melanoma cell lines led to either significant reduction or complete inhibition of the plk-1 protein expression." SIGNOR-174036 SRPK2 protein P78362 UNIPROT CCND1 protein P24385 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 19592491 f lperfetto "Compared with control, srpk2 wild type evidently elevated cyclin d1 transcription, and the catalytic activity was lost in srpk2 kd, suggesting that kinase activity of srpk2 is required for this effect." SIGNOR-186763 DYRK2 protein Q92630 UNIPROT SIAH2 protein O43255 UNIPROT up-regulates phosphorylation Ser16 PSANKPCsKQPPPQP 9606 22878263 t llicata "In the present study, we identify the serine/threonine kinase dyrk2 as siah2 interaction partner that phosphorylates siah2 at five residues (ser16, thr26, ser28, ser68, and thr119). accordingly, phosphorylated siah2 is more active than the wild-type e3 ligase and shows an increased ability to trigger the hif-1?-Mediated transcriptional response and angiogenesis." SIGNOR-198721 AREL1 protein O15033 UNIPROT DIABLO protein Q9NR28 UNIPROT "down-regulates quantity by destabilization" ubiquitination Lys191 RNHIQLVkLQVEEVH 9606 BTO:0002552 31732561 t lperfetto "AREL1 ubiquitinated SMAC, primarily on Lys62 and Lys191 |E701A substitution in the AREL1 HECT domain substantially increased its autopolyubiquitination and SMAC ubiquitination activity, whereas deletion of the last three amino acids at the C terminus completely abrogated AREL1 autoubiquitination and reduced SMAC ubiquitination." SIGNOR-267672 AMPK complex SIGNOR-C15 SIGNOR HDAC7 protein Q8WUI4 UNIPROT down-regulates phosphorylation Ser155 FPLRKTVsEPNLKLR 9606 21892142 t lperfetto "Another recently described set of transcriptional regulators targeted by ampk and its related family members across a range of eukaryotes are the class iia family of histone deacetylases (hdacs)." SIGNOR-216554 MAPK8 protein P45983 UNIPROT JUN protein P05412 UNIPROT "up-regulates activity" phosphorylation Ser73 VGLLKLAsPELERLI 9534 BTO:0000298 8137421 t miannu "JNK1 binds to the c-Jun transactivation domain and phosphorylates it on Ser-63 and Ser-73. The effect on AP-1 transcriptional activity results, in part, from enhanced phosphorylation of the c-Jun NH2-terminal activation domain." SIGNOR-250122 MAPK8 protein P45983 UNIPROT MCL1 protein Q07820 UNIPROT up-regulates phosphorylation Thr163 TDGSLPStPPPAEEE 9606 BTO:0000150 18676833 t gcesareni "Mcl-1 can be rapidly degraded by certain death-inducing signals, but it is able to be readily induced by diverse survival cytokines such as epidermal growth factor, vascular endothelial growth factor, granulocyt-macrophage colony-stimulating factor, and interleukin 3 through phosphatidy-linositol-3-oh kinase/akt, mek/mapk, or janus-activated kinase/stat signaling cascades" SIGNOR-179816 "BMS 794833" chemical CID:44155856 PUBCHEM KDR protein P35968 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-190419 CHRM5 protein P08912 UNIPROT GNAZ protein P19086 UNIPROT "up-regulates activity" binding 9606 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257125 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR USP9X protein Q93008 UNIPROT "up-regulates activity" phosphorylation Ser2547 YEGSEEVsPPQTKDQ 32152317 t "Phosphosites were derived from Figure S1" lperfetto "Here, we find that CDC14B antagonizes CDK1-mediated activating mitotic phosphorylation of the deubiquitinase USP9X at serine residue 2563, which we show to be essential for USP9X to mediate mitotic survival. Starting from an unbiased proteome-wide screening approach, we specify Wilms' tumor protein 1 (WT1) as the relevant substrate that becomes deubiquitylated and stabilized by serine 2563-phosphorylated USP9X in mitosis." SIGNOR-275612 STAT1 protein P42224 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR down-regulates 9606 21433395 f miannu "The signal transducer and activator of transcription (STAT) family of transcription factors transduce signals from a variety of extracellular stimuli, and are important mediators of inflammation, cell survival, differentiation, and proliferation. STATs are activated in response to growth factors, cytokines, and G-CSF binding to cell surface receptor tyrosine kinases. Although structurally similar, the seven STAT family members possess diverse biological roles. For example, STAT1 activation is pro-inflammatory and anti-proliferative, while STAT3 activation is anti-inflammatory and pro-apoptotic." SIGNOR-263651 MAPK1 protein P28482 UNIPROT MCL1 protein Q07820 UNIPROT up-regulates phosphorylation Thr163 TDGSLPStPPPAEEE 9606 12223490 t gcesareni "We found that jnk phosphorylated ser-121 and thr-163 of mcl-1 in response to stimulation with h(2)o(2) and that transfection of unphosphorylatable mcl-1 resulted in an enhanced anti-apoptotic activity in response to stimulation with h(2)o(2). Jnk-dependent phosphorylation and thus inactivation of mcl-1 may be one of the mechanisms through which oxidative stress induces cellular damage." SIGNOR-92593 PIM proteinfamily SIGNOR-PF34 SIGNOR CDKN1B protein P46527 UNIPROT down-regulates phosphorylation Thr157 GIRKRPAtDDSSTQN 9606 18593906 t gcesareni "We show, herein, that all the pim family members (pim1, pim2, and pim3) bind to and directly phosphorylate the cyclin-dependent kinase inhibitor p27(kip1) at threonine-157 and threonine-198 residues in cells and in vitro." SIGNOR-259426 KLHL8 protein Q9P2G9 UNIPROT RAPSN protein Q13702 UNIPROT "down-regulates quantity by destabilization" binding 10090 BTO:0000944 19158078 t miannu "We found that rapsyn was polyubiquitinated by KLHL8-containing E3 ligase, but not by KEAP1-containing E3 ligase, clearly indicating that rapsyn is a direct substrate of KLHL8-containing E3 ligase in mammals. We next examined the effect of KLHL-8 depletion on the ubiquitination of rapsyn by performing RNAi experiments in mammalian cells. We found that knockdown of KLHL8 in 3T3 cells reduced the level of rapsyn ubiquitination (Fig. 5C), again indicating that the maintenance mechanism for rapsyn stability is conserved in mammals.The in vitro ubiquitination of mammalian rapsyn by CUL3-containing E3 ligase and the effect of KLHL8 knockdown on the ubiquitination of rapsyn." SIGNOR-271781 KAT5 protein Q92993 UNIPROT NOTCH1 protein P46531 UNIPROT down-regulates acetylation Lys2029 NAVDDLGkSALHWAA 9606 17636029 t gcesareni "This result implies that the residues k2019, k2039, k2044, and k2068 of notch1-ic are the major targets of the acetyltransferase activity of tip60." SIGNOR-156911 PRKCZ protein Q05513 UNIPROT IKBKB protein O14920 UNIPROT "up-regulates activity" phosphorylation Ser181 DQGSLCTsFVGTLQY 9606 10022904 t lperfetto "Activation of IkappaB kinase beta by protein kinase C isoforms. | Interestingly, recombinant active zetaPKC and alphaPKC are able to stimulate in vitro the activity of IKKbeta but not that of IKKalpha. In addition, evidence is presented here that recombinant zetaPKC directly phosphorylates IKKbeta in vitro, involving Ser177 and Ser181. Collectively, these results demonstrate a critical role for the PKC isoforms in the NF-kappaB pathway at the level of IKKbeta activation and IkappaB degradation." SIGNOR-249016 DYRK2 protein Q92630 UNIPROT JUN protein P05412 UNIPROT down-regulates phosphorylation Ser243 PGETPPLsPIDMESQ 9606 BTO:0000150 22307329 t lperfetto "Degradation of c-jun/c-myc is a critical process for the g(1)/s transition, which is initiated upon phosphorylation by glycogen synthase kinase 3 ? (gsk3?). However, a specific kinase or kinases responsible for priming phosphorylation events that precede this gsk3? Modification has not been definitively identified. Here, we found that the dual-specificity tyrosine phosphorylation-regulated kinase dyrk2 functions as a priming kinase of c-jun and c-myc.The finding that kinase-active dyrk2 phosphorylated gst_c-jun210_310-wt by detection with an anti_phospho_c-jun(ser243) antibody demonstrated that dyrk2 is a ser243 kinase in vitro" SIGNOR-195771 PLK1 protein P53350 UNIPROT PINX1 protein Q96BK5 UNIPROT down-regulates phosphorylation Ser117 SFSLEEKsKISKNRV 9606 20573420 t lperfetto "Here, we show that polo-like kinase 1 (plk1) is a novel interacting protein of pinx1. Plk1 interacts with and phosphorylates pinx1 in vivo and in vitro. Moreover, plk1-mediated phosphorylation of pinx1 at five phosphorylation sites is essential for its plk1-induced degradation." SIGNOR-166321 RHOA protein P61586 UNIPROT RDX protein P35241 UNIPROT "up-regulates activity" phosphorylation Thr564 AGRDKYKtLRQIRQG 9606 BTO:0000132 35267019 t miannu "Rev-erbα interacted with OPHN-1, promoted RhoA activity and phosphorylation of ERM. etection of phosphorylated ezrin (Thr567)/radixin (Thr564)/moesin (Thr558)(p-ERM) in Rev-erbαfl/flCre− and Rev-erbαfl/flPF4Cre+ platelets using phospho-specific antibodies." SIGNOR-268430 MAP2K1 protein Q02750 UNIPROT ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR "up-regulates activity" phosphorylation 10090 11730323 t "Raf proteins have been shown to phosphorylate and activate MAPKKs (MAP kinase kinases) called MEKs (MAPK or ERK kinases) which in turn phosphorylate and activate MAPKs (MAP kinases) called ERKs" SIGNOR-258992 FOXO proteinfamily SIGNOR-PF27 SIGNOR PPARG protein P37231 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 10116 16670091 f lperfetto " FOXO1 coexpression dose-dependently repressed transcription from either the PPARgamma 1 or PPARgamma2 promoter reporter by 65%, whereas insulin (100 nm, 20-24 h) either partially or completely reversed this effect. " SIGNOR-252910 H3C1 protein P68431 UNIPROT Transcritpional_activation phenotype SIGNOR-PH205 SIGNOR "up-regulates activity" 9606 22266761 f Gianni "Widely described to be associated with active chromatin, H3K36 methylation has also been implicated in transcriptional repression, alternative splicing, dosage compensation, DNA replication and repair" SIGNOR-269072 INS protein P01308 UNIPROT FOXO1 protein Q12778 UNIPROT "down-regulates activity" 9606 10358076 f lperfetto "Insulin disrupts irs-dependent transactivation by fkhr, and phosphorylation of ser-256 by pkb is necessary and sufficient to mediate this effect." SIGNOR-68155 "AP-2 complex" complex SIGNOR-C245 SIGNOR Endocytosis phenotype SIGNOR-PH123 SIGNOR up-regulates 10116 BTO:0000142 15496985 f lperfetto "Intersectins 1 and 2, epsin2, NECAP and sorting nexin9 were identified as α‐appendage ligands in mass spectrometry of these samples" SIGNOR-260416 RalGAP2 complex SIGNOR-C469 SIGNOR RALA protein P11233 UNIPROT "down-regulates activity" "guanine nucleotide exchange factor" 10090 BTO:0000011 21148297 t miannu "Here we report the identification and characterization of a Ral GAP complex (RGC) that mediates the activation of RalA downstream of the PI 3-kinase/Akt pathway. The complex is composed of an RGC1 regulatory subunit and an RGC2 catalytic subunit (previously identified as AS250) that directly stimulates the guanosine triphosphate hydrolysis of RalA. RGC2 negatively regulates RalA activity in adipocytes. When immunoprecipitated from cell lysates of 3T3-L1 adipocytes by an anti-RGC2 antibody, RGC proteins efficiently enhanced GTP hydrolysis of recombinant RalA in vitro, compared with RalA alone or RalA incubated with various control immunoprecipitates (Figure 2C)." SIGNOR-269796 PRKCG protein P05129 UNIPROT HABP4 protein Q5JVS0 UNIPROT "down-regulates activity" phosphorylation Thr375 GRGARGGtRGGRGRI 9606 BTO:0004974 14699138 t lperfetto "We found a strong phosphorylation of Ki-1/57 by PKCalphabeta, PKCdelta, PKClambda/zeta, and especially by PKCsigma, however not by PKCmi. These data show that Ki-1/57 can serve in principal as a substrate for a wide variety of different PKC isoforms but also that its phosphorylation is strongest with PKCsigma. | This suggests that the two threonine residues present in this fragment (Thr354 and Thr375) might be the main target residues for phosphorylation by PKC in vitro. | Ki-1/57 Exits the Nucleus upon PMA Activation" SIGNOR-249255 IL3 protein P08700 UNIPROT NFIL3 protein Q16649 UNIPROT up-regulates 10090 10082541 f lperfetto "We previously reported that NFIL3 is an IL-3-responsive gene in Baf-3 cells" SIGNOR-242763 MAPK8 protein P45983 UNIPROT RCSD1 protein Q6JBY9 UNIPROT "down-regulates activity" phosphorylation Ser83 PKFKVKSsPLIEKLQ -1 15850461 t miannu "CapZIP was also phosphorylated rapidly by SAPK3/p38γ and SAPK4/p38δ, and even faster and more extensively by JNK1α1, these protein kinases phosphorylating CapZIP in vitro to >3, approx. 2 and >5 mol of phosphate/mol of protein respectively within a few minutes. Following tryptic digestion and C18 chromatography, further sites phosphorylated by JNK1α1 were identified as Ser-68, Ser-83 and Ser-216 (results not shown), and are highlighted in Figure 3.Using this antibody, we showed by immunoblotting that bacterially expressed CapZIP was phosphorylated at Ser-108 by SAPK4/p38δ, JNK1α1 and ERK2 in vitro, as well as by SAPK3/p38γ (results not shown).An important clue to the function of CapZIP and its phosphorylation came from the finding that it binds to the actin-capping protein CapZ (Figure 7A), and that cellular stresses trigger the dissociation of these two proteins (Figure 7B).Such an effect is presumably lost when CapZIP is phosphorylated and dissociates from CapZ." SIGNOR-263086 MAPK8 protein P45983 UNIPROT STK4 protein Q13043 UNIPROT up-regulates phosphorylation Ser82 SIMQQCDsPHVVKYY 9606 20028971 t llicata "C-jun n-terminal kinase enhances mst1-mediated pro-apoptotic signaling through phosphorylation at serine 82." SIGNOR-162327 CD40LG protein P29965 UNIPROT PTPN7 protein P35236 UNIPROT down-regulates 9606 BTO:0000776 19047375 f gcesareni "Coimmunoprecipitation and western blot analysis showed that heptp was phosphorylated in a pka-dependent manner, which inactivated heptp and allowed for increased free p38 mapk to be phosphorylated by the mapk cascade that was activated by cd40l" SIGNOR-182519 CAMKK2 protein Q96RR4 UNIPROT CAMK4 protein Q16566 UNIPROT "up-regulates activity" phosphorylation Thr200 EHQVLMKtVCGTPGY 7615569 t llicata "Phosphorylation and activation of Ca(2+)-calmodulin-dependent protein kinase IV by Ca(2+)-calmodulin-dependent protein kinase Ia kinase. Phosphorylation of threonine 196 is essential for activation." SIGNOR-250718 IL20 protein Q9NYY1 UNIPROT IL20RB protein Q6UXL0 UNIPROT up-regulates binding 9606 11163236 t gcesareni "An IL-20 receptor was identified as a heterodimer of two orphan class II cytokine receptor subunits. Both receptor subunits are expressed in skin and are dramatically upregulated in psoriatic skin. Taken together, these results demonstrate a role in epidermal function and psoriasis for IL-20, a novel cytokine identified solely by bioinformatics analysis." SIGNOR-151874 MAPK1 protein P28482 UNIPROT MAP3K5 protein Q99683 UNIPROT up-regulates 9606 BTO:0000130 16709866 f gcesareni "The role of members of the arrestin family to mediate kinase activation is also a well-established phenomenon, including activation of members of the src family, erk1/2, and jnk3. Activation often includes the recruitment and interaction of arrestins with upstream mapks (ask1, mek3, mkk3, and mek kinase-2)." SIGNOR-146751 CDK18 protein Q07002 UNIPROT AQP2 protein P41181 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser261 RQSVELHsPQSLPRG 9606 BTO:0000007 32164329 t lperfetto "CDK18 controls AQP2 through phosphorylation at serine 261 and STUB1-mediated ubiquitination. |We had previously observed that a decrease in the phosphorylation of AQP2 at S261 is associated with a decrease in its poly-ubiquitination and an increase in its abundance" SIGNOR-264562 DIO3 protein P55073 UNIPROT 3,3',5'-triiodothyronine smallmolecule CHEBI:28774 ChEBI "up-regulates quantity" "chemical modification" 9606 12746313 t scontino "Human type III iodothyronine deiodinase (D3) catalyzes the conversion of T(4) to rT(3) and of T(3) to 3, 3'-diiodothyronine (T2) by inner-ring deiodination. Like types I and II iodothyronine deiodinases, D3 protein contains selenocysteine (SeC) in the highly conserved core catalytic center at amino acid position 144." SIGNOR-266942 BCR-Dl complex SIGNOR-C436 SIGNOR SYK protein P43405 UNIPROT "up-regulates activity" binding 9606 32323266 t scontino "The tyrosine phosphorylation of the ITAM of CD79 promotes the activation of the non-SRC family tyrosine kinase, spleen tyrosine kinase (SYK), which becomes a key part of a signalosome formed by many other kinases and adaptor proteins. The SYK which is recruited to the phosphorylated CD79- ITAM facilitates the complex formation of B-cell linker protein (BLNK), leading to activation of Bruton’s tyrosine kinase (BTK)." SIGNOR-268442 INSR protein P06213 UNIPROT INSR protein P06213 UNIPROT "up-regulates activity" phosphorylation Tyr1361 SYEEHIPyTHMNGGK -1 3166375 t lperfetto "This approach revealed that insulin stimulates autophosphorylation of the insulin-receptor beta-subunit in vitro on at least seven tyrosine residues distributed among three distinct domainsAt least two further tyrosine residues appeared to be phosphorylated after those in domains 2 and 3. These residues probably residue within a domain lying in close proximity to the inner face of the plasma membrane containing tyrosines 953, 960 and 972" SIGNOR-233560 "Multiaminoacyl-tRNA synthetase" complex SIGNOR-C472 SIGNOR tRNA(Arg) smallmolecule CHEBI:29171 ChEBI "down-regulates quantity" "chemical modification" 9606 28271488 t miannu "Aminoacyl-tRNA synthetases (AARSs) are essential enzymes that specifically aminoacylate one tRNA molecule by the cognate amino acid. In mammals, nine synthetases, those specific for amino acids Arg, Asp, Gln, Glu, Ile, Leu, Lys, Met and Pro, associate into a multi-aminoacyl-tRNA synthetase complex, an association which is believed to play a key role in the cellular organization of translation, but also in the regulation of the translational and nontranslational functions of these enzymes." SIGNOR-270363 CyclinD3/CDK11B complex SIGNOR-C543 SIGNOR SPDEF protein O95238 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser243 TDSEVDSsCSGQPIH 9606 BTO:0000007 26885618 t lperfetto "In this study we provide evidence that the cell cycle kinase CDK11p58, a protein involved in G2/M transition and degradation of several transcription factors, directly interacts with and phosphorylates SPDEF on serine residues|Western blot analysis demonstrated that only one of the mutant constructs, consisting of mutations of serine 238, 242 and 243, resulted in increased levels of SPDEF protein expression as compared to wild type SPDEF, leading to subsequent ubiquitination and degradation of SPDEF through the proteasome pathway.|" SIGNOR-273128 FGFR1 protein P11362 UNIPROT BCAR1 protein P56945 UNIPROT up-regulates phosphorylation Tyr128 SKAQQGLyQVPGPSP 9606 11019781 t lperfetto "Five tyrosine phosphorylation sites were identified in p130cas on tyr-128, tyr-249, tyr-306, tyr-327, and tyr-410. These tyrosine residues are all located in the substrate domain of p130cas that mediates binding to the sh2 domain of the adaptor molecule crk. Fgf-1-transduced fibroblasts demonstrated a > 10-fold increase in migration, an observation correlated with increased tyrosine phosphorylation of p125fak and p130cas." SIGNOR-82760 chlorpromazine chemical CHEBI:3647 ChEBI DRD2 protein P14416 UNIPROT "down-regulates activity" "chemical inhibition" 10029 BTO:0000246 1975644 t miannu "Molecular cloning and characterization of a novel dopamine receptor (D3) as a target for neuroleptics. A dopamine receptor has been characterized which differs in its pharmacology and signalling system from the D1 or D2 receptor and represents both an autoreceptor and a postsynaptic receptor. Table1. pharmacology of D2 and D3 receptors expressed in CHO cells." SIGNOR-258370 MLH1 protein P40692 UNIPROT DNA_repair phenotype SIGNOR-PH57 SIGNOR "up-regulates activity" 10090 9500552 f "Germline mutations in the human MSH2, MLH1, PMS2 and PMS1 DNA mismatch repair (MMR) gene homologues appear to be responsible for most cases of hereditary non-polyposis colorectal cancer" SIGNOR-257595 AKT proteinfamily SIGNOR-PF24 SIGNOR NCF1 protein P14598 UNIPROT up-regulates phosphorylation Ser328 QDAYRRNsVRFLQQR 9606 BTO:0000130 10559253 t esanto "Akt phosphorylates p47phox and mediates respiratory burst activity in human neutrophils. A direct interaction between p47(phox) and akt was shown. Active recombinant akt phosphorylated recombinant p47(phox) in vitro. Mutation analysis indicated that 2 aa residues, ser(304) and ser(328), were phosphorylated by akt. Inhibition of akt activity also inhibited fmlp-stimulated neutrophil chemotaxis." SIGNOR-72137 AKT3 protein Q9Y243 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR down-regulates phosphorylation Ser253 APRRRAVsMDNSNKY 9606 BTO:0000150;BTO:0001130;BTO:0001271;BTO:0000527 19188143 t gcesareni "Akt-dependent phosphorylation of foxo3a (thr32, ser253, and ser315 for human foxo3) enhances foxo3a/14?3?3 Interaction and promotes foxo3a nuclear export to the cytoplasm, resulting in the repression of foxo3a transcriptional function" SIGNOR-252877 IMP smallmolecule CHEBI:17202 ChEBI "5'-xanthylic acid" smallmolecule CHEBI:15652 ChEBI "up-regulates quantity" "precursor of" 9606 19480389 t miannu "IMPDH controls the gateway to guanine nucleotides, making it an ‚Äúenzyme of consequence‚Äù for virtually every organism. Humans and other mammals have two IMPDH genes, encoding hIMPDH1 and hIMPDH2. The IMPDH-catalyzed conversion of IMP to XMP is the first committed and rate-limiting step in guanine nucleotide biosynthesis. XMP is subsequently converted to GMP by the action of GMP synthetase (GMPS)." SIGNOR-267330 PI-103 chemical CHEBI:90524 ChEBI PIK3C2B protein O00750 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-206160 SRC protein P12931 UNIPROT BCAR1 protein P56945 UNIPROT "up-regulates activity" phosphorylation Tyr192 AGMGHDIyQVPPSMD 10090 12972425 t lperfetto "Cas is a member of the focal adhesion complex. Phosphorylation of Cas by Src is an important event leading to cell transformation. Using mass spectrometry, we have mapped 11 sites in Cas that are phosphorylated by Src. These sites are all located between residues 132 and 414 of CasBased on these data, 11 tyrosine residues (132, 169, 183, 196, 238, 253, 271, 291, 301, 391, and 414) were phosphorylated by Src|the biological activity of Cas depends on its phosphorylation by Src (16–18). After phosphorylation, Cas associates with a number of proteins, including Crk, Src, phosphatidylinositol 3-kinase, Nck, and phospholipase Cgamma, via SH2 binding motifs" SIGNOR-246393 CSNK2A1 protein P68400 UNIPROT MAX protein P61244 UNIPROT down-regulates phosphorylation Ser11 NDDIEVEsDEEQPRF 9606 8018564 t gcesareni "Max activity is affected by phosphorylation at two nh2-terminal sites, ser2 and ser11." SIGNOR-35768 ARID1A protein O14497 UNIPROT "SWI/SNF ACTL6A-ARID1A-SMARCA2 variant" complex SIGNOR-C470 SIGNOR "form complex" binding 9606 30397315 t miannu "Mammalian SWI/SNF (mSWI/SNF) complexes are ATP-dependent chromatin remodelers that modulate genomic architecture and DNA accessibility, enabling timely and appropriate control of gene expression. They are combinatorially assembled from the products of 29 total genes into three final-form complexes: canonical BAF, PBAF (polybromo-associated BAF complexes), and a newly-defined non-canonical BAF (ncBAF), with specific subunits specifying distinct complexes, such as PBRM1, ARID2, and BRD7 in PBAF complexes, ARID1A/ARID1B and DPF2 in canonical BAF (cBAF) complexes, and GLTSCR1/GLTSCR1L and BRD9 in ncBAF complexes" SIGNOR-269818 CASP6 protein P55212 UNIPROT PSEN1 protein P49768 UNIPROT "up-regulates activity" cleavage Asp345 EEWEAQRdSHLGPHR -1 10069390 t lperfetto "Remarkably, the caspases acting on PS1 could be subdivided in two groups. One group, containing caspase-8, -6 and -11, cleaved PS1 after residues ENDD329 and to a lesser extent after residues AQRD341. A second group consisting of caspase-3, -7 and -1 acted uniquely on AQRD341. Importantly, these two cleavage sites were also recognized by caspases in the C-terminal PS1 fragment produced by constitutive proteolysis." SIGNOR-261759 NR0B2 protein Q15466 UNIPROT ESR2 protein Q92731 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 10648597 f gcesareni "These novel insights provide a mechanistic explanation for the inhibitory role of shp in nuclear receptor signaling, and they may explain how shp functions as a negative coregulator or corepressor for ligand-activated receptors, a novel and unique function for an orphan nuclear receptor." SIGNOR-74291 GALR3 protein O60755 UNIPROT GNAI1 protein P63096 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-256719 GATA1 protein P15976 UNIPROT ITGA2B protein P08514 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 17725493 f miannu "We and others have previously shown that RUNX1 and GATA-1 physically interact and cooperate in the activation of megakaryocytic promoters such as alpha IIb integrin and glycoprotein Ibalpha." SIGNOR-254192 NODAL protein Q96S42 UNIPROT Cell_death phenotype SIGNOR-PH109 SIGNOR up-regulates 9606 BTO:0004094 15531507 f Regulation miannu "Nodal induces apoptosis and inhibits proliferation in human epithelial ovarian cancer cells via activin receptor-like kinase 7." SIGNOR-256656 Ub:HECT_E3 complex SIGNOR-C518 SIGNOR Protein_ubiquitination phenotype SIGNOR-PH214 SIGNOR up-regulates 9606 34199813 f miannu "The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5′-triphosphate (ATP)-dependent manner to form a thioester-linked E1‒Ub conjugate. The activated Ub is then delivered to an E2 enzyme via a transthiolation reaction. Finally, an E3 enzyme, which can bind both a substrate and an E2‒Ub conjugate, mediates the covalent linkage of Ub to the target protein as a tag." SIGNOR-271382 CSNK2A1 protein P68400 UNIPROT MAPK9 protein P45984 UNIPROT unknown phosphorylation Thr404 SSMSTEQtLASDTDS 9606 11062067 t lperfetto "The phosphorylation of thr-404 and ser-407 is not increased in response to other agonists that activate mkk7 and sapk1/jnk, suggesting that phosphorylation of these residues is catalysed by another protein kinase, such as ck2, which also phosphorylates thr-404 and ser-407 in vitro." SIGNOR-83715 PTK6 protein Q13882 UNIPROT ARAP1 protein Q96P48 UNIPROT "up-regulates activity" phosphorylation Tyr231 PEFDDSDyDEVPEEG 9606 BTO:0000007 20554524 t miannu "ARAP1 associated with PTK6 in an EGF/EGF receptor (EGFR)-dependent manner. In addition, the SH2 domain of PTK6, particularly the Arg(105) residue that contacts the phosphate group of the tyrosine residue, was essential for the association. Moreover, PTK6 phosphorylated residue Tyr(231) in the N-terminal domain of ARAP1. Expression of ARAP1, but not of the Y231F mutant, inhibited the down-regulation of EGFR in HEK293 cells expressing PTK6. These results demonstrate that PTK6 enhances EGFR signaling by inhibition of EGFR down-regulation through phosphorylation of ARAP1 in breast cancer cells." SIGNOR-263188 LYST protein Q99698 UNIPROT RAB5C protein P51148 UNIPROT "down-regulates activity" binding 7227 33725482 t lperfetto "Mauve interacts with Rab5, Msps, and gamma-tubulin|Mauve/LYST opposes Rab5, which promotes vesicle fusion affecting PCM recruitment" SIGNOR-266003 GUCA2B protein Q16661 UNIPROT GUCY2C protein P25092 UNIPROT up-regulates binding 9606 10845107 t gcesareni "Guanylins activate two receptors, gc-c and ok-gc, which are expressed in intestine and/or kidney." SIGNOR-78120 KIT protein P10721 UNIPROT SLA protein Q13239 UNIPROT "down-regulates activity" phosphorylation Tyr273 SFFSSPPyFED 9534 BTO:0001538 24284075 t miannu "Oncogenic c-Kit-D816V phosphorylates SLAP on residues Y120, Y258 and Y273. Mutation of the SLAP tyrosine phosphorylation sites rescues its activity" SIGNOR-263142 "Polycomb repressive complex 2" complex SIGNOR-C130 SIGNOR HOXA9 protein P31269 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 20565746 f irozzo "These data support the proposed regulatory impact of particular PRC2-proteins in expression of HOXA9 and HOXA10 in NK/T-cells. In mammalian cells knockdown of PRC2 components EZH2 or PHF1 led to upregulated HOXA gene expression." SIGNOR-256126 GPR65 protein Q8IYL9 UNIPROT GNAI1 protein P63096 UNIPROT "up-regulates activity" binding 9606 27287411 t "GPR65 is playing a critical role in phagocytic cells that require high levels of V-ATPase activity to maintain phagosomal and lysosomal pH, and this activity aids in the direct clearance of enteric pathogens." SIGNOR-272502 MAPK1 protein P28482 UNIPROT RAI14 protein Q9P0K7 UNIPROT unknown phosphorylation Thr249 SQDADLKtPTKPKQH 10090 BTO:0000944 22028470 t miannu "We have optimized a chemical genetic system using analog-sensitive ERK2, a form of ERK2 engineered to use an analog of adenosine 5'-triphosphate (ATP), to tag and isolate ERK2 substrates in vitro. This approach identified 80 proteins phosphorylated by ERK2, 13 of which are known ERK2 substrates. With this improved methodology, we detected 98 sites directly phosphorylated by ERK2 on 80 proteins from NIH 3T3-L1 fibroblasts. Thirteen of these proteins are known substrates and the rest represent previously unknown kinase/substrate interactions. (table1)" SIGNOR-262760 3-iodo-L-tyrosine smallmolecule CHEBI:27847 ChEBI "L-alanine zwitterion" smallmolecule CHEBI:57972 ChEBI "up-regulates quantity" "precursor of" 9606 28153798 t scontino "The synthesis of T3 and T4 is achieved through the transfer of an iodophenoxyl group from a MIT or DIT residue called a ‚Äúdonor‚Äù onto a DIT residue called an ‚Äúacceptor‚Äù. TPO seems to be primarily responsible for catalyzing the oxidations of iodotyrosines." SIGNOR-268123 PIM proteinfamily SIGNOR-PF34 SIGNOR MAP3K5 protein Q99683 UNIPROT down-regulates phosphorylation Ser83 ATRGRGSsVGGGSRR 9606 BTO:0002552 19749799 t lperfetto "Pim1 phosphorylates and negatively regulates ask1-mediated apoptosispim1 phosphorylation of ask1 on ser83 inhibited ask1-mediated c-jun n-terminal kinase phosphorylation" SIGNOR-259410 pazopanib chemical CHEBI:71219 ChEBI FLT4 protein P35916 UNIPROT "down-regulates activity" "chemical inhibition" -1 22037378 t Luana "Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here." SIGNOR-258261 PPP1CA protein P62136 UNIPROT CASP2 protein P42575 UNIPROT "up-regulates activity" dephosphorylation Ser164 STDTVEHsLDNKDGP -1 19531356 t llicata "nutrient-replete oocytes inhibit C2 via S135 phosphorylation catalyzed by calcium/calmodulin-dependent protein kinase II. We now show that C2 phosphorylated at S135 binds 14-3-3zeta, thus preventing C2 dephosphorylation. Moreover, we determined that S135 dephosphorylation is catalyzed by protein phosphatase-1 (PP1), which directly binds C2." SIGNOR-248564 MAP2K3 protein P46734 UNIPROT MAPK12 protein P53778 UNIPROT up-regulates phosphorylation 9606 11062067 t fstefani "Mkk3, mkk4 and mkk6 all show a strong preference for phosphorylation of the tyrosine residue of the thr-gly-tyr motifs in their known substrates sapk2a/p38, sapk3/p38 gamma and sapk4/p38 delta. we therefore examined the phosphorylation of sapk2a/p38, sapk3/p38? And sapk4/p38? By mkk3, mkk4 and mkk6, which are all known to be capable of activating these enzymes in vitro." SIGNOR-83718 LPAR3 protein Q9UBY5 UNIPROT GNA13 protein Q14344 UNIPROT up-regulates binding 9606 15856019 t gcesareni "Lysophosphatidic acid (lpa), a major g protein coupled receptor (gpcr)-activating ligand present in serum, elicits growth factor like responses by stimulating specific gpcrs coupled to heterotrimeric g proteins such as g(i), g(q), and g12/13." SIGNOR-135846 CAD protein P27708 UNIPROT "L-glutamine zwitterion" smallmolecule CHEBI:58359 ChEBI "down-regulates quantity" "chemical modification" 9606 28552578 t miannu "CAD is a 243 kDa polypeptide formed by the fusion of four enzymatic domains that initiate the de novo biosynthesis of pyrimidine nucleotides . The first two domains, glutaminase (GLN) and carbamoyl phosphate synthetase (CPS-II), initiate the pathway, catalyzing the formation of carbamoyl phosphate (CP) from bicarbonate, glutamine, and two ATP molecules. Next, the labile CP is partially channeled to the C-terminal aspartate transcarbamoylase (ATC) domain where it reacts with aspartate to form carbamoyl aspartate. Then, carbamoyl aspartate is condensated to dihydroorotate, the cyclic precursor of the pyrimidine ring, by the dihydroorotase (DHO), a Zn metalloenzyme fused between CPS and ATC domains." SIGNOR-267418 MAPK3 protein P27361 UNIPROT RRN3 protein Q9NYV6 UNIPROT up-regulates phosphorylation Ser649 PVLYMQPsPL 9606 12620228 t llicata "Erk-dependent phosphorylation of the transcription initiation factor tif-ia is required for rna polymerase i transcription and cell growth. phosphopeptide mapping and mutational analysis reveals two serine residues (s633 and s649) that are phosphorylated by erk and rsk kinases. Replacement of s649 by alanine inactivates tif-ia, inhibits pre-rrna synthesis, and retards cell growth." SIGNOR-98984 APOH protein P02749 UNIPROT cardiolipin smallmolecule CHEBI:28494 ChEBI "down-regulates quantity by destabilization" binding 9606 9596664 t lperfetto "The most relevant physiological role of beta2GPI is supposed to be the regulation of the function of anionic phospholipids like cardiolipin (CL). |Anticardiolipin antibodies or lupus anticoagulants are strongly associated with thrombosis. In these autoimmune diseases with anti-phospholipid antibody syndrome, beta2GPI is a cofactor in the recognition of the phospholipid antigen, CL, by anti-CL antibodies." SIGNOR-266998 PRKAA1 protein Q13131 UNIPROT CDKN1B protein P46527 UNIPROT "up-regulates quantity by stabilization" phosphorylation Thr198 PGLRRRQt 10090 30033086 t Luana "P27Kip1-Mediated Cell Survival Is Dependent on AMPK-Specific Thr198 Phosphorylation|AMPK-dependent phosphorylation of p27Kip1 on Thr198 promotes p27Kip1 protein stability, resulting in more autophagy and less apoptosis." SIGNOR-259859 CDK1 protein P06493 UNIPROT GORASP1 protein Q9BQQ3 UNIPROT "down-regulates activity" phosphorylation Ser274 DPLPGPGsPSHSAPD 10116 BTO:0000951 15834132 t miannu "Here we show that GRASP65 is phosphorylated on serine 277 in interphase cells, and this is strongly enhanced in response to the addition of serum or epidermal growth factor. This is directly mediated by ERK suggesting that GRASP65 has some role in growth factor signal transduction. Phosphorylation of Ser-277 is also dramatically increased during mitosis, however this is mediated by Cdk1 and not by ERK. These results argue against Ser-277 phosphorylation alone causing the dissolution of GRASP65 oligomers and cisternal unstacking, although it may make a significant contribution to these events." SIGNOR-262840 REEP5 protein Q00765 UNIPROT CXCR1 protein P25024 UNIPROT "up-regulates activity" binding 9606 27966653 t miannu "In this study, we found that CXCR1 interacted with REEP5 and REEP6, but CXCR2 did not. Overexpression of REEP5 and REEP6 enhanced IL-8-stimulated cellular responses through CXCR1, whereas depletion of the proteins led to the downregulation of the responses." SIGNOR-261366 EEF1A2 protein Q05639 UNIPROT Gln-tRNA(Gln) smallmolecule CHEBI:29166 ChEBI up-regulates relocalization 9606 23699257 t lperfetto "During protein synthesis, eEF1A binds to and delivers aminoacylated tRNAs (aa-tRNAs) to the elongating ribosome (Fig. 1). GTP bound to eEF1A is hydrolyzed upon codon-anticodon match between an aa-tRNA in the A site of the ribosome and mRNA bound to the ribosome." SIGNOR-269530 MAPK3 protein P27361 UNIPROT KARS1 protein Q15046 UNIPROT up-regulates phosphorylation Ser207 PYEITLLsPCLHMLP 9606 19524539 t gcesareni "Lysrs serves as a key signaling molecule in the immune response by regulating gene expression. Lysrs was phosphorylated on serine 207 in a mapk-dependent manner, released from the multisynthetase complex, and translocated into the nucleus." SIGNOR-186125 TNFRSF21 protein O75509 UNIPROT ROS stimulus SIGNOR-ST2 SIGNOR down-regulates 9606 32454942 f miannu "Further, data from our laboratories indicate that selective agonism of TNFR2 rescues neurons from oxidative stress-induced cell death [160] and excitotoxic cell death [161, 162]. Similarly, TNFR2 activation induces expression of antiapoptotic and detoxifying proteins and protects OPCs against oxidative stress." SIGNOR-263830 PLK1 protein P53350 UNIPROT CENPU protein Q71F23 UNIPROT down-regulates phosphorylation Ser77 TFDPPLHsTAIYADE 9606 17081991 t lperfetto "S77 and t78 of pbip1 are important for plk1-dependent pbip1 phosphorylation and degradation. Here, we demonstrate that a pbd-binding protein, pbip1, is crucial for recruiting plk1 to the interphase and mitotic kinetochores. Unprecedentedly, plk1 phosphorylated pbip1 at t78. Later in mitosis, plk1 also induced pbip1 degradation in a t78-dependent manner, thereby enabling itself to interact with other components critical for proper kinetochore functions" SIGNOR-150453 DYRK1A protein Q13627 UNIPROT DYRK1A protein Q13627 UNIPROT "up-regulates activity" phosphorylation Tyr321 LGQRIYQyIQSRFYR 9606 BTO:0000298 11672423 t lperfetto "Direct identification of phosphorylated residues by tandem ms confirmed that tyr-321, but not tyr-319, was phosphorylated. When expressed in cos-7 cells, dyrk1a was found to be fully phosphorylated on tyr-321. A catalytically inactive mutant of dyrk1a contained no detectable phosphotyrosine, indicating that tyr-321 is autophosphorylated by dyrk1a." SIGNOR-111145 TP53 protein P04637 UNIPROT SCO2 protein O43819 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 27692180 t miannu "P53 regulates basal expression of AIF and SCO2 and facilitates oxidative phosphorylation. The expression of GLUT1, GLUT4, and HK2 is negatively regulated by p53, whereas TIGAR expression is induced by p53. The net result of p53-mediated regulation of these glycolytic enzymes is the suppression of glycolysis. In addition, p53 directly binds and inhibits G6PD activity and downregulates the pentose phosphate pathway." SIGNOR-267463 HEY2 protein Q9UBP5 UNIPROT NOTCH1 protein P46531 UNIPROT down-regulates binding 9606 16682003 t "The NotchIC-RBP-Jkappa complex activates target genes, such as those encoding the Hrt and Hes families. The interaction did not interfere with the formation or DNA-binding of the NotchIC-RBP-Jkappa complex, indicating direct inhibition by Hrt and Hes as co-repressors." gcesareni "Here we show that hrt2 and hes1 interact with rbp-jkappa to negatively regulate notch-dependent activation of hrt and hes expression." SIGNOR-146690 CDK1 protein P06493 UNIPROT TPX2 protein Q9ULW0 UNIPROT "down-regulates activity" phosphorylation Thr72 NLQQAIVtPLKPVDN -1 25688093 t lperfetto "In this study, we characterize the phosphorylation of threonine 72 (Thr(72)) in human TPX2, a residue highly conserved across species. We find that Cdk1/2 phosphorylate TPX2 in vitro and in vivo. |Endogenous TPX2 phosphorylated at Thr(72) does not associate with the mitotic spindle. Furthermore, ectopic GFP-TPX2 T72A preferentially concentrates on the spindle" SIGNOR-265096 STAT6 protein P42226 UNIPROT MRC1 protein P22897 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 20508200 f lperfetto "Phosphorylated STAT6 dimerizes and translocates to the nucleus where it induces the expression of its target genes, including markers (Arg1, Chi3l3, Mrc1, Mgl1, and Retnla) and regulators (Pparalpha, Ppargamma and PGC-1?) of alternative activation." SIGNOR-249535 TRAF2 protein Q12933 UNIPROT BIRC3 protein Q13489 UNIPROT up-regulates binding 9606 18621737 t gcesareni "A traf2 trimer interacts with one ciap2 both in the crystal and in solution through its death domain and amino-terminal region, tradd recruits rip1 (receptor-interacting protein), traf2, and through its interaction with traf2, c-iap1 and c-iap2 (13). Traf2 recruit ciap1 and ciap2. A traf2 trimer interacts with one ciap2 both in the crystal and in solution." SIGNOR-179452 AURKA protein O14965 UNIPROT FADD protein Q13158 UNIPROT up-regulates phosphorylation Ser203 MSWNSDAsTSEAS 9606 21978935 t lperfetto "Here, we report that aur-a phosphorylates s203 of the fas associated with death domain protein (fadd)phosphorylation of s203 by aur-a serves to prime fadd for plk1-mediated phosphorylation at s194" SIGNOR-176739 STK4 protein Q13043 UNIPROT MOB1A protein Q9H8S9 UNIPROT up-regulates phosphorylation Thr12 FSSRSSKtFKPKKNI 9606 21808241 t "MOB1a and MOB1b are near identical to each other with protein sequence homology>90%, and more importantly, both of them are putative tumor suppressors." gcesareni "Mob1, which forms a complex with lats1/2, is also phosphorylated by mst1/2, resulting in an enhanced lats1/2mob1 interaction." SIGNOR-175829 CDK11B protein P21127 UNIPROT EIF3F protein O00303 UNIPROT "up-regulates activity" phosphorylation Thr119 GAARVIGtLLGTVDK 19245811 t lperfetto "Here, we identified a second eIF3f phosphorylation site (Thr119) by CDK11(p46) during apoptosis. We demonstrated that eIF3f is directly phosphorylated by CDK11(p46) in vivo. Phosphorylation of eIF3f plays an important role in regulating its function in translation and apoptosis. Phosphorylation of eIF3f enhances the association of eIF3f with the core eIF3 subunits during apoptosis. " SIGNOR-273131 TGFB1 protein P01137 UNIPROT PAX8 protein Q06710 UNIPROT "down-regulates activity" binding 9606 14623893 t miannu "DNA Binding Activity of Pax8 to the NIS Promoter Is Reduced by Smad3. TGF-β decreases Pax8 DNA binding to the NIS promoter and also found a physical interaction between Pax8 and Smad3." SIGNOR-251993 NLGN4X protein Q8N0W4 UNIPROT NRXN2 protein P58401 UNIPROT "up-regulates activity" binding 9606 BTO:0000938 18923512 t brain lperfetto "Pre- and postsynaptic plasma membranes are always precisely aligned, and are separated by a synaptic cleft of ~20 nm. The cleft contains an undefined proteinaceous material in the middle, and is presumably bridged by synaptic cell-adhesion molecules such as Nrxns and Nlgns that align the pre- and postsynaptic elements and mediate trans-synaptic signaling.|Nlgns bind to both alpha- and beta-Nrxns with nanomolar affinities; binding involves the sixth LNS-domain of alpha-Nrxns which corresponds to the only LNS-domain of beta-Nrxns52. The binding affinities differ characteristically between various pairs of Nlgns and Nrxns, and are controlled by alternative splicing of both Nrxns and Nlgns (Figure 1c)" SIGNOR-264160 VAV1 protein P15498 UNIPROT ZAP70 protein P43403 UNIPROT "up-regulates activity" binding 9606 BTO_0000725 9151714 t Barakat "In summary, we demonstrate here that Y315 in ZAP-70 is required to interact with the Vav SH2 domain, and is critical for ZAP-70–mediated gene activation." SIGNOR-274150 DYRK2 protein Q92630 UNIPROT CARHSP1 protein Q9Y2V2 UNIPROT unknown phosphorylation Ser32 RSRERSPsPLRGNVV 9606 BTO:0000671 15910284 t lperfetto "Dyrk2 (dual-specificity tyrosine-phosphorylated and -regulated protein kinase 2) phosphorylated crhsp24 at ser30, ser32 and ser41 in vitro, and ser41 was identified as a site phosphorylated in cells." SIGNOR-137478 NFE2 protein Q16621 UNIPROT HBB protein P68871 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 BTO:0000426 16287851 f "Regulation of expression" miannu "NF-E2 is a transcription activator for the regulation of a number of erythroid- and megakaryocytic lineage-specific genes. Here we present evidence that the large subunit of mammalian NF-E2, p45, is sumoylated in vivo in human erythroid K562 cells. we demonstrated by stable transfection assay that only the wild-type p45, but not its mutant form p45 (K368R), could efficiently rescue β-globin gene expression in the p45-null, erythroid cell line CB3. These data together point to a model of mammalian β-like globin gene activation by sumoylated p45/NF-E2 in erythroid cells." SIGNOR-251839 PRKCD protein Q05655 UNIPROT GRK2 protein P25098 UNIPROT "up-regulates activity" phosphorylation Ser29 ATPAARAsKKILLPE 9606 BTO:0000007 11042191 t lperfetto "Phosphorylation of GRK2 by protein kinase C abolishes its inhibition by calmodulin. In vitro, GRK2 was preferentially phosphorylated by PKC isoforms alpha, gamma, and delta. Two-dimensional peptide mapping of PKCalpha-phosphorylated GRK2 showed a single site of phosphorylation, which was identified as serine 29 by HPLC-MS. A S29A mutant of GRK2 was not phosphorylated by PKC in vitro and showed no phorbol ester-stimulated phosphorylation when transfected into human embryonic kidney (HEK)293 cells." SIGNOR-249059 STK11 protein Q15831 UNIPROT SIK1 protein P57059 UNIPROT up-regulates phosphorylation Thr182 KSGEPLStWCGSPPY 9606 14976552 t lperfetto "Lkb1 is a master kinase that activates 13 kinases of the ampk subfamily, including mark/par-1we recently demonstrated that the lkb1 tumour suppressor kinase, in complex with the pseudokinase strad and the scaffolding protein mo25, phosphorylates and activates amp-activated protein kinase (ampk). A total of 12 human kinases (nuak1, nuak2, brsk1, brsk2, qik, qsk, sik, mark1, mark2, mark3, mark4 and melk) are related to ampk. Here we demonstrate that lkb1 can phosphorylate the t-loop of all the members of this subfamily, apart from melk, increasing their activity >50-fold" SIGNOR-122784 DUSP2 protein Q05923 UNIPROT MAPK14 protein Q16539 UNIPROT down-regulates dephosphorylation 9606 BTO:0000782 8626452 t gcesareni "We show that the in vivo substrate specificities of individual phosphatases are unique. Pac1, mkp-2, and mkp-1 recognize erk and p38, erk and jnk, and erk, p38, and jnk, respectively" SIGNOR-40918 MAPK1 protein P28482 UNIPROT SCNN1B protein P51168 UNIPROT "down-regulates quantity by destabilization" phosphorylation Thr615 QALPIPGtPPPNYDS -1 11805112 t lperfetto "Using a number of different approaches it was demonstrated that the protein kinase acting on betaThr-613 and gammaThr-623 is the extracellular regulated kinase (ERK). It is suggested that an ERK-mediated phosphorylation of betaThr-613 and gammaThr-623 down-regulates the channel by facilitating its interaction with Nedd4." SIGNOR-249446 PI3K complex SIGNOR-C156 SIGNOR AKT2 protein P31751 UNIPROT up-regulates 9606 BTO:0000586 16293724 f gcesareni "We show that pge2 stimulates colon cancer cell growth through its heterotrimeric guanine nucleotide-binding protein (g protein)coupled receptor, ep2, by a signaling route that involves the activation of phosphoinositide 3-kinase and the protein kinase akt by free g protein bg subunits and the direct association of the g protein as subunit with the regulator of g protein signaling (rgs) domain of axin." SIGNOR-252716 5-[(Z)-(5-Fluoro-2-oxo-1H-indol-3-ylidene)methyl]-N-[(2S)-2-hydroxy-3-morpholin-4-ylpropyl]-2,4-dimethyl-3H-pyrrole-3-carboxamide chemical CID:73755145 PUBCHEM KDR protein P35968 UNIPROT "down-regulates activity" "chemical inhibition" -1 22037378 t miannu "Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here." SIGNOR-259809 HTR1A protein P08908 UNIPROT GNAQ protein P50148 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257088 "Ub:E1 (UBA1 substrate)" complex SIGNOR-C495 SIGNOR UBE2L5 protein A0A1B0GUS4 UNIPROT "up-regulates activity" ubiquitination 9606 34199813 t miannu "The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t" SIGNOR-271331 NPFF protein O15130 UNIPROT NPFFR2 protein Q9Y5X5 UNIPROT up-regulates binding 9606 11024015 t gcesareni "Npff specifically bound to npff1 (k(d) = 1.13 nm) and npff2 (k(d) = 0.37 nm), and both receptors were activated by npff in a variety of heterologous expression systems" SIGNOR-82961 JAK1 protein P23458 UNIPROT IFNGR2 protein P38484 UNIPROT "up-regulates activity" phosphorylation 9606 19041276 t lperfetto "The activation of this signaling pathway involves the binding of IFN-g to two IFN-g receptor (IFN-gR) subunits, made up of respective IFNgR1:IFNgR2 pairs, which dimerize upon IFN-g binding to form the IFN-gR complex. Two JAKs, JAK1and JAK2,which bind to each IFN-gR subunits, respectively through their N-terminal domains, both become activated by tyrosine phosphorylation in a JAK2-dependent process." SIGNOR-249491 palmitoyl-CoA(4-) smallmolecule CHEBI:57379 ChEBI O-palmitoyl-L-carnitine smallmolecule CHEBI:17490 ChEBI "up-regulates quantity" "precursor of" 9606 14517221 t miannu "Carnitine palmitoyltransferase 1A (CPT1A) is the key regulatory enzyme of hepatic long-chain fatty acid beta-oxidation. The first component of this system is CPT1, an integral mitochondrial outer membrane protein, which catalyzes the transfer of long-chain acyl group of the acyl-CoA ester to carnitine. CPT1 is tightly regulated by its physiological inhibitor malonyl-CoA, the first intermediate in fatty acid biosynthesis. Three CPT1 isoforms with various tissue distribution and encoded by distinct genes have been identified (1., 2.): a liver (CPT1A or L-CPT1) (8.), a muscle (CPT1B or M-CPT1) (9.), and a brain isoform (CPT1C)." SIGNOR-268107 pazopanib chemical CHEBI:71219 ChEBI KIT protein P10721 UNIPROT "down-regulates activity" "chemical inhibition" 9606 BTO:0001949 18620382 t Luana "Pyrimidine 13 showed good potency against all the human VEGFR receptors with an IC50 of 10, 30, and 47 nM for VEGFR-1, -2, and -3, respectively. Significant activity was also seen against the closely related tyrosine receptor kinases PDGFRβ, c-Kit, FGF-R1, and c-fms with IC50’s of 84, 74, 140, and 146 nM, respectively." SIGNOR-257736 MEGF10 protein Q96KG7 UNIPROT ABCA1 protein O95477 UNIPROT "up-regulates activity" binding 9606 BTO:0000567 17205124 t miannu "ABCA1 and MEGF10 interact during engulfment. MEGF10 function can be modulated by the ATP binding cassette transporter ABCA1, ortholog to CED-7. by the combined use of cellular and biochemical approaches we provide evidence that ABCA1 and MEGF10 interact at the molecular level." SIGNOR-265165 MIB1 protein Q86YT6 UNIPROT MIB1 protein Q86YT6 UNIPROT "down-regulates quantity by destabilization" polyubiquitination -1 12351649 t miannu "The RING finger motifs of DIP-1 have E3 ligase activity that can auto-ubiquitinate DIP-1 in vitro. In vivo, DIP-1 is detected as a polyubiquitinated protein, suggesting that the intracellular levels of DIP-1 are regulated by the ubiquitin-proteasome system. " SIGNOR-272603 BIRC3 protein Q13489 UNIPROT BIRC3 protein Q13489 UNIPROT "down-regulates activity" ubiquitination 9606 BTO:0000567 14960576 t amattioni "Ciap1 and ciap2 undergo autoubiquitination and degradation upon binding to the iap antagonist second mitochondrial activator of caspases (smac)/direct iap-binding protein with low pi (diablo), which is released from the mitochondria." SIGNOR-121880 FOXO3 protein O43524 UNIPROT CDKN1B protein P46527 UNIPROT "up-regulates quantity" "transcriptional regulation" 10090 BTO:0004245 10783894 t gcesareni "AFX transcriptionally activates p27kip1, resulting in increased protein levels." SIGNOR-238610 NAE complex SIGNOR-C131 SIGNOR CUL3 protein Q13618 UNIPROT "up-regulates activity" neddylation 9606 25504797 t lperfetto "The family of cullin proteins is the most established target for NEDD8. In humans, it is composed of seven cullins (Cul1, 2, 3, 4A, 4B, 5 and 7), whereas PARC (CUL9) and APC2 (component of the anaphase promoting complex APC) contain a cullin-homology domain. All cullins are modified with NEDD8The role of cullin NEDDylation is to enhance the activity of the CRLs and subsequent ubiquitination and degradation of the regulated substrates." SIGNOR-243157 PRKCG protein P05129 UNIPROT GRIN1 protein Q05586 UNIPROT "up-regulates activity" phosphorylation Ser890 ITSTLASsFKRRRSS 10116 BTO:0000938 15936117 t miannu "Serines 890 and 896 of the NMDA receptor subunit NR1 are differentially phosphorylated by protein kinase C isoforms. The results show that PKC alpha phosphorylates preferentially S896 and PKC gamma preferentially S890." SIGNOR-263176 MAPK11 protein Q15759 UNIPROT SMAD2 protein Q15796 UNIPROT down-regulates phosphorylation 9606 20820849 t gcesareni "Smads can also be phosphorylated in the linker region most prominently by the action of mitogen-activated protein (map) kinaseslinker region phosphorylation can prevent nuclear translocation of smads and inhibit tgf-_ signalling, potentially leading to oncogenesis." SIGNOR-167848 SLC4A8 protein Q2Y0W8 UNIPROT hydrogencarbonate smallmolecule CHEBI:17544 ChEBI "up-regulates quantity" relocalization 9606 BTO:0000938 26136660 t miannu "Slc4a10 is a Na+-coupled Cl−-HCO3− exchanger, which is expressed in principal and inhibitory neurons as well as in choroid plexus epithelial cells of the brain. In neurons, bicarbonate transport is mainly mediated by members of the SLC4A family of proteins. While the Na+-independent anion-exchanger SLC4A3 lowers the intraneuronal bicarbonate concentration, the Na+-dependent anion exchangers SLC4A8 (NDCBE) and SLC4A10 (NCBE) use the sodium gradient to accumulate bicarbonate in exchange of chloride" SIGNOR-264918 ZBTB47 protein Q9UFB7 UNIPROT CBFA2T3/ZNF651 complex SIGNOR-C197 SIGNOR "form complex" binding 9606 BTO:0000007 20116376 t "Previously we reported that a classical C2H2 zinc finger DNA binding protein ZNF652 functionally interacts with CBFA2T3 to repress transcription of genes containing ZNF652 consensus DNA binding sequence within the promoters of these target genes. Here we show that ZNF651 is a ZNF652 paralogue that shares a common DNA binding sequence with ZNF652 and represses target gene expression through the formation of a CBFA2T3-ZNF651 corepressor complex." SIGNOR-253957 "Av/b3 integrin" complex SIGNOR-C177 SIGNOR PTK2 protein Q05397 UNIPROT "up-regulates activity" 9606 15688067 f miannu "Focal adhesion kinase (FAK) is activated by growth factors and integrins during migration, and functions as a receptor-proximal regulator of cell motility. At contacts between cells and the extracellular matrix, FAK functions as an adaptor protein to recruit other focal contact proteins or their regulators, which affects the assembly or disassembly of focal contacts. Whereas it was first hypothesized that FAK might bind directly to the cytoplasmic tails of integrins, accumulated evidence supports an indirect association of FAK with integrins through binding to integrin-associated proteins such as paxillin and talin." SIGNOR-257719 1-(4-((6,7-Dimethoxyquinolin-4-yl)oxy)-2-methoxyphenyl)-3-(1-(thiazol-2-yl)ethyl)urea chemical CID:9869779 PUBCHEM CSF1R protein P07333 UNIPROT "down-regulates activity" "chemical inhibition" -1 22037378 t miannu "Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here." SIGNOR-259750 MYT1 protein Q01538 UNIPROT YAP1 protein P46937 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0005949 30312684 t miannu "Myt1 and Myt1l transcription factors limit proliferation in GBM cells by repressing YAP1 expression. Examination of the gene expression changes in cells expressing Myt1 or Myt1l suggests that both repress expression of the YAP1 transcriptional coactivator, which functions primarily in the Hippo signaling pathway. Expression of YAP1 and its target genes is reduced in Myt-expressing cells, and there is an inverse correlation between YAP1 and MYT1/MYT1L expression in human brain cancer datasets. Together, our data suggest that Myt1 and Myt1l directly repress expression of YAP1, a protein which promotes proliferation and GBM growth." SIGNOR-266777 IL23R protein Q5VWK5 UNIPROT JAK2 protein O60674 UNIPROT up-regulates binding 9606 BTO:0000782 12023369 t gcesareni "Il-23 activates the same jak-stat signaling molecules as il-12: jak2, tyk2, and stat1, -3, -4, and -5, but stat4 activation is substantially weaker and different dna-binding stat complexes form in response to il-23 compared with il-12." SIGNOR-87808 MAPK7 protein Q13164 UNIPROT MAPK7 protein Q13164 UNIPROT "up-regulates activity" phosphorylation Ser567 VLSDNDRsLLERWTR 9606 BTO:0000567 20667468 t miannu "Activated ERK5 undergoes autophosphorylation on its C-terminal half, necessary for maximal activation of ERK5 transcriptional activation. The Ser731 and Thr733 sites were previously shown to be ERK5 autophosphorylation sites in vitro and also in ERK5-overexpressing cells.Our data coincide with a recent study examining whole protein phosphorylation in HeLa cells arrested in G1 and mitotic phases [37] reported that Ser731 and Thr733, as well as Ser720, are phosphorylated in ERK5 during mitosis. We also identified two unreported ERK5 phosphorylation sites, Ser567 and Ser803." SIGNOR-259823 SGK1 protein O00141 UNIPROT NDRG1 protein Q92597 UNIPROT down-regulates phosphorylation Ser330 LMRSRTAsGSSVTSL 9606 20416281 t llicata "Ndrg1/cap43 is phosphorylated at serine/threonine sites in its c-terminal domain by serum- and glucocorticoid-regulated kinase 1 (sgk1). we further introduced mutations at the serine and threonine sites at 328 [t328a], 330 [s330a] and 346 [t346a], which are susceptible to phosphorylation by sgk1, and also constructed double mutants [t328a, s330a], [t328a, t346a] and [s330a, t346a]. Expression of all these mutants, with the exception of [s330a, t346a], suppressed the production of cxc chemokine to similar levels as their wild-type counterpart." SIGNOR-164898 BNIP3 protein Q12983 UNIPROT RHEB protein Q15382 UNIPROT down-regulates binding 9606 17928295 t gcesareni "Bnip3, a hypoxia-inducible bcl-2 homology 3 domain-containing protein, directly binds rheb and inhibits the mtor pathway. Bnip3 decreases rheb gtp levels in a manner depending on the binding to rheb." SIGNOR-158274 CDK5 protein Q00535 UNIPROT MAPT protein P10636 UNIPROT down-regulates phosphorylation Thr522 SSPGSPGtPGSRSRT 9606 BTO:0000590 12226093 t "The effect has been demonstrated using P10636-8" lperfetto "Phosphopeptide mapping revealed enhanced phosphorylation of ser(202)/thr(205) residues by p25-cdk5 considering the fact that phosphorylation of ser(202)/thr(205) antagonizes the tau-mediated nucleation of tubulin, p25-cdk5 may play a pivotal role in neuronal cell death in alzheimer's disease." SIGNOR-92607 TCF4 protein P15884 UNIPROT MYC protein P01106 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 18852287 t "Association of c-Jun, β-catenin, and TCF4 specifically with the downstream enhancer underlies mitogen stimulation of c-Myc transcription." SIGNOR-253324 MAPK9 protein P45984 UNIPROT MFN2 protein O95140 UNIPROT down-regulates phosphorylation Ser27 HMAEVNAsPLKHFVT 9606 22748923 t lperfetto "Jnk phosphorylation of mitofusin 2 in response to cellular stress leads to recruitment of the ubiquitin ligase (e3) huwe1/mule/arf-bp1/hecth9/e3histone/lasu1 to mitofusin 2, with the bh3 domain of huwe1 implicated in this interaction. This results in ubiquitin-mediated proteasomal degradation of mitofusin 2these data establish that mfn2 is phosphorylated on ser27 in response to a variety of cellular stresses and implicate jnk in this process" SIGNOR-198054 PTPN13 protein Q12923 UNIPROT INSR protein P06213 UNIPROT down-regulates dephosphorylation Tyr1185 FGMTRDIyETDYYRK 9606 15611135 t gcesareni "We demonstrate that ptpl1, like ptp1b, interacts with and dephosphorylates a bis-phosphorylated insulin receptor peptide more efficiently than monophosphorylated peptides, indicating that ptpl1 may down-regulate the phosphatidylinositol 3-kinase pathway, by dephosphorylating insulin or growth factor receptors that contain tandem phosphotyrosines." SIGNOR-132551 MT-ND3 protein P03897 UNIPROT "Mitochondrial respiratory chain complex I" complex SIGNOR-C277 SIGNOR "form complex" binding 30030361 t lperfetto "Thus, we now know the complete mammalian cI structure [22,23] and how the subunits are organized in six modules (N, Q, ND1, ND2, ND4 and ND5)|The ND2-module is formed by an initial intermediate that contains MT-ND2, NDUFC1 and NDUFC2 bound to NDUFAF1/CIA30 [49,50], ECSIT [51] and ACAD9 [52,53]. Then, MT-ND3 is added together with TMEM126B [54], forming a larger intermediate to which subunits MT-ND6 and MT-ND4L bind. The latest assembly stages involve the incorporation of subunits NDUFA1, NDUFA10 and NDUFS5 [24,34]." SIGNOR-262145 IL2RB protein P14784 UNIPROT SHC1 protein P29353 UNIPROT up-regulates binding 9606 BTO:0000782;BTO:0001271;BTO:0000785 24737791 t milica "The signaling mechanism utilizes an adaptor protein, shc, which binds to a phosphotyrosine residue on the il-2/15r?, Resulting in activation of grb2 and onto akt via the shc-grb2-gab2-pi3k-akt signaling pathway to increase cell proliferation and/or survival" SIGNOR-204975 olodaterol chemical CHEBI:82700 ChEBI ADRB2 protein P07550 UNIPROT "up-regulates activity" "chemical activation" -1 20371707 t Luana "In vitro, olodaterol showed a potent, nearly full agonistic response at the hbeta(2)-AR (EC(50) = 0.1 nM; intrinsic activity = 88% compared with isoprenaline) and a significant selectivity profile (241- and 2299-fold [corrected] against the hbeta(1)- and hbeta(3)-ARs, respectively). " SIGNOR-257834 PAK4 protein O96013 UNIPROT ITGB5 protein P18084 UNIPROT up-regulates phosphorylation Ser759 REFAKFQsERSRARY 9606 20507994 t llicata "Pak4 specifically phosphorylated the integrin beta5 subunit at ser-759 and ser-762 within the beta5-sers-motif. Point mutation of these two serine residues abolished the pak4-induced cell migration, indicating a functional role for these phosphorylations in migration." SIGNOR-165702 ITGAM protein P11215 UNIPROT Differentiation phenotype SIGNOR-PH37 SIGNOR up-regulates 9606 12393465 f apalma "CD11b, another marker for differentiation, was also less expressed in patients with t(8;21) in comparison to patients without t(8;21)" SIGNOR-255662 SRC protein P12931 UNIPROT VCL protein P18206 UNIPROT "down-regulates activity" phosphorylation Tyr1133 WVRKTPWyQ 9534 15229287 t lperfetto "The phosphorylation of vinculin on tyrosine residues 100 and 1065, mediated by SRC kinases, affects cell spreadingWhen phosphorylated, the vinculin tail exhibited significantly less binding to the vinculin head domain than the unphosphorylated tail." SIGNOR-247428 YBX1 protein P67809 UNIPROT CDH1 protein P12830 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0001023 17072343 f miannu "YB-1 knockdown by siRNA upregulated 344 genes, including MDR1, thymidylate synthetase, S100 calcium binding protein and cyclin B, and downregulated 534 genes, including CXCR4, N-myc downstream regulated gene 1, E-cadherin and phospholipase C." SIGNOR-255610 CRHR1 protein P34998 UNIPROT Corticotropin protein P01189-PRO_0000024969 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0001073 23504413 f lperfetto "CRH, as a principal mediator of endocrine stress response, activates the HPA axis (Hypothalamic–pituitary–adrenal axis) by binding to the CRHR1 in the anterior pituitary. This, through a cascade of reactions, increases the expression of proopiomelanocortin (POMC) gene and the subsequent release of POMC-derived peptides, adrenocorticotropic hormone (ACTH) and β-endorphin. ACTH, in turn, stimulates the secretion of glucocorticoids from adrenal cortex (Vale et al. 1981)." SIGNOR-268613 SLBP protein Q14493 UNIPROT H2AW protein Q7L7L0 UNIPROT "up-regulates quantity by expression" "translation regulation" 9606 BTO:0001938 19155325 t lperfetto "Synthesis of mature histone mRNA requires only a single processing reaction: an endonucleolytic cleavage between a conserved stem-loop and a purine-rich downstream element to form the 3' end. The stem-loop binding protein (SLBP) is required for processing, and following processing, histone mRNA is transported to the cytoplasm, where SLBP participates in translation of the histone mRNA|We used radiolabeled probes generated by PCR targeting the open reading frame (ORF) to detect histones H2A, H2B, H3, H4, and H1 and used 7SK snRNA as a loading control (Fig. 2A). The abundance of histone H2A, H2B, H3, and H4 mRNAs is reduced to 37% to 70% of control levels in the SLBP knockdown cells when compared to the C2 control." SIGNOR-265409 MAPK14 protein Q16539 UNIPROT RPS6KA4 protein O75676 UNIPROT up-regulates phosphorylation Ser196 EEKERTFsFCGTIEY 9606 BTO:0000567 10806207 t llicata "Rskb, a 90-kda ribosomal s6 protein kinase family (rsk) member with two complete catalytic domains connected by a linker, is activated through p38- and erk-mitogen-activated protein kinases. unlike other rsks, the activation loop phosphorylation sites of both catalytic domains of rskb, ser(196) and thr(568), were required for activity. Rskb activation depended on phosphorylation of linker ser(343) and ser(360) and associated with phosphorylation of nonconserved ser(347), but ser(347)-deficient rskb retained partial activity." SIGNOR-77204 PDK2 protein Q15119 UNIPROT PDHA1 protein P08559 UNIPROT "down-regulates activity" phosphorylation Ser232 NRYGMGTsVERAAAS -1 11485553 t lperfetto "Here we report that the four isoenzymes of protein kinase responsible for the phosphorylation and inactivation of pyruvate dehydrogenase (pdk1, pdk2, pdk3 and pdk4) differ in their abilities to phosphorylate the enzyme. Pdk1 can phosphorylate all three sites (s232, s293, s300), whereas pdk2, pdk3 and pdk4 each phosphorylate only s232 and s293." SIGNOR-109559 linifanib chemical CHEBI:91435 ChEBI CSF1R protein P07333 UNIPROT "down-regulates activity" "chemical inhibition" -1 22037378 t Luana "Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here." SIGNOR-258241 FGF2 protein P09038 UNIPROT ALPL protein P05186 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0004473 19049325 f miannu "FGF2 increases PC-1 and Ank expression while inhibiting Tnap expression in primary pre-osteoblast cells. Additionally, we show that the induction of PC-1 by FGF2 is cell type specific and mediated by the transcription factor, Runx2." SIGNOR-252194 VIPAS39 protein Q9H9C1 UNIPROT "CHEVI complex" complex SIGNOR-C269 SIGNOR "form complex" binding 9606 BTO:0000007 29778605 t lperfetto "It has been recently suggested that VPS33B and VIPAR comprise two subunits of a novel multi-subunit tethering complex (named ""CHEVI"")" SIGNOR-261831 PAK1 protein Q13153 UNIPROT PA2G4 protein Q9UQ80 UNIPROT up-regulates phosphorylation Thr261 QYGLKMKtSRAFFSE 9606 BTO:0000150 18283314 t llicata "We found that pak1 phosphorylated ebp1 in vitro and mapped the phosphorylation site to threonine 261. these studies demonstrate for the first time that ebp1 is a substrate of pak1 and the importance of the pak1 phosphorylation site for the functional activity of ebp1 in breast cancer cells." SIGNOR-160963 AR protein P10275 UNIPROT Survival phenotype SIGNOR-PH13 SIGNOR up-regulates 9606 15861399 f miannu "AR homodimers recruit a panoply of factors including coactivators and mediator proteins whose enzymatic activities promote chromatin remodeling and transcriptional regulation of target genes leading to cell differentiation, survival, and proliferation" SIGNOR-251539 MARCHF9 protein Q86YJ5 UNIPROT CEMIP2 protein Q9UHN6 UNIPROT "down-regulates quantity by destabilization" ubiquitination 9606 BTO:0001522 19457934 t miannu "MARCH9, a member of the RING-CH family of transmembrane E3 ubiquitin ligases, down-regulates CD4, major histocompatibility complex-I (MHC), and ICAM-1 in lymphoid cells. To identify novel MARCH9 substrates, we used high throughput flow cytometry and quantitative mass spectrometry by stable isotope labeling by amino acids in cell culture (SILAC) to determine the differential expression of plasma membrane proteins in a MARCH9-expressing B cell line. This combined approach identified 13 potential new MARCH9 targets. " SIGNOR-271533 CSNK2A2 protein P19784 UNIPROT AQP4 protein P55087 UNIPROT "down-regulates activity" phosphorylation Ser316 EKKGKDQsGEVLSSV 9615 11742978 t llicata "We found that the stress-induced kinase casein kinase (CK)II phosphorylates the Ser276 immediately preceding the tyrosine motif, increasing AQP4-mu 3A interaction and enhancing AQP4-lysosomal targeting and degradation. | To determine whether Ser276 is an actual CKII substrate, we used GST–AQP4‐Cter proteins in which only one out of the three C‐terminal CKII consensus sites was sequentially conserved (Ser276, Ser285 and Ser315, respectively). Figure 7B (right panel) shows that the three serine residues, including Ser276, were indeed efficiently phosphorylated by CKII." SIGNOR-250976 SIRT3 protein Q9NTG7 UNIPROT CYP11A1 protein P05108 UNIPROT "up-regulates quantity by stabilization" deacetylation Lys148 LKKSAAWkKDRVALN 9606 BTO:0002588 22585829 t lperfetto "Resveratrol stimulates cortisol biosynthesis by activating SIRT-dependent deacetylation of P450scc.|Stable overexpression of SIRT3 abrogates the cellular content of acetylated P450scc, concomitant with an increase in P450scc protein expression and cortisol secretion. Mutation of K148 and K149 to alanine stabilizes the expression of P450scc and results in a 1.5-fold increase in pregnenolone biosynthesis." SIGNOR-268717 GABRB1 protein P18505 UNIPROT "GABA-A (a1-b1-g2) receptor" complex SIGNOR-C330 SIGNOR "form complex" binding 9606 BTO:0000227 18790874 t "brain, See table 3 for identified complexes" lperfetto "The assembly of GABAA-R as heteropentamers produces complex subtype heterogeneity in structure, which is the major determinant of their pharmacological profile.|Evidence is greatly in favor of a pentameric receptor and most GABAA-R subtypes are formed from two copies of a single alpha, two copies of a single beta, and one copy of another subunit, such as gamma, delta, or epsilon." SIGNOR-263751 Ub:E2 complex SIGNOR-C497 SIGNOR TRIM69 protein Q86WT6 UNIPROT "up-regulates activity" ubiquitination 9606 34199813 t miannu "The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t" SIGNOR-271188 FUBP1 protein Q96AE4 UNIPROT TNFSF10 protein P50591 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 19637194 f irozzo "FBP1 down-regulates cell cycle inhibitors and proapoptotic genes. Interestingly, we also observed the up-regulation of proapoptotic genes following FBP1 knockdown in Hep3B cells. In addition, mRNA levels of the death ligands tumor necrosis factor (TNF) α and tumor necrosis factor–related apoptosis-inducing ligand (TRAIL) were significantly increased." SIGNOR-259129 CTDSP1 protein Q9GZU7 UNIPROT POLR2A protein P24928 UNIPROT "up-regulates activity" dephosphorylation Ser1654 SPSYSPTsPSYSPTS -1 22137580 t "Phosphorylation and dephosphorylation of the C-terminal domain (CTD) of RNA polymerase II (Pol II) represent a critical regulatory checkpoint for transcription. Transcription initiation requires Fcp1/Scp1-mediated dephosphorylation of phospho-CTD. | This combined structure-function analysis discloses the residues in Scp1 involved in CTD binding and its preferential dephosphorylation of P.Ser5 of the CTD heptad repeat." SIGNOR-248771 "mono(2-ethylhexyl) phthalate" chemical CHEBI:17243 ChEBI OXER1 protein Q8TDS5 UNIPROT "up-regulates activity" "chemical activation" 9534 BTO:0001538 27551952 t miannu "MEHP and MiNP exhibit potent activation of hCAR2 and hPXR with higher affinities for these receptors than for the hPPARs. The rank order potency for MEHP and MiNP was hCAR2 > hPXR > hPPARs." SIGNOR-268776 TOMM70 protein O94826 UNIPROT "TOM40 complex" complex SIGNOR-C421 SIGNOR "form complex" binding 9606 BTO:0000567 18331822 t lperfetto "The fungal preprotein translocase of the mitochondrial outer membrane (TOM complex) comprises import receptors Tom70, Tom20, and Tom22, import channel Tom40, and small Tom proteins Tom5, Tom6, and Tom7, which regulate TOM complex assembly. These components are conserved in mammals; unlike the other components, however, Tom5 and Tom6 remain unidentified in mammals. We immuno-isolated the TOM complex from HeLa cells expressing hTom22-FLAG and identified the human counterparts of Tom5 and Tom6, together with the other components including Tom7. These small Tom proteins are associated with Tom40 in the TOM complex." SIGNOR-267677 E2F1 protein Q01094 UNIPROT RRM1 protein P23921 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000972 14618416 f miannu "To assess transactivating activity of E2F1/DP-1, we also analyzed expression of ten putative transcriptional targets of this complex in HCCs. Expression levels of TFDP1 and E2F1 correlated with those of seven transcriptional targets ( TYMS, DHFR, PCNA, RRM1, CCNE1, CDC2, and MYBL2) that play important roles in the G1/S transition, and down-regulation of TFDP1 inhibited growth of Hep3B cells." SIGNOR-253852 FZD6 protein O60353 UNIPROT DVL1 protein O14640 UNIPROT "up-regulates activity" binding 9606 22944199 t amattioni "When canonical wnts bind to their respective fzd receptors, heterotrimeric g-proteins and dsh get activated and lead to the recruitment of axin to the fzd co-receptor lrp." SIGNOR-198828 7-[4-[4-(2,3-Dichlorophenyl)-1,4-diazepan-1-yl]butoxy]-3,4-dihydro-1H-1,8-naphthyridin-2-one chemical CID:56593482 PUBCHEM DRD2 protein P14416 UNIPROT "up-regulates activity" "chemical activation" 9606 22025698 t Luana "Through a robust diversity-oriented modification of the scaffold represented by aripiprazole (1), we discovered UNC9975 (2), UNC0006 (3), and UNC9994 (4) as unprecedented β-arrestin–biased D2R ligands. " SIGNOR-258321 BCR-ABL "fusion protein" SIGNOR-FP6 SIGNOR CTNNB1 protein P35222 UNIPROT up-regulates phosphorylation Tyr654 RNEGVATyAAAVLFR 9606 BTO:0001271 17318191 t lperfetto "Bcr-abl stabilizes beta-catenin in chronic myeloid leukemia through its tyrosine phosphorylationthe notion that y86 and y654 are located respectively within the n_ and c_terminal transcriptional domains of __catenin suggests that one or both residues might regulate the transactivating function of __catenin. In this regard, phosphorylation of y654 was reported to strengthen __catenin association with the basal transcription factor tata_binding protein (tbp)" SIGNOR-153431 PTEN protein P60484 UNIPROT PINK1 protein Q9BXM7 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 11494141 f miannu "Defects in PTEN, a tumor suppressor, have been found in cancers arising in a variety of human tissues. To elucidate the tumor-suppressive function of this gene, we have been analysing expression profiles of cancer cells after introduction of exogenous PTEN. Those experiments identified 99 candidate genes that were transcriptionally transactivated. Among them, we report here the further analyses of eight genes, EGR2/Krox-20, BPOZ, APS, HCLS1/HS1, DUSP1/MKP1, NDRG1/Drg1/RTP, NFIL3/E4BP4, and a novel gene (PINK1, PTEN-induced putative kinase)." SIGNOR-260056 TBCK protein Q8TEA7 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 23977024 f miannu "Depletion of TBCK significantly inhibits cell proliferation, reduces cell size, and disrupts the organization of actin, but not microtubule." SIGNOR-266700 MAPK12 protein P53778 UNIPROT SNTA1 protein Q13424 UNIPROT up-regulates phosphorylation Ser201 PLQRQPSsPGPTPRN 9606 BTO:0001103 10212242 t lperfetto "Sapk3 phosphorylates alpha1-syntrophin at serine residues 193 and 201 in vitro and phosphorylation is dependent on binding to the pdz domain of alpha1-syntrophin. The finding that sapk3 co-localizes with _1-syntrophin in skeletal muscle, that it binds to the pdz domain of _1-syntrophin, and that phosphorylation of _1-syntrophin depends on this interaction identifies a novel mechanism for targeting a protein kinase to its substrates." SIGNOR-67065 UBE2J1 protein Q9Y385 UNIPROT DIO proteinfamily SIGNOR-PF83 SIGNOR "down-regulates quantity by destabilization" ubiquitination 9606 BTO:0001379 29892818 t "inferred from family member" scontino "ER residency places D2 physically close to an array of proteins that interact and modify the D2 molecule via ubiquitination and targeting to the proteasomal system, explaining its relatively short half-life. Both ubiquitin conjugases UBC6 and or UBC7 interact with D2 and support D2 ubiquitination. Two Lys residues in D2 are involved in this process, K237 and K244." SIGNOR-270242 CDK19 protein Q9BWU1 UNIPROT NOTCH1 protein P46531 UNIPROT "down-regulates quantity by destabilization" phosphorylation Thr2511 VPEHPFLtPSPESPD -1 25344755 t lperfetto "Mapping of cyclin C-dependent phosphosites on ICN1, using mass spectrometry revealed that several of them are located within the PEST-domain of Notch1, which controls ICN1 degradation38,39 (Fig. 5g and Supplementary Table 1). Three of them (T2512, S2514 and S2517) are localized within the consensus motif, “Cdc4 phosphodegron”, which is shared by most substrates of Fbw7 (Cdc4) ubiquitin ligase38. Two of these residues (S2514 and S2517) were previously shown by Fryer et al.20 to be phosphorylated by cyclin C-CDK8 in vitro, and all three were shown to play a role in controlling ICN1 stability via Fbw740. We verified that cyclin C-CDK8, C-CDK19 and C-CDK3 phosphorylate ICN1 on these three residues" SIGNOR-273137 CREBL2 protein O60519 UNIPROT PPARG protein P37231 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 BTO:0000011 21728997 f Luana "Accordingly, the results of QPCR and immunoblot analysis showed that during adipogenesis, both the mRNA (Figures 4D and 4E) and protein (Figure 4F) levels of PPARγ , as well as C/EBPα, in 3T3-L1 preadipocytes transfected with either siCREBL2-1 or siCREBL2-2 were significantly decreased compared with the control (P < 0.05), suggesting that knockdown of CREBL2 protein suppress 3T3-L1 preadipocyte differentiation via inhibition of PPARγ and C/EBPα expression." SIGNOR-261573 CyclinD/CDK4 complex SIGNOR-C18 SIGNOR RB1 protein P06400 UNIPROT "down-regulates activity" phosphorylation Thr5 tPRKTAAT -1 9139732 t llicata "In summary, we have shown evidence that CDK4-cyclin D1 phosphorylates Thr5, Ser249, Thr252, Thr356, Thr373, Ser788, Ser795, Ser807, Ser811, and Thr826 of pRB." SIGNOR-250762 BAK1 protein Q16611 UNIPROT CYCS protein P99999 UNIPROT up-regulates relocalization 9606 11175253 t "Translocation from Mitochondria to Cytosol" amattioni "Allosteric activation of bak induces its intramembranous oligomerization into a proposed pore for cytochrome c efflux" SIGNOR-105206 EFNA1 protein P20827 UNIPROT EPHA1 protein P21709 UNIPROT up-regulates binding 9606 9576626 t tpavlidou "Ephrin-a1 binds and activates the tyrosine kinase activity of eph-a2, and has a dissociation constant of 20_30 nm. ephrin-a1 interacts with all the other epha subclass receptors as well, although with different affinity" SIGNOR-56898 TAB3 protein Q8N5C8 UNIPROT MAP3K7 protein O43318 UNIPROT "up-regulates activity" binding 9606 14670075 t lperfetto "We have identified a new binding partner of the tgfbeta (transforming growth factor-beta)-activated protein kinase (tak1), termed tab.two distinct tak1 complexes are present in cells. One comprises tak1 complexed with tab1 and tab2, and the other tak1 complexed with tab1 and tab3 (tak1-binding protein-3). Both complexes are activated in response to tumour necrosis factor-alpha or interleukin-1." SIGNOR-120325 EIF1AY protein O14602 UNIPROT Ternary_GTP_eIF2_tRNA_complex complex SIGNOR-C452 SIGNOR "up-regulates activity" relocalization 9606 12514125 t lperfetto "Translation initiation factor 1A (eIF1A) is predicted to bind in the decoding site of the 40S ribosome and has been implicated in recruitment of the eIF2-GTP-Met-tRNA i Met ternary complex (TC) and ribosomal scanning. " SIGNOR-269148 TLN1 protein Q9Y490 UNIPROT "A6/b4 integrin" complex SIGNOR-C174 SIGNOR "up-regulates activity" binding 10090 BTO:0000132 19118207 t miannu "Over the past 10 years, the binding of talin to the cytoplasmic tail of integrin-β subunits has been established to have a key role in integrin activation. Binding of the phosphotyrosinebinding (PTB)-domain-like subdomain of the protein 4.1, ezrin, radixin, moesin (FERM) domain of talin to the conserved WxxxNP(I/L)Y motif of the β-integrin tail permits additional weaker interactions between talin and the membrane-proximal region of the tail that trigger integrin activation, probably through the disruption of inhibitory interactions between α- and β-subunit cytoplasmic tails." SIGNOR-257628 TLRs proteinfamily SIGNOR-PF20 SIGNOR TIRAP protein P58753 UNIPROT "up-regulates activity" binding 9606 20404851 t lperfetto "These differences are explained by the discovery of TIR domain’containing adaptor molecules, including MyD88, TIRAP (Mal), TRIF and TRAM, which are recruited by distinct TLRs and activate distinct signaling pathways" SIGNOR-216298 AKT proteinfamily SIGNOR-PF24 SIGNOR FOXO4 protein P98177 UNIPROT "down-regulates activity" phosphorylation Ser197 APRRRAAsMDSSSKL 10090 BTO:0004245 10217147 t "Here we show that protein kinase B phosphorylates AFX, a human orthologue of daf -16 (refs 5, 6, 9), both in vitro and in vivo." SIGNOR-251477 STK3 protein Q13188 UNIPROT LATS2 protein Q9NRM7 UNIPROT up-regulates phosphorylation Ser872 HQRCLAHsLVGTPNY 9606 23431053 t milica "MST1/2 directly phosphorylate Lats1/2 at the hydrophobic motif (Lats1 T1079 and Lats2 T1041), and this phosphorylation is required for Lats1/2 activation" SIGNOR-201274 AKT1 protein P31749 UNIPROT MTOR protein P42345 UNIPROT up-regulates phosphorylation 9606 BTO:0001103 15829723 t apalma "Once phosphorylated, Akt can act on a broad spectrum of substrates that can influence cell survival and proliferation and protein synthesis (65). Phosphorylation of mTOR by Akt leads to mTOR activation (40, 52) and the subsequent activation of p70S6K" SIGNOR-255107 "CKM complex" complex SIGNOR-C406 SIGNOR SMAD3 protein P84022 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser213 NLSPNPMsPAHNNLD 9606 19914161 t lpetrilli "Similarly, tgf-?-Induced and cdk8/9-mediated phosphorylation of smad3 at threonine 179 (t179) is important for binding of the nedd4l e3 ubiquitin ligase, which accelerates smad3 turnover;cdk8 and cyclint-cdk9 showed a preference for s206 and s214 but also phosphorylated s186 and s195 in the case of smad1;and t179, s208 and s213 in the case of smad3." SIGNOR-273147 ITGB1 protein P05556 UNIPROT "A10/b1 integrin" complex SIGNOR-C167 SIGNOR "form complex" binding 16988024 t lperfetto "Integrins are one of the major families of cell adhesion receptors (Humphries, 2000; Hynes, 2002). All integrins are non-covalently-linked, heterodimeric molecules containing an α and a β subunit. Both subunits are type I transmembrane proteins, containing large extracellular domains and mostly short cytoplasmic domains (Springer and Wang, 2004; Arnaout et al., 2005). Mammalian genomes contain 18 α subunit and 8 β subunit genes, and to date 24 different α,β combinations have been identified at the protein level. Although some subunits only appear in a single heterodimer, twelve integrins contain the β1 subunit, and five contain αV." SIGNOR-253186 "AE/b7 integrin" complex SIGNOR-C186 SIGNOR PTK2 protein Q05397 UNIPROT "up-regulates activity" 9606 15688067 f miannu "Focal adhesion kinase (FAK) is activated by growth factors and integrins during migration, and functions as a receptor-proximal regulator of cell motility. At contacts between cells and the extracellular matrix, FAK functions as an adaptor protein to recruit other focal contact proteins or their regulators, which affects the assembly or disassembly of focal contacts. Whereas it was first hypothesized that FAK might bind directly to the cytoplasmic tails of integrins, accumulated evidence supports an indirect association of FAK with integrins through binding to integrin-associated proteins such as paxillin and talin." SIGNOR-257727 WASHC3 protein Q9Y3C0 UNIPROT "WASH complex" complex SIGNOR-C258 SIGNOR "form complex" binding 23721880 t lperfetto "The WASH complex is composed of five proteins: KIAA1033 (also known as SWIP), Strumpellin, FAM21, WASH1 and CCDC53." SIGNOR-261017 MTOR protein P42345 UNIPROT EIF4EBP1 protein Q13541 UNIPROT "down-regulates activity" phosphorylation Thr70 RNSPVTKtPPRDLPT 9606 BTO:0000007 SIGNOR-C3 12747827 t lperfetto "Here, we show that a functional TOS motif is required for 4E-BP1 to bind to raptor (a recently identified mTOR-interacting protein), for 4E-BP1 to be efficiently phosphorylated in vitro by themTOR/raptor complex, and for 4E-BP1 to be phosphorylated in vivo at all identified mTOR-regulated sites. mTOR/raptor regulated phosphorylation is necessary for 4E-BP’s efficient release from the translational initiation factor eIF4E. We find that the TOS motif is absolutely required for efficient phosphorylation of 4E-BP1 at all the identified mTOR-regulated sites, namely, Thr37/46, Ser65, and Thr70 in vivo." SIGNOR-101127 methiothepin chemical CHEBI:64203 ChEBI HTR2B protein P41595 UNIPROT "down-regulates activity" "chemical inhibition" 10036 BTO:0000452 9459568 t miannu "The data in Table 2 show the affinity of a number of compounds for the [3H]rauwolscine labeled human 5-HT2B receptor. All of the competition curves for these compounds yielded slope values that were near unity, i.e, they did not significantly fit a two-site binding model better than a one-site binding model. sured against [3H]rauwolscine (Fig. 4), as would be expected since antagonists typically do not discriminate between the agonist high- and low-affinity states. Note that the correlation line is about 0.25 log units from the line of identity, while still having a slope near unity. In fact many compounds, including haloperidol, m-CPP, rauwolscine, ritanserin, spiroxatrine, yohimbine and 1-NP displayed significantly higher affinity for the [3H]rauwolscine than for the [3H]5-HT labeled human 5-HT2B receptor. measured against [3H]5-HT versus the pKi when mea-" SIGNOR-258687 TOMM6 protein Q96B49 UNIPROT "TOM40 complex" complex SIGNOR-C421 SIGNOR "form complex" binding 9606 BTO:0000567 18331822 t lperfetto "The fungal preprotein translocase of the mitochondrial outer membrane (TOM complex) comprises import receptors Tom70, Tom20, and Tom22, import channel Tom40, and small Tom proteins Tom5, Tom6, and Tom7, which regulate TOM complex assembly. These components are conserved in mammals; unlike the other components, however, Tom5 and Tom6 remain unidentified in mammals. We immuno-isolated the TOM complex from HeLa cells expressing hTom22-FLAG and identified the human counterparts of Tom5 and Tom6, together with the other components including Tom7. These small Tom proteins are associated with Tom40 in the TOM complex." SIGNOR-267676 MC5R protein P33032 UNIPROT GNAS protein Q5JWF2 UNIPROT "up-regulates activity" binding 9606 BTO:0000142 20371771 t lperfetto "The melanocortin (MC) receptor family consists of five Gs-coupled receptors that control various physiological functions in response to four distinct agonists, adrenocorticotropic hormone (ACTH, also known as corticotrophin) and alpha, beta, and gamma melanocyte-stimulating hormone (MSH), which are derived from the proopiomelanocortin precursor protein, and two inverse agonists, agouti and agouti-related proteins" SIGNOR-268712 INTS11 protein Q5TA45 UNIPROT "Integrator complex" complex SIGNOR-C265 SIGNOR "form complex" binding 7227 26220997 t lperfetto "Integrator is a metazoan-specific multisubunit, multifunctional protein complex composed of 14 subunits named Int1–Int14 (Integrator subunits) " SIGNOR-261462 "Ub:E1 (UBA6 substrate)" complex SIGNOR-C496 SIGNOR UBE2J2 protein Q8N2K1 UNIPROT "up-regulates activity" ubiquitination 9606 34199813 t miannu "The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t" SIGNOR-271373 MSH2 protein P43246 UNIPROT DNA_repair phenotype SIGNOR-PH57 SIGNOR "up-regulates activity" 10090 9500552 f "Germline mutations in the human MSH2, MLH1, PMS2 and PMS1 DNA mismatch repair (MMR) gene homologues appear to be responsible for most cases of hereditary non-polyposis colorectal cancer" SIGNOR-257594 NAT8L protein Q8N9F0 UNIPROT N-acetyl-L-aspartate(2-) smallmolecule CHEBI:16953 ChEBI "up-regulates quantity" "chemical modification" 9606 19524112 t miannu "The biosynthetic enzyme, aspartate-N-acetyltransferase (Asp-NAT; EC 2.3.1.17) is a CNS specific enzyme that catalyzes the transfer of acetate from acetyl-CoA to L-aspartate forming NAA." SIGNOR-267523 EIF3E protein P60228 UNIPROT PLAU protein P00749 UNIPROT "up-regulates quantity" "translation regulation" 9606 "BTO:0000815; BTO:0001938" 20453879 f irozzo "Validated mRNA targets regulated positively at the translational level by eIF3e included urokinase-type plasminogen activator and apoptotic regulator BCL-XL, whereas synthesis of proteins including the mitotic checkpoint component MAD2L1 was negatively regulated. Taken together, our study data suggest that eIF3e has a positive role in breast cancer progression." SIGNOR-259155 STK39 protein Q9UEW8 UNIPROT SLC12A1 protein Q13621 UNIPROT "up-regulates activity" phosphorylation Ser91 ASFHAYDsHTNTYYL 9606 BTO:0000007 21321328 t miannu "We establish that the SPAK and OSR1 kinases activated by WNK interact with an RFQV motif on NKCC2 and directly phosphorylate Thr95, Thr100, Thr105 and, possibly, Ser91. Our data indicate that a SPAK-OSR1-independent kinase, perhaps AMP-activated protein kinase (AMPK), phosphorylates Ser130 and that phosphorylation of Thr105 and Ser130 plays the most important roles in stimulating NKCC2 activity." SIGNOR-263130 JAK3 protein P52333 UNIPROT JAK3 protein P52333 UNIPROT up-regulates phosphorylation Tyr939 QICKGMEyLGSRRCV 9606 18250158 t lperfetto "Y904 and y939 are required for optimal jak3 autophosphorylation and kinase activity in vitro" SIGNOR-160668 PLK1 protein P53350 UNIPROT CENPQ protein Q7L2Z9 UNIPROT "down-regulates quantity by destabilization" phosphorylation Thr256 SQMKSMStFIEEAYK 9606 BTO:0000567 25670858 t lperfetto "Notably, although Plk1 did not alter the level of PBIP1 and CENP-Q ubiquitination, Plk1-dependent phosphorylation and delocalization of these proteins from kinetochores appeared to indirectly lead to their degradation in the cytosol. From these analyses, we identified nine CENP-Q residues (Thr-123, Thr-135, Ser-138, Ser-139, Ser-248, Ser-249, Ser-253, Ser-255, and Thr-256) that were phosphorylated in both in vitro and in vivo samples (Fig. 4B), suggesting that Plk1 phosphorylates these sites." SIGNOR-265229 Ub:E2 complex SIGNOR-C497 SIGNOR CHFR protein Q96EP1 UNIPROT "up-regulates activity" ubiquitination 9606 34199813 t miannu "The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t" SIGNOR-271061 NEUROD1 protein Q13562 UNIPROT MGAT5B protein Q3V5L5 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 BTO:0001976 21771782 f miannu "By EMSA and ChIP analyses we identified two regulatory proteins, NeuroD1 and CTCF that bind to and activate the GnT-IX promoter. We also revealed that GnT-IX expression was suppressed in CTCF- and NeuroD1-depleted cells, indicating that a NeuroD1- and CTCF-dependent epigenetic mechanism governs brain-specific GnT-IX expression." SIGNOR-253825 SMAD5 protein Q99717 UNIPROT SMAD5/SMAD4 complex SIGNOR-C205 SIGNOR "form complex" binding 9606 "BTO:0000165;BTO:0002974; BTO:0002809" 9442019 t ggiuliani "These data suggest that activation of Smad5 and subsequent Smad5-DPC4 complex formation are key steps in the BMP signaling pathway, which mediates BMP-2-induced osteoblastic differentiation of the C2C12 mesenchymal cells." SIGNOR-255775 CHEK2 protein O96017 UNIPROT CHEK2 protein O96017 UNIPROT "up-regulates activity" phosphorylation Ser516 PQVLAQPsTSRKRPR 9606 BTO:0002201 12855706 t lperfetto "Chk2 is also autophosphorylated following dna damage. It is proposed that autophosphorylation of chk2 may contribute to chk2 activation. To fully understand the regulation of chk2, we mapped an in vitro chk2 autophosphorylation site at c-terminal serine 516 site (ser-516). Ser-516 of chk2 is phosphorylated following radiation in vivo, and this phosphorylation depends on the kinase activity of chk2." SIGNOR-103544 BCL9 protein O00512 UNIPROT CTNNB1 protein P35222 UNIPROT up-regulates binding 9606 BTO:0000776 11955446 t amattioni "Bcl9 exert its function by physically linking pygo to beta-catenin. The recruitment of pygo permits beta-catenin to transcriptionally activate wnt target genes." SIGNOR-116552 INS protein P01308 UNIPROT APOB protein P04114 UNIPROT "down-regulates quantity by destabilization" 9606 23721961 f miannu "Insulin decreases ApoB secretion by promoting ApoB degradation in the hepatocyte. Though insulin does not alter ApoB mRNA levels, it inhibits ApoB translation by promoting the trafficking of ApoB mRNA into P-bodies, aggregates of translationally repressed mRNAs" SIGNOR-252114 MSH2 protein P43246 UNIPROT MSH2/MSH6 complex SIGNOR-C60 SIGNOR "form complex" binding 9606 15064730 t miannu "The human msh2/6 complex is essential for mismatch recognition during the repair of replication errors." SIGNOR-123702 EED protein O75530 UNIPROT SUZ12/EED complex SIGNOR-C76 SIGNOR "form complex" binding 9606 16712789 t miannu "Suz12 is a polycomb group protein that forms polycomb repressive complexes (prc2/3) together with eed and histone methyltransferase ezh2." SIGNOR-146755 miR221 mirna URS0000245997_9606 RNAcentral ZEB2 protein O60315 UNIPROT "down-regulates quantity by repression" destabilization 10090 26762731 t "We identified miR-143 as a regulator of the insulin growth factor-binding protein 5 (Igfbp5) in primary myoblasts and show that the expression of miR-143 and its target gene is disrupted in satellite cells from old mice." SIGNOR-255939 ZEB1 protein P37275 UNIPROT CDH1 protein P12830 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 15311212 f miannu "known E-cadherin transcriptional repressors, such as SLUG (SNAI2), SIP1 (ZEB2), TWIST1, SNAIL (SNAI1) and ZEB1 (TCF8), but not E12/E47 (TCF3), had a lack of upregulation in cells expressing mutated E-cadherin compared to WT." SIGNOR-255158 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR PCBP2 protein Q15366 UNIPROT "up-regulates quantity by stabilization" phosphorylation Ser173 MLETLSQsPPKGVTI 10090 BTO:0000664 17475908 t miannu "All together, these data indicate that ERK-dependent phosphorylation of hnRNP-E2 at serines 173, 189, and 272, and threonine 213 is responsible for increased hnRNP-E2 protein stability in BCR/ABL-transformed cells." SIGNOR-262668 "Ub:E1 (UBA1 substrate)" complex SIGNOR-C495 SIGNOR UBE2Q2 protein Q8WVN8 UNIPROT "up-regulates activity" ubiquitination 9606 34199813 t miannu "The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t" SIGNOR-271329 zotepine chemical CHEBI:32316 ChEBI HTR1B protein P28222 UNIPROT "down-regulates activity" "chemical inhibition" 10116 BTO:0001311 8935801 t miannu "Risperidone and its active metabolite 9-OH-risperidone were compared to reference antipsychotic drugs (haloperidol, pipamperone, fluspirilene, clozapine, zotepine) and compounds under development (olanzapine, seroquel, sertindole, ORG-5222, ziprasidone) for in vitro binding to neurotransmitter receptors in brain tissue and on membranes of recombinant cells expressing cloned human receptors and for in vivo occupancy of neurotransmitter receptors in rat and guinea-pig brain following acute treatment (2 h., s.c.). The binding affinities of the compounds for various neurotransmitter receptors were measured using membrane preparations of animal brain regions and of recombinant cells expressing cloned, mostly human receptors. Receptors, tissues and cells are indicated in Table I; results are shown in Table 4A-B." SIGNOR-258554 GRHL2 protein Q6ISB3 UNIPROT ZEB1 protein P37275 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0000150 23814079 f miannu "we could further demonstrate that expression of GRHL2 is directly suppressed by the transcription factor zinc finger enhancer-binding protein 1 (ZEB1), which in turn is a direct target for repression by GRHL2, suggesting that the EMT transcription factors GRHL2 and ZEB1 form a double negative regulatory feedback loop in breast cancer cells." SIGNOR-255624 DLK1 protein P80370 UNIPROT NOTCH1 protein P46531 UNIPROT "down-regulates activity" binding 10090 BTO:0002572 21419176 t gcesareni "Moreover, the interaction of DLK1 with NOTCH1 caused an inhibition of basal NOTCH signaling in preadipocytes and mesenchymal multipotent cells. In this work, we demonstrate, for the first time, that DLK2 interacts with itself, with DLK1, and with the same NOTCH1 receptor region as DLK1 does. We demonstrate also that the interaction of DLK2 with NOTCH1 similarly results in an inhibition of NOTCH signaling in preadipocytes and Mouse Embryo fibloblasts." SIGNOR-172830 PRKG1 protein Q13976 UNIPROT GABRR1 protein P24046 UNIPROT unknown phosphorylation Ser444 QRKSQRSsYVSMRID -1 12175859 t miannu "Here, we have identified phosphorylation sites on the human ρ1 GABA receptor for six protein kinases widely expressed in the brain: protein kinase C (PKC); cAMP‐dependent protein kinase (PKA); calmodulin‐dependent kinase (CaMKII); casein kinase (CKII); mitogen‐activated protein kinase (MAPK); and cGMP‐dependent protein kinase (PKG). The 1 IC-loop does not have consensus sequences for PKG, but we found that this enzyme phosphorylated the same sites as PKA: S422, S423 (Fig. 5A).An extensive functional analysis comparing wild type 1 receptors and receptors with select or multiple phosphorylation sites removed as well as pharmacological manipulation of five kinase pathways failed to reveal any functional effects of phosphorylation" SIGNOR-262757 PIAS1 protein O75925 UNIPROT FHL1 protein Q13642 UNIPROT down-regulates sumoylation Lys300 PRGPGLVkAPVWWPM 9606 17509614 t gcesareni "Pias1 (the protein inhibitor of activated stat1) interacts with kyot2 directly and attenuates kyot2-mediated transcriptional repression. We demonstrate that kyot2 is modified by sumoylation at two lysine residues, k144 and k171. Sumoylation of the transfected kyot2 is enhanced by pias1" SIGNOR-154805 RNF34 protein Q969K3 UNIPROT PPARGC1A protein Q9UBK2 UNIPROT "down-regulates quantity by destabilization" ubiquitination 26971449 t lperfetto "We then examined the effect of necdin on ubiquitin-dependent degradation of PGC-1α using Rnf34, a PGC-1α E3 ubiquitin ligase22. Rnf34 reduced the PGC-1α level, and necdin completely inhibited the reduction (Fig. 4i). In addition, necdin strongly suppressed Rnf34-mediated ubiquitination of PGC-1α (Fig. 4j). Necdin also protected PGC-1α against ubiquitination mediated by Fbxw7, another PGC-1α E3 ubiquitin ligase23 (Fig. 4k). These data indicate that necdin stabilizes PGC-1α by inhibiting its degradation in the ubiquitin-proteasomal system." SIGNOR-253393 CSNK2B protein P67870 UNIPROT CTNNB1 protein P35222 UNIPROT "up-regulates activity" phosphorylation Thr112 EGMQIPStQFDAAHP 9606 12432063 t llicata "We show that CKII phosphorylates the N-terminal region of beta-catenin and we identified Ser29, Thr102, and Thr112 as substrates for the enzyme. We provide evidence that CKII regulates the cytoplasmic stability of beta-catenin and acts synergistically with GSK-3beta in the multi-protein complex that controls the degradation of beta-catenin" SIGNOR-251067 LAMTOR5 protein O43504 UNIPROT LAMTOR complex SIGNOR-C26 SIGNOR "form complex" binding 9606 20381137 t lperfetto "Mammals express four rag proteinsRaga, ragb, ragc, and ragdthat form heterodimers consisting of raga or ragb with ragc or ragd. Raga and ragb, like ragc and ragd, are highly similar to each other and are functionally redundant" SIGNOR-164781 RASGEF1B protein Q0VAM2 UNIPROT NRAS protein P01111 UNIPROT up-regulates binding 9606 19201597 t gcesareni "Gefs catalyse the transition from gdp-bound, inactive ras to gtp-bound, active ras." SIGNOR-161481 MAPK3 protein P27361 UNIPROT SMAD2 protein Q15796 UNIPROT up-regulates phosphorylation Ser250 TGSPAELsPTTLSPV 9606 BTO:0000763;BTO:0000149 10197981 t gcesareni "These results suggest that oncogenic ras, acting through mek1 and erk kinases, induces the phosphorylation of smad2 and smad3 .we show that phosphorylation of smad2, a mediator of the activin/transforming growth factor-beta signal, by activated extracellular signal-regulated kinase 1 (erk1) increases the amount of smad2 protein and leads to enhanced transcriptional activity" SIGNOR-66763 KCNQ2 protein O43526 UNIPROT potassium(1+) smallmolecule CHEBI:29103 ChEBI "up-regulates quantity" relocalization 9606 19298256 t miannu "KCNQ genes encode five Kv7 K+ channel subunits (Kv7.1–Kv7.5). Four of these (Kv7.2–Kv7.5) are expressed in the nervous system. Kv7.2 and Kv7.3 are the principal molecular components of the slow voltage-gated M-channel, which widely regulates neuronal excitability, although other subunits may contribute to M-like currents in some locations." SIGNOR-265982 EREG protein O14944 UNIPROT EGFR protein P00533 UNIPROT up-regulates binding 9606 BTO:0001253 20513444 t "Epiregulin may be a mediator of localized cell proliferation" gcesareni "Remarkably, three members of the epidermal growth factor (egf) family (ereg, areg, and epgn) showed increased expression that was associated with elevated epidermal activation of the egf receptor (egfr) and stat3, a downstream effector of egfr signaling." SIGNOR-165782 ATP7A protein Q04656 UNIPROT copper(1+) smallmolecule CHEBI:49552 ChEBI "up-regulates quantity" relocalization 28389643 t lperfetto "Menkes disease (MD) is caused by mutations in ATP7A, encoding a copper- transporting P-type ATPase which exhibits copper-dependent trafficking. ATP7A is found in the Trans-Golgi Network (TGN) at low copper concentrations, and in the post-Golgi compartments and the plasma membrane at higher concentrations. " SIGNOR-272298 "CKM complex" complex SIGNOR-C406 SIGNOR SMAD3 protein P84022 UNIPROT "down-regulates quantity by destabilization" phosphorylation Thr179 PQSNIPEtPPPGYLS 9606 19914161 t lpetrilli "Similarly, tgf-?-Induced and cdk8/9-mediated phosphorylation of smad3 at threonine 179 (t179) is important for binding of the nedd4l e3 ubiquitin ligase, which accelerates smad3 turnover;cdk8 and cyclint-cdk9 showed a preference for s206 and s214 but also phosphorylated s186 and s195 in the case of smad1;and t179, s208 and s213 in the case of smad3." SIGNOR-273142 COPS4 protein Q9BT78 UNIPROT "COP9 signalosome variant 1" complex SIGNOR-C489 SIGNOR "form complex" binding 9606 18850735 t miannu "The COP9 signalosome (CSN) is a multiprotein complex that plays a critical role in diverse cellular and developmental processes in various eukaryotic organisms. we have performed a comprehensive proteomic analysis of the human CSN complex using a new purification method and quantitative mass spectrometry. Purification of the human CSN complex from a stable 293 cell line expressing N-terminal HBTH-tagged CSN5 subunit was achieved by high-affinity streptavidin binding with TEV cleavage elution." SIGNOR-270773 MAFA protein Q8NHW3 UNIPROT PC protein P11498 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 17149590 f miannu "the expression of important beta cell genes, e.g. those encoding solute carrier family 2 (facilitated glucose transporter), member 2 (formerly known as GLUT2), pancreatic and duodenal homeobox factor 1 (PDX1), NK6 transcription factor-related, locus 1 (NKX6-1), glucagon-like peptide 1 receptor (GLP1R), prohormone convertase 1/3 (PCSK1) and pyruvate carboxylase (PC), was regulated positively by MAFA and negatively by DN-MAFA." SIGNOR-254561 SMAD3/SMAD4 complex SIGNOR-C9 SIGNOR CDKN2B protein P42772 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 11013220 f irozzo "Our data demonstrate the physical interactions and functional cooperativity of Sp1 with a complex of Smad2, Smad3 and Smad4 in the induction of the p15Ink4B gene. These findings explain the tumor suppressor roles of Smad2 and Smad4 in growth arrest signaling by TGF-β." SIGNOR-256286 SRC protein P12931 UNIPROT STAP2 protein Q9UGK3 UNIPROT "up-regulates activity" phosphorylation Tyr322 GDGPAVDyENQDVAS 9606 12540842 t lperfetto "To examine this possibility, STAP-2 was co-transfected with constitutively active tyrosine kinases in HEK-293 cells. STAP-2 was strongly phosphorylated by various tyrosine kinases, including v-Src (Fig.2 A-a), a JAK2 tyrosine kinase Tyr-22 and Tyr-322 are the major tyrosine phosphorylation sites by v-Src." SIGNOR-247337 PAXIP1 protein Q6ZW49 UNIPROT PAX2 protein Q02962 UNIPROT "up-regulates activity" binding 9606 BTO:0000007 17925232 t "PTIP promotes assembly of the ALR complex and H3K4 methylation at a PAX2-binding DNA element. Without PTIP, Pax2 binds to this element but does not assemble the ALR complex" SIGNOR-251711 Ub:E2 complex SIGNOR-C497 SIGNOR SMURF1 protein Q9HCE7 UNIPROT "up-regulates activity" ubiquitination 9606 34199813 t miannu "The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t" SIGNOR-271290 glyburide chemical CHEBI:5441 ChEBI CFTR protein P13569 UNIPROT "down-regulates activity" "chemical inhibition" 10090 BTO:0000944 1281220 t miannu "The sulfonylureas, tolbutamide and glibenclamide, inhibited whole-cell CFTR Cl- currents at half-maximal concentrations of approximately 150 and 20 microM, respectively." SIGNOR-258344 GABRG2 protein P18507 UNIPROT "GABA-A (a1-b1-g2) receptor" complex SIGNOR-C330 SIGNOR "form complex" binding 9606 BTO:0000227 18790874 t "brain, See table 3 for identified complexes" lperfetto "The assembly of GABAA-R as heteropentamers produces complex subtype heterogeneity in structure, which is the major determinant of their pharmacological profile.|Evidence is greatly in favor of a pentameric receptor and most GABAA-R subtypes are formed from two copies of a single alpha, two copies of a single beta, and one copy of another subunit, such as gamma, delta, or epsilon." SIGNOR-263752 MAPK3 protein P27361 UNIPROT MED1 protein Q15648 UNIPROT up-regulates phosphorylation Thr1032 SSSNRPFtPPTSTGG 9606 12356758 t lperfetto "Phosphorylation of transcriptional coactivator peroxisome proliferator-activated receptor (ppar)-binding protein (pbp). Stimulation of transcriptional regulation by mitogen-activated protein kinase" SIGNOR-93989 UBE2D1 protein P51668 UNIPROT TRIM2 protein Q9C040 UNIPROT "up-regulates activity" binding 9606 BTO:0000567 18687884 t miannu "Here, we show that TRIM RING finger protein TRIM2, highly expressed in the nervous system, is an UbcH5a-dependent ubiquitin ligase. We further demonstrate that TRIM2 binds to neurofilament light subunit (NF-L) and regulates NF-L ubiquitination. Together, our results indicate that TRIM2 is an ubiquitin ligase that binds to and ubiquitinates NF-L and that TRIM2 deficiency leads to neurodegeneration in mice likely by altering NF-L metabolism with consequent NF-L accumulation in axons and impairment of axonal transport." SIGNOR-271775 "CKM complex" complex SIGNOR-C406 SIGNOR SMAD1 protein Q15797 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser206 SSSTYPHsPTSSDPG 9606 19914161 t lpetrilli "Phosphorylation of the linker region of smad1, a receptor-activated smad (r-smad), at serine 206 (s206) and s214 induced by bmp and mediated by cdk8/9 is critical for binding of the e3 ubiquitin ligase smurf1. Binding of smurf1 leads to polyubiquitination of smad1 and its degradation by the proteasome;cdk8 and cyclint-cdk9 showed a preference for s206 and s214 but also phosphorylated s186 and s195 in the case of smad1;and t179, s208 and s213 in the case of smad3." SIGNOR-273144 "CKM complex" complex SIGNOR-C406 SIGNOR SMAD1 protein Q15797 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser187 NSHPFPHsPNSSYPN 9606 19914161 t lpetrilli "Phosphorylation of the linker region of smad1, a receptor-activated smad (r-smad), at serine 206 (s206) and s214 induced by bmp and mediated by cdk8/9 is critical for binding of the e3 ubiquitin ligase smurf1. Binding of smurf1 leads to polyubiquitination of smad1 and its degradation by the proteasome;cdk8 and cyclint-cdk9 showed a preference for s206 and s214 but also phosphorylated s186 and s195 in the case of smad1;and t179, s208 and s213 in the case of smad3." SIGNOR-273145 "Neuronal AP-3" complex SIGNOR-C445 SIGNOR Platelet_dense_granule_formation phenotype SIGNOR-PH181 SIGNOR up-regulates 9606 BTO:0000132 12019270 f miannu "BLOC-1, a novel complex containing the pallidin and muted proteins involved in the biogenesis of melanosomes and platelet-dense granules|Interestingly, immunofluorescence and in vitro binding experiments demonstrated that pallidin/BLOC-1 is able to associate with actin filaments. We propose that BLOC-1 mediates the biogenesis of lysosome-related organelles by a mechanism that may involve self-assembly and interaction with the actin cytoskeleton." SIGNOR-268523 GHSR protein Q92847 UNIPROT GNAI1 protein P63096 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257054 SPOP protein O43791 UNIPROT "Cullin 3-RBX1-Skp1" complex SIGNOR-C526 SIGNOR "up-regulates activity" binding 9606 BTO:0000007 15897469 t miannu "Here, we describe an E3 ubiquitin ligase consisting of SPOP and CULLIN3 that is able to ubiquitinate the PcG protein BMI1 and the variant histone MACROH2A1. To investigate whether BMI1 can form a complex with SPOP and CULLIN3 in vivo, we reconstituted the complex in 293HEK cells. We find that BMI1 readily immunoprecipitates both hemagglutinin (HA)-SPOP and CULLIN3, and, conversely, CULLIN3 immunoprecipitates BMI1 (Fig. 2a). Complex formation depends on the presence of SPOP, in accordance with BMI1 binding to the MATH domain of SPOP (Fig. 1b) and previously published data showing SPOP–CULLIN interaction by means of the BTB/POZ domain of SPOP (30)." SIGNOR-272659 HSP90AA1 protein P07900 UNIPROT TGFBR1 protein P36897 UNIPROT up-regulates binding 9606 18591668 t lpetrilli "The data in fig. 5 suggest that hsp90 specifically interacts with t?RI And t?RII In vitro and in vivo. Coupled with our data showing that loss of hsp90 function decreases t?R Levels and blocks tgf?-Induced smad2/3 activation and transcription, this result suggests that hsp90 controls tgf? Signaling as an essential component for stabilizing t?Rs." SIGNOR-179268 MGluR proteinfamily SIGNOR-PF55 SIGNOR calcium(2+) smallmolecule CHEBI:29108 ChEBI "up-regulates quantity" relocalization 9606 29953871 t miannu "Ca2+ is arguably the most important second messenger in the brain because of its pivotal roles in presynaptic neurotransmitter release, postsynaptic responses, and plasticity induction. iGluRs and mGluRs can generate intracellular Ca2+ signals, albeit by different mechanisms, whose crosstalk has not been thoroughly explored (Figure 2C). iGluRs allow the influx of extracellular Ca2+ upon pore opening." SIGNOR-264930 PTPN1 protein P18031 UNIPROT ROS1 protein P08922 UNIPROT down-regulates dephosphorylation Tyr2115 DIYKNDYyRKRGEGL 9606 17416557 t gcesareni "In an approach to gain insight into the sequence-dependent dephosphorylation of multiple phosphotyrosyl-containing peptides by the phosphatases shp-1 and ptp1b, we applied a chromatographic technique for the analysis of the dephosphorylation products." SIGNOR-154207 CAMK2A protein Q9UQM7 UNIPROT FBXO43 protein Q4G163 UNIPROT "up-regulates activity" phosphorylation Ser192 NLEKNIPsSASGFSR -1 16407128 t Manara "CaMKII and polo-like kinase 1 sequentially phosphorylate the cytostatic factor Emi2/XErp1 to trigger its destruction and meiotic exit. | these results implicate the 192RSST motif of Emi2 as a critical molecular target of CaMKII during CSF release" SIGNOR-260907 BMPR1A protein P36894 UNIPROT SMAD1 protein Q15797 UNIPROT up-regulates phosphorylation 9606 19620713 t gcesareni "Two types of bmp-induced signaling pathways are known, the smad and p38 mapk pathways. In the former case, bmpr1 phosphorylates smad-1,-5,-8, which forms a complex with smad4 that translocates into the nucleus and regulates gene expression." SIGNOR-187181 "glutamic acid" smallmolecule CHEBI:18237 ChEBI GRM5 protein P41594 UNIPROT "up-regulates activity" "chemical activation" 9606 25042998 t miannu "Metabotropic glutamate receptors are class C G-protein-coupled receptors which respond to the neurotransmitter glutamate" SIGNOR-264070 CXCL1 protein P09341 UNIPROT PLCE1 protein Q9P212 UNIPROT up-regulates binding 9606 17251915 t gcesareni "In the non-canonical wnt pathway, frizzled uses galfaq or galfai and gbetagamma dimers to activate phospholipase c (plc), resulting in protein kinase c (pkc) activation and calcium mobilization that regulates the transcription factor nfat, and frizzled also signals through the small gtpases rho and rac to c-jun n-terminal kinase (jnk), which activates the ap1 transcription factor." SIGNOR-152591 N-[3-[[5-iodo-4-[3-[[oxo(thiophen-2-yl)methyl]amino]propylamino]-2-pyrimidinyl]amino]phenyl]-1-pyrrolidinecarboxamide chemical CHEBI:91439 ChEBI TBK1 protein Q9UHD2 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-190795 "Neurokinin B" smallmolecule CHEBI:80312 ChEBI TACR3 protein P29371 UNIPROT "up-regulates activity" "chemical activation" 9606 BTO:0002524 31160049 t "Ligand-GPCR dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257588 Raltegravir chemical CID:54671008 PUBCHEM UGT1A1 protein P22309 UNIPROT "down-regulates activity" "chemical inhibition" 9606 21030469 t Luana "Fourteen of the compounds studied inhibited both bilirubin and estradiol glucuronidation (Table 1). Among these 14 compounds, ritonavir, anthraflavic acid, levothyroxine, riluzole, baicalein, farnesol, 4′-OH-phenytoin, 4-methylumbelliferone, raltegravir, and 1-naphthol exhibited very similar IC50 values (differences less than 2-fold) on both bilirubin glucuronidation and estradiol-3-glucuronidation (Table 1). Ketoconazole, carvedilol, and niflumic acid exhibited more disparity with respect to inhibition of the two reactions in that these compounds exhibited at least a 2-fold higher IC50 value against bilirubin glucuronidation than against estradiol-3-glucuronidation. SN-38 only weakly inhibited bilirubin glucuronidation (IC50 = 356 μM) and seemed to be a partial inhibitor of estradiol-3-glucuronidation." SIGNOR-258162 (R)-(+)-sulpiride chemical CHEBI:64122 ChEBI DRD2 protein P14416 UNIPROT "down-regulates activity" "chemical inhibition" 10029 8301582 t miannu "The most selective compound from this group were (+)butaclamol and domperidone which showed 5-fold D3 selectivity. A number of high affinity dopamine receptor agonists, including apomorphine and bromocriptine, also failed to demonstrate selectivity. In contrast, the natural ligand dopamine and the efficacious synthetic agonists quinpirole, (+)4-propyl-9-hydroxynapthoxazine (PHNO), 2-amino-6,7-dihydroxy-1,2,3,4-tetrahydronaphthalene (6,7-ADTN), 7-OH DPAT and N-0434 showed marked apparent human dopamine D3 (hD3) receptor selectivity. In the aminotetralin series, this selectivity was observed preferentially with analogs of the 6,7-rotamer compared with compounds from the 5,6-rotamer series. Functional coupling of the hD3 receptor was investigated in a number of cell lines in which the hD3 receptor was stably expressed, including CHO cells, the neuroblastoma-glioma hybrid cell line NG108-15 and a rat 1 fibroblast cell line." SIGNOR-258735 "propionic acid" chemical CHEBI:30768 ChEBI FFAR2 protein O15552 UNIPROT "up-regulates activity" "chemical activation" 9606 BTO:0002524 31160049 t "Ligand-GPCR dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257489 L-thyroxine smallmolecule CHEBI:18332 ChEBI 3,3',5'-triiodothyronine smallmolecule CHEBI:28774 ChEBI "up-regulates quantity" "precursor of" 9606 1400883 t scontino "The type I 5' iodothyronine deiodinase (5' DI) catalyzes the deiodination of T4 to the biologically active hormone T3 and accounts for a significant fraction of its production." SIGNOR-266943 PRKCB protein P05771 UNIPROT PSEN1 protein P49768 UNIPROT "up-regulates activity" phosphorylation Ser346 EWEAQRDsHLGPHRS 9606 14576165 t lperfetto "A phosphorylation site at serine residue 346 was identified that is selectively phosphorylated by PKC but not by PKA. This site is localized within a recognition motif for caspases, and phosphorylation strongly inhibits proteolytic processing of PS1 by caspase activity during apoptosis." SIGNOR-249237 IL1A protein P01583 UNIPROT SERPINA3 protein P01011 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0002600 11027208 f miannu "We characterize a molecular mechanism responsible for both IL-1 and TNF-induced expression of ACT gene in astrocytes. We identify the 5' distal IL-1/TNF-responsive enhancer of the ACT gene located 13 kb upstream of the transcription start site. This 413-bp-long enhancer contains three elements, two of which bind nuclear factor kB (NF-kB) and one that binds activating protein 1 (AP-1). All of these elements contribute to the full responsiveness of the ACT gene to both cytokines, as determined by deletion and mutational analysis. The 5' NF-kB high-affinity binding site and AP-1 element contribute most to the enhancement of gene transcription in response to TNF and IL-1." SIGNOR-254807 CDK1 protein P06493 UNIPROT KRT8 protein P05787 UNIPROT up-regulates phosphorylation Ser432 SAYGGLTsPGLSYSL 9606 9524113 t lperfetto "With regard to k8 phosphorylation at ser-431, it increases dramatically upon stimulation of cells with epidermal growth factor (egf) or after mitotic arrest and is the major k8 phosphorylated residue after incubating k8 immunoprecipitates with mitogen-activated protein or cdc2 kinases." SIGNOR-56054 CyclinA2/CDK2 complex SIGNOR-C83 SIGNOR CABLES1 protein Q8TDN4 UNIPROT unknown phosphorylation Ser273 PGQGGSTsAFEQLQR -1 11733001 t llicata "Here, we report that Ser274 of p70ik3-1 is phosphorylated by cdk2 or cdk3 bound to cyclin A and to cyclin E in vitro. We also found that in COS7 cells in which cyclin E and cdk3 were ectopically overexpressed, the phosphorylation level of Ser274 in coexpressed p70ik3-1 is upregulated. We therefore conclude that p70ik3-1 is a substrate for cdk3-mediated phosphorylation." SIGNOR-250756 LCK protein P06239 UNIPROT IL2RB protein P14784 UNIPROT unknown phosphorylation Tyr418 LSGEDDAyCTFPSRD -1 10214954 t "Recombinant p56(lck) phosphorylates in vitro tyrosine residues within the IL-2Rbeta chain. p56(lck) phosphorylates tyrosine residues 355, 358 and 361 but not 338 of the IL-2Rbeta chain acidic subdomain. p56(lck) also phosphorylates very efficiently the two tyrosines present in the IL-2Rbeta chain C-terminal region, Tyr-392 and Tyr-510." SIGNOR-251378 MAPK14 protein Q16539 UNIPROT ATF2 protein P15336 UNIPROT up-regulates phosphorylation Thr71 IVADQTPtPTRFLKN 9606 10085140 t gcesareni "On the other hand, sapks such as jnks and p38 phosphorylate atf-2 at thr-69, thr-71, and ser-90 which lie close to the n-terminal transcriptional activation domain and stimulate itstrans-activating capacity our results indicate that atf-2 not only directly binds to smad3/4 hetero-oligomers but also that atf-2 is phosphorylated by tgf- signaling via tak1 and p38." SIGNOR-65601 MRPS23 protein Q9Y3D9 UNIPROT "28S mitochondrial small ribosomal subunit" complex SIGNOR-C266 SIGNOR "form complex" binding 9606 25838379 t miannu "The mammalian mitochondrial ribosome (mitoribosome) has a highly protein-rich composition with a small sedimentation coefficient of 55 S, consisting of 39 S large and 28 S small subunits. . We report here the identification of 28 S small subunit proteins." SIGNOR-261435 GP9 protein P14770 UNIPROT "GPIb-IX-V complex" complex SIGNOR-C270 SIGNOR "form complex" binding 9606 16293600 t lperfetto "The GPIb-V-IX receptor consists of 4 transmembrane subunits: GPIbalpha, disulfide-linked to GPIbbeta, and the noncovalently associated GPIX and GPV components, in ratios of 2:2:2:1." SIGNOR-261848 NMBR protein P28336 UNIPROT GNAQ protein P50148 UNIPROT "up-regulates activity" binding 9606 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257373 "GABA-A (a6-b2-d) receptor" complex SIGNOR-C328 SIGNOR CRHR2 protein Q13324 UNIPROT down-regulates 9606 BTO:0000614 33536967 f lperfetto "OT inhibits corticotropin-releasing factor (CRF) mRNA expression at the hypothalamus, resulting in antistress and anti-anxiety effects| It has been demonstrated that the inhibitory effect of OT on CRF mRNA expression is not a direct one on CRF neurons. GABAergic neurons are present in the surroundings of the PVN (peri-PVN). These GABA-projecting neurons into the PVN inhibits CRF expression via GABAA receptors" SIGNOR-268597 KAT2B protein Q92831 UNIPROT H3-2 protein Q5TEC6 UNIPROT "down-regulates activity" acetylation Lys15 ARKSTGGkAPRKQLA 9606 SIGNOR-C465 34811519 t "Acetlyation of H3 causes transcriptional activation, thus has an inhibitory role on H3" lperfetto "The HAT module within the SAGA and ADA complexes acetylates histone H3, mainly on residues K9 and K14." SIGNOR-269624 MECP2 protein P51608 UNIPROT CRH protein P06850 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 10090 BTO:0000142 17108082 t Luana "Collectively, these results point to a specific association between WT MeCP2 and the methylated promoter region of Crh in vivo. In contrast, the MeCP2308 protein was not detected at the Crh promoter. | Thus, the results of seqChIP indicate that MeCP2 preferentially associates with a transcriptionally inactive, dimethyl-histone H3 Lys-9-rich form of the Crh promoter in mice." SIGNOR-264548 CSNK2A2 protein P19784 UNIPROT SET protein Q01105-2 UNIPROT down-regulates phosphorylation Ser9 SAPAAKVsKKELNSN 9606 23374587 t "The effect has been demonstrated using Q01105-2" miannu "Ckii-mediated phosphorylation at ser9 hinders nuclear import of set" SIGNOR-200802 SIM2 protein Q14190 UNIPROT ARNT protein P27540 UNIPROT "up-regulates activity" binding -1 9020169 t 2 miannu "We demonstrate that both SIM1 and SIM2 can heterodimerize via their helix-loop-helix·PAS regions with ARNT, but not with AHR, and that they do not form homodimers. Furthermore, SIM1 may have a dual role, both negatively affecting AHR·ARNT binding to the XRE and also acting in concert with ARNT as a novel DNA-binding heterodimer." SIGNOR-240808 WIPF1 protein O43516 UNIPROT Endocytosis phenotype SIGNOR-PH123 SIGNOR up-regulates 9606 19121306 f lperfetto "However, we did detect WAFL binding to bothWIP and actin by immunoprecipitation (Fig. 4). In conclusion, we propose a model whereby WAFL associates toendocytic vesicles by its coiled-coil domain and is involved in actin-based movement of early endosomes via WIP and binding to actin." SIGNOR-260609 AKT proteinfamily SIGNOR-PF24 SIGNOR PPARGC1A protein Q9UBK2 UNIPROT "down-regulates activity" phosphorylation Ser571 RMRSRSRsFSRHRSC 9606 BTO:0000759 17554339 t lperfetto "Here we describe a mechanism by which insulin, through the intermediary protein kinase akt2/protein kinase b (pkb)-beta, elicits the phosphorylation and inhibition of the transcriptional coactivator peroxisome proliferator-activated receptor-coactivator 1alpha (pgc-1alpha), a global regulator of hepatic metabolism during fasting / phosphorylation of pgc-1alpha At ser570 Is required for akt to inhibit recruitment of pgc-1alpha To chromatin." SIGNOR-155532 H2BC11 protein P06899 UNIPROT "Nucleosome_H3.1 variant" complex SIGNOR-C324 SIGNOR "form complex" binding -1 21812398 t miannu "The elemental repeating unit of chromatin is the nucleosome core particle (NCP), which consists of 146 base pairs of DNA wrapped in 1.65 left-handed superhelical turns around the histone octamer. The histone octamer comprises two each of the core histones, H2A, H2B, H3 and H4, which form two H2A/H2B dimers and an H3/H4 tetramer, respectively, in the NCP." SIGNOR-263720 PHA-767491 chemical CID:11715767 PUBCHEM CDK9 protein P50750 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-206115 PRKAA1 protein Q13131 UNIPROT HDAC7 protein Q8WUI4 UNIPROT down-regulates phosphorylation Ser155 FPLRKTVsEPNLKLR 9606 SIGNOR-C15 21892142 t gcesareni "Another recently described set of transcriptional regulators targeted by ampk and its related family members across a range of eukaryotes are the class iia family of histone deacetylases (hdacs)." SIGNOR-176487 UBE2I protein P63279 UNIPROT PLAG1 protein Q6DJT9 UNIPROT down-regulates sumoylation Lys263 CNVSVPIkDELLPVM 9606 15208321 t miannu "Sumoylation decreases the transcriptional activity of plag1 / plag1 is sumoylated at 2 specific lysine residues (lys-244 and lys-263)" SIGNOR-126048 CyclinE/CDK2 complex SIGNOR-C16 SIGNOR PRKAR1A protein P10644 UNIPROT up-regulates phosphorylation Ser83 DSREDEIsPPPPNPV 9606 BTO:0000093 16582606 t lperfetto "In this context, we have identified rialpha as a novel substrate for the g(1)/s-cyclin-dependent kinase, cdk2/cyclin e, and found that rialpha is specifically phosphorylated at the serine residue." SIGNOR-216729 PTGER1 protein P34995 UNIPROT GNAS protein Q5JWF2 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-256811 TRIM63 protein Q969Q1 UNIPROT PSMD4 protein P55036 UNIPROT "down-regulates quantity by destabilization" polyubiquitination Lys365 SLASQATkDGKKDKK -1 19240029 t miannu "S5a/Rpn10 is a ubiquitin (Ub)-binding protein that is a subunit of the 26S proteasome but also exists free in the cytosol. It binds poly-Ub chains through its two Ub-interacting motifs (UIMs). We discovered that, unlike typical substrates of Ub ligases (E3s), S5a can be ubiquitinated by all E3s tested including multimeric and monomeric Ring finger E3s (MuRF1, Siah2, Parkin, APC, and SCF(betaTRCP1)), the U-box E3, CHIP, and HECT domain E3s (E6AP and Nedd4) when assayed with UbcH5 or related Ub-conjugating enzymes.The short half-life of S5a presumably is because of the presence of the UIM domain and reflects the ubiquitination of free S5a by many E3s. Surprisingly, the same four Lys residues on S5a, Lys-74, Lys-122, Lys-262, and Lys-365 were ubiquitinated by MuRF1 and E6AP (Fig. 10)." SIGNOR-272741 TBX2 protein Q13207 UNIPROT Skeletal_muscle_differentiation phenotype SIGNOR-PH1 SIGNOR down-regulates 9606 24470334 f "TBX2 blocks myogenesis and promotes proliferation in rhabdomyosarcoma cells" SIGNOR-251563 calcium(2+) smallmolecule CHEBI:29108 ChEBI KCNMA1 protein Q12791 UNIPROT "up-regulates activity" "chemical activation" 9606 BTO:0000938 31152168 t miannu "The large-conductance Ca2+- and voltage-activated K+ (BK) channel is a tetramer consisting of four α-subunits encoded by the KCNMA1 gene on chromosome 10q22.3. The BK channel can be allosterically activated by both changes in the membrane voltage (voltage-dependent activation pathway) and intracellular [Ca2+] concentration (calcium-dependent activation pathway)" SIGNOR-269199 ESR1 protein P03372 UNIPROT SCN9A protein Q15858 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 10090 BTO:0000938 BTO:0001264 22169964 f miannu "17β-Estradiol regulates the gene expression of voltage-gated sodium channels. . In this study, we investigate the mRNA expressions of Nav channel subtypes mediated differentially by the ERs in the DRGs of wild-type (WT) and estrogen receptor knockout (αERKO and βERKO) mice. In the present study, by means of quantitative real-time PCR, we found that the expressions of Nav1.1, Nav1.7, Nav1.8, and Nav1.9 subtypes were elevated in αERKO and βERKO mice" SIGNOR-253469 EGFR protein P00533 UNIPROT GAB1 protein Q13480 UNIPROT "up-regulates activity" phosphorylation Tyr307 MRHVSISyDIPPTPG -1 10734310 t lperfetto "Gab1 is also phosphorylated in response to epidermal growth factor (egf) but is unable to induce tubule formation. nine tyrosines are phosphorylated by both receptors. Three of them (y307, y373, y407) bind phospholipase c-gamma (plc-gamma)." SIGNOR-233233 CDK1 protein P06493 UNIPROT BCL2L11 protein O43521 UNIPROT "up-regulates activity" phosphorylation Ser104 FSFDTDRsPAPMSCD 9606 22071694 t lperfetto "Furthermore, active recombinant Cdk1/cyclin B1 phosphorylates BimEL and BimL in vitro and Serine 44 on BimL has been identified as a Cdk1 phosphorylation site. Collectively, these results suggest that Cdk1/cyclin B1-dependent hyper-phosphorylation of Bim during prolonged mitotic arrest is an important cell death signal." SIGNOR-267985 4E2RCat chemical CID:2287236 PUBCHEM EIF4E protein P06730 UNIPROT "down-regulates activity" "chemical inhibition" 9606 BTO:0000414 21507972 t miannu "Characterization of 4E2RCat, an inhibitor of eIF4E-eIF4G interaction. Herein we describe a molecule from this screen that prevents the interaction between eIF4E (the cap-binding protein) and eIF4G (a large scaffolding protein), inhibiting cap-dependent translation. This inhibitor significantly decreased human coronavirus 229E (HCoV-229E) replication, reducing the percentage of infected cells and intra- and extracellular infectious virus titers." SIGNOR-260187 MAPK3 protein P27361 UNIPROT POLR2A protein P24928 UNIPROT down-regulates phosphorylation Ser1675 SPSYSPTsPSYSPTS 9606 14662762 t lperfetto "Erk1/2 are major ser-5 kinases after h2o2 treatment. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination." SIGNOR-120192 EPHB2 protein P29323 UNIPROT RASA1 protein P20936 UNIPROT up-regulates binding 9606 9233798 t gcesareni "We have localized an in vitro rasgap-binding site to conserved tyrosine residues y604 and y610 in the juxtamembrane region of ephb2, and demonstrated that substitution of these amino acids abolishes ephrin-b1-induced signalling events in ephb2-expressing ng108-15 cells." SIGNOR-50100 Ub:E2 complex SIGNOR-C497 SIGNOR MKRN3 protein Q13064 UNIPROT "up-regulates activity" ubiquitination 9606 34199813 t miannu "The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t" SIGNOR-271132 MAPK1 protein P28482 UNIPROT TNKS1BP1 protein Q9C0C2 UNIPROT unknown phosphorylation Thr1032 GGLFSPStAHVPDGA 10090 BTO:0000944 22028470 t miannu "We have optimized a chemical genetic system using analog-sensitive ERK2, a form of ERK2 engineered to use an analog of adenosine 5'-triphosphate (ATP), to tag and isolate ERK2 substrates in vitro. This approach identified 80 proteins phosphorylated by ERK2, 13 of which are known ERK2 substrates. With this improved methodology, we detected 98 sites directly phosphorylated by ERK2 on 80 proteins from NIH 3T3-L1 fibroblasts. Thirteen of these proteins are known substrates and the rest represent previously unknown kinase/substrate interactions. (table1)" SIGNOR-262781 "Melanin-concentrating hormone" smallmolecule CHEBI:80254 ChEBI MCHR1 protein Q99705 UNIPROT "up-regulates activity" "chemical activation" 9606 BTO:0002524 31160049 t "Ligand-GPCR dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257540 PABPC3 protein Q9H361 UNIPROT "messenger RNA" smallmolecule CHEBI:33699 ChEBI "up-regulates quantity by stabilization" binding 9606 25480299 t lperfetto "As poly(A)+ mRNAs are associated with poly(A) binding protein (PABP) in cells|his result suggests that PABPC1 binds preferentially to long poly(A) tails and protects them from TUT4/7 and thereby enhances the selectivity of uridylation according to poly(A) tail length." SIGNOR-268321 ITGB2 protein P05107 UNIPROT "Av/b2 integrin" complex SIGNOR-C176 SIGNOR "form complex" binding 16988024 t lperfetto "Integrins are one of the major families of cell adhesion receptors (Humphries, 2000; Hynes, 2002). All integrins are non-covalently-linked, heterodimeric molecules containing an α and a β subunit. Both subunits are type I transmembrane proteins, containing large extracellular domains and mostly short cytoplasmic domains (Springer and Wang, 2004; Arnaout et al., 2005). Mammalian genomes contain 18 α subunit and 8 β subunit genes, and to date 24 different α,β combinations have been identified at the protein level. Although some subunits only appear in a single heterodimer, twelve integrins contain the β1 subunit, and five contain αV." SIGNOR-253204 CDT1 protein Q9H211 UNIPROT CDT1 protein Q9H211 UNIPROT "up-regulates activity" binding 9606 BTO:0000007 14672932 t "We further show that Cdc6 physically associates with Cdt1 via its N-terminal noncatalytic domain, a region we had previously shown to be essential for Cdc6 function." SIGNOR-261682 TGFBI protein Q15582 UNIPROT "a7/b1 integrin" complex SIGNOR-C126 SIGNOR "up-regulates activity" binding 26387839 t lperfetto "BIGH3 binds molecules of the ECM, including fibronectin, laminin and different collagens ( Hashimoto et al., 1997 ; Hanssen et al., 2003) and serves as a ligand for several integrins|BIGH3 has been shown to interact with α3β1, αvβ3, αvβ5, α1β1, α6β4 and α7β1 integrin heterodimers" SIGNOR-253266 CCKAR protein P32238 UNIPROT GNAQ protein P50148 UNIPROT up-regulates binding 9606 BTO:0001130;BTO:0000551 11313903 t gcesareni "These neuropeptides, including gastrin-releasing peptide, neuromedin b, neurotensin, gastrin, cholecystokinin and arginine vasopressin bind seven transmembrane-spanning receptors that couple to heterotrimeric g proteins. Studies with human small cell lung cancer (sclc) cells support a requirement for balanced signaling through g(q) and g(12/13) proteins leading to intracellular ca2+ mobilization, pkc activation and regulation of the erk and jnk map kinase pathways." SIGNOR-106998 KIFC1 protein Q9BW19 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 33361741 f miannu "Kinesin Family Member C1 (KIFC1) Regulated by Centrosome Protein E (CENPE) Promotes Proliferation, Migration, and Epithelial-Mesenchymal Transition of Ovarian Cancer" SIGNOR-266114 MYC protein P01106 UNIPROT HNRNPA2B1 protein P22626 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 20010808 t "We also demonstrate that the oncogenic transcription factor c-Myc upregulates transcription of PTB, hnRNPA1 and hnRNPA2," SIGNOR-268691 ATOH1 protein Q92858 UNIPROT HES6 protein Q96HZ4 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 17826772 f miannu "Electrophoretic mobility shift assays and luciferase assays show that ATOH1 activates HES6 transcription through binding to three clustered E boxes of its promoter." SIGNOR-253754 TOP2A protein P11388 UNIPROT Chromosome_segregation phenotype SIGNOR-PH44 SIGNOR up-regulates 9606 20562910 f lperfetto "Topoisomerase IIalpha (topoIIalpha) is an essential mammalian enzyme that topologically modifies DNA and is required for chromosome segregation during mitosis." SIGNOR-242530 ARVCF protein O00192 UNIPROT ERBIN protein Q96RT1 UNIPROT "up-regulates activity" binding 9606 BTO:0000938 11821434 t miannu "We characterized the interactions between the Erbin PDZ domain and both ARVCF and δ-catenin in vitro and in vivo. endogenous δ-catenin and Erbin co-localized in and co-immunoprecipitated from neurons. These results suggest that δ-catenin and ARVCF may function to mediate the association of Erbin with the junctional cadherin-catenin complex." SIGNOR-252119 ELL protein P55199 UNIPROT ELL/ICE1 complex SIGNOR-C48 SIGNOR "form complex" binding 9606 BTO:0001271 22195968 t miannu "The ell-ice complex is called lec for its proposed role in transcriptional regulation of the littlesnrna genes." SIGNOR-193458 NMUR2 protein Q9GZQ4 UNIPROT GNA12 protein Q03113 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257402 LCK protein P06239 UNIPROT DAPP1 protein Q9UN19 UNIPROT "up-regulates activity" phosphorylation Tyr139 KVEEPSIyESVRVHT 10880360 t lperfetto "Src family kinases mediate receptor-stimulated, phosphoinositide 3-kinase-dependent, tyrosine phosphorylation of dual adaptor for phosphotyrosine and 3-phosphoinositides-1 in endothelial and B cell lines|yrosine phosphorylation of DAPP-1 appears important for appropriate intracellular targeting and creates a potential binding site for Src homology 2 domain-containing proteins." SIGNOR-249373 FCER1 complex SIGNOR-C200 SIGNOR SRC_kinase_family proteinfamily SIGNOR-PF32 SIGNOR up-regulates 9606 BTO:0000830 16470226 f "Alessandro Palma" "It is clear that these initial signalling events involve coalescence of the aggregated receptors with specialized microdomains of the plasma membrane known as lipid rafts9, activation of SRC-family kinases and, subsequently, tyrosine phosphorylation of the receptor subunits" SIGNOR-254955 PRKG1 protein Q13976 UNIPROT SEPTIN3 protein Q9UH03 UNIPROT "up-regulates activity" phosphorylation Ser91 SQVSRKAsSWNREEK -1 15107017 t miannu "Mutation of Ser-91 to Ala in recombinant Sept3 also abolished PKG phosphorylation, confirming that Ser-91 is the major site in vitro. Therefore Sept3 is phosphorylated on Ser-91 in nerve terminals and its phosphorylation may contribute to the regulation of its subcellular localization in neurons." SIGNOR-263183 FLT3 protein P36888 UNIPROT FLT3 protein P36888 UNIPROT "up-regulates activity" phosphorylation Tyr589 TGSSDNEyFYVDFRE 10090 BTO:0001516 16627759 t lperfetto "In vitro mapping of FLT3 autophosphorylation sites|Tryptic peptides covering more than 80% of the FLT3 kinase domain were recovered, and 5 tyrosine residues (Y591, Y726, Y842, Y955, and Y969) within this region were phosphorylated.|This finding suggests that the combination of tyrosine residues 589 and 591 is required for activation of STAT-5 signaling pathways." SIGNOR-271926 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR SCRIB protein Q14160 UNIPROT unknown phosphorylation Ser1448 TSRQSPAsPPPLGGG 9606 BTO:0000007 20622900 t miannu "HScrib is a substrate of ERK and PKA. Under normal growth conditions, hScrib is phosphorylated at S853, most likely by ERK, and at S1445 by PKA. Interestingly, stimulation of MAPK by osmotic stress results in a marked loss of phosphorylation at the PKA site S1445, but a concomitant increase in phosphorylation at S1448, presumably also by ERK. At present, we have no information as to what are the functional consequences of ERK or PKA phosphorylation of hScrib. However, we can speculate that this will most likely affect the ability of hScrib to interact with some of its cellular partners, and studies are currently in progress to investigate these aspects further." SIGNOR-263064 AURKA protein O14965 UNIPROT TACC3 protein Q9Y6A5 UNIPROT "up-regulates activity" phosphorylation Ser558 ESALRKQsLYLKFDP 9606 BTO:0001109 17545617 t miannu "We show that this conserved serine on human TACC3 (Ser(558)) is also phosphorylated by Aurora A. Moreover, phosphorylation of TACC3 by Aurora A in human cells is essential for its proper localization to centrosomes and proximal mitotic spindles. Inhibition of Aurora A with the selective small molecule inhibitor MLN8054 in cultured human tumor cells resulted in mislocalization of TACC3 away from mitotic spindles in a concentration-dependent manner." SIGNOR-262655 WNT7A protein O00755 UNIPROT PRKACA protein P17612 UNIPROT "up-regulates activity" 9606 BTO:0001103 21902831 f gcesareni "Wnt1 and wnt7a stimulation of precursor cells activates protein kinase a (pka), which, through the phosphorylation of creb, induces the expression of the myogenic transcription factors myf5, myod and pax3, resulting in the myogenic commitment of embryonic precursors." SIGNOR-176575 OSM protein P13725 UNIPROT AHR protein P35869 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 24127753 f gcesareni "The il-6-type cytokine oncostatin m induces ahr expression in a stat3-ependent manner in human hepg2 hepatoma cells." SIGNOR-202963 ULK1 protein O75385 UNIPROT GABARAP protein O95166 UNIPROT up-regulates binding 9606 BTO:0000567;BTO:0000938 BTO:0000142 11146101 t gcesareni "N-terminal proline/serine rich (ps) domain of ulk1 (amino acid 287-416) is required for ulk1-gate-16 and ulk1-gabarap protein interactions" SIGNOR-85614 NFE2L2 protein Q16236 UNIPROT GCLC protein P48506 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 24024136 t irozzo "In both models, the inducer-modified and Nrf2-bound Keap1 is inactivated and, consequently, newly synthesized Nrf2 proteins bypass Keap1 and translocate into the nucleus, bind to the ARE and drive the expression of Nrf2 target genes such as NAD(P)H quinone oxidoreductase 1 (NQO1), heme oxygenase 1 (HMOX1), glutamate-cysteine ligase (GCL) and glutathione S transferases (GSTs)." SIGNOR-256277 FGFR3 protein P22607 UNIPROT STAT1 protein P42224 UNIPROT "up-regulates activity" phosphorylation Tyr701 DGPKGTGyIKTELIS 9606 BTO:0000007 10918587 t "Activation of Stat1 and Stat3 by FGFR derivatives. Lysates of 293T cells transfected as indicated were analysed by Western blotting using Phospho-Stat1 (Y701) antisera (top) or Stat1 antisera (bottom). (b) The same lysates in (a) were re-examined for phosphorylated Stat3 by Western blotting with Phospho-Stat3 (Y705) (top). all three FGFR family members examined here are able to lead to Stat activation. Expression of the 'TDII-like' derivatives of FGFR1, FGFR3, and FGFR4, as well as myrR1-WT, led to phosphorylation of both Stat1 and Stat3." SIGNOR-251138 TGFBR2 protein P37173 UNIPROT TGFBR2 protein P37173 UNIPROT "up-regulates activity" phosphorylation Ser409 LRLDPTLsVDDLANS 9606 BTO:0000972 phosphorylation:Ser213 TRKLMEFsEHCAIIL 9155023 t lperfetto "Ser213, in the membrane-proximal segment outside the kinase domain, undergoes intra-molecular autophosphorylation which is essential for the activation of TbetaRII kinase activity, activation of TbetaRI and TGF-beta-induced growth inhibition. In contrast, phosphorylation of Ser409 and Ser416, located in a segment corresponding to the substrate recognition T-loop region in a three-dimensional structural model of protein kinases, is enhanced by receptor dimerization and can occur via an intermolecular mechanism. Phosphorylation of Ser409 is essential for TbetaRII kinase signaling, while phosphorylation of Ser416 inhibits receptor function." SIGNOR-246743 SNIP1 protein Q8TAD8 UNIPROT SMAD4 protein Q13485 UNIPROT down-regulates binding 9606 SIGNOR-C6 10887155 t gcesareni "In this study, we characterize a novel nuclear protein, termed snip1 its principal mechanism of action appears to be through transcription by binding to cbp/p300 and interfering with the ability of these coactivators to interact with smad4" SIGNOR-78984 KIF13A protein Q9H1H9 UNIPROT TTC19 protein Q6DKK2 UNIPROT "up-regulates activity" binding 9606 20208530 t miannu "We show that PtdIns(3)P localizes to the midbody during cytokinesis and recruits a centrosomal protein, FYVE-CENT (ZFYVE26), and its binding partner TTC19, which in turn interacts with CHMP4B, an endosomal sorting complex required for transport (ESCRT)-III subunit implicated in the abscission step of cytokinesis. On the basis of these data and the high-content microscopy described above, we propose that PtdIns(3)P controls the KIF13A-dependent recruitment of FYVE-CENT and TTC19 to the midbody, and that TTC19 is the most downstream effector of the three, possibly controlling the function of CHMP4B." SIGNOR-265540 YWHAQ protein P27348 UNIPROT GEM protein P55040 UNIPROT "up-regulates quantity by stabilization" binding 9534 14701738 t miannu "In order to address whether Gem binds specific isoforms of 14-3-3, we determined the coassociation of Gem and 14-3-3 in the neuroblastoma cell line SY5Y. 14-3-3ζ, -γ, -τ, and -β were observed to bind to Gem. 14-3-3-bound Gem has a twofold-longer half-life than nonbound Gem (Fig. ​(Fig.6).6). A similar increase in protein stability following 14-3-3 binding has been described for the Wee1 kinase" SIGNOR-261714 ATM protein Q13315 UNIPROT TP53 protein P04637 UNIPROT "up-regulates quantity by stabilization" phosphorylation Ser20 PLSQETFsDLWKLLP 9606 BTO:0001938 15254178 t lperfetto "Although the stabilization of p53 was apparently concordant with its phosphorylation on N-terminal serine residues in HFFF-2 cells, it did not require the phosphorylation of Ser15 or Ser20 by ATM, a cellular kinase known to phosphorylate and promote the stabilization of p53 in response to DNA damage." SIGNOR-126757 PPP1CB protein P62140 UNIPROT AHCYL1 protein O43865 UNIPROT unknown dephosphorylation Ser68 RSLSRSIsQSSTDSY 10090 17635105 t "Moreover, IRBIT-associated PP1 specifically dephosphorylated Ser68 of IRBIT. Phosphorylation of Ser68 was required for subsequent phosphorylation of Ser71 and Ser74, but the latter two sites were not targeted by PP1. We found that phosphorylation of Ser71 and Ser74 were sufficient to enable inhibition of IP3 binding to the IP3R|Given the importance of phosphorylation for the function of IRBIT in suppressing IP3R activity [7,10], in the present study, we searched for a protein phosphatase involved in the dephosphorylation and, hence, inactivation of IRBIT. We found that IRBIT contains a specific well-conserved binding site for PP1." SIGNOR-248571 NLGN4Y protein Q8NFZ3 UNIPROT NRXN2 protein P58401 UNIPROT "up-regulates activity" binding 9606 BTO:0000938 18923512 t brain lperfetto "Pre- and postsynaptic plasma membranes are always precisely aligned, and are separated by a synaptic cleft of ~20 nm. The cleft contains an undefined proteinaceous material in the middle, and is presumably bridged by synaptic cell-adhesion molecules such as Nrxns and Nlgns that align the pre- and postsynaptic elements and mediate trans-synaptic signaling.|Nlgns bind to both alpha- and beta-Nrxns with nanomolar affinities; binding involves the sixth LNS-domain of alpha-Nrxns which corresponds to the only LNS-domain of beta-Nrxns52. The binding affinities differ characteristically between various pairs of Nlgns and Nrxns, and are controlled by alternative splicing of both Nrxns and Nlgns (Figure 1c)" SIGNOR-264158 CDH24 protein Q86UP0 UNIPROT CTNNB1 protein P35222 UNIPROT "up-regulates activity" binding 9606 21255999 t miannu "At its C-terminus, cadherin interacts with β-catenin, which dynamically associates with α-catenin, a direct binding partner of filamentous actin" SIGNOR-265862 PTPRG protein P23470 UNIPROT PDGFRA protein P16234 UNIPROT "up-regulates activity" dephosphorylation Tyr754 ERKEVSKySDIQRSL -1 25624455 t miannu "PTPRG activation by the P1-WD peptide affected the tyrosine phosphorylation of several signaling molecules. Data analysis identified 31 molecules whose phosphorylation was modified in a statistically significant manner (Table I). inhibition of ABL1, BMX, BTK, DAB1, ITGB1, JAK2, KDR, KIT, LIMK1, MET, PDGFRB, SHC1, and VCL correlates with tyrosine dephosphorylation. In contrast, SRC inhibition correlates with hyperphosphorylation of the inhibitory Tyr530 residue and with dephosphorylation of the activatory Tyr419. Moreover, CDK2 and CTTN inhibition correlates with a hyperphosphorylation of the inhibitory Tyr15 and Tyr470, respectively. In contrast, a subgroup of 13 proteins, including BLNK, DOK2, ERBB2, GRIN2B, INSR, PDGFRA, PRKCD, PXN, STAT1, STAT2, STAT3, STAT5A, and ZAP70, appears to be activated by PTPRG activity." SIGNOR-254714 VAV1 protein P15498 UNIPROT RAC1 protein P63000 UNIPROT "up-regulates activity" "guanine nucleotide exchange factor" 9606 BTO:0000007 32203420 t Luana "We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2)." SIGNOR-260581 NOX1 protein Q9Y5S8 UNIPROT ROS stimulus SIGNOR-ST2 SIGNOR up-regulates 9606 17237347 t lperfetto "Over the last years, six homologs of the cytochrome subunit of the phagocyte NADPH oxidase were found: NOX1, NOX3, NOX4, NOX5, DUOX1, and DUOX2. Together with the phagocyte NADPH oxidase itself (NOX2/gp91phox), the homologs are now referred to as the NOX family of NADPH oxidases. These enzymes share the capacity to transport electrons across the plasma membrane and to generate superoxide and other downstream reactive oxygen species (ROS)." SIGNOR-264714 TBK1 protein Q9UHD2 UNIPROT IRF3 protein Q14653 UNIPROT "up-regulates activity" phosphorylation Ser402 ISNSHPLsLTSDQYK -1 18440553 t lperfetto "Virus-induced phosphoactivation of irf-3, thought to be mediated directly or indirectly by ikk? And/or tbk1 occurs in the c-terminal region of irf-3 at seven ser/thr residues, 385sslentvdlhisnshplslts405 (fig. 1a).Within This region, irf-3 has two phosphorylation sites: site 1 includes ser385 and ser386, whereas site 2 includes ser396, ser398, ser402, ser405, and thr404." SIGNOR-178407 GSK3B protein P49841 UNIPROT NfKb-p65/p50 complex SIGNOR-C13 SIGNOR up-regulates phosphorylation 9606 17183360 t lperfetto "Rela is phosphorylated at: ser276 by the catalytic subunit of protein kinase a (pkac), msk1 and msk2; at ser311 by the atypical pkczeta; at ser468 by ikkbeta, ikkepsilon and glycogen-synthase kinase-3beta (gsk3beta); at ser529 by ck2; and at ser536 by ikkbeta, ikkalfa, ikkepsilon, nf-kb activating kinase (nak, also known as tank-binding kinase-1 tbk1)) and rsk1 (also known as p90 ribosomal protein s6 kinase (p90s6k) ." SIGNOR-217367 FGR protein P09769 UNIPROT FGR protein P09769 UNIPROT "up-regulates activity" phosphorylation Tyr412 RLIKDDEyNPCQGSK -1 8612628 t "Autophosphorylation of c-Fgr under basal conditions involves Tyr-400 (homologous of c-Src Tyr-416) but not, to any appreciable extent, Tyr-511. Both Tyr-511 and Tyr-400, however, incorporate phosphate if autophosphorylation is performed in the presence of polycationic peptides, such as polylysine, histones H1 and protamines. Such a double phosphorylation induced by polylysine gives rise to an upshifted form of c-Fgr on SDS-PAGE and correlates with a stimulation of catalytic activity instead of a down-regulation" SIGNOR-251143 IL6ST protein P40189 UNIPROT SHC1 protein P29353 UNIPROT up-regulates binding 9606 9126968 t milica "Shc mediates IL-6 signaling by interacting with gp130 and Jak2 kinase." SIGNOR-250574 FOXO1 protein Q12778 UNIPROT G6PC1 protein P35575 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 20577053 f gcesareni "In the gk gene regulation, foxo1 represses hnf-4-potentiated transcription of the gene, whereas it synergizes with hnf-4 in activating the g6pase gene transcription." SIGNOR-166349 ASNS protein P08243 UNIPROT L-glutamate(1-) smallmolecule CHEBI:29985 ChEBI "up-regulates quantity" "chemical modification" 9606 29084849 t miannu "Asparagine synthetase (ASNS) converts aspartate and glutamine to asparagine and glutamate in an ATP-dependent reaction. ASNS is present in most, if not all, mammalian organs, but varies widely in basal expression. Human ASNS activity is highly responsive to cellular stress, primarily by increased transcription from a single gene located on chromosome 7." SIGNOR-267535 5-[(Z)-(5-Fluoro-2-oxo-1H-indol-3-ylidene)methyl]-N-[(2S)-2-hydroxy-3-morpholin-4-ylpropyl]-2,4-dimethyl-3H-pyrrole-3-carboxamide chemical CID:73755145 PUBCHEM PDGFRB protein P09619 UNIPROT "down-regulates activity" "chemical inhibition" -1 22037378 t miannu "Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here." SIGNOR-259808 ATM protein Q13315 UNIPROT DBF4 protein Q9UBU7 UNIPROT down-regulates phosphorylation Ser539 GLITINSsQEHLTVQ 9606 22123827 t lperfetto "Dbf4/cdc7 (dbf4-dependent kinase (ddk)) is activated at the onset of s-phase, and its kinase activity is required for dna replication initiation from each origin. We identified novel atm/atr phosphorylation sites on dbf4 and showed that atm/atr-mediated phosphorylation of dbf4 is critical for the intra-s-phase checkpoint to inhibit dna replication." SIGNOR-177797 tolcapone chemical CHEBI:63630 ChEBI COMT protein P21964 UNIPROT "down-regulates activity" "chemical inhibition" 10090 26919286 t miannu "The present work illustrates the potential therapeutic efficacy of COMT inhibition in alleviating cognitive impairment. A brain-penetrant COMT inhibitor, tolcapone, was tested in normal and phencyclidine-treated rats and COMT-Val transgenic mice." SIGNOR-258475 NTNG2 protein Q96CW9 UNIPROT LRRC4 protein Q9HBW1 UNIPROT "up-regulates activity" binding 9606 BTO:0000938 19467332 t miannu "The NGL (netrin-G ligand; LRRC4) family of synaptic cell adhesion molecules belongs to the superfamily of leucine-rich repeat (LRR) proteins. The three known members of the NGL family, NGL-1, NGL-2, and NGL-3, are mainly localized to the postsynaptic side of excitatory synapses, and interact with the presynaptic ligands, netrin-G1, netrin-G2, and LAR, respectively." SIGNOR-264048 CDT1 protein Q9H211 UNIPROT MCM complex SIGNOR-C268 SIGNOR "up-regulates activity" binding 9606 BTO:0000007 14672932 t "Chromosomal DNA replication requires the recruitment of the six-subunit minichromosome maintenance (Mcm) complex to chromatin through the action of Cdc6 and Cdt1." SIGNOR-261679 EPHA3 protein P29320 UNIPROT EPHA3 protein P29320 UNIPROT "up-regulates activity" phosphorylation Tyr602 TYVDPHTyEDPTQAV 9606 11870224 t "Eph receptor activation leads to tyrosine phosphorylation of three major autophosphorylation sites. these residues function to regulate kinase activity, their phosphorylation being required for full intrinsic enzyme activity. these tyrosines (EphA3 Y596, Y602 and Y779) as the prominent autophosphorylation sites of EphA3" SIGNOR-251116 AKT proteinfamily SIGNOR-PF24 SIGNOR INSIG2 protein Q9Y5U4 UNIPROT "down-regulates activity" 10090 BTO:0000759 21723501 f "MTORC1 activation is not sufficient to stimulate hepatic SREBP1c in the absence of Akt signaling, revealing the existence of an additional downstream pathway also required for this induction. We provide evidence that this mTORC1-independent pathway involves Akt-mediated suppression of Insig2a, a liver-specific transcript encoding the SREBP1c inhibitor INSIG2." SIGNOR-256212 PTCH1 protein Q13635 UNIPROT SMO protein Q99835 UNIPROT "down-regulates activity" binding 9606 14556242 t lperfetto "In the responding cell, active Hedgehog binds to its receptor Patched, a 12-pass transmembrane protein, which frees Smoothened, an adjacent 7-pass transmembrane protein, for downstream signaling.Thus, a balance is created by the antagonism of Hedgehog and Patched, whose relative concentrations alternate with respect to each other." SIGNOR-118609 FAM107A protein O95990 UNIPROT AKT3 protein Q9Y243 UNIPROT up-regulates binding 9606 BTO:0000782;BTO:0001271 10983986 t miannu "Full-length tcl1 and its isoforms bind to akt / in in vitro kinase assays using gsk-3_ as a substrate, we found that the presence of any of the tcl1 family proteins (tcl1, mtcp1, or tcl1b) as gst fusion proteins significantly enhanced akt-induced gsk-3_ phosphorylation" SIGNOR-81800 PIM1 protein P11309 UNIPROT RP9 protein Q8TA86 UNIPROT unknown phosphorylation Ser212 KKRKHKSsKSNEGSD -1 10931201 t miannu "PAP-1 was phosphorylated in vitro by Pim-1, but not a kinase-negative Pim-1 mutant. The two serine residues of PAP-1 at amino acids 204 and 206 near the C-terminus were phosphorylated by Pim-1. PAP-1 is thus thought to be a target protein for Pim-1 kinase." SIGNOR-263029 ARHGEF28 protein Q8N1W1 UNIPROT RHOA protein P61586 UNIPROT "up-regulates activity" "guanine nucleotide exchange factor" 9606 BTO:0000007 32203420 t Luana "We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2)." SIGNOR-260546 IRAK4 protein Q9NWZ3 UNIPROT IRAK4 protein Q9NWZ3 UNIPROT "up-regulates activity" phosphorylation Thr345 KFAQTVMtSRIVGTT 9606 BTO:0000876 24567333 t lperfetto "We show irak4 autophosphorylation occurs by an intermolecular reaction and that autophosphorylation is required for full catalytic activity of the kinase. Phosphorylation of any two of the residues thr-342, thr-345, and ser-346 is required for full activity" SIGNOR-204661 CAPN2 protein P17655 UNIPROT F2RL1 protein P55085 UNIPROT "down-regulates activity" cleavage Gly71 FSASVLTgKLTTVFL -1 10978167 t lperfetto "PAR1E and PAR2E (10 microM) were incubated in the presence of the different proteases | The enzymes were used at the following concentrations: 0.5 unit/mL thrombin, 2.5 nM trypsin, 20 nM plasmin, 20 nM cathepsin G, 20 nM elastase, 20 nM proteinase 3, and 2 units/mL calpain I and II|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus.|Mass spectrometry studies of PAR2E predicted activation of PAR2 by trypsin through cleavage at the Arg36-Ser37 site, no effect of thrombin, and inactivation of the receptor by plasmin, calpain and leukocyte elastase, cathepsin G, and proteinase 3" SIGNOR-263581 PRKACA protein P17612 UNIPROT HMGN1 protein P05114 UNIPROT "down-regulates activity" phosphorylation Ser7 sSAEGAAK 9606 11438671 t miannu "PKA preferentially phosphorylates serine 6 in human HMGN1. specific phosphorylation of the NBD of HMGN proteins serves to prevent the interaction of these proteins with their chromatin targets during mitosis." SIGNOR-249993 5-{3-[4-(2,3-Dichlorophenyl)piperidin-1-yl]propoxy}-1,3-benzothiazole chemical CID:56599142 PUBCHEM DRD2 protein P14416 UNIPROT "up-regulates activity" "chemical activation" 9606 BTO:0002181 22025698 t Luana "Through a robust diversity-oriented modification of the scaffold represented by aripiprazole (1), we discovered UNC9975 (2), UNC0006 (3), and UNC9994 (4) as unprecedented β-arrestin–biased D2R ligands. " SIGNOR-258322 KATNB1 protein Q9BVA0 UNIPROT Microtubule_polimerization phenotype SIGNOR-PH106 SIGNOR down-regulates 9606 BTO:0000567 10751153 f miannu "Katanin, a heterodimeric microtubule-severing ATPase, is found localized at mitotic spindle poles. In this paper we demonstrate that human p60 katanin and the C-terminal domain of human p80 katanin both bind microtubules in vitro. Association of these two proteins results in an increased microtubule affinity and increased microtubule-severing activity in vitro. Association of these subunits in transfected HeLa cells increases microtubule disassembly activity and targeting to spindle poles. " SIGNOR-267181 ABR protein Q12979 UNIPROT RAC1 protein P63000 UNIPROT "down-regulates activity" "gtpase-activating protein" 9606 BTO:0000007 32203420 t Luana "We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2)." SIGNOR-260525 CyclinA2/CDK2 complex SIGNOR-C83 SIGNOR RUNX1 protein Q01196 UNIPROT "down-regulates activity" phosphorylation Ser276 VHPATPIsPGRASGM 9606 17015473 t "The effect has been demonstrated using Q01196-8" lperfetto "Previous studies have shown that phosphorylation of aml1, particularly at serines 276 and 303, affects its transcriptional activation. Here, we report that phosphorylation of aml1 serines 276 and 303 can be blocked in vivo by inhibitors of the cyclin-dependent kinases (cdks) cdk1 and cdk2. Furthermore, these residues can be phosphorylated in vitro by purified cdk1/cyclin b and cdk2/cyclin a." SIGNOR-217340 UBE3A protein Q05086 UNIPROT PSMD4 protein P55036 UNIPROT "down-regulates quantity by destabilization" polyubiquitination Lys365 SLASQATkDGKKDKK -1 19240029 t miannu "S5a/Rpn10 is a ubiquitin (Ub)-binding protein that is a subunit of the 26S proteasome but also exists free in the cytosol. It binds poly-Ub chains through its two Ub-interacting motifs (UIMs). We discovered that, unlike typical substrates of Ub ligases (E3s), S5a can be ubiquitinated by all E3s tested including multimeric and monomeric Ring finger E3s (MuRF1, Siah2, Parkin, APC, and SCF(betaTRCP1)), the U-box E3, CHIP, and HECT domain E3s (E6AP and Nedd4) when assayed with UbcH5 or related Ub-conjugating enzymes.The short half-life of S5a presumably is because of the presence of the UIM domain and reflects the ubiquitination of free S5a by many E3s. Surprisingly, the same four Lys residues on S5a, Lys-74, Lys-122, Lys-262, and Lys-365 were ubiquitinated by MuRF1 and E6AP (Fig. 10). Two additional Lys residues (Lys-126 and -135) were ubiquitinated by E6AP." SIGNOR-272745 PRKCE protein Q02156 UNIPROT ADAP1 protein O75689 UNIPROT unknown phosphorylation Thr276 GFRKRWFtMDDRRLM -1 12893243 t lperfetto "The sites of phosphorylation by PKCalpha on centaurin-alpha1‚ were identified as S87 (peptide ARFEK) and T276 (peptide WFMDDRR) (‚ Fig. 5).‚ | The phosphorylation site analysis was carried out twice after phosphorylation of centaurin-alpha1‚ with PKCalpha and once with PKC_. A similar pattern of phosphopeptides was obtained each time." SIGNOR-249226 MAPK3 protein P27361 UNIPROT RPS6KA5 protein O75582 UNIPROT "up-regulates activity" phosphorylation Ser376 EKLFQGYsFVAPSIL 15568999 t lperfetto "In the present study, we show that, in addition to being phosphorylated on Thr-581 and Ser-360 by ERK1/2 or p38, MSK1 can autophosphorylate on at least six sites: Ser-212, Ser-376, Ser-381, Ser-750, Ser-752 and Ser-758. Of these sites, the N-terminal T-loop residue Ser-212 and the 'hydrophobic motif' Ser-376 are phosphorylated by the C-terminal kinase domain of MSK1, and their phosphorylation is essential for the catalytic activity of the N-terminal kinase domain of MSK1" SIGNOR-249479 Inner_mitochondrial_membrane complex SIGNOR-C411 SIGNOR "Mitochondrial respiratory chain complex II" complex SIGNOR-C278 SIGNOR up-regulates relocalization 9606 25627476 t lperfetto "One of the main functions of the IMM is the housing of proteins that make up the electron transport chain (ETC) which ultimately produces ATP. " SIGNOR-267006 LRRK2 protein Q5S007 UNIPROT MSN protein P26038 UNIPROT "up-regulates activity" phosphorylation Thr558 LGRDKYKtLRQIRQG 9606 17447891 t lperfetto "This led to the discovery that moesin, a protein which anchors the actin cytoskeleton to the plasma membrane, is efficiently phosphorylated by lrrk2, at thr558. Moesin phosphorylation could be essential to support the cytoskeletal changes accompanying this process." SIGNOR-154498 CAMK2G protein Q13555 UNIPROT RYR1 protein P21817 UNIPROT unknown phosphorylation Ser2843 KKKTRKIsQSAQTYD 8380342 t llicata "Phosphorylation of serine 2843 in ryanodine receptor-calcium release channel of skeletal muscle by cAMP-, cGMP- and CaM-dependent protein kinase." SIGNOR-250704 CBLB protein Q13191 UNIPROT FLT3 protein P36888 UNIPROT "down-regulates activity" ubiquitination 10090 BTO:0001516 19276253 t miannu "Functionally, CBL negatively regulated FMS-like tyrosine kinase 3 (FLT3) activity and interacted with human FLT3 via the autophosphorylation sites Y589 and Y599 and colocalized in vivo." SIGNOR-260106 CDK1 protein P06493 UNIPROT VCPIP1 protein Q96JH7 UNIPROT "down-regulates activity" phosphorylation Thr761 GPSSAPAtPTKAPYS 23500464 t lperfetto "We clarified that VCIP135, an essential factor in both p97 membrane fusion pathways, is phosphorylated on Threonine-760 and Serine-767 by Cdc2 at mitosis and that this phosphorylated VCIP135 does not bind to p97. " SIGNOR-265037 MAPK8 protein P45983 UNIPROT ATF2 protein P15336 UNIPROT up-regulates phosphorylation Thr71 IVADQTPtPTRFLKN 9606 7737130 t gcesareni "Stimulation of atf-2-dependent transactivation by genotoxic agents requires the presence of threonines 69 and 71 located in the n-terminal transactivation domain. These sites are the target of p54 and p46 stress-activated protein kinases (sapks) which bind to, and phosphorylate atf-2 in vitro." SIGNOR-32425 ERG protein P11308 UNIPROT ICAM1 protein P05362 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 22235125 f miannu "It has been shown that ERG is a positive regulator of several EC-restricted genes including VE-cadherin, endoglin, and von Willebrand factor, and a negative regulator of other genes such as interleukin (IL)-8 and intercellular adhesion molecule (ICAM)-1." SIGNOR-253917 KAT2A protein Q92830 UNIPROT H3C1 protein P68431 UNIPROT "down-regulates activity" acetylation Lys15 ARKSTGGkAPRKQLA 9606 SIGNOR-C465 34811519 t "Acetlyation of H3 causes transcriptional activation, thus has an inhibitory role on H3" lperfetto "The HAT module within the SAGA and ADA complexes acetylates histone H3, mainly on residues K9 and K14." SIGNOR-269602 BRD8 protein Q9H0E9 UNIPROT "NuA4 complex" complex SIGNOR-C459 SIGNOR "form complex" binding 9606 14966270 t miannu "NuA4 (for nucleosome acetyltransferase of H4) is a 12-subunit HAT complex responsible for acetylation of histone H4 and H2A N-terminal tails." SIGNOR-269304 GLUL protein P15104 UNIPROT L-glutamate(1-) smallmolecule CHEBI:29985 ChEBI "down-regulates quantity" "chemical modification" 9606 30158707 t miannu "Glutamine synthetase, encoded by the gene GLUL, is an enzyme that converts glutamate and ammonia to glutamine. certain cell types express glutamine synthetase (GS; also called glutamate-ammonia ligase; GLUL), the enzyme capable of de novo glutamine production from glutamate and ammonia in an ATP and Mg2+/Mn2+ requiring reaction." SIGNOR-267824 progesterone smallmolecule CHEBI:17026 ChEBI Corticotropin protein P01189-PRO_0000024969 UNIPROT down-regulates 24631756 f lperfetto "ACTH and corticosterone responses to the same acute stress stimulus are higher in the pro-estrus phase of the cycle, when the serum concentrations of estrogen are the highest (Viau and Meaney, 1991). In the same study, it was shown that progesterone inhibits the sensitizing effects of estrogen on ACTH release during stress, as the ACTH levels and HPA output decreased with increasing amounts of progesterone in the estrous and diestrous phases." SIGNOR-268727 MICU2 protein Q8IYU8 UNIPROT MCU_MICU2_variant complex SIGNOR-C502 SIGNOR "form complex" binding 9606 32315830 t miannu "MCU is a Ca2+-selective channel that mediates mitochondrial Ca2+ influx. The human channel contains tetrameric pore-forming MCU, regulatory subunits MICU1/2, and EMRE that is required both for channel function and MICU1/2-mediated Ca2+ regulation." SIGNOR-270877 DDX58 protein O95786 UNIPROT MAVS protein Q7Z434 UNIPROT "up-regulates activity" binding 9606 19052324 t miannu "Initially, RIG-I and MDA5 sense dsRNA in the cytoplasm, produced as a by-product of RNA virus replication.Once one or both of these sensors are activated, they interact with a mitochondrial membrane protein called MAVS (mitochondrial antiviral) (also called IPS1, Cardif, and VISA). They signal to the mitochondrial membrane protein MAVS, which in turn activates the kinases TBK1 and IKKɛ." SIGNOR-260139 E2F1 protein Q01094 UNIPROT SERPINB5 protein P36952 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0001938 20197383 f lperfetto "Importantly, we show that E2F1-mediated upregulation of maspin is enhanced by chemotherapeutic drugs, and inhibition of maspin expression significantly impairs the ability of E2F1 to promote chemotherapy-induced apoptosis. Summarily, our data indicate that maspin is an important effector of E2F1-induced chemosensitization." SIGNOR-254135 CSNK2A1 protein P68400 UNIPROT PSEN2 protein P49810 UNIPROT "up-regulates activity" phosphorylation Ser330 MEEDSYDsFGEPSYP -1 9558331 t llicata "In vitro the large hydrophilic loop of PS-2 between transmembrane domains 6 and 7 can be phosphorylated by casein kinase-1 (CK-1) and CK-2, but not by PKA or PKC. Quantitative analysis of in vitro phosphorylation demonstrates the presence of two phosphorylation sites for CK-1 and a single site for CK-2. A deletion analysis revealed that the CTF of PS-2 is phosphorylated in vivo within an acidic sequence containing three potential phosphorylation sites for CKs (serines 327, 330, and 335). These data suggest that CK type protein kinases phosphorylate the CTF of PS-2 within its hydrophilic loop domain in vivo. Interestingly, the potential phosphorylation sites are located directly adjacent to the recently identified caspase cleavage sites." SIGNOR-250934 TWIST2 protein Q8WVJ9 UNIPROT MYB protein P10242 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0004828 19051271 f miannu "we performed microarray analysis to compare the gene expression profiles in HGC-27 cells, with or without small interfering RNA (siRNA)-mediated depletion of TWIST. Our results showed that NF1, RAP1A, SRPX, RBL2, PFDN4, ILK, F2R, ERBB3, and MYB were up-regulated, whereas AKR1C2, FOS, GDF15, NR2F1, ATM, and CTPS were down-regulated after TWIST depletion" SIGNOR-255495 PRKCA protein P17252 UNIPROT SRF protein P11831 UNIPROT up-regulates phosphorylation Thr159 DNKLRRYtTFSKRKT 10090 12809504 t llicata "Myotonic dystrophy protein kinase (DMPK), a muscle- and neuron-restricted kinase, enhanced SRF-mediated promoter activity of the skeletal and cardiac alpha-actin genes in C2C12 myoblasts as well as in nonmyogenic cells. | Threonine 159 in the MADS box alphaI coil was a specific phosphorylation target in vitro as well as in vivo of both DMPK and protein kinase C-alpha. " SIGNOR-188181 PAK proteinfamily SIGNOR-PF13 SIGNOR MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR up-regulates phosphorylation 9606 BTO:0000567 16129686 t lperfetto "Inhibition of pak kinase activity dramatically decreased phosphorylation of mek1 at ser(298) in response to either pdgf or egf." SIGNOR-244920 PP2CA_R1A_R2A complex SIGNOR-C132 SIGNOR PPME1 protein Q9Y570 UNIPROT "up-regulates activity" dephosphorylation Ser15 MHLGRLPsRPPLPGS 9606 BTO:0000007 24841198 t lperfetto "The results subsequently revealed that phosphorylated PME-1/Ser15 is dephosphorylated by SIK2·PP2A (Fig. 5G). |Our results also demonstrated that the phosphorylated levels of PME-1/Ser15 and CaMKI/Thr177 are inversely correlated with the phosphatase activity of SIK2·PP2A complex, further implying that the demethylase activity of phosphorylated PME-1/Ser15 may be higher than that of its unphosphorylated state." SIGNOR-265752 JAK2 protein O60674 UNIPROT EPOR protein P19235 UNIPROT "up-regulates activity" phosphorylation Tyr504 AEPLPPSyVACS 12441334 t "JAK2 in turn phosphorylates several tyrosine residues on the EpoR-cytosolic domain and probably on JAK2 itself that serve as docking sites for SH2 or protein tyrosine binding domains of downstream signal transduction proteins such as STAT5, phosphatidylinositol 3-kinase, Shc, and tyrosine phosphatases SHP1 and SHP2" SIGNOR-251355 PKA proteinfamily SIGNOR-PF17 SIGNOR PPP1R1B protein Q9UD71 UNIPROT "up-regulates activity" phosphorylation Thr34 MIRRRRPtPAMLFRL 9606 BTO:0000938 10604473 t miannu "DARPP-32 (dopamine and cyclic AMP-regulated phospho-protein, relative molecular mass 32,000) is converted into an inhibitor of protein phosphatase 1 when it is phosphorylated by protein kinase A (PKA) at threonine 34.‚ " SIGNOR-264956 RELA protein Q04206 UNIPROT NfKb-p65/p50 complex SIGNOR-C13 SIGNOR "form complex" binding 9606 9450761 t gcesareni "Here we report the crystal structure at 2.9 a resolution of the p50/p65 heterodimer bound to the kappab dna" SIGNOR-55381 ECM stimulus SIGNOR-ST20 SIGNOR "Av/b5 integrin" complex SIGNOR-C178 SIGNOR up-regulates 9606 30889378 t miannu "Upon binding to the extracellular matrix (ECM), the integrins organize the cytoskeleton and activate intracellular signaling, regulating complex cellular behaviors, including survival, proliferation, migration, and various cell fate transitions" SIGNOR-259038 3-phosphonatooxypyruvate(3-) smallmolecule CHEBI:18110 ChEBI 3-phosphonato-D-glycerate(3-) smallmolecule CHEBI:58272 ChEBI "up-regulates quantity" "precursor of" 9606 25406093 t lperfetto "PHDGH catalyzes the first reaction of de novo serine biosynthesis, producing 3-phosphohydroxypyruvate by NAD+-coupled oxidation of 3-phosphoglycerate (3PG).|The PHGDH reaction is reversible and, under standard conditions, thermodynamically favors the direction from 3-phosphohydroxypyruvate to 3PG." SIGNOR-268566 NBR1 protein Q14596 UNIPROT GABARAPL1 protein Q9H0R8 UNIPROT up-regulates binding 9606 BTO:0000007 19250911 t gcesareni "We performed glutathione s-transferase (gst) pull-down assays using extracts from hek293 cells overexpressing an ha-tagged nbr1(d50r) mutant, which lacks the ability to bind p62 (lamark et al., 2003) (figures s1a and s1b, available online), and gst fusions of six human atg8 homologs: gabarap, gabarapl1, gabarapl2, lc3a, lc3b, and lc3c. Indeed, nbr1 interacted with all these members of the mammalian atg8 protein family" SIGNOR-184264 SB-202190 chemical CHEBI:79090 ChEBI PCSK7 protein Q16549 UNIPROT down-regulates "chemical inhibition" 9606 BTO:0000876 9738669 t gcesareni "Sb202190, a selective inhibitor of p38 mitogen activated protein kinase, is a powerful regulator of lps-induced mrnas in monocytes." SIGNOR-60130 Protocadherin_beta proteinfamily SIGNOR-PF102 SIGNOR ITGB1 protein P05556 UNIPROT "up-regulates activity" binding 9606 BTO:0000227 16697637 t miannu "The clustered protocadherins comprise the largest subfamily of the cadherin superfamily and are predominantly expressed in the nervous system. Pcdh-alpha proteins interact with beta1-integrin to promote cell adhesion." SIGNOR-269039 INSR protein P06213 UNIPROT PI3K complex SIGNOR-C156 SIGNOR "up-regulates activity" phosphorylation Tyr580 LRKTRDQyLMWLTQK 9534 BTO:0000298 8385099 t "The alpha-type 85-kDa subunit of phosphatidylinositol 3-kinase is phosphorylated at tyrosines 368, 580, and 607 by the insulin receptor." SIGNOR-252691 AKT1 protein P31749 UNIPROT ACAP1 protein Q15027 UNIPROT unknown phosphorylation Ser554 SIRPRPGsLRSKPEP 9606 16256741 t llicata "Akt phosphorylates s554 in acap1" SIGNOR-252483 CDK1 protein P06493 UNIPROT BRCA1 protein P38398 UNIPROT up-regulates phosphorylation Ser1497 EPGVERSsPSKCPSL 9606 BTO:0000150 10550055 t gcesareni "However, shrna-mediated depletion of cdk1 alone or small molecule cdk1 inhibition abrogated s phase cell-cycle arrest and the phosphorylation of a subset of atr/atm targets after dna damage. Loss of dna damage-induced checkpoint control was caused by a reduction in formation of brca1-containing foci. Mutation of brca1 at s1497 and s1189/s1191 resulted in loss of cdk1-mediated phosphorylation and also compromised formation of brca1-containing foci." SIGNOR-72087 Ub:E2 complex SIGNOR-C497 SIGNOR WWP2 protein O00308 UNIPROT "up-regulates activity" ubiquitination 9606 34199813 t miannu "The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t" SIGNOR-271288 IPO5 protein O00410 UNIPROT DSCAML1 protein Q8TD84 UNIPROT "up-regulates activity" relocalization 9606 BTO:0000938 30745319 t miannu "DSCAM and DSCAML1 specifically interacted with the importin beta IPO5, whereas deletion of the identified NLSs abolished this specific interaction and suppressed nuclear translocation of the DSCAM/L1 ICDs in cell lines and cultured neurons. This suggests a direct role of IPO5 in the nuclear import of the DSCAM/L1 ICDs." SIGNOR-264274 SPOP protein O43791 UNIPROT CUL3 protein Q13618 UNIPROT "up-regulates activity" binding 9606 BTO:0000007 34599168 t miannu "Here we show that the CULLIN3 E3 ubiquitin ligase adaptor protein SPOP binds Geminin at endogenous level and regulates DNA replication. SPOP promotes K27-linked non-degradative poly-ubiquitination of Geminin at lysine residues 100 and 127." SIGNOR-268927 PHKA2 protein P46019 UNIPROT PHKG1 protein Q16816 UNIPROT "down-regulates activity" binding 9606 10487978 t "Phk is among the most complex of the protein kinases so far elucidated. It has one catalytic (gamma) subunit and three different regulatory (alpha, beta, and delta) subunits, a molecular mass of 1.3 X 106 daltons, and each holoenzyme molecule is presumed to contain four molecules of each subunit. The three regulatory subunits inhibit the phosphotransferase activity of the gamma subunit." SIGNOR-267404 TP53 protein P04637 UNIPROT BAX protein Q07812 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 9122197 f gcesareni "P53 can transcriptionally activate bax, a bcl-2 family member that promotes apoptosis" SIGNOR-47541 FGR protein P09769 UNIPROT ACO2 protein Q99798 UNIPROT unknown phosphorylation Tyr71 TLSEKIVyGHLDDPA -1 17997986 t miannu "Here, we provide evidence that the flavoprotein of succinate dehydrogenase and aconitase are ""in vitro"" substrates of Fgr tyrosine kinase. Fgr phosphorylates flavoprotein of succinate dehydrogenase at Y535 and Y596 and aconitase at Y71, Y544 and Y665. Further experiments will be necessary to verify if Fgr is the tyrosine kinase responsible for the tyrosine phosphorylation of these proteins in vivo and to elucidate the role of these phosphorylations." SIGNOR-262871 NFYC protein Q13952 UNIPROT SOX18 protein P35713 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000567 18496767 f miannu "co-transfection experiments revealed that over-expression of Sp3 and ZBP-89 down-regulate, while over-expression of NF-Y up-regulates SOX18 promoter activity in HeLa cells" SIGNOR-254822 SMAD9 protein O15198 UNIPROT SMAD8/SMAD4 complex SIGNOR-C206 SIGNOR "form complex" binding 9606 20957627 t lperfetto "Whereas alk5 signalling is mediated by phosphorylation of smad2 and smad3 proteins, alk1 signalling is mediated by smad1, smad5, and smad8. Activated smads form a complex with the common smad (co-smad; smad4 in mammals) and shuttle into the nucleus." SIGNOR-255268 PRKCZ protein Q05513 UNIPROT NCF1 protein P14598 UNIPROT up-regulates phosphorylation Ser370 PAVPPRPsADLILNR 9606 BTO:0000130 12056906 t lperfetto "Phosphopeptide mapping of p47(phox) showed that, as opposed to pkc zeta, pkc alpha, beta ii, and delta are able to phosphorylate all the major pkc sites. The use of p47(phox) mutants identified serines 303, 304, 315, 320, 328, 359, 370, and 379 as targets of pkc alpha, beta ii, and delta.Taken together, these results suggest that pkc alpha, beta ii, delta, and zeta expressed in human neutrophils can individually phosphorylate p47(phox) and induce both its translocation and nadph oxidase activation." SIGNOR-89284 AKT1 protein P31749 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR down-regulates phosphorylation Ser262 TFRPRSSsNASSVST 9606 16272144 t lperfetto "Foxo4 transcription factor, also referred to afx, contains three putative phosphorylation motif sites for protein kinase b (pkb), thr32, ser197, and ser262, and it is proposed that phosphorylated foxo4 stays in the cytosol and is imported to the nucleus through dephosphorylation to induce target gene expression" SIGNOR-252854 Unfolded_Proteins stimulus SIGNOR-ST22 SIGNOR Protein_aggregates phenotype SIGNOR-PH142 SIGNOR up-regulates 9502314 f lperfetto "Inclusion body formation and other aggregates formed during protein folding have been assumed to arise from hydrophobic aggregation of the unfolded or denatured states" SIGNOR-262268 AMPK complex SIGNOR-C15 SIGNOR FOXO proteinfamily SIGNOR-PF27 SIGNOR "up-regulates activity" phosphorylation 9606 17900900 t lperfetto "The energy sensor amp-activated protein kinase (ampk) has been shown to directly phosphorylate foxo factors at six regulatory sites that are distinct from the akt." SIGNOR-252889 PTPN12 protein Q05209 UNIPROT GIT2 protein Q14161 UNIPROT down-regulates dephosphorylation Tyr392 QDNDQPDyDSVASDE 9606 16317044 t fspada "Conversely, a gfp-pkl phosphorylation mutant, y286/392/592f (gfp-pkl triple yf) (brown et al., 2005), was not phosphorylated during adhesion and the addition of ptp-pest had no effect, suggesting one or more of these tyrosine residues are dephosphorylated by ptppest. Taken together, these data strongly suggest pkl as a direct substrate for ptp-pest." SIGNOR-142715 HCK protein P08631 UNIPROT HCK protein P08631 UNIPROT up-regulates phosphorylation Tyr411 RVIEDNEyTAREGAK 9606 BTO:0000007 10934191 t gcesareni "Tyr(416) is the autophosphorylation site in the activation loop. Autophosphorylation of tyr(416) is required for hck activation." SIGNOR-80340 PDHB protein P11177 UNIPROT PDH complex SIGNOR-C402 SIGNOR "form complex" binding 9606 20160912 t miannu "The human (h) pyruvate dehydrogenase complex (hPDC) consists of multiple copies of several components: pyruvate dehydrogenase (E1), dihydrolipoamide acetyltransferase (E2), dihydrolipoamide dehydrogenase (E3), E3-binding protein (BP), and specific kinases and phosphatases. Mammalian PDC has a well organized structure with an icosahedral symmetry of the central E2/BP core to which the other component proteins bind non-covalently." SIGNOR-266547 nivolumab antibody DB09035 DRUGBANK PDCD1 protein Q15116 UNIPROT "down-regulates activity" binding 9606 BTO:0001023 26351349 t miannu "Nivolumab is an anti-PD-1 antibody that blocks PD-1 signaling. We assessed the safety and antitumor activity of nivolumab in patients with platinum-resistant ovarian cancer." SIGNOR-259895 AKT proteinfamily SIGNOR-PF24 SIGNOR STK3/4 proteinfamily SIGNOR-PF41 SIGNOR down-regulates phosphorylation 9606 20086174 t "inferred from 70% of family members" lperfetto "We determined that mst2 phosphorylation by akt limits mst2 activity in two ways: first, by blocking its binding to rassf1a and by promoting its association into the raf-1 inhibitory complex, and second, by preventing homodimerization of mst2, which is needed for its activation. we identified t117 and t384 as akt phosphorylation sites in mst2." SIGNOR-269944 SCNN1G protein P51170 UNIPROT CACNA1H protein O95180 UNIPROT "up-regulates activity" binding 9606 BTO:0000142 30736831 t miannu "This study describes the functional interaction between Cav3.2 calcium channels and the Epithelial Sodium Channel (ENaC). β- and γ-ENaC subunits could be co-immunoprecipitated with Cav3.2 calcium channels from brain lysates, dorsal horn and lumbar dorsal root ganglia. Αβγ-ENaC channels enhanced Cav3.2 calcium channel trafficking to the plasma membrane in tsA-201 cells. This effect was reciprocal such that Cav3.2 channel expression also enhanced β-ENaC trafficking to the cell surface. these findings reveal ENaC as an interactor and potential regulator of Cav3.2 calcium channels expressed in neuronal tissues." SIGNOR-269274 SARS1 protein P49591 UNIPROT MYC protein P01106 UNIPROT "down-regulates activity" binding 9606 BTO:0000007 24940000 t "Using in vitro, cell and animal experiments, we show here that SerRS intervenes by antagonizing c-Myc, the major transcription factor promoting VEGFA expression, through a tandem mechanism. First, by direct head-to-head competition, nuclear-localized SerRS blocks c-Myc from binding to the VEGFA promoter. Second, DNA-bound SerRS recruits the SIRT2 histone deacetylase to erase prior c-Myc-promoted histone acetylation." SIGNOR-259368 AKT proteinfamily SIGNOR-PF24 SIGNOR S1PR1 protein P21453 UNIPROT "up-regulates activity" phosphorylation Thr236 RTRSRRLtFRKNISK 9606 11583630 t lperfetto "Activated akt binds to edg-1 and phosphorylates the third intracellular loop at the t(236) residue. Transactivation of edg-1 by akt is not required for g(i)-dependent signaling but is indispensable for rac activation, cortical actin assembly, and chemotaxis" SIGNOR-110845 DAPK3 protein O43293 UNIPROT MYL12B protein O14950 UNIPROT up-regulates phosphorylation Ser20 KRPQRATsNVFAMFD 9606 1178183 t lperfetto "Hzipk phosphorylated the regulatory light chain of myosin ii (mrlc) at both ser19 and thr18 in vitro. Phosphorylation of mrlc is required to generate the driving force in the migration of the cells but not necessary for localization of myosin ii at the leading edge." SIGNOR-16043 PIK3CA protein P42336 UNIPROT Survival phenotype SIGNOR-PH13 SIGNOR up-regulates 9534 BTO:0004055 14665640 f lperfetto "Signal transduction pathways triggered by Tie2 have been extensively examined. Tyr-1101of Tie2 directly associates in a phosphotyrosine (pTyr)-dependent manner with the p85 regulatory subunit of phosphatidylinositol (PI) 3-kinase, which in turn activate PI 3-kinase, leading to cell motility and survival" SIGNOR-242649 PRKACA protein P17612 UNIPROT CACNB2 protein Q08289 UNIPROT "up-regulates activity" phosphorylation Ser534 KSQHRSSsSAPHHNH 10441130 t miannu "Voltage-dependent L-type calcium (Ca) channels are heteromultimeric proteins that are regulated through phosphorylation by cAMP-dependent protein kinase (PKA) Mutagenesis of a single residue at Ser459 resulted in the loss of one site of phosphorylation by PKA, and mutagenesis of two residues at Ser478/479 resulted in the loss of approximately two sites of PKA-mediated phosphorylation" SIGNOR-250341 SMAD3 protein P84022 UNIPROT FOXP3 protein Q9BZS1 UNIPROT up-regulates 9606 19701891 t "TGF-beta1-activated Smad3 plays a major role in the expression of Foxp3, since TGF-beta1-induced-Treg generation from Smad3(-/-) mice is markedly reduced and abolished by inactivating Smad2" SIGNOR-254362 PAK2 protein Q13177 UNIPROT ABL1 protein P00519 UNIPROT down-regulates phosphorylation Ser618 APTPPKRsSSFREMD 9606 18161990 t lperfetto "The interaction of c-abl with the abl interactor protein abi2 is shown to be negatively regulated by phosphorylation of serines 637 and 638. These serines are adjacent to the pxxp motif (ptppkrs637s638sfr) that binds the sh3 domain of abi. phosphorylation of c-abl by pak2 inhibits the interaction between the sh3 domain of abi2 and the pxxp motif of c-abl." SIGNOR-160215 PPAT protein Q06203 UNIPROT "5-phospho-α-D-ribose 1-diphosphate" smallmolecule CHEBI:58017 ChEBI "down-regulates quantity" "chemical modification" 9606 9914248 t miannu "Glutamine PRPP amidotransferase (GPATase) catalyzes the first step of de novo purine biosynthesis, the conversion of 5-phosphoribosyl-(~)l-pyrophosphate (PRPP) to 5-phosphoribosyl-([3)l-amine (PRA). The nitrogen source for the reaction is the amide group of glutamine." SIGNOR-267293 PRKCB protein P05771 UNIPROT NFE2L2 protein Q16236 UNIPROT up-regulates phosphorylation Ser40 SREVFDFsQRRKEYE 9606 12198130 t miannu "Phosphorylation of nrf2 at ser-40 by protein kinase c regulates antioxidant response element-mediated transcription / recently we reported evidence for the involvement of protein kinase c (pkc) in phosphorylating nrf2 and triggering its nuclear translocation in response to oxidative stress" SIGNOR-91830 CDK1 protein P06493 UNIPROT KAT7 protein O95251 UNIPROT up-regulates phosphorylation Thr88 QQQPTPVtPKKYPLR 9606 18250300 t lperfetto "Here, we show that the interaction between plk1 and hbo1 is mitosis-specific and that plk1 phosphorylates hbo1 on ser-57 in vitro and in vivo. During mitosis, cdk1 phosphorylates hbo1 on thr-85/88, creating a docking site for plk1 to be recruited. Significantly, the overexpression of hbo1 mutated at the plk1 phosphorylation site (s57a) leads to cell-cycle arrest in the g1/s phase, inhibition of chromatin loading of the minichromosome maintenance (mcm) complex, and a reduced dna replication rate." SIGNOR-160747 SIRT6 protein Q8N6T7 UNIPROT CLOCK/BMAL1 complex SIGNOR-C195 SIGNOR "up-regulates activity" binding 9606 BTO:0000007 25083875 t miannu "SIRT6 is involved in circadian control of gene expression and metabolism. SIRT6 Interacts with CLOCK:BMAL1 and Controls Their Chromatin Recruitment. SIRT6 physically interacts with CLOCK and BMAL1, individually or together, as shown by coimmunoprecipitation (co-IP) (Figures 4A and 4B). SIRT6 directs chromatin recruitment of CLOCK:BMAL1 and SREBP1." SIGNOR-268157 IL2 protein P60568 UNIPROT IL2RG protein P31785 UNIPROT up-regulates binding 9606 16477002 t miannu "Il-2 is a cytokine that functions as a growth factor and central regulator in the immune system and mediates its effects through ligand-induced hetero-trimerization of the receptor subunits il-2r alpha, il-2r beta, and gamma(c)." SIGNOR-144543 PAMPs stimulus SIGNOR-ST11 SIGNOR "AP-1/clathrin vescicle" complex SIGNOR-C251 SIGNOR up-regulates 9606 25720354 f scontino "APCs have several cell surface receptors that facilitate antigen entry into antigen-processing compartments through clathrin-mediated endocytosis." SIGNOR-267855 MAPK1 protein P28482 UNIPROT PCBP2 protein Q15366 UNIPROT "up-regulates quantity by stabilization" phosphorylation Thr213 SASFPHTtPSMCLNP 9606 BTO:0000664 17475908 t miannu "We also identified 4 hnRNP-E2 MAPKERK1/2 phosphorylation sites and demonstrated that hnRNP-E2 is a bona fide MAPKERK1/2 substrate and that MAPKERK1/2-dependent phosphorylation of hnRNP-E2 at these amino acid residues is essential for increased hnRNP-E2 expression in BCR/ABL-expressing cells. Serine/threonine to alanine substitution abolishes hnRNP-E2 phosphorylation and markedly decreases its stability in BCR/ABL-expressing myeloid precursors. Consistent with the existence of a BCR/ABL-MAPK pathway that posttranslationally regulates hnRNP-E2 expression, sequence analysis of hnRNP-E2 revealed the presence of 4 consensus ERK phosphorylation sites (S/T-P)35,36 at amino acid residues 173, 189, 213, and 272 (Figure 2B)." SIGNOR-262913 MDGA2 protein Q7Z553 UNIPROT TP53 protein P04637 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 26206665 f miannu "Enhanced protein expression of p53 and p21 by MDGA2 was confirmed in MDGA2 overexpressed cells and xenograft tumours." SIGNOR-264241 CDC7 protein O00311 UNIPROT MCM2 protein P49736 UNIPROT up-regulates phosphorylation Ser27 GNDPLTSsPGRSSRR 9606 BTO:0000567 16899510 t gcesareni "In the present study, we report the identification of cdc7/dbf4 phosphorylation sites on mcm2 and determine the functional role of cdc7/dbf4 phosphorylation of mcm2 in the initiation of dna replication in human cells." SIGNOR-148713 TGFBR2 protein P37173 UNIPROT TGFBR2 protein P37173 UNIPROT "up-regulates activity" phosphorylation Tyr336 AKGNLQEyLTRHVIS -1 9169454 t lperfetto "Tryptic mapping and amino acid sequencing of in vitro autophosphorylated type ii receptor cytoplasmic domain allowed the localization of the sites of tyrosine phosphorylation to positions 259, 336, and 424. Replacement of all three tyrosines with phenylalanines strongly inhibited the kinase activity of the receptor, suggesting that tyrosine autophosphorylation may play an autoregulatory role for the kinase activity of this receptor." SIGNOR-48863 Oxytocin protein P01178-PRO_0000020495 UNIPROT "GABA-A (a4-b1-g2) receptor" complex SIGNOR-C333 SIGNOR up-regulates 9606 33536967 f lperfetto "OT inhibits corticotropin-releasing factor (CRF) mRNA expression at the hypothalamus, resulting in antistress and anti-anxiety effects| It has been demonstrated that the inhibitory effect of OT on CRF mRNA expression is not a direct one on CRF neurons. GABAergic neurons are present in the surroundings of the PVN (peri-PVN). These GABA-projecting neurons into the PVN inhibits CRF expression via GABAA receptors" SIGNOR-268582 DLX5 protein P56178 UNIPROT Osteoblast_differentiation phenotype SIGNOR-PH9 SIGNOR up-regulates 10090 12000792 f "Giulio Giuliani" "In conclusion, Dlx5 and Dlx6 are dynamic regulators of mammalian development, which are absolutely required for proper craniofacial and skeletal development and which display overlapping genetic functions in all tissues in which they are expressed. In addition, they appear to act as essential regulators of chondrogenesis and osteogenesis." SIGNOR-255450 ASXL2 protein Q76L83 UNIPROT TET2 protein Q6N021 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 28516957 f miannu "Interestingly, this identified a number of genes known to promote leukemogenesis (either alone or in the context of AML1-ETO leukemia) as differentially expressed by ASXL2 loss. These include downregulation of TET2 as well as NOTCH2 with ASXL2 loss in human AML1-ETO-expressing cells, downregulation of which have been previously shown to functionally promote myeloid leukemogenesis when altered in expression" SIGNOR-260074 GGCX protein P38435 UNIPROT SMAD2 protein Q15796 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10116 31539109 f miannu "GGCX can regulate osteoporosis via promoting the TGFβ/smad signaling pathway, facilitating BMSCs osteogenic differentiation, and inhibiting BMSCs adipogenic differentiation. The transfection of pcDNA-GGCX plasmid significantly promoted BMSC cell proliferation, increased calcified nodule formation, inhibited adipogenic differentiation, enhanced ALP activity, elevated RUNX2, and OPN mRNA expressions, and upregulated TGFβ1, Smad2, and Smad7 expressions (p < 0.05)." SIGNOR-261232 LCK protein P06239 UNIPROT DEF6 protein Q9H4E7 UNIPROT "up-regulates activity" phosphorylation Tyr210 SMAIHEVyQELIQDV -1 12923183 t "In vitro kinase assays indeed demonstrated that Lck can phosphorylate wild-type IBP but not the Y210F mutant. IBP Binds PI(3,4,5)P3 upon Phosphorylation by Lck" SIGNOR-251372 PTPRJ protein Q12913 UNIPROT INSR protein P06213 UNIPROT down-regulates dephosphorylation Tyr1189 RDIYETDyYRKGGKG 9606 10734133 t gcesareni "These results, combined with secondary dephosphorylation tests, confirm and extend earlier findings that ptp-1b and t-cell ptp are physiological enzymes for the insulin receptor kinase." SIGNOR-76092 FNIP1 protein Q8TF40 UNIPROT HSP90AA1 protein P07900 UNIPROT "down-regulates activity" binding 9606 BTO:0000007 27353360 t miannu "FNIP1 and FNIP2 facilitate FLCN binding to Hsp90 chaperone. Our results suggest that FNIP1 is a potent inhibitor of Hsp90 ATPase activity, as 200 nM of FNIP1 inhibits Hsp90 ATPase activity by 50-fold. FNIP2 also has shown inhibitory activity towards Hsp90; however, it required 1.6 μM of FNIP2 to inhibit the ATPase activity by eightfold. Although we use the term ‘inhibition' here, FNIPs seem only to be slowing the chaperone cycle." SIGNOR-261413 MAPK3 protein P27361 UNIPROT APBB1 protein O00213 UNIPROT unknown phosphorylation Ser287 WEPPGRAsPSQGSSP 9606 14697653 t lperfetto "Thus, fe65 has at least two apparently disparate functions and may also be involved in the pathogenesis of alzheimer's disease. The mechanisms by which fe65 trafficking and metabolism are regulated to fulfil these different roles are unclear. Our findings reported here, which demonstrate that fe65 is a phosphoprotein that is targeted by erk1/2 and which identify four in vivo phosphorylation sites, provide one possible mechanism whereby functional diversity might be achieved." SIGNOR-120475 NDUFA10 protein O95299 UNIPROT "Mitochondrial respiratory chain complex I" complex SIGNOR-C277 SIGNOR "form complex" binding 30030361 t lperfetto "Thus, we now know the complete mammalian cI structure [22,23] and how the subunits are organized in six modules (N, Q, ND1, ND2, ND4 and ND5)|The ND2-module is formed by an initial intermediate that contains MT-ND2, NDUFC1 and NDUFC2 bound to NDUFAF1/CIA30 [49,50], ECSIT [51] and ACAD9 [52,53]. Then, MT-ND3 is added together with TMEM126B [54], forming a larger intermediate to which subunits MT-ND6 and MT-ND4L bind. The latest assembly stages involve the incorporation of subunits NDUFA1, NDUFA10 and NDUFS5 [24,34]." SIGNOR-262151 MAPK3 protein P27361 UNIPROT RPS6KA1 protein Q15418 UNIPROT "up-regulates activity" phosphorylation Ser732 RRVRKLPsTTL 9534 9430688 t lperfetto "Several lines of evidence indicate that the mapkap-k1 isoforms are also activated by mapks in vivo via the ras-dependent protein kinase cascade that is triggered by growth factors or tumor-promoting phorbol esters, such as phorbol 12-myristate 13-acetate (pma). here we identify six sites in mapkap-k1a that become phosphorylated in transfected cos-1 cells. The inactive form of mapkap-k1a in unstimulated cells is partially phosphorylated at ser222 and ser733. Stimulation with phorbol 12-myristate 13-acetate induces the phosphorylation of thr360, ser364, thr574, and ser381 and increases the phosphorylation of ser222 and ser733." SIGNOR-219345 CDK1 protein P06493 UNIPROT MCL1 protein Q07820 UNIPROT "down-regulates quantity by destabilization" phosphorylation Thr92 EVPDVTAtPARLLFF 9606 SIGNOR-C17 20526282 t gcesareni "Mcl-1 is phosphorylated at two sites in mitosis, ser64 and thr92. Phosphorylation of thr92 by cyclin-dependent kinase 1 (cdk1)-cyclin b1 initiates degradation of mcl-1 in cells arrested in mitosis by microtubule poisons." SIGNOR-165867 PRKCA protein P17252 UNIPROT NRGN protein Q92686 UNIPROT "up-regulates activity" phosphorylation Ser36 AAAKIQAsFRGHMAR -1 8080473 t lperfetto "Phosphorylation of RC3 by PKC alpha, beta, or gamma was stimulated by Ca2+, phospholipid, and diacylglycerol. A single site, Ser36, which is adjacent to the predicted calmodulin (CaM)-binding domain, was phosphorylated by these enzymes. Phosphorylation of RC3 by PKC or PKM, a protease-degraded PKC, was inhibited by CaM. The effect of CaM apparently targets at RC3, as phosphorylation of protamine sulfate by PKM was not inhibited by CaM." SIGNOR-248913 "1-phosphatidyl-1D-myo-inositol 3,5-bisphosphate(5-)" smallmolecule CHEBI:57923 ChEBI "1-phosphatidyl-1D-myo-inositol 5-phosphate(3-)" smallmolecule CHEBI:57795 ChEBI "up-regulates quantity" "precursor of" 9606 18429927 t miannu "PtdIns(3,5)P2 can be dephosphorylated by the 3-phosphatase myotubularins (MTMs), leading to the production of PtdIns5P. Myotubularins also dephosphorylate PtdIns3P into PtdIns" SIGNOR-269806 SPC25 protein Q9HBM1 UNIPROT "Ndc80 complex" complex SIGNOR-C361 SIGNOR "form complex" binding 27881301 t lperfetto "Kinetochores, multisubunit protein assemblies, connect chromosomes to spindle microtubules to promote chromosome segregation. The 10-subunit KMN assembly (comprising KNL1, MIS12, and NDC80 complexes, designated KNL1C, MIS12C, and NDC80C) binds microtubules and regulates mitotic checkpoint function through NDC80C and KNL1C, respectively. |NDC80C contains the NDC80, NUF2, SPC24, and SPC25 subunits" SIGNOR-265186 NMBR protein P28336 UNIPROT GNA12 protein Q03113 UNIPROT up-regulates binding 9606 BTO:0001130;BTO:0000551 11313903 t gcesareni "These neuropeptides, including gastrin-releasing peptide, neuromedin b, neurotensin, gastrin, cholecystokinin and arginine vasopressin bind seven transmembrane-spanning receptors that couple to heterotrimeric g proteins. Studies with human small cell lung cancer (sclc) cells support a requirement for balanced signaling through g(q) and g(12/13) proteins leading to intracellular ca2+ mobilization, pkc activation and regulation of the erk and jnk map kinase pathways." SIGNOR-107025 CyclinD/CDK4 complex SIGNOR-C18 SIGNOR RB1 protein P06400 UNIPROT "down-regulates activity" phosphorylation Ser788 PIPHIPRsPYKFPSS -1 9139732 t llicata "In summary, we have shown evidence that CDK4-cyclin D1 phosphorylates Thr5, Ser249, Thr252, Thr356, Thr373, Ser788, Ser795, Ser807, Ser811, and Thr826 of pRB." SIGNOR-250759 RPN1 protein P04843 UNIPROT "OST-B complex" complex SIGNOR-C536 SIGNOR "form complex" binding 9606 31831667 t miannu "Oligosaccharyltransferase (OST) catalyzes the transfer of a high-mannose glycan onto secretory proteins in the endoplasmic reticulum. Mammals express two distinct OST complexes that act in a cotranslational (OST-A) or posttranslocational (OST-B) manner. Here, we present high-resolution cryo-electron microscopy structures of human OST-A and OST-B. Although they have similar overall architectures, structural differences in the catalytic subunits STT3A and STT3B facilitate contacts to distinct OST subunits, DC2 in OST-A and MAGT1 in OST-B. In OST-A, interactions with TMEM258 and STT3A allow ribophorin-I to form a four-helix bundle that can bind to a translating ribosome, whereas the equivalent region is disordered in OST-B. " SIGNOR-272072 MAP3K5 protein Q99683 UNIPROT DAXX protein Q9UER7 UNIPROT "up-regulates quantity by stabilization" phosphorylation Ser184 QSPRTRGsRRQIQRL 9606 BTO:0000567 19789335 t lperfetto "we show that TNFalpha treatment induces the accumulation of Daxx protein through ASK1 activation by preventing its proteasome-dependent degradation. ASK1 directly phosphorylates Daxx at Ser(176) and Ser(184) and Daxx is required for the sustained activation of JNK. Our results indicate that Daxx not only activates ASK1 but also is a downstream target of ASK1 and that accumulated Daxx further activates ASK1." SIGNOR-109684 CTDSP1 protein Q9GZU7 UNIPROT NLI/Lmx1.1/Isl1 complex SIGNOR-C103 SIGNOR "form complex" binding 9606 BTO:0000007 9452425 t lperfetto "Interactions between LIM transcription factors were also evaluated in vivo. Cotransfected FLAG-Lmx1.1 and HA-Isl1 were capable of interacting. the NLI-dependent interaction observed between Isl1 and Lmx1.1 is likely to represent a physiologically significant complex found in the endocrine cells of the pancreas." SIGNOR-236839 EEF1A1P5 protein Q5VTE0 UNIPROT Arg-tRNA(Arg) smallmolecule CHEBI:18366 ChEBI up-regulates relocalization 9606 23699257 t lperfetto "During protein synthesis, eEF1A binds to and delivers aminoacylated tRNAs (aa-tRNAs) to the elongating ribosome (Fig. 1). GTP bound to eEF1A is hydrolyzed upon codon-anticodon match between an aa-tRNA in the A site of the ribosome and mRNA bound to the ribosome." SIGNOR-269545 AKT proteinfamily SIGNOR-PF24 SIGNOR FOXO1 protein Q12778 UNIPROT "down-regulates activity" phosphorylation Ser319 TFRPRTSsNASTISG 9606 11237865 t lperfetto "The transcription factor, forkhead in rhabdomyosarcoma (fkhr), is phosphorylated at three amino acid residues (thr-24, ser-256 and ser-319) by protein kinase b (pkb)alpha.Fkhr (forkhead in rhabdomyosarcoma), afx (all1 fused gene from chromosome x) and fkhrl1 (fkhr-like 1) are phosphorylated directly by pkb in cells, preventing them from stimulating gene transcription and leading to their exit from the nucleus" SIGNOR-252349 PPP1R1B protein Q9UD71 UNIPROT PPP1CC protein P36873 UNIPROT "down-regulates activity" binding 9606 BTO:0000938 10604473 t miannu "DARPP-32 (dopamine and cyclic AMP-regulated phospho-protein, relative molecular mass 32,000) is converted into an inhibitor of protein phosphatase 1 when it is phosphorylated by protein kinase A (PKA) at threonine 34.‚ " SIGNOR-264958 TNF protein P01375 UNIPROT LPL protein P06858 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 16106106 f Regulation miannu "TNF-α and IL-6 inhibit lipoprotein lipase" SIGNOR-251855 Isradipine chemical CHEBI:6073 ChEBI CACNA1C protein Q13936 UNIPROT "down-regulates activity" "chemical inhibition" 9606 10072735 t miannu "The protein expression as measured by3H-(+)-PN 200-110-binding (Bmax) and Western Blot analysis withcalsequestrin as reference was similar in left ventricular failing and non-failing myocardium. However, both werereduced in atrial compared to ventricular tissue in failing and non-failing hearts. The KDremained unchanged." SIGNOR-259076 EYA1 protein Q99502 UNIPROT H2AX protein P16104 UNIPROT down-regulates dephosphorylation Tyr143 ATQASQEy 9606 20965415 t gcesareni "Tyr142 is dephosphorylated by the tyr phosphatases eya1 and eya3." SIGNOR-168879 USP9X protein Q93008 UNIPROT SMN1 protein Q16637 UNIPROT "up-regulates quantity by stabilization" deubiquitination 9606 BTO:0000007 23112048 t lperfetto "Ubiquitin-specific Protease 9x Deubiquitinates and Stabilizes the Spinal Muscular Atrophy Protein-Survival Motor Neuron" SIGNOR-253113 MAPK1 protein P28482 UNIPROT EIF4EBP1 protein Q13541 UNIPROT "down-regulates activity" phosphorylation Thr46 GGTLFSTtPGGTRII 9606 BTO:0000007 11691836 t lperfetto "The 4E-BPs inhibit translation in a reversible manner. Hypophosphorylated 4E-BPs interact avidly with eIF4E, whereas 4E-BP hyperphosphorylation, elicited by stimulation of cells with hormones, cytokines, or growth factors, results in an abrogation of eIF4E-binding activity.|These results are at variance with reports that have characterized the 4E-BP1/eIF4E interaction utilizing recombinant 4E-BP1 proteins phosphorylated in vitro with ERK, and harboring alanine substitutions at Thr 37, Thr 46, Thr 70, and Ser 83 |phosphorylation of either Thr 46 or Ser 65 was reported to result in a decrease in eIF4E binding" SIGNOR-249393 SLC5A5 protein Q92911 UNIPROT iodide smallmolecule CHEBI:16382 ChEBI "up-regulates quantity" relocalization 10116 28192058 t scontino "Active iodide (I-) transport in both the thyroid and some extrathyroidal tissues is mediated by the Na+/I- symporter (NIS). In the thyroid, NIS-mediated I- uptake plays a pivotal role in thyroid hormone (TH) biosynthesis. " SIGNOR-266960 SEC23IP protein Q9Y6Y8 UNIPROT "phosphatidic acid" smallmolecule CHEBI:16337 ChEBI "down-regulates quantity" "chemical modification" 9606 22922100 t miannu "Members of the intracellular phospholipase A1 family of proteins have been implicated in organelle biogenesis and membrane trafficking. The mammalian family comprises three members: phosphatidic acid-preferring phospholipase A1 (PA-PIA1)/DDHD1, p125/Sec23ip and KIAA0725p/DDHD2, all of which have a DDHD domain." SIGNOR-269651 TNKS protein O95271 UNIPROT PSMF1 protein Q92530 UNIPROT "down-regulates quantity by destabilization" ADP-ribosylation 9606 BTO:0000007 23622245 t lperfetto "We identify the ADP-ribosyltransferase tankyrase (TNKS) and the 19S assembly chaperones dp27 and dS5b as direct binding partners of the proteasome regulator PI31. TNKS-mediated ADP-ribosylation of PI31 drastically reduces its affinity for 20S proteasome alpha subunits to relieve 20S repression by PI31." SIGNOR-263387 RRM2B protein Q7LG56 UNIPROT RRM1 protein P23921 UNIPROT "up-regulates activity" binding 9606 BTO:0001061 14583450 t miannu "Taken together, we conclude that UV-induced activation of p53R2 transcription and binding of p53R2 to hRRM1 to form RR holoenzyme are impaired in the p53-mutant cell line PC3." SIGNOR-259366 Crenolanib chemical CID:10366136 PUBCHEM PDGFRB protein P09619 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-191124 PIM2 protein Q9P1W9 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR down-regulates 16146838 f lperfetto "The results of 2 microarray experiments demonstrated that the aberrant activation of STAT proteins by Flt3-ITDs resulted in the up-regulation of several STAT5-responsive genes, such as Pim-1, Pim-2, and members of the SOCS (suppressor of cytokine signaling) protein family. These results are particularly interesting because recent data point to an important role of Pim kinases in the antiapoptosis of hematopoietic cells." SIGNOR-256575 EPB41 protein P11171 UNIPROT DLG1 protein Q12959 UNIPROT "up-regulates activity" relocalization 9615 BTO:0000837 12807908 t lperfetto "Together, our results demonstrate that in addition to the N-terminal targeting domain, the alternatively spliced I3 insertion plays a critical role in recruiting hDlg to the lateral membrane in epithelial cells via its interaction with protein 4.1R." SIGNOR-266011 "Cullin 1-RBX1-Skp1" complex SIGNOR-C529 SIGNOR ARF6 protein P62330 UNIPROT "down-regulates quantity by destabilization" 9534 BTO:0000298 18094045 t miannu "Fbx8 Is a Component of the SCF Complex and Mediates Ubiquitination of Arf6. We first examined whether Fbx8 makes a complex with Cul1, through its binding to Skp1. We expressed GST-tagged Fbx8 together with FLAG-tagged Skp1 and Myc-tagged Cul1 in Cos-7 cells and found that Myc-Cul1 is coprecipitated with GST-Fbx8 in the presence of FLAG-Skp1 (Figure 1A)." SIGNOR-271766 MRPL4 protein Q9BYD3 UNIPROT "39S mitochondrial large ribosomal subunit" complex SIGNOR-C285 SIGNOR "form complex" binding -1 25838379 t lperfetto "We have determined the structure of the intact mitoribosome to 3.5 angstrom resolution by single-particle electron cryo-microscopy. It reveals 80 extensively interconnected proteins, 36 of which are specific to mitochondria, and three rRNA molecules" SIGNOR-262357 LIF protein P15018 UNIPROT LIFR protein P42702 UNIPROT up-regulates binding 9606 9143707 t gcesareni "Lif binds at low-affinity to lifr, the structure of which is closely related to that of gp130 (42). Lifr then becomes heterodimerized with gp130 to form the high-affinity and signaling-competent complex (43). Osm utilizes this type of heterodimer, i.e. the lifr/gp130 complex (43, 44)." SIGNOR-48111 MAPK7 protein Q13164 UNIPROT MAPK7 protein Q13164 UNIPROT "up-regulates activity" phosphorylation Ser731 DPLPPVFsGTPKGSG 9606 BTO:0000567 20667468 t miannu "Activated ERK5 undergoes autophosphorylation on its C-terminal half, necessary for maximal activation of ERK5 transcriptional activation. The Ser731 and Thr733 sites were previously shown to be ERK5 autophosphorylation sites in vitro and also in ERK5-overexpressing cells.Our data coincide with a recent study examining whole protein phosphorylation in HeLa cells arrested in G1 and mitotic phases [37] reported that Ser731 and Thr733, as well as Ser720, are phosphorylated in ERK5 during mitosis. We also identified two unreported ERK5 phosphorylation sites, Ser567 and Ser803." SIGNOR-259821 BRAF protein P15056 UNIPROT MAP2K1 protein Q02750 UNIPROT "up-regulates activity" phosphorylation Ser222 LIDSMANsFVGTRSY -1 8413257 t lperfetto "Raf-1 phosphorylation of MEK activated it, as judged by its ability to stimulate the phosphorylation of myelin basic protein by glutathione S-transferase-ERK1." SIGNOR-39054 EEF1A1P5 protein Q5VTE0 UNIPROT Ile-tRNA(Ile) smallmolecule CHEBI:29160 ChEBI up-regulates relocalization 9606 23699257 t lperfetto "During protein synthesis, eEF1A binds to and delivers aminoacylated tRNAs (aa-tRNAs) to the elongating ribosome (Fig. 1). GTP bound to eEF1A is hydrolyzed upon codon-anticodon match between an aa-tRNA in the A site of the ribosome and mRNA bound to the ribosome." SIGNOR-269552 JNK proteinfamily SIGNOR-PF15 SIGNOR TP53 protein P04637 UNIPROT up-regulates phosphorylation 9606 14699954 t "inferred from 70% family members" amattioni "The targets of jnk include the transcription factors p53. P75ntr-mediated apoptosis was shown to be dependent of p53" SIGNOR-269985 TTN protein Q8WZ42 UNIPROT TCAP protein O15273 UNIPROT unknown phosphorylation Ser157 GALRRSLsRSMSQEA 10090 9804419 t lperfetto "These data indicate that the activation of titin kinase in differentiating myocytes and the resulting phosphorylation of telethonin are involved in the reorganization of the cytoskeleton during myofibrillogenesis." SIGNOR-246925 GATA6 protein Q92908 UNIPROT SEMA3C protein Q99985 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 19666519 f lperfetto "Genes encoding the neurovascular guiding molecule semaphorin 3C (SEMA3C) and its receptor plexin A2 (PLXNA2) appear to be regulated directly by GATA6, and both GATA6 mutant proteins failed to transactivate these genes." SIGNOR-253150 NfKb-p65/p50 complex SIGNOR-C13 SIGNOR IL1B protein P01584 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0001103 20219869 f apalma "Once in the nucleus, NF-kB can induce the transcription of iNOS, TNF-alpha, and IL-1, which may then promote further NF-kB activation, as well as elevate the expression of other inflammatory mediators such as CCL2 and IL-6." SIGNOR-255355 CSNK2A1 protein P68400 UNIPROT XRCC1 protein P18887 UNIPROT up-regulates phosphorylation Ser485 QDNGAEDsGDTEDEL 9606 20471329 t lperfetto "Xrcc1 phosphorylation by ck2 is required for its stability and efficient dna repair" SIGNOR-165419 CRBN protein Q96SW2 UNIPROT SALL4 protein Q9UJQ4 UNIPROT "down-regulates quantity by destabilization" ubiquitination 9606 32071327 t miannu "Thalidomide-induced teratogenicity is dependent on its binding to cereblon (CRBN), the substrate receptor of the Cul4A-DDB1-CRBN-RBX1 E3 ubiquitin ligase complex. Thalidomide binding to CRBN elicits subsequent ubiquitination and proteasomal degradation of CRBN neosubstrates including SALL4, a transcription factor of which polymorphisms phenocopy thalidomide-induced limb defects in humans." SIGNOR-272206 SNAI1 protein O95863 UNIPROT HPGD protein P15428 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 10090 19010907 f miannu "We show an interaction between Snail and HDAC2 and the binding of HDAC2 to the 15-PGDH promoter. These data suggest that class I HDACs, specifically HDAC2, and the transcriptional repressor Snail play a central role in the suppression of 15-PGDH expression." SIGNOR-254237 SMARCE1 protein Q969G3 UNIPROT "Embryonic stem cell-specific SWI/SNF" complex SIGNOR-C484 SIGNOR "form complex" binding 10090 BTO:0001086 19279220 t miannu "An embryonic stem cell chromatin remodeling complex, esBAF, is essential for embryonic stem cell self-renewal and pluripotency" SIGNOR-270720 JAK2 protein O60674 UNIPROT RAF1 protein P04049 UNIPROT "up-regulates activity" phosphorylation Tyr340 RGQRDSSyYWEIEAS 10090 BTO:0001482 8876196 t " JAK2 phosphorylated Raf-1. e sites at 340/341 are indeed phosphorylated by JAK2 and that this phosphorylation represents a major component of the activation process." SIGNOR-251361 IKBKB protein O14920 UNIPROT TSC1 protein Q92574 UNIPROT down-regulates phosphorylation Ser511 DSPFYRDsLPGSQRK 9606 BTO:0000150;BTO:0001130;BTO:0001271;BTO:0000527 19188143 t gcesareni "Here we show that ikkbeta, a major downstream kinase in the tnfalpha signaling pathway, physically interacts with and phosphorylates tsc1 at ser487 and ser511, resulting in suppression of tsc1phosphorylation of tsc2 (by akt and erk;refs. 28, 29) and tsc1(by ikkbeta;ref. 30) results in the disruption of the tsc1/2 complex, and thereby activates the oncogenic mtor signaling contributing to tumor progression." SIGNOR-183692 CHD8 protein Q9HCK8 UNIPROT SOX3 protein P41225 UNIPROT "down-regulates quantity" "transcriptional regulation" 10090 32839322 t Gianni "Many of the most significantly up-regulated genes in Chd8+/− and Chd8−/− NPCs are involved in later stages of neuronal development, including Ascl1 [a central driver of neural reprogramming (29)], Dcx, Map2, Nefm, Neurod4, and Neurog1 (Fig. 2 E and F). Additionally, we found that Sox3 is derepressed in both Chd8+/− and Chd8−/− NPCs, and several other Sox TF members (Sox2, Sox7, and Sox11) became derepressed in the Chd8−/− cells" SIGNOR-268920 BRD4 protein O60885 UNIPROT KDM5C protein P41229 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 30921702 f miannu " KDM5C was transcriptionally upregulated by bromodomain-containing protein 4 (BRD4), and knockdown KDM5C sensitized the therapeutic effects of CRPC cells to the bromodomain and extraterminal (BET) inhibitor. " SIGNOR-264311 NEK6 protein Q9HC98 UNIPROT RPS6KB1 protein P23443 UNIPROT "up-regulates activity" phosphorylation Ser403 DDSTLSEsANQVFLG -1 12023960 t miannu "Here we demonstrate that in addition to phosphorylating S6K1 and SGK1 at their hydrophobic motif, NEK6 also phosphorylates S6K1 at two other sites and phosphorylates SGK1 at one other site in vitro. Analysis of the peptides phosphorylated by NEK6 (Fig 2), performed in the present study has confirmed this, and identified two novel sites on S6K1 (Ser53 and Ser403) as major sites of NEK6 phosphorylation." SIGNOR-262953 AKT1 protein P31749 UNIPROT RANBP3 protein Q9H6Z4 UNIPROT unknown phosphorylation Ser126 VKRERTSsLTQFPPS 9606 18280241 t llicata "Akt regulates ranbp3 phosphorylation in vitro and in vivo" SIGNOR-252504 ITCH protein Q96J02 UNIPROT ERBB4 protein Q15303 UNIPROT "down-regulates quantity by destabilization" ubiquitination 9534 BTO:0000298 18334649 t miannu " Itch catalyzed ubiquitination of ErbB4 CYT-1, promoted its localization into intracellular vesicles, and stimulated degradation of ErbB4 CYT-1" SIGNOR-271416 TMOD1 protein P28289 UNIPROT TPM3 protein P06753 UNIPROT "down-regulates activity" binding 9606 8002995 t irozzo "Tropomodulin is a 40.6-kDa protein that binds to one end of the rod-like tropomyosin and inhibits its cooperativity and binding to actin. [.] we demonstrate that it is the N-terminus of tropomyosin that interacts with tropomodulin. Among several tropomyosin isoforms tested, hTM5 encoded by the human gamma-tropomyosin gene has the highest affinity toward human erythrocyte tropomodulin." SIGNOR-259111 INTS10 protein Q9NVR2 UNIPROT "Integrator complex" complex SIGNOR-C265 SIGNOR "form complex" binding 7227 26220997 t lperfetto "Integrator is a metazoan-specific multisubunit, multifunctional protein complex composed of 14 subunits named Int1–Int14 (Integrator subunits) " SIGNOR-261473 MCU_MICUB_variant complex SIGNOR-C499 SIGNOR calcium(2+) smallmolecule CHEBI:29108 ChEBI "up-regulates quantity" relocalization 9606 32315830 t miannu "MCU is a Ca2+-selective channel that mediates mitochondrial Ca2+ influx. The human channel contains tetrameric pore-forming MCU, regulatory subunits MICU1/2, and EMRE that is required both for channel function and MICU1/2-mediated Ca2+ regulation." SIGNOR-270864 RIMS2 protein Q9UQ26 UNIPROT UNC13B protein O14795 UNIPROT "up-regulates activity" relocalization 9606 31679900 t miannu "N-terminal interactions of RIMs with RAB3 and MUNC13 regulate DCV fusion. Through N-terminal interactions, RIMs position MUNC13 and recruit DCVs via RAB3, which is located on the vesicle" SIGNOR-264383 "glutamic acid" smallmolecule CHEBI:18237 ChEBI "NMDA receptor_2C" complex SIGNOR-C349 SIGNOR "up-regulates activity" "chemical activation" 9606 12871085 t miannu "The NMDA receptor, a ligand-gated ion channel composed of the NR1 and NR2 subunits, is located mainly at synapses of CNS neurons. Each receptor has two binding sites for glycine and two binding sites for glutamate" SIGNOR-264130 ISCU protein Q9H1K1 UNIPROT "Mitochondrial Fe-S Cluster Assembly Complex" complex SIGNOR-C276 SIGNOR "form complex" binding -1 27519411 t lperfetto "As the architecture of the human machinery remains undefined, we co-expressed in Escherichia coli the following four proteins involved in the initial step of Fe-S cluster synthesis: FXN42-210 (iron donor); [NFS1]·[ISD11] (sulfur donor); and ISCU (scaffold upon which new clusters are assembled). We purified a stable, active complex consisting of all four proteins with 1:1:1:1 stoichiometry." SIGNOR-262128 MAP2K6 protein P52564 UNIPROT MAPK14 protein Q16539 UNIPROT "up-regulates activity" phosphorylation 9606 10480932 t lperfetto "We have found that p38 mitogen-activated protein kinase, and its direct activator MKK6 are rapidly activated in response to TGF-beta." SIGNOR-70607 CSNK2A1 protein P68400 UNIPROT BRMS1 protein Q9HCU9 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser30 MNGEEEEsEEERSGS -1 26980766 t miannu "We show that BRMS1 is posttranslationally regulated by TNF-induced casein kinase 2 catalytic subunit (CK2α') phosphorylation of nuclear BRMS1 on serine 30 (S30), resulting in 14-3-3ε-mediated nuclear exportation, increased BRMS1 cytosolic expression, and ubiquitin-proteasome-induced BRMS1 degradation." SIGNOR-266407 PRKACA protein P17612 UNIPROT AURKA protein O14965 UNIPROT "up-regulates activity" phosphorylation Thr288 APSSRRTtLCGTLDY -1 11039908 t miannu "Aurora2 is regulated by phosphorylation. phosphorylation occurs on a conserved residue, Threonine 288, within the activation loop of the catalytic domain of the kinase and results in a significant increase in the enzymatic activity. Threonine 288 resides within a consensus motif for the cAMP dependent kinase and can be phosphorylated by PKA in vitro." SIGNOR-250337 IL1B protein P01584 UNIPROT IL1R1 protein P14778 UNIPROT up-regulates binding 9606 BTO:0001253 9625767 t gcesareni "Il-1 binding to its receptor triggers a cascade of signaling events, including activation of the stress-activated mitogen-activated protein (map) kinases, c-jun nh2-terminal kinase (jnk) and p38 map kinase, as well as transcription factor nuclear factor kappab (nf-kappab)." SIGNOR-58122 CXCL12 protein P48061 UNIPROT Angiogenesis phenotype SIGNOR-PH46 SIGNOR up-regulates 9606 BTO:0000093 15882617 f lperfetto "Stromal fibroblast-derived SDF-1 enhances tumor growth both by stimulating angiogenesis through recruiting circulating EPCs into the tumor mass (endocrine effect) and by direct paracrine stimulation of tumor cells through CXCR4 expressed on carcinoma cells" SIGNOR-252267 RAB5A protein P20339 UNIPROT "Early Endosome" complex SIGNOR-C246 SIGNOR "form complex" binding 9606 19924646 t lperfetto "The Rab proteins primarily localized to the EE include Rab5 and Rab4, which regulate distinct early endocytic events. In addition to these two Rab proteins, some of the other less well-characterized Rabs at the EE include Rab10 , Rab14 , Rab21 and Rab22" SIGNOR-260616 UBE3A protein Q05086 UNIPROT PSMD4 protein P55036 UNIPROT "down-regulates quantity by destabilization" polyubiquitination Lys126 DNEKDLVkLAKRLKK -1 19240029 t miannu "S5a/Rpn10 is a ubiquitin (Ub)-binding protein that is a subunit of the 26S proteasome but also exists free in the cytosol. It binds poly-Ub chains through its two Ub-interacting motifs (UIMs). We discovered that, unlike typical substrates of Ub ligases (E3s), S5a can be ubiquitinated by all E3s tested including multimeric and monomeric Ring finger E3s (MuRF1, Siah2, Parkin, APC, and SCF(betaTRCP1)), the U-box E3, CHIP, and HECT domain E3s (E6AP and Nedd4) when assayed with UbcH5 or related Ub-conjugating enzymes.The short half-life of S5a presumably is because of the presence of the UIM domain and reflects the ubiquitination of free S5a by many E3s. Surprisingly, the same four Lys residues on S5a, Lys-74, Lys-122, Lys-262, and Lys-365 were ubiquitinated by MuRF1 and E6AP (Fig. 10). Two additional Lys residues (Lys-126 and -135) were ubiquitinated by E6AP." SIGNOR-272746 MCHR2 protein Q969V1 UNIPROT GNAS protein Q5JWF2 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-256795 SCF-betaTRCP complex SIGNOR-C5 SIGNOR YBX1 protein P67809 UNIPROT "down-regulates quantity by destabilization" polyubiquitination 9606 BTO:0000007 16797541 t miannu "Here we identify FBX33 as a component of an SCF E3-ubiquitin ligase that targets the multifunctional regulator Y-box binding protein 1 (YB-1)/dbpB/p50 for polyubiquitination and destruction by the proteasome. By targeting YB-1 for proteasomal degradation, FBX33 negatively interferes with YB-1 mediated functions.  FBX33 recruits Skp-1/Cul1 to YB-1" SIGNOR-271606 CREB5 protein Q02930 UNIPROT ATF2 protein P15336 UNIPROT "up-regulates activity" binding 9534 BTO:0000318 8378084 t miannu "CRE-BPa specifically binds to CRE as a homodimer or heterodimer with c-Jun or CRE-BP1. In CAT cotransfection experiments using CV-1 cells, transient expression of each of four CRE-BPa proteins caused a 1.6- to 3.4-fold increase of CRE-dependent transcription" SIGNOR-219655 SF3A3 protein Q12874 UNIPROT "U2 snRNP complex" complex SIGNOR-C479 SIGNOR "form complex" binding 9606 30765414 t lperfetto "The major spliceosomal building blocks are the U1, U2, U4/U6, and U5 small nuclear ribonucleoproteins (snRNPs). Each consists of a small nuclear RNA (snRNA) (or two, in the case of U4/U6), seven Sm proteins that form a ring (or seven Lsm proteins in the case of U6), and a variable number of snRNP-specific proteins (Fig. 1F) (Will and Lührmann 2011). Under splicing conditions, the U4/U6 and U5 snRNPs form a 25S U4/U6.U5 tri-snRNP, in which the U4 and U6 snRNAs are base-paired, forming a three-way junction." SIGNOR-270663 CRP protein P02741 UNIPROT NOS3 protein P29474 UNIPROT "down-regulates quantity by destabilization" 17942113 f miannu "C-reactive protein (CRP), a cardiovascular risk marker, induces endothelial dysfunction. CRP decreases endothelial nitric oxide synthase (eNOS) expression and bioactivity in human aortic endothelial cells (HAECs). CRP treatment significantly decreased levels of BH4 thereby promoting eNOS uncoupling. we found that CRP decreased the eNOS dimer/monomer ratio further supporting eNOS uncoupling." SIGNOR-252217 HCRTR2 protein O43614 UNIPROT GNA14 protein O95837 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257290 ATM protein Q13315 UNIPROT NBN protein O60934 UNIPROT up-regulates phosphorylation Ser615 VPESSKIsQENEIGK 9606 10839545 t lperfetto "In vivo, nbs was phosphorylated on many serine residues, of which s343, s397 and s615 were phosphorylated by atm in vitro. Reconstituting nbs cells with a mutant form of nbs that cannot be phosphorylated at selected, atm-dependent serine residues led to a specific reduction in clonogenic survival after gamma-radiation." SIGNOR-78034 CDH23 protein Q9H251 UNIPROT CTNNB1 protein P35222 UNIPROT "up-regulates activity" binding 9606 21255999 t miannu "At its C-terminus, cadherin interacts with β-catenin, which dynamically associates with α-catenin, a direct binding partner of filamentous actin" SIGNOR-265861 dacomitinib chemical CHEBI:132268 ChEBI EGFR protein P00533 UNIPROT down-regulates "chemical inhibition" 9606 23405260 t gcesareni "The goal of this study was to compare dacomitinib (pf-00299804), a next generation small molecule tyrosine kinase inhibitor that irreversibly blocks multiple her family receptors (her-1 (egfr), her-2 and her-4 tyrosine kinases), to cetuximab, the current fda approved anti-egfr medication for hnscc and erlotinib, an egfr specific small molecule tyrosine kinase inhibitor." SIGNOR-200902 C5AR2 protein Q9P296 UNIPROT SELL protein P14151 UNIPROT "down-regulates quantity by repression" 1847994 f lperfetto "The C5a receptor mediates the pro-inflammatory and chemotactic actions of the complement anaphylatoxin C5a. In addition to stimulating chemotaxis, granule enzyme release and superoxide anion production, this receptor stimulates upregulation of expression and activity of the adhesion molecule MAC-1, and of CR1, and a decrease in cell-surface glycoprotein 100MEL-14 on neutrophils." SIGNOR-263467 GSK3B protein P49841 UNIPROT NACA protein E9PAV3 UNIPROT down-regulates phosphorylation Thr2022 NIQENTQtPTVQEES 9606 BTO:0000007 15005626 t gcesareni "Gsk3 beta-dependent phosphorylation of the alpha nac coactivator regulates its nuclear translocation and proteasome-mediated degradation." SIGNOR-123262 P2RY11 protein Q96G91 UNIPROT GNAS protein Q5JWF2 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-256788 mTORC1 complex SIGNOR-C3 SIGNOR TFEB protein P19484 UNIPROT "down-regulates activity" phosphorylation Ser211 LVGVTSSsCPADLTQ 9606 BTO:0000567 SIGNOR-C3 22692423 t gcesareni "Our data points to the lysosome as the site where mTORC1-dependent phosphorylation of TFEB occurs. [...]Our study has revealed a specific role for phosphorylation of TFEB S211 in the negative regulation of the nuclear abundance of TFEB. This occurs through the promotion of 14-3-3 binding and the masking of the nearby NLS on TFEB." SIGNOR-248274 MARCHF8 protein Q5T0T0 UNIPROT HLA-DRB3 protein P79483 UNIPROT "down-regulates quantity by destabilization" polyubiquitination Lys254 FIYFRNQkGHSGLQP 9606 19117940 t miannu "Two E3 ligases, MARCH I and MARCH VIII, have been shown to polyubiquitinate lysine residue 225 in the cytoplasmic tail of I-Abeta and HLA-DRbeta. We show that lysine residue 219 in the cytoplasmic tail of DRalpha is also subject to polyubiquitination." SIGNOR-271408 GUCY1A1 protein Q02108 UNIPROT GUCY1A3-B2 complex SIGNOR-C139 SIGNOR "form complex" binding 9606 10977868 t gcesareni "This enzyme is a heterodimeric protein consisting of - and ²-subunits, and expression of both subunits is required for catalytic activity" SIGNOR-244116 "SAGA complex" complex SIGNOR-C465 SIGNOR H3-5 protein Q6NXT2 UNIPROT "down-regulates activity" acetylation Lys10 RTKQTARkSTGGKAP 9606 34811519 t "Acetlyation of H3 causes transcriptional activation, thus has an inhibitory role on H3" lperfetto "The HAT module within the SAGA and ADA complexes acetylates histone H3, mainly on residues K9 and K14." SIGNOR-269634 HBA1 protein P69905 UNIPROT Hemoglobin complex SIGNOR-C209 SIGNOR "form complex" binding 9606 18179859 t miannu "AHSP does not bind to β-hemoglobin (βHb) or the hemoglobin tetramer, instead, it specifically binds to free αHb, avoiding its precipitation and its pro-oxidant activity. In the presence of βHb, the αHb-AHSP complex is dismembered and βHb displaces AHSP to generate the quaternary structure of hemoglobin" SIGNOR-255274 ERGIC1 protein Q969X5 UNIPROT ERGIC3 protein Q9Y282 UNIPROT "up-regulates quantity by stabilization" binding 9606 BTO:0000599 15308636 t Giorgia "Among novel cycling proteins we have characterized ERGIC-32, a new ERGIC protein that interacts with human Erv46, a protein previously characterized in yeast and functioning in ER to Golgi protein trafficking. ERGIC-32 interacts with human Erv46 (hErv46) as revealed by covalent cross-linking and mistargeting experiments, and silencing of ERGIC-32 by small interfering RNAs increases the turnover of hErv46. We propose that ERGIC-32 functions as a modulator of the hErv41-hErv46 complex by stabilizing hErv46." SIGNOR-260637 WWP1 protein Q9H0M0 UNIPROT AMOTL2 protein Q9Y2J4 UNIPROT "up-regulates activity" ubiquitination Lys408 ANRRLASkTQEAQAG 9606 BTO:0000007 34404733 t lperfetto "AMOTL2 mono-ubiquitination by WWP1 promotes contact inhibition by facilitating LATS activation|Here, we provide evidence that the E3 ligase WWP1 (WW-domain containing protein 1) mono-ubiquitinates AMOTL2 (angiomotin-like 2) at K347 and K408." SIGNOR-271874 PRKCD protein Q05655 UNIPROT HMGA1 protein P17096 UNIPROT down-regulates phosphorylation Ser44 PGTALVGsQKEPSEV 9606 10617144 t fspada "In this study, we showed that the pkc-mediated phosphorylation of hmg-i exerted a very potent inhibition on the binding of this protein to the at-rich promoter regions of both pkc g and ng genes. The purified hmg-i can be phosphorylated by pkc a,b, g, and d but is poorly phosphorylated by pkc e and z. We have mapped two major sites of phosphorylation by pkc at ser44 and ser64" SIGNOR-73606 SP1 protein P08047 UNIPROT UGT1A4 protein P22310 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000599 19546240 f miannu "our data indicate that up-regulation of UGT1A4 expression by E(2) is mediated by both ER alpha and Sp1 and is a potential mechanism contributing to the enhanced elimination of lamotrigine in pregnancy." SIGNOR-254076 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR CACNB1 protein Q02641 UNIPROT "up-regulates activity" phosphorylation Ser161 CEVGFIPsPVKLDSL 9534 BTO:0000298 16406008 t miannu "Thus, Ser-447 on Ca(v)2.2 and Ser-161 and Ser-348 of Ca(v)beta1b appear to be both necessary and sufficient for ERK-dependent modulation of these channels. Together, our data strongly suggest that modulation of neuronal N-type VDCCs by ERK involves phosphorylation of Ca(v)2.2alpha1 and to a lesser extent possibly also Ca(v)beta subunits. On the basis of the evidence presented here, it is therefore suggested that ERK-dependent up-regulation of Cav2.2 channels is primarily mediated by phosphorylation of Ser-447 on the I–II loop of Cav2.2 and possibly also the two SP sites conserved on Cavβs." SIGNOR-262966 RACK1 protein P63244 UNIPROT LARP4B protein Q92615 UNIPROT "up-regulates activity" binding 9606 BTO:0005238 20573744 t miannu "Here we show that LARP4B is a cytoplasmic protein that co-sediments with polysomes and accumulates upon stress induction in stress granules. Biochemical studies further show that the protein interacts with two key factors of the translational machinery, namely, the cytoplasmic poly(A) binding protein (PABPC1) and the receptor for activated C Kinase (RACK1). The biochemical and functional data of LARP4B presented in this study suggest a possible mode of action of LARP4B in translation. Assuming that LARP4B interacts with mRNA-associated PABPC1 and RACK1 simultaneously, it may form a bridge between the 3′ end of mRNAs and the initiating ribosome. This process would lead to mRNA circularization, possibly in an analogous way as it has been described for PABPC1 and eIF4G, the scaffold protein of the cap-binding complex." SIGNOR-260941 FOXO proteinfamily SIGNOR-PF27 SIGNOR Proliferation phenotype SIGNOR-PH4 SIGNOR down-regulates 9606 BTO:0000007 14976264 f lperfetto "Sirt1 increased foxo3's ability to induce cell cycle arrest and resistance to oxidative stress" SIGNOR-252938 DAB2IP protein Q5VWQ8 UNIPROT STAT3 protein P40763 UNIPROT "down-regulates activity" binding 9606 BTO:0001033 26512963 t miannu "DAB2IP could interact with the signal transducer and activator of transcription 3 (STAT3) via its unique PR domain and suppress STAT3 phosphorylation and transactivation, leading to the inhibition of survivin expression in PCa cells." SIGNOR-254761 MYOD1 protein P15172 UNIPROT MYOG protein P15173 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 18676376 f gcesareni "€ provide a novel transcriptional paradigm for the first steps of myogenesis, where a calcineurin/NFATc3 pathway regulates myogenin induction in cooperation with MyoD during myogenesis." SIGNOR-235009 PRKCE protein Q02156 UNIPROT KIR3DL1 protein P43629 UNIPROT down-regulates phosphorylation Ser415 QRKITRPsQRPKTPP 9606 17911614 t gcesareni "Functional studies of the wild-type receptor and serine/threonine mutants indicated that phosphorylation of ser(394) by protein kinase c slightly suppresses kir3dl1 inhibitory function, and reduces receptor internalization and turnover." SIGNOR-158129 PHF5A protein Q7RTV0 UNIPROT "U2 snRNP complex" complex SIGNOR-C479 SIGNOR "form complex" binding 9606 30765414 t lperfetto "The major spliceosomal building blocks are the U1, U2, U4/U6, and U5 small nuclear ribonucleoproteins (snRNPs). Each consists of a small nuclear RNA (snRNA) (or two, in the case of U4/U6), seven Sm proteins that form a ring (or seven Lsm proteins in the case of U6), and a variable number of snRNP-specific proteins (Fig. 1F) (Will and Lührmann 2011). Under splicing conditions, the U4/U6 and U5 snRNPs form a 25S U4/U6.U5 tri-snRNP, in which the U4 and U6 snRNAs are base-paired, forming a three-way junction." SIGNOR-270670 PRKAA1 protein Q13131 UNIPROT PPARGC1A protein Q9UBK2 UNIPROT "up-regulates activity" phosphorylation Thr178 NHNHRIRtNPAIVKT 9606 BTO:0000887;BTO:0001103 SIGNOR-C15 17609368 t lperfetto "Ampk phosphorylates pgc-1alpha directly both in vitro and in cells. These direct phosphorylations of the pgc-1alpha protein at threonine-177 and serine-538." SIGNOR-156780 NFIB protein O00712 UNIPROT NEUROD4 protein Q9HD90 UNIPROT "up-regulates quantity" "transcriptional regulation" 10090 31838646 t Gianni "For example, within the NFI targetome, we identified 6 collagen genes, 13 genes encoding potassium channel or glutamate receptor subunits and a range of factors related to axon guidance (e.g. Slit1, Robo1, Epha4, Epha5, Epha8)" SIGNOR-268898 ATR protein Q13535 UNIPROT FANCD2 protein Q9BXW9 UNIPROT up-regulates phosphorylation Ser717 KDGGPVTsQESGQKL 9606 16943440 t lperfetto "In the present study, we identify two novel dna damage-inducible phosphorylation sites on fancd2, threonine 691 and serine 717. Atr phosphorylates fancd2 on these two sites, thereby promoting fancd2 monoubiquitination and enhancing cellular resistance to dna cross-linking agents" SIGNOR-149305 WNT3A protein P56704 UNIPROT ALPL protein P05186 UNIPROT up-regulates 9606 19175684 f gcesareni "Wnt3a and bmp-9 enhanced each other's ability to induce alp in mscs." SIGNOR-183538 RPL24 protein P83731 UNIPROT "60S cytosolic large ribosomal subunit" complex SIGNOR-C287 SIGNOR "form complex" binding -1 25901680 t lperfetto "Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins." SIGNOR-262475 MAPK9 protein P45984 UNIPROT BCL2L11 protein O43521 UNIPROT "up-regulates activity" phosphorylation Ser59 GDSCPHGsPQGPLAP 12818176 t miannu "JNKs specifically phosphorylate BIMEL at Ser55, 65, and/or 73. several observations demonstrate that the phosphorylation of BIMEL is a physiologically important mechanism for enhancing its proapoptotic activity." SIGNOR-250134 IKBKB protein O14920 UNIPROT IKBKB protein O14920 UNIPROT "down-regulates activity" phosphorylation Ser689 SQPGQLMsQPSTASN 9606 10195894 t "Once activated, IKKbeta autophosphorylated at a carboxyl-terminal serine cluster. Such phosphorylation decreased IKK activity and may prevent prolonged activation of the inflammatory response." SIGNOR-251279 HNuRF complex SIGNOR-C448 SIGNOR Neurite_outgrowth phenotype SIGNOR-PH134 SIGNOR up-regulates 9606 BTO:0000142 14609955 f miannu "Human NURF (hNURF) is enriched in brain, and we demonstrate that it regulates human Engrailed, a homeodomain protein that regulates neuronal development in the mid-hindbrain. Furthermore, we show that hNURF potentiates neurite outgrowth in cell culture. Taken together, our data suggess a role for an ISWI complex in neuronal growth." SIGNOR-268838 MAPK1 protein P28482 UNIPROT RUNX1 protein Q01196 UNIPROT "up-regulates activity" phosphorylation Ser276 VHPATPIsPGRASGM 9606 16046550 t "The effect has been demonstrated using Q01196-8" miannu "We have identified four phosphorylation sites on AML1c that are necessary for transcriptional activity of AML1c in K562 and 293T cells (27).4 Mutation of these four sites (serine 276, serine 293, serine 303, and threonine 300) to alanine abolishes transcriptional activation, whereas mutation of these sites to aspartic acid (which mimics phosphorylation) results in a hyperactive protein. The presence of these mutations results in an increase in the amount of ubiquitinated AML1c in the matrix, and increases the half-life of this insoluble AML1c. One possible model to explain these observations is that phosphorylation might be necessary for the normal process of both proteasome degradation and transcriptional activation." SIGNOR-138985 KIT protein P10721 UNIPROT JAK2 protein O60674 UNIPROT "up-regulates activity" binding 9606 15526160 t miannu "C-Kit stimulates rapid and transient tyrosine phosphorylation of JAK2. JAK2 was found to be constitutively associated with c-Kit, with increased association after ligand stimulation of c-Kit" SIGNOR-254954 PLK1 protein P53350 UNIPROT CCNB1 protein P14635 UNIPROT "up-regulates activity" phosphorylation Ser128 LVDTASPsPMETSGC 9606 BTO:0000567 11242082 t lperfetto "Phosphorylation of cyclin b1 is central to its nuclear translocationduring cell-cycle progression in hela cells, a change in the kinase activity of endogenous plk1 toward s147 and/or s133 correlates with a kinase activity in the cell extractsa mutant cyclin b1 in which s133 and s147 are replaced by alanines remains in the cytoplasm, whereas wild-type cyclin b1 accumulates in the nucleus during prophase.Together, these results suggest that phosphorylation of s133 and s147 is necessary for the nuclear translocation of cyclin b1 during prophase, and that phosphorylation of s126 and s128 may stimulate the nuclear translocation." SIGNOR-105711 AKT proteinfamily SIGNOR-PF24 SIGNOR TBX3 protein O15119 UNIPROT "up-regulates activity" phosphorylation Ser719 AEKEAATsELQSIQR 9606 25595898 t lperfetto "We have identified TBX3 as a key substrate of AKT3 in melanomagenesis. we have identified the AKT3 target site at serine residue 720 in the TBX3 protein and show that this site is phosphorylated in vivo. the phosphorylation at S720 promotes TBX3 protein stability, nuclear localization, transcriptional repression of E-cadherin, and its role in cell migration and invasion." SIGNOR-244353 Tosedostat chemical CID:15547703 PUBCHEM ANPEP protein P15144 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-207372 BBS1 protein Q8NFJ9 UNIPROT "BBsome complex" complex SIGNOR-C288 SIGNOR "form complex" binding 9606 BTO:0004910 19081074 t lperfetto "We recently showed that seven highly conserved BBS proteins form a stable complex, the BBSome, that functions in membrane trafficking to and inside the primary cilium.|As a first step in characterizing this protein, we investigated the biochemical properties of its binding to the core BBSome (previously defined as the BBS1, -2, -4, -5, -7, -8, and -9 complex). We subjected the native LAP-BBS4 eluate to velocity sedimentation analysis (Figure 1C). BBIP10 clearly cosedimented with BBS4 at 14S, suggesting that BBIP10 strongly associates with the core BBSome" SIGNOR-262558 CSNK1A1 protein P48729 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR down-regulates phosphorylation Ser321 NSNASTVsGRLSPIM 9606 20110348 t lperfetto "Casein kinase (ck) 1 mediates the hierarchical phosphorylation of foxo3a at s318 and s321, which like foxo1 (rena et al., 2002 blue right-pointing triangle, 2004 blue right-pointing triangle), is probably to enhance its rate of nuclear export" SIGNOR-252900 PTPN1 protein P18031 UNIPROT GHR protein P10912 UNIPROT "down-regulates activity" dephosphorylation Tyr487 SLSNIDFyAQVSDIT 10029 12907755 t "PTPH1 only bound Tyr534, whereas PTP1B and TC-PTP bound multiple phosphopeptides. Earlier work suggests that Tyr332, Tyr487, Tyr534, Tyr566, and Tyr627 are all phosphorylated after GH stimulation (21). Apart from Tyr627, all of these also appear good PTP substrates" SIGNOR-248419 CSNK2B protein P67870 UNIPROT CTNNB1 protein P35222 UNIPROT "up-regulates activity" phosphorylation Thr102 RAAMFPEtLDEGMQI 9606 BTO:0000007 12432063 t llicata "We show that CKII phosphorylates the N-terminal region of beta-catenin and we identified Ser29, Thr102, and Thr112 as substrates for the enzyme. We provide evidence that CKII regulates the cytoplasmic stability of beta-catenin and acts synergistically with GSK-3beta in the multi-protein complex that controls the degradation of beta-catenin" SIGNOR-251066 F2RL1 protein P55085 UNIPROT TNFRSF12A protein Q9NP84 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 21072196 f miannu "Both PAR2 and PAR1 activation resulted in up-regulated expression of several genes (CD44, FOSL1, TNFRSF12A, RAB3A, COPEB, CORO1C, THBS1, SDC4) known to be important in cancer." SIGNOR-254837 Ubiquitin proteinfamily SIGNOR-PF89 SIGNOR Ub:E2 complex SIGNOR-C497 SIGNOR "form complex" ubiquitination 9606 34199813 t miannu "The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t" SIGNOR-270839 N-[4-[(2-amino-3-chloro-4-pyridinyl)oxy]-3-fluorophenyl]-4-ethoxy-1-(4-fluorophenyl)-2-oxo-3-pyridinecarboxamide chemical CHEBI:91409 ChEBI MET protein P08581 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-190404 HCRTR2 protein O43614 UNIPROT GNAQ protein P50148 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257216 CSNK2A1 protein P68400 UNIPROT EXOSC9 protein Q06265 UNIPROT up-regulates phosphorylation Ser392 QDAPIILsDSEEEEM 9606 19217413 t lperfetto "Indeed recombinant pmscl1 undergoes ck2-mediated phosphorylation in vitro at various serine residues, including serines 409 and 411, which reside within the phosphosim region. the exchange of hydrophobic core residues or serines 409 and 411 to alanine attenuates binding of sumo to the phosphosim-containing fragment of pmscl1 in a yeast two-hybrid assay" SIGNOR-184031 ADORA1 protein P30542 UNIPROT GNAI1 protein P63096 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-256697 G6PD protein P11413 UNIPROT NADPH(4-) smallmolecule CHEBI:57783 ChEBI "up-regulates quantity" "chemical modification" 9606 24769394 t miannu "The major NADPH-producing enzymes in the cell are glucose-6-phosphate dehydrogenase (G6PD) and 6-phosphogluconate dehydrogenase (6PGD) in the pentose phosphate pathway (PPP), malic enzyme (ME) in the pyruvate cycling pathway, and isocitrate dehydrogenase (IDH) in the tricarboxylic acid (TCA) cycle" SIGNOR-267052 ZAP70 protein P43403 UNIPROT LCP2 protein Q13094 UNIPROT up-regulates phosphorylation Tyr423 NSLNEEWyVSYITRP 9606 BTO:0000782 8702662 t lperfetto "A fourth peptide derived from slp-76 encompassing tyr residues 423 and 426 was also phosphorylated by zap-70 but with a 10-15-fold lesser efficiency compared to tyr-113, _128, and _145. Phosphorylation of slp-76 by the zap-70 protein-tyrosine kinase is required for t-cell receptor function" SIGNOR-42972 ANKRD1 protein Q15327 UNIPROT NPPA protein P01160 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0000567 18273862 t "In vitro calpain-mediated degradation assays, coupled to reporter gene analysis in transfected HeLa cells, strongly suggested that this mutation enhances both the stability of the ANKRD1/CARP protein and its transcriptional repression activity upon the cardiac-specific atrial natriuretic factor (ANF) promoter." SIGNOR-253647 pazopanib chemical CHEBI:71219 ChEBI KDR protein P35968 UNIPROT "down-regulates activity" "chemical inhibition" -1 22037378 t Luana "Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here." SIGNOR-258262 SCHEMBL14517914 chemical CID:10016910 PUBCHEM CHEK2 protein O96017 UNIPROT down-regulates "chemical inhibition" 9606 20068082 t gcesareni "Xl844 (exelixis) a potent atp-competitive inhibitor of chk1 (ki, 2.2nm) and chk2 (ki, 0.07nm)." SIGNOR-163234 BRAF protein P15056 UNIPROT MAP2K1 protein Q02750 UNIPROT "up-regulates activity" phosphorylation Ser218 VSGQLIDsMANSFVG 10090 BTO:0000944 8131746 t lperfetto "Activation of mek family kinases requires phosphorylation of two conserved ser/thr residueserine residues 218 and 222 of human mek1 are the primary sites for phosphorylation by c-raf." SIGNOR-235475 dothiepin chemical CHEBI:36798 ChEBI SLC6A2 protein P23975 UNIPROT "down-regulates activity" "chemical inhibition" 9606 BTO:0000007 9537821 t miannu "At the human norepinephrine transporter, among the antidepressants desipramine was the most potent with a KD=0.83±0.05 nM. All the tetracyclic antidepressants, except mirtazapine, which is a structural analog of mianserin, were more potent at the norepinephrine transporter than at the serotonin transporter. Tomoxetine, considered from animal data to be very selective for the norepinephrine transporter, had high affinity for the human norepinephrine transporter (KD=2.03±0.06 nM). However, at the human serotonin transporter, tomoxetine was nearly as potent and close to that for dothiepin and venlafaxine. Venlafaxine, considered a serotonin and norepinephrine re-uptake inhibitor based on animal data, was very weak at the human norepinephrine transporter. Its KD value was 5× less that than for norepinephrine. All of the serotonin selective re-uptake inhibitors, with the exception of paroxetine, were also weak at the human norepinephrine transporter. " SIGNOR-258878 AR protein P10275 UNIPROT TMPRSS2 protein O15393 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 21761340 t lperfetto "The prostate-specific TMPRSS2 gene, while upregulated by AR activity in luminal cells, is also transcribed in basal populations, confirming that AR acts as an expression modulator." SIGNOR-253687 PIK-90 chemical CID:6857685 PUBCHEM PIK3CA protein P42336 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-206223 PPP2R2A protein P63151 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR "down-regulates activity" binding 10090 BTO:0000944 18042541 t gcesareni "Regulation of phosphorylation of Thr-308 of Akt, cell proliferation, and survival by the B55alpha regulatory subunit targeting of the protein phosphatase 2A holoenzyme to Akt.|Phosphorylation of Akt at regulatory residues Thr-308 and Ser-473 leads to its full activation. The protein phosphatase 2A (PP2A) has long been known to negatively regulate Akt activity. The PP2A holoenzyme consists of the structural |Here we report the identification of the specific B regulatory subunit that targets the PP2A holoenzyme to Akt. We found endogenous association of PP2A AB55C holoenzymes with Akt by co-immunoprecipitation analyses in pro-lymphoid FL5.12 cells.subunit (A), catalytic subunit (C), and a variable regulatory subunit (B)." SIGNOR-243526 GSK3B protein P49841 UNIPROT ESR1 protein P03372 UNIPROT up-regulates phosphorylation Ser106 PLNSVSPsPLMLLHP 9606 16076840 t gcesareni "The gsk-3 inhibitor lithium chloride was used to determine the role of gsk-3 in phosphorylation of ser-102, -104, and -106 and ser-118 in vivo and to explore the role of these serines in the regulation of eralpha function. Treatment of cells with lithium chloride resulted in dephosphorylation of ser-104 and -106 and ser-118, which suggests these serine residues as targets for gsk-3 in vivo. Our results further suggest that eralpha phosphorylation by gsk-3 stabilizes eralpha under resting conditions and modulates eralpha transcriptional activity upon ligand binding. Estradiol and phorbol ester cause phosphorylation of serine 118 in the human estrogen receptor. Potentiation of human estrogen receptor alpha transcriptional activation through phosphorylation of serines 104 and 106 by the cyclin a-cdk2 complex." SIGNOR-139320 PTPN2 protein P17706 UNIPROT KDR protein P35968 UNIPROT "down-regulates activity" dephosphorylation Tyr1214 VCDPKFHyDNTAGIS 9606 BTO:0000007 18840653 t "We show that a TCPTP substrate-trapping mutant interacts with VEGFR2. Moreover, TCPTP dephosphorylates VEGFR2 in a phosphosite-specific manner, inhibits its kinase activity and prevents its internalization from the cell surface. |The autophosphorylation sites Tyr1054/1059 and Tyr1214 were dephosphorylated by TCPTP (Fig. 4B). Tyr996, the functional significance of which is currently uncertain (Olsson et al., 2006), was a TCPTP target as well." SIGNOR-248401 "BBsome complex" complex SIGNOR-C288 SIGNOR RAB8A protein P61006 UNIPROT "up-regulates activity" binding 9606 17574030 t lperfetto "Interestingly, the BBSome is required for ciliogenesis but is dispensable for centriolar satellite function. This ciliogenic function is mediated in part by the Rab8 GDP/GTP exchange factor, which localizes to the basal body and contacts the BBSome." SIGNOR-262562 PRKCA protein P17252 UNIPROT TNNI3 protein P19429 UNIPROT "down-regulates activity" phosphorylation Ser166 LGARAKEsLDLRAHL -1 11121119 t lperfetto "In addition to the established phosphorylation sites (S22 and S23) we found that S38 and S165 were the other two main sites of phosphorylation. | Overphosphorylation of troponin I reduced its affinity for troponin C, as measured by isothermal titration microcalorimetry. Phosphorylation of S22/23A also decreased its affinity for troponin C indicating that phosphorylation of S38 and/or S165 impedes binding of troponin I to troponin C. Formation of a troponin I/troponin C complex prior to cAMP-dependent protein kinase treatment did not prevent overphosphorylation." SIGNOR-249069 AURKA protein O14965 UNIPROT FAF1 protein Q9UNN5 UNIPROT "down-regulates activity" phosphorylation Ser289 ITDVHMVsDSDGDDF 9606 18790738 t llicata "This study reports that aurora-a (aur-a) phosphorylates fas-associated factor-1 (faf1) at ser-289 and ser-29 our findings support the negative feedback regulation of aur-a via phosphorylation of the death-promoting protein, faf1" SIGNOR-180887 TFIIH complex SIGNOR-C457 SIGNOR POLR2A protein P24928 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser1892 TPKYSPTsPTYSPTS 9606 14662762 t lperfetto "Although there is some inconsistency in the literature, it is generally thought that cdk7, a component of the transcription factor (tf) iih, is a major ser-5 kinase, whereas cdk9, a component of positive transcription elongation factor (p-tef) b, is a major ser-2 kinase within cells. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination." SIGNOR-269346 SNUPN protein O95149 UNIPROT "U1 snRNP complex" complex SIGNOR-C480 SIGNOR "up-regulates quantity" relocalization 9606 BTO:0000567 9670026 t miannu "Here, we describe the isolation and cDNA cloning of a 45 kDa protein, termed snurportin1, which interacts specifically with m3G-cap but not m7G-cap structures. Snurportin1 enhances the m3G-capdependent nuclear import of U snRNPs in both Xenopus laevis oocytes and digitonin-permeabilized HeLa cells, demonstrating that it functions as an snRNP-specific nuclear import receptor." SIGNOR-272080 APC-c complex SIGNOR-C150 SIGNOR CCNF protein P41002 UNIPROT "down-regulates quantity by destabilization" ubiquitination 9606 27653696 t miannu "We show that cyclin F, a cell-cycle-regulated substrate receptor (F-box protein) for the SCF, is targeted for degradation by APC/C. Furthermore, we establish that Cdh1 is itself a substrate of SCF(cyclin F). Cyclin F loss impairs Cdh1 degradation and delays S-phase entry, and this delay is reversed by simultaneous removal of Cdh1." SIGNOR-266362 SRC protein P12931 UNIPROT IGF1R protein P08069 UNIPROT "up-regulates activity" phosphorylation Tyr1166 DIYETDYyRKGGKGL -1 7493944 t lperfetto "The insulin-like growth factor type I (IGF-I) receptor can become tyrosine phosphorylated and enzymatically activated either in response to ligand or because of the activity of the Src tyrosine kinaseWe mapped the sites of IGF-I receptor autophosphorylation to peptides representing three different receptor domains: tyrosines 943 and 950 in the juxtamembrane region; tyrosines 1131, 1135, and 1136 within the kinase domain; and tyrosine 1316 in the carboxyl-terminal domain." SIGNOR-246268 MAPK8 protein P45983 UNIPROT AP1 complex SIGNOR-C154 SIGNOR "up-regulates activity" phosphorylation Ser63 KNSDLLTsPDVGLLK 9534 BTO:0004055 8137421 t lperfetto "The jnk-mediated phosphorylation of both ser63 and ser73 within the transactivation domain of c-jun potentiates its transcriptional activity." SIGNOR-252354 FKBP5 protein Q13451 UNIPROT Synaptic_plasticity phenotype SIGNOR-PH158 SIGNOR up-regulates 10090 BTO:0000142 30685540 f Luana "Loss of FKBP5 Affects Neuron Synaptic Plasticity | In this study, a reduction in LTP in Fkbp5 knockout (KO) mice was observed when compared to WT mice, which correlated with changes to the glutamatergic and GABAergic signaling pathways." SIGNOR-265798 MAP3K1 protein Q13233 UNIPROT MAP2K7 protein O14733 UNIPROT up-regulates phosphorylation Ser271 ISGRLVDsKAKTRSA 9606 9312068 t lperfetto "Here we show that jnkk2, a novel member of the map kinase kinase family, was phosphorylated and activated by mekk1" SIGNOR-51207 MAPK1 protein P28482 UNIPROT RPS6K proteinfamily SIGNOR-PF26 SIGNOR "up-regulates activity" phosphorylation Thr573 AENGLLMtPCYTANF 9606 9687510 t lperfetto "Thus, MAPK1/ERK1 and MAPK2/ERK2 activate three closely related protein kinases known as MAPK_activated protein kinases_1a, _1b and _1c (MAPKAP_K1a/b/c; also known as RSK1/2/3)" SIGNOR-252753 FGF2 protein P09038 UNIPROT HBA1 protein P69905 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 8142649 f Regulation miannu "Basic fibroblast growth factor (bFGF) and transforming growth factor-beta 1 (TGF-beta) have both been shown to act on hematopoietic progenitor cells. bFGF antagonized the TGF-beta-mediated induction of hemoglobin in a dose-dependent manner, with 0.1 ng/mL bFGF inhibiting hemoglobin induction by 40% and 10 ng/mL bFGF completely abrogating hemoglobin production." SIGNOR-251796 Gbeta proteinfamily SIGNOR-PF4 SIGNOR SREBF1 protein P36956 UNIPROT "up-regulates activity" phosphorylation 9606 BTO:0000599 10915800 t "inferred from 70% family members" lperfetto "Map kinases erk1/2 phosphorylate sterol regulatory element-binding protein (srebp)-1a at serine 117 in vitro. mutation of serine 117 to alanine abolished erk2-mediated phosphorylation in vitro and the map kinase-related transcriptional activation of srebp-1a by insulin and platelet-derived growth factor in vivo." SIGNOR-270081 TARS1 protein P26639 UNIPROT tRNA(Thr) smallmolecule CHEBI:29180 ChEBI "down-regulates quantity" "chemical modification" 9606 25824639 t miannu "Here we show, using X-ray crystal structures and functional analyses, that a single molecule of borrelidin simultaneously occupies four distinct subsites within the catalytic domain of bacterial and human ThrRSs. These include the three substrate-binding sites for amino acid, ATP and tRNA associated with aminoacylation, and a fourth 'orthogonal' subsite created as a consequence of binding." SIGNOR-270501 "1-phosphatidyl-1D-myo-inositol 4-phosphate" smallmolecule CHEBI:17526 ChEBI "AP-1/clathrin vescicle" complex SIGNOR-C251 SIGNOR "form complex" binding 9606 23103167 t lperfetto "Clathrin-coated pits and vesicles are diffraction-limited objects with typical diameters ranging between 75 and 130 nm. The smaller ∼75 nm coats contain at least 36 copies of clathrin, a heterohexameric protein of three heavy chains and three light chains, and about half that number of copies of the heterotetrameric AP adaptor complex | Intracellular clathrin-coated vesicles contain AP1 or AP3 adaptors" SIGNOR-260675 RUNX3 protein Q13761 UNIPROT ING4 protein Q9UNL4 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0002384 17956589 f miannu "Comprehensive analysis using a cDNA microarray showed that RUNX3 upregulated 17 apoptosis-related genes (including FADD, TRAF6, caspase-2, ING1, ING4, Calpain 10, and DNase1) and downregulated 135 apoptosis-related genes (including FLIP, PEA15, TXN2, HSPD1, IKK, and TIAL1) in MKN-1 cells." SIGNOR-255096 MTOR protein P42345 UNIPROT AMOTL2 protein Q9Y2J4 UNIPROT "down-regulates activity" phosphorylation Ser759 SSSQRAAsLDSVATS 25998128 t lperfetto "AMOTL2 is phosphorylated at serine 760 by mTORC2. Mutation of AMOTL2 mimicking constitutive Ser(760) phosphorylation blocks its ability to bind and repress YAP leading to increased relative expression of known YAP gene targets." SIGNOR-272086 HSF1 protein Q00613 UNIPROT HSPA6 protein P17066 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 12813038 f miannu "These experiments suggest that HSF2 is involved in the stress response, but unlike the ubiquitous HSF1 operates in a cell-line specific manner through differential expression of alternatively spliced isoforms. Curiously, HSF2A could not be activated by heat shock in cells deficient in functional HSF1 and required the expression of HSF1 for heat induction of the hsp70B gene in cells." SIGNOR-254477 KDM4C protein Q9H3R0 UNIPROT H2AC4 protein P04908 UNIPROT "down-regulates activity" demethylation "Lys 10" GRGKQGGkARAKAKT 9606 29207681 t miannu "As one member of the Jumonji-C histone demethylase family, JMJD2C has the ability to demethylate tri- or di-methylated histone 3 and 2 in either K9 (lysine residue 9) or K36 (lysine residue 36) sites by an oxidative reaction, thereby affecting heterochromatin formation, genomic imprinting, X-chromosome inactivation, and transcriptional regulation of genes.JMJD2C has been proved to be a demethylase for H3K9 methylation, in the manner of catalyzing the demethylation of H3K9me3/me2 (the known repressive markers of gene regulation), a histone mark found in heterochromatin associated with euchromatic transcriptional silencing and heterochromatin formation" SIGNOR-263863 MPHOSPH10 protein O00566 UNIPROT IMP4 protein Q96G21 UNIPROT "up-regulates activity" binding -1 28813493 t miannu "Mpp10 represents a platform for the interaction of multiple factors within the 90S pre-ribosome. In eukaryotes, ribosome assembly is a highly complex process that involves more than 200 assembly factors that ensure the folding, modification and processing of the different rRNA species as well as the timely association of ribosomal proteins. One of these factors, Mpp10 associates with Imp3 and Imp4 to form a complex that is essential for the normal production of the 18S rRNA." SIGNOR-261174 MAPK1 protein P28482 UNIPROT POLR2A protein P24928 UNIPROT down-regulates phosphorylation Ser1675 SPSYSPTsPSYSPTS 9606 14662762 t lperfetto "Erk1/2 are major ser-5 kinases after h2o2 treatment. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination." SIGNOR-120100 BMP7 protein P18075 UNIPROT ACVR1/BMPR2 complex SIGNOR-C30 SIGNOR up-regulates binding 10090 BTO:0000165 11282024 t lperfetto "Bmp-4 and gdf-5 are known to bind to activin receptor-like kinase 3 (alk-3) and/or alk-6 (also termed bmp type ia and type ib receptors, respectively), whereas bmp-6 and bmp-7 preferentially bind to alk-2" SIGNOR-235364 "GABA-B receptor" complex SIGNOR-C336 SIGNOR GNB/GNG complex SIGNOR-C202 SIGNOR "up-regulates activity" binding 9606 BTO:0000938 20655485 t miannu "The main G b/g-dependent effectors of presynaptic GABAB receptors are P/Q-and N-type voltage-dependent Ca2+ channels. GABAB receptors inhibit these Ca2+ channels at excitatory and inhibitory terminals, thereby restricting neurotransmitter release." SIGNOR-265068 JUN protein P05412 UNIPROT SMAD4 protein Q13485 UNIPROT "up-regulates activity" binding 9615 9312063 t lperfetto "Our analysis of the regulation of dpc4 transcriptional activity by c-jun was consistent with the possibility that c-jun and dpc4 could interact and produce trans-activation of the 3tp-lux reporter." SIGNOR-236139 TCAP protein O15273 UNIPROT Sarcomere_organization phenotype SIGNOR-PH165 SIGNOR "up-regulates activity" binding 9606 BTO:0001103 9804419 t lperfetto "The giant muscle protein titin (connectin) is essential in the temporal and spatial control of the assembly of the highly ordered sarcomeres (contractile units) of striated muscle. " SIGNOR-264855 PPP1CB protein P62140 UNIPROT AKT1 protein P31749 UNIPROT down-regulates dephosphorylation Thr450 TAQMITItPPDQDDS 9606 20186153 t gcesareni "Akt activation is achieved through a series of phosphorylation steps, the first being akt phosphorylation at thr-450 by jnk kinases. Pp-1 acts as a major phosphatase to dephosphorylate akt at thr-450 and thus modulate its functions." SIGNOR-163965 HRAS protein P01112 UNIPROT PIK3CG protein P48736 UNIPROT up-regulates binding 9606 9727023 t gcesareni "Grb2 binds and activates sos, which then activates ras, and this activates p110 independently of p85. it was also described that ras interacts with pi3k in a direct manner. lysine residue 227 is essential for the interaction of ras with pi3k we show here, however, that in vivo there are marked quantitative differences in the ability of ki- and ha-ras to activate raf-1 and phosphoinositide 3 kinase. the mechanism of raf-1 activation is complex, but it is clear that one important role of ras is to recruit raf-1 to the plasma membrane where a series of events is initiated that ultimately leads to full raf-1 activation. These events include tyrosine, serine, and threonine phosphorylation plus interactions with ras, phospholipids, 14-3-3 proteins and their associated proteins, and possibly dimerization." SIGNOR-59816 "Immune complexes" stimulus SIGNOR-ST15 SIGNOR FCAR protein P24071 UNIPROT "up-regulates activity" relocalization 12768205 f lperfetto "Both monomeric and dimeric IgA can bind to FcalphaRI, and monomeric or dimeric IgA immune complexes can activate phagocytosis and other immune responses through the clustering of FcalphaRI" SIGNOR-264859 CDK1 protein P06493 UNIPROT PML protein P29590 UNIPROT down-regulates phosphorylation 9606 21840486 t gcesareni "Here, we show that klhl20, a cullin3 (cul3) substrate adaptor induced by hif-1, coordinates with the actions of cdk1/2 and pin1 to mediate hypoxia-induced pml proteasomal degradation." SIGNOR-176033 PTPRG protein P23470 UNIPROT MET protein P08581 UNIPROT "down-regulates activity" dephosphorylation Tyr1003 VSNESVDyRATFPED -1 25624455 t miannu "PTPRG activation by the P1-WD peptide affected the tyrosine phosphorylation of several signaling molecules. Data analysis identified 31 molecules whose phosphorylation was modified in a statistically significant manner (Table I). inhibition of ABL1, BMX, BTK, DAB1, ITGB1, JAK2, KDR, KIT, LIMK1, MET, PDGFRB, SHC1, and VCL correlates with tyrosine dephosphorylation. In contrast, SRC inhibition correlates with hyperphosphorylation of the inhibitory Tyr530 residue and with dephosphorylation of the activatory Tyr419. Moreover, CDK2 and CTTN inhibition correlates with a hyperphosphorylation of the inhibitory Tyr15 and Tyr470, respectively. In contrast, a subgroup of 13 proteins, including BLNK, DOK2, ERBB2, GRIN2B, INSR, PDGFRA, PRKCD, PXN, STAT1, STAT2, STAT3, STAT5A, and ZAP70, appears to be activated by PTPRG activity." SIGNOR-254712 USP15 protein Q9Y4E8 UNIPROT BRAP protein Q7Z569 UNIPROT "up-regulates quantity by stabilization" deubiquitination 9606 BTO:0000007 23105109 t miannu "Here we report on a novel interaction between the E3 ligase BRAP (also referred to as IMP), a negative regulator of the MAPK scaffold protein KSR, and two closely related deubiquitylases, USP15 and USP4. USP15 as well as USP4 oppose the autoubiquitylation of BRAP, whereas BRAP promotes the ubiquitylation of USP15." SIGNOR-272030 RPS6K proteinfamily SIGNOR-PF26 SIGNOR METTL1 protein Q9UBP6 UNIPROT down-regulates phosphorylation Ser27 YYRQRAHsNPMADHT 9606 BTO:0000007;BTO:0000567 15861136 t gcesareni "Pkb and ribosomal s6 kinase (rsk) both phosphorylated mettl1 at ser27 in vitro." SIGNOR-252800 GSK3B protein P49841 UNIPROT MYC protein P01106 UNIPROT "down-regulates quantity by destabilization" phosphorylation Thr58 KKFELLPtPPLSPSR 9606 16023596 t gcesareni "Similar to c-myc, we report here that phosphorylation of c-jun by gsk3 creates a high-affinity binding site for the e3 ligase fbw7, which targets c-jun for polyubiquitination and proteasomal degradation." SIGNOR-138603 MT-ND1 protein P03886 UNIPROT "Mitochondrial respiratory chain complex I" complex SIGNOR-C277 SIGNOR "form complex" binding 30030361 t lperfetto "Thus, we now know the complete mammalian cI structure [22,23] and how the subunits are organized in six modules (N, Q, ND1, ND2, ND4 and ND5)|The Q-module is built through the association of NDUFA5, NDUFS2 and NDUFS3 plus NDUFS7 and NDUFS8. The chaperones NDUFAF3/C3ORF60 and NDUFAF4/C6ORF66 [36,37] remain bound to this module until the final assembly steps [34]. NDUFAF6/C8ORF38 [38] also seems to participate in the assembly of the Q-module [24,39]. NDUFAF3, 4 and 6, are necessary to maintain normal MT-ND1 synthesis [40,41]. NDUFAF5 adds a hydroxyl group to Arg73 of NDUFS7 [42] and NDUFAF7 dimethylates NDUFS2 in Arg85 [43], an essential modification for cI assembly [44]. NUBPL/IND1 delivers [4Fe–4S] clusters specifically to the N- and Q-module subunits [45,46]." SIGNOR-262143 SLC36A4 protein Q6YBV0 UNIPROT proline smallmolecule CHEBI:26271 ChEBI "up-regulates quantity" relocalization 8355 21097500 t lperfetto "HPAT4 in Xenopus oocytes mediated sodium-independent, electroneutral uptake of [(3)H]proline, with the highest rate of uptake when the uptake medium pH was 7.4 and an affinity of 3.13 μM. Tryptophan was also an excellently transported substrate with a similarly high affinity (1.72 μM)." SIGNOR-264736 HSD17B1 protein P14061 UNIPROT 17beta-estradiol smallmolecule CHEBI:16469 ChEBI "up-regulates quantity" "chemical modification" -1 8994190 t Luana "Human 17 beta-hydroxysteroid dehydrogenase (17-HSD) type 1 catalyzes the conversion of the low activity estrogen, estrone, into highly active estradiol, both in the gonads and in target tissues. " SIGNOR-269760 PPP1CA protein P62136 UNIPROT AXIN1 protein O15169 UNIPROT "down-regulates activity" dephosphorylation Ser77 YEPEGSAsPTPPYLK 9606 17318175 t "The data suggest that PP1 controls Wnt signaling through interaction with, and regulated dephosphorylation of, axin| Axin phosphorylation markedly enhances the binding of glycogen synthase kinase 3, leading to a more active beta-catenin destruction complex. Wnt-regulated changes in axin phosphorylation, mediated by PP1, may therefore determine beta-catenin transcriptional activity| Four sites, S80, S82, S222, and S473, were identified to be PP1 regulated" SIGNOR-248552 CSNK2B protein P67870 UNIPROT CTNNB1 protein P35222 UNIPROT "up-regulates activity" phosphorylation Ser29 VSHWQQQsYLDSGIH 9606 BTO:0000007 12432063 t llicata "We show that CKII phosphorylates the N-terminal region of beta-catenin and we identified Ser29, Thr102, and Thr112 as substrates for the enzyme. We provide evidence that CKII regulates the cytoplasmic stability of beta-catenin and acts synergistically with GSK-3beta in the multi-protein complex that controls the degradation of beta-catenin" SIGNOR-251065 trimipramine chemical CHEBI:9738 ChEBI SLC6A3 protein Q01959 UNIPROT "down-regulates activity" "chemical inhibition" 9606 9537821 t miannu "At the human dopamine transporter, sertraline and nomifensine were the most potent with KD's of 25±2 and 56±3, respectively. Except for these two compounds, most antidepressants were not potent at the human dopamine transporter." SIGNOR-258740 PRKACA protein P17612 UNIPROT AQP5 protein P55064 UNIPROT "up-regulates activity" phosphorylation Ser156 STDSRRTsPVGSPAL 9606 BTO:0000007 26569106 t lperfetto "AQP5 can be directly phosphorylated by PKA at Ser 156 |Our data hint at a mechanism whereby phosphorylation of Ser 156 in AQP5 increases its membrane localization, thereby enhancing cancer cell proliferation." SIGNOR-272088 TINF2 protein Q9BSI4 UNIPROT "Shelterin complex" complex SIGNOR-C306 SIGNOR "form complex" binding 9606 BTO:0000567 15383534 t lperfetto "Telosome, a mammalian telomere-associated complex formed by multiple telomeric proteins|Gel filtration reveals a complex consisting of POT1 , RAP1, TRF1, ACD, TERF2 and TINF2 proteins." SIGNOR-263320 RBM8A protein Q9Y5S9 UNIPROT "Exon junction complex" complex SIGNOR-C369 SIGNOR "form complex" binding -1 16923391 t miannu "The EJC is deposited onto mRNA during splicing and is transported to the cytoplasm where it influences translation, surveillance, and localization of the spliced mRNA. The complex is formed by the association of four proteins (eIF4AIII, Barentsz [Btz], Mago, and Y14), mRNA, and ATP." SIGNOR-265242 EIF3E protein P60228 UNIPROT BCL2L1 protein Q07817 UNIPROT "up-regulates quantity" "translation regulation" 9606 "BTO:0000815; BTO:0001938" 20453879 f irozzo "Validated mRNA targets regulated positively at the translational level by eIF3e included urokinase-type plasminogen activator and apoptotic regulator BCL-XL, whereas synthesis of proteins including the mitotic checkpoint component MAD2L1 was negatively regulated. Taken together, our study data suggest that eIF3e has a positive role in breast cancer progression." SIGNOR-259156 Quadazocine chemical CID:115077 PUBCHEM OPRD1 protein P41143 UNIPROT "down-regulates activity" "chemical inhibition" 10029 BTO:0000246 9686407 t miannu "Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors." SIGNOR-258419 PRKCA protein P17252 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR down-regulates 9606 BTO:0000599 15730925 f irozzo "PKC-alpha asODN (antisense oligonucleotides) could inhibit the growth and proliferation of HepG2 and induce its apoptosis by blocking the cell signal transduction related to PKC-alpha in vitro, and may be potentially used in the prevention and management of recurrent and metastatic HCC." SIGNOR-256267 BMPR2 protein Q13873 UNIPROT BMPR1A protein P36894 UNIPROT "up-regulates activity" binding 10090 10712517 t ggiuliani "Using several complementary approaches, we investigated the formation of homomeric and heteromeric complexes between the two known BMP type I receptors (BR-Ia and BR-Ib) and the BMP type II receptor (BR-II). Coimmunoprecipitation studies detected the formation of heteromeric and homomeric complexes among all the BMP receptor types even in the absence of ligand." SIGNOR-255781 ATR protein Q13535 UNIPROT RPA2 protein P15927 UNIPROT unknown phosphorylation Ser33 GFGSPAPsQAEKKSR 9606 19843584 t llicata "Atr phosphorylates s33 in response to replication stress" SIGNOR-188666 HNRNPU protein Q00839 UNIPROT HOXA2 protein O43364 UNIPROT "up-regulates quantity by stabilization" "post transcriptional regulation" 17174306 f lperfetto "In the present study, we show that hnRNP-U specifically enhances the expression of tumor necrosis factor alpha mRNA by increasing its stability, possibly through binding to the 3' untranslated region. We also show that hnRNP-U enhances the expression of several other genes as well, including GADD45A, HEXIM1, HOXA2, IER3, NHLH2, and ZFY, by binding to and stabilizing these mRNAs." SIGNOR-262284 somatostatin smallmolecule CHEBI:64628 ChEBI SSTR3 protein P32745 UNIPROT "up-regulates activity" "chemical activation" 9606 BTO:0002524 31160049 t "Ligand-GPCR dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257583 PTPRG protein P23470 UNIPROT GRIN2B protein Q13224 UNIPROT "up-regulates activity" dephosphorylation Tyr1474 GSSNGHVyEKLSSIE -1 25624455 t miannu "PTPRG activation by the P1-WD peptide affected the tyrosine phosphorylation of several signaling molecules. Data analysis identified 31 molecules whose phosphorylation was modified in a statistically significant manner (Table I). inhibition of ABL1, BMX, BTK, DAB1, ITGB1, JAK2, KDR, KIT, LIMK1, MET, PDGFRB, SHC1, and VCL correlates with tyrosine dephosphorylation. In contrast, SRC inhibition correlates with hyperphosphorylation of the inhibitory Tyr530 residue and with dephosphorylation of the activatory Tyr419. Moreover, CDK2 and CTTN inhibition correlates with a hyperphosphorylation of the inhibitory Tyr15 and Tyr470, respectively. In contrast, a subgroup of 13 proteins, including BLNK, DOK2, ERBB2, GRIN2B, INSR, PDGFRA, PRKCD, PXN, STAT1, STAT2, STAT3, STAT5A, and ZAP70, appears to be activated by PTPRG activity." SIGNOR-254702 EGLN1 protein Q9GZT9 UNIPROT HIF1A protein Q16665 UNIPROT "down-regulates quantity by destabilization" hydroxylation 9606 BTO:0000567 32755251 t lperfetto "Hypoxia-inducible factor-1 (HIF-1) is a key regulator of erythropoiesis. In this article, we report 3 novel mutations, P378S, A385T, and G206C, on the EGLN1 gene encoding the negative HIF-1α regulator prolyl hydroxylase domain-2 (PHD2) in 3 patients with isolated erythrocytosis. These mutations impair PHD2 protein stability and partially reduce PHD2 activity, leading to increased HIF-1α protein levels in cultured cells.|Oxygen-dependent hydroxylation by the prolyl hydroxylase domain-2 (PHD2) protein marks HIF-1alpha for ubiquitination by the von Hippel Lindau (VHL) tumor suppressor protein, leading to proteasomal degradation" SIGNOR-261994 "MLL2 complex" complex SIGNOR-C88 SIGNOR H3-3A protein P84243 UNIPROT "down-regulates activity" methylation Lys5 kQTARKST 9606 24680668 t miannu "Dimethylation of h3k4 requires a sub-complex including wrad (wdr5, rbbp5, ash2l, and dpy-30), which binds to each set1 family member forming a minimal corecomplexthat is required for multiple lysine methylation." SIGNOR-268799 CSNK1A1 protein P48729 UNIPROT AHCYL1 protein O43865 UNIPROT unknown phosphorylation Ser77 SSTDSYSsAASYTDS 9534 17635105 t lperfetto "Residue 68 resides in a consensus phosphorylation site for PKD (Figure 1A) [22,23]. Interestingly, phosphorylation of Ser68 could allow for subsequent phosphorylation of Ser71, Ser74, Ser77 and Ser80 by CK1, for which the consensus phosphorylation site is pS/T-X-X-S/T" SIGNOR-249185 glucose chemical CHEBI:17234 ChEBI HK2 protein P52789 UNIPROT "up-regulates quantity by stabilization" 9606 BTO:0004424 26323688 t "Consistently, treatment of cells with 2-deoxy-d-glucose (2DG), which completely inhibits glucose metabolism, leads to HK2 degradation and cell death in combination with C43" SIGNOR-261323 KMT2D protein O14686 UNIPROT "MLL2 complex" complex SIGNOR-C88 SIGNOR "form complex" binding 9606 24680668 t miannu "The mixed lineage leukemia-1 (mll1) enzyme is a histone h3 lysine 4 (h3k4) monomethyltransferase and has served as a paradigm for understanding the mechanism of action of the human set1 family of enzymes that include mll1_Mll4 and setd1a,b. Dimethylation of h3k4 requires a sub-complex including wrad (wdr5, rbbp5, ash2l, and dpy-30), which binds to each set1 family member forming a minimal core complex that is required for multiple lysine methylation." SIGNOR-204816 APLNR protein P35414 UNIPROT GNAI1 protein P63096 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-256681 SH2B1 protein Q9NRF2 UNIPROT CD79B protein P40259 UNIPROT "down-regulates activity" dephosphorylation 9606 BTO:0000776 "SIGNOR-C433; SIGNOR-C434; SIGNOR-C435; SIGNOR-C436" 32323266 t scontino "SHP-1 is recruited by the phosphorylated ITIM-bearing receptors such as CD22 and it dephosphorylates proximal BCR signaling molecules such as CD79, SYK, BLNK." SIGNOR-268458 IL13 protein P35225 UNIPROT IL4R protein P24394 UNIPROT "up-regulates activity" binding 9606 19880493 t lperfetto "IL-4 and IL-13 have overlapping but distinct effects on MFs, dependent on a common IL-4R, with profound changes in the expression of a range of cellular proteins and functions broadly implicated in the regulation of inflammation and repair." SIGNOR-249528 TPR protein P12270 UNIPROT NPC complex SIGNOR-C263 SIGNOR "form complex" binding 27016207 t lperfetto "The protein inventory of the NPC has been studied for a very diverse set of eukaryotes, including trypanosomes, fungi, plants, animals, and humans [4], [5], [6], [7], [8], [9]. In all cases, about 30 different Nups were found (Fig. 2)." SIGNOR-262070 SP1 protein P08047 UNIPROT KLK3 protein P07288 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0001033 15708372 t "We characterized four Sp1/Sp3 binding sites in the proximal promoter of the PSA gene. In a luciferase assay, these sites contributed to the basal promoter activity in prostate cancer cells. In an electrophoretic mobility shift assay and chromatin immunoprecipitation assay, we confirmed that Sp1 and Sp3 bind to these sites. Overexpression of wild-type Sp1 and Sp3 further upregulated the promoter activity, whereas overexpression of the Sp1 dominant-negative form or addition of mithramycin A significantly reduced the promoter activity and the endogenous mRNA level of PSA." SIGNOR-253664 CCDC102B protein Q68D86 UNIPROT LRRC45 protein Q96CN5 UNIPROT "up-regulates activity" binding 30404835 t lperfetto "CCDC102B is recruited to the centrosome by C-Nap1 (also known as CEP250) and interacts with the centrosome linker components rootletin and LRRC45. CCDC102B decorates and facilitates the formation of rootletin filaments. Furthermore, CCDC102B is phosphorylated by Nek2A (an isoform encoded by NEK2) and is disassociated from the centrosome at the onset of mitosis." SIGNOR-275627 HOXC11 protein O43248 UNIPROT HNF1A protein P20823 UNIPROT up-regulates 9606 9582375 f miannu "The observed stimulatory effect of hoxc11 on hnf1_ may be due to a similar stabilizing effect on hnf1_ dna binding and/or an increase in transcriptional activity of hnf1_." SIGNOR-57484 Ub:E2 complex SIGNOR-C497 SIGNOR TRIM10 protein Q9UDY6 UNIPROT "up-regulates activity" ubiquitination 9606 34199813 t miannu "The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t" SIGNOR-270972 Gbeta proteinfamily SIGNOR-PF4 SIGNOR CIITA protein P33076 UNIPROT down-regulates phosphorylation 9606 18245089 t "inferred from 70% family members" gcesareni "In this study we show that the extracellular signal-regulated kinases 1 and 2 (erk1/2) interact directly with ciita, targeting serine residues in the amino terminus of the protein, including serine 288. These data suggest a model whereby erk1/2-mediated phosphorylation of ciita down-regulates ciita activity by priming it for nuclear export, thus providing a means for cells to tightly regulate the extent of antigen presentation." SIGNOR-270067 MAPK1 protein P28482 UNIPROT RPS6KB1 protein P23443 UNIPROT up-regulates phosphorylation Ser447 GSPRTPVsPVKFSPG 9606 14967450 t gcesareni "Erk phosphorylates multiple cytoplasmatic and cytoskeletal proteins, including mapk-activated protein kinases and the ribosomal p70-s6 kinase" SIGNOR-121988 "all-trans-retinoic acid" smallmolecule CHEBI:15367 ChEBI AFP protein P02771 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0000972 9792724 f miannu "In this report, we show a distinctive effect of all-trans-retinoic acid (RA) in Hep3B cells. RA caused a marked decrease in AFP transcripts." SIGNOR-254443 PTPN1 protein P18031 UNIPROT INSR protein P06213 UNIPROT "down-regulates activity" dephosphorylation Tyr1190 DIYETDYyRKGGKGL 9606 16582879 t "Binding of insulin to the IR results in autophosphorylation of each beta‐subunit on at least six different tyrosines. This autophosphorylation occurs first on three tyrosines located in the activation loop of the kinase domain (Y1158, 1162 and 1163), resulting in the stabilization of the kinase in an active conformation.|Termination of the signal involves inactivation of the IR by dephosphorylation of the three tyrosines of the kinase domain (Tonks, 2003). PTP1B is a protein tyrosine phosphatase located in the endoplasmic reticulum that has an important role in the dephosphorylation of these tyrosines after internalization of the IR" SIGNOR-248410 CDK1 protein P06493 UNIPROT NPM1 protein P06748 UNIPROT "down-regulates activity" phosphorylation Thr234 SFKKQEKtPKTPKGP 9606 14670079 t gcesareni "We have recently found that nucleophosmin (npm/b23), a phosphoprotein primarily found in nucleolus, associates with unduplicated centrosomes and is a direct substrate of cdk2-cyclin e in centrosome duplication." SIGNOR-120330 NRTN protein Q99748 UNIPROT GFRA1 protein P56159 UNIPROT up-regulates binding 9606 BTO:0000938 BTO:0000142 9182803 t gcesareni "A receptor complex comprised of trnr1 (gdnfr alpha) and ret was recently identified and found to be capable of mediating both gdnf and ntn signaling" SIGNOR-49119 PRKACA protein P17612 UNIPROT VASP protein P50552 UNIPROT unknown phosphorylation Ser239 GAKLRKVsKQEEASG 9606 12576312 t miannu "Three phosphorylation sites have been identified in VASP: Ser157, Ser239, and Thr278, all of which can be phosphorylated by either PKA or PKG in vitro" SIGNOR-250063 PRKACG protein P22612 UNIPROT MYBPC3 protein Q14896 UNIPROT up-regulates phosphorylation Ser275 LSAFRRTsLAGGGRR 9606 BTO:0000887 20151718 t miannu "Phosphorylation of cmybp-c by pka speeds actomyosin interactions and contributes to increased cardiac contractility following _-adrenergic stimulation.7, 8 phosphorylation by pka is essential for proper cardiac function /for the human isoform, three pka sites were previously identified (ser275, ser284, and ser304) /our results indicate that pka phosphorylates up to four sites in both the murine and human m-domains including a novel site not previously described for either protein (ser307 for mouse and ser311 for human)." SIGNOR-163784 LYRM4 protein Q9HD34 UNIPROT "Mitochondrial Fe-S Cluster Assembly Complex" complex SIGNOR-C276 SIGNOR "form complex" binding -1 27519411 t lperfetto "As the architecture of the human machinery remains undefined, we co-expressed in Escherichia coli the following four proteins involved in the initial step of Fe-S cluster synthesis: FXN42-210 (iron donor); [NFS1]·[ISD11] (sulfur donor); and ISCU (scaffold upon which new clusters are assembled). We purified a stable, active complex consisting of all four proteins with 1:1:1:1 stoichiometry." SIGNOR-262126 CSNK2A1 protein P68400 UNIPROT MDC1 protein Q14676 UNIPROT up-regulates phosphorylation 9606 19230643 t gcesareni "Mdc1 also undergoes phosphorylation by ck2 after dna damage to generate a phospho-motif on mdc1, which binds directly to nbs1." SIGNOR-184130 POMT2 protein Q9UKY4 UNIPROT POMT complex SIGNOR-C372 SIGNOR "form complex" binding 9606 BTO:0000007 16698797 t miannu " Here we have shown that POMT1 forms a complex with POMT2 and the complex possesses protein O-mannosyltransferase activity. Results indicate that POMT1 and POMT2 associate physically and functionally in vivo.  Mutations in the POMT1 and POMT2 genes are considered to be the cause of Walker-Warburg syndrome. Here, we have demonstrated that POMT1 and POMT2 form a functional complex in vivo using immunoprecipitating techniques. Furthermore, we showed that the mutations of POMT1 protein found in WWS patients do not prevent complex formation with POMT2 but they do abolish activity of the complex." SIGNOR-265429 CHMP4B protein Q9H444 UNIPROT ESCRT-III complex SIGNOR-C379 SIGNOR "form complex" binding -1 26775243 t miannu "The ESCRT machinery drives a diverse collection of membrane remodeling events, including multivesicular body biogenesis, release of enveloped retroviruses and both reformation of the nuclear envelope and cytokinetic abscission during mitotic exit. ESCRT-III subunits (CHMPs, for Charged Multivesicular Body Proteins [32], or Chromatin Modifying Proteins [33]) transition between soluble and polymerising states, and assemble in a defined order to form a membrane-remodeling filament that brings about membrane fission." SIGNOR-265533 CDK8 protein P49336 UNIPROT SMAD1 protein Q15797 UNIPROT down-regulates phosphorylation Ser214 PTSSDPGsPFQMPAD 9606 19914161 t lpetrilli "Phosphorylation of the linker region of smad1, a receptor-activated smad (r-smad), at serine 206 (s206) and s214 induced by bmp and mediated by cdk8/9 is critical for binding of the e3 ubiquitin ligase smurf1. Binding of smurf1 leads to polyubiquitination of smad1 and its degradation by the proteasome;cdk8 and cyclint-cdk9 showed a preference for s206 and s214 but also phosphorylated s186 and s195 in the case of smad1;and t179, s208 and s213 in the case of smad3." SIGNOR-189141 SLC27A1 protein Q6PCB7 UNIPROT "Fatty acid" stimulus SIGNOR-ST19 SIGNOR "up-regulates quantity" relocalization 9606 28457600 t miannu "Astrocytes and endothelial cells, two major components of the blood brain barrier, are the major contributors to the transportation of PUFAs from the circulation to brain. There are four classes of lipid transportation proteins involved in lipid synthesis and transportation in adult brain, including fatty acid translocase (FAT/CD36), caveolin-1, fatty acid binding proteins (FABPs) long chain acyl-coA synthase (ACS) and fatty acid transportation proteins (FATPs)." SIGNOR-264463 CHEK1 protein O14757 UNIPROT SYK protein P43405 UNIPROT down-regulates phosphorylation Ser295 GIISRIKsYSFPKPG 9606 22585575 t llicata "We found that chk1 phosphorylated the tumor suppressor spleen tyrosine kinase (l) (syk[l]) and identified the phosphorylation site at ser295. Furthermore, chk1 phosphorylation of syk(l) promoted its subsequent proteasomal degradation." SIGNOR-197528 valine smallmolecule CHEBI:27266 ChEBI Val-tRNA(Val) smallmolecule CHEBI:29164 ChEBI "up-regulates quantity" "precursor of" 9606 30755602 t miannu "Aminoacyl-tRNA synthetases (ARSs) function to transfer amino acids to cognate tRNA molecules, which are required for protein translation. VARS encodes the only known valine cytoplasmic-localized aminoacyl-tRNA synthetase." SIGNOR-270532 Laminin-8 complex SIGNOR-C181 SIGNOR "A6/b1 integrin" complex SIGNOR-C164 SIGNOR "up-regulates activity" binding 12123670 t lperfetto "We have developed a cell-free assay for binding of solubilized beta1 integrins to their physiologically relevant ligands using an electrochemiluminescent detection method|Binding was clearly optimal for the presumed physiological ligands, i.e., collagen IV for a1b1, collagen I for a2b1, VCAM-Ig for a4b1, fibronectin (the 120-kDa cell attachment fragment was used) for a5b1, and laminin for a6b1." SIGNOR-253220 CFL1 protein P23528 UNIPROT F-actin_assembly phenotype SIGNOR-PH18 SIGNOR "down-regulates quantity" binding 9606 BTO:0000132 27871158 t lperfetto "Cofilin also binds to actin and contributes to the disassembly of actin filaments and the subsequent release of actin monomers." SIGNOR-261836 carbamazepine chemical CHEBI:3387 ChEBI SCN2A protein Q99250 UNIPROT "down-regulates activity" "chemical inhibition" 10116 1658608 t miannu "This study examined the actions of phenytoin, carbamazepine, lidocaine, and verapamil on rat brain type IIA Na+ channels functionally expressed in mammalian cells, using the whole-cell voltage-clamp recording technique. The drugs blocked Na+ currents in both a tonic and use-dependent manner." SIGNOR-258353 "Class II MHC" complex SIGNOR-C428 SIGNOR "Class II MHC:Antigen" complex SIGNOR-C429 SIGNOR "form complex" binding 9606 33374673 t scontino "The major histocompatibility complex (MHC) molecules, or human leukocyte antigens (HLA) in humans, bind these peptides to present them to T cells that recognise them with their surface T cell receptors (TCR)." SIGNOR-267872 naloxone chemical CHEBI:7459 ChEBI OPRD1 protein P41143 UNIPROT "down-regulates activity" "chemical inhibition" 10029 BTO:0000246 9686407 t miannu "Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors." SIGNOR-258942 GSK3B protein P49841 UNIPROT AXIN1 protein O15169 UNIPROT "up-regulates activity" phosphorylation Thr481 HVQRVLRtPGRQSPG 9606 10581160 t "Axin residues T609 and S614 are physiological GSK3beta targets. Axin phosphorylation in the regulation of b-catenin stability. When active (left), GSK3b phosphorylates Axin as well as APC and b-catenin. The phosphorylated form of Axin binds strongly to b-catenin and promotes the phosphorylation of b-catenin by GSK3b, leading to strong interaction with b-TrCP" SIGNOR-251222 ARID5B protein Q14865 UNIPROT RUNX1 protein Q01196 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 29326336 f miannu "We also observed that ARID5B regulates the expression of four major components of the TAL1 complex (namely, TAL1,GATA3, RUNX1, and MYB) in Jurkat cells. Knockdown of ARID5B resulted in reductions of the H3K27ac signals at those enhancer loci (Supplemental Fig. S6E–H) and down-regulation of all four factors at the mRNA (Fig. 6E) and protein levels (Fig. 6F)." SIGNOR-256159 PAX7-FOXO1 "fusion protein" SIGNOR-FP11 SIGNOR SUV39H1 protein O43463 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 23435416 f lperfetto "In addition, KMT1A has recently been shown to play a role in ARMS by inhibiting myogenic differentiation. Although not shown directly, the authors speculated that KMT1A levels may be regulated by PAX3-FOXO1, as KMT1A expression was only increased on induction of differentiation in PAX3-FOXO1 positive cell lines" SIGNOR-249598 FERMT1 protein Q9BQL6 UNIPROT FBLIM1 protein Q8WUP2 UNIPROT "up-regulates activity" binding 10090 BTO:0000944 24165133 t miannu "Kindlin binds migfilin tandem LIM domains and regulates migfilin focal adhesion localization and recruitment dynamics. Two integrin-binding proteins present in FAs, kindlin-1 and kindlin-2, are important for integrin activation, FA formation, and signaling. By binding filamin, migfilin provides a link between kindlin and the actin cytoskeleton." SIGNOR-266103 "CKM complex" complex SIGNOR-C406 SIGNOR SMAD1 protein Q15797 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser214 PTSSDPGsPFQMPAD 9606 19914161 t lpetrilli "Phosphorylation of the linker region of smad1, a receptor-activated smad (r-smad), at serine 206 (s206) and s214 induced by bmp and mediated by cdk8/9 is critical for binding of the e3 ubiquitin ligase smurf1. Binding of smurf1 leads to polyubiquitination of smad1 and its degradation by the proteasome;cdk8 and cyclint-cdk9 showed a preference for s206 and s214 but also phosphorylated s186 and s195 in the case of smad1;and t179, s208 and s213 in the case of smad3." SIGNOR-273148 "CKM complex" complex SIGNOR-C406 SIGNOR NOTCH1 protein P46531 UNIPROT "down-regulates quantity by destabilization" phosphorylation 9606 15546612 t gcesareni "Purified recombinant cycc:cdk8 phosphorylates the notch icd within the tad and pest domains, and expression of cycc:cdk8 strongly enhances notch icd hyperphosphorylation and pest-dependent degradation by the fbw7/sel10 ubiquitin ligase in vivo." SIGNOR-273150 "CKM complex" complex SIGNOR-C406 SIGNOR SMAD3 protein P84022 UNIPROT "down-regulates activity" phosphorylation Ser208 DAGSPNLsPNPMSPA 9606 19914161 t lpetrilli "Similarly, tgf-?-Induced and cdk8/9-mediated phosphorylation of smad3 at threonine 179 (t179) is important for binding of the nedd4l e3 ubiquitin ligase, which accelerates smad3 turnover;cdk8 and cyclint-cdk9 showed a preference for s206 and s214 but also phosphorylated s186 and s195 in the case of smad1;and t179, s208 and s213 in the case of smad3." SIGNOR-273151 HDLBP protein Q00341 UNIPROT RAD51 protein Q06609 UNIPROT "up-regulates activity" binding 9606 BTO:0000150 33941620 t miannu "We show that vigilin interacts with the DNA damage response (DDR) proteins RAD51 and BRCA1, and vigilin depletion impairs their recruitment to DSB sites." SIGNOR-266697 AMBRA1 protein Q9C0C7 UNIPROT HUWE1 protein Q7Z6Z7 UNIPROT "up-regulates activity" relocalization 9606 BTO:0000567 phosphorylation:Ser1043 CRPEALNsGVEYYWD 30217973 t lperfetto "AMBRA1 regulates mitophagy at two critical steps. Upon mitophagy stimulation, AMBRA1 mediates the HUWE1 E3 ubiquitin ligase translocation from cytosol to mitochondria (light blue). AMBRA1 acts as a cofactor for HUWE1 E3 ubiquitin ligase activity, favouring its binding to its substrate MFN2 (and maybe other OMM substrates) and targeting it to the proteasome" SIGNOR-272962 AMBRA1 protein Q9C0C7 UNIPROT PPP2CB protein P62714 UNIPROT "up-regulates activity" binding 9606 BTO:0000567 25438055 t "phosphorylation site remapping based on mass spec table" lperfetto "We found that AMBRA1 favours the interaction between c-Myc and its phosphatase PP2A and that, when mTOR is inhibited, it enhances PP2A activity on this specific target, thereby reducing the cell division rate. As expected, such a de-regulation of c-Myc correlates with increased tumorigenesis in AMBRA1-defective systems, thus supporting a role for AMBRA1 as a haploinsufficient tumour suppressor gene." SIGNOR-272964 RPS6KA1 protein Q15418 UNIPROT VASP protein P50552 UNIPROT down-regulates phosphorylation Thr278 LARRRKAtQVGEKTP 9606 BTO:0000551 21423205 t lperfetto "Rsk1 phosphorylated vasp on t278, a site regulating its binding to actin." SIGNOR-172899 AGTR1 protein P30556 UNIPROT GNAI1 protein P63096 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-256738 SUZ12 protein Q15022 UNIPROT "Polycomb repressive complex 2" complex SIGNOR-C130 SIGNOR "form complex" binding 9606 23110252 t lperfetto "The PRC2 core, conserved from Drosophila to humans, is composed of four proteins that add up to about 230 kDa (Figure 1A) (see Margueron and Reinberg, 2010 for a recent review): EED (present in different isoforms), either one of the two methyltranferases Ezh1 or Ezh2 (Ezh1/2), Suz12, and either RbAp46 or RbAp48 (RbAp46/48)." SIGNOR-241900 MCHR2 protein Q969V1 UNIPROT GNAI3 protein P08754 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257180 RTN4 protein Q9NQC3 UNIPROT LINGO1 protein Q96FE5 UNIPROT up-regulates binding 9606 BTO:0000938 15694321 t flangone "Nogo-a, myelin-associated glycoprotein (mag), and oligodendrocyte myelin glycoprotein (omgp)...signal through a common receptor complex in neurons, which includes the ligand binding nogo-66 receptor (ngr), and two signal-transducing binding partners, p75 and lingo-1," SIGNOR-133752 WNT7A protein O00755 UNIPROT FZD3 protein Q9NPG1 UNIPROT "up-regulates activity" binding 9606 15578921 t gcesareni "Wnt proteins bind to the frizzled receptors and lrp5/6 co-receptors, and through stabilizing the critical mediator betBeta-catenin, initiate a complex signaling cascade that plays an important role in regulating cell proliferation and differentiation." SIGNOR-131897 IYD protein Q6PHW0 UNIPROT iodide smallmolecule CHEBI:16382 ChEBI "up-regulates quantity" "chemical modification" 9606 28153798 t scontino "MIT and DIT, which are deiodinated by iodotyrosine dehalogenase (DEHAL1) that seems to be present in the apical plasma membrane. MIT and DIT are liberated, and the deiodination of these molecules by DEHAL1 is important for providing a sustained source of intrathyroidal iodide." SIGNOR-267034 PHA-680632 chemical CID:11249084 PUBCHEM AURKA protein O14965 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-206097 PP1 proteinfamily SIGNOR-PF54 SIGNOR AXIN1 protein O15169 UNIPROT "down-regulates activity" dephosphorylation Ser217 YTRTGSEsPKVCSDQ 9606 17318175 t lperfetto "The data suggest that PP1 controls Wnt signaling through interaction with, and regulated dephosphorylation of, axin| Axin phosphorylation markedly enhances the binding of glycogen synthase kinase 3, leading to a more active beta-catenin destruction complex. Wnt-regulated changes in axin phosphorylation, mediated by PP1, may therefore determine beta-catenin transcriptional activity| Four sites, S80, S82, S222, and S473, were identified to be PP1 regulated" SIGNOR-264660 ZMYND8 protein Q9ULU4 UNIPROT MMP3 protein P08254 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0001033 27477906 t lperfetto "Our quantitative ChIP experiments confirmed that ZMYND8 and JARID1D were co-localized at Slug, CD44, VEGFA, and EGFR genes (Figures 4F–4I). Our ChIP results also showed that ZMYND8 repressed and occupied other JARID1D target genes, such as the matrix metalloproteinase 1 (MMP1) and MMP3, that we previously reported" SIGNOR-262043 CSNK2A2 protein P19784 UNIPROT SPIB protein Q01892 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser129 PYPSPVLsEEEDLPL 9606 BTO:0000567 10618498 t llicata "Phosphorylation of the Spi-B transcription factor reduces its intrinsic stability. | Serine residues 37 in the transactivation domain and 129, 144 and 146 in the PEST domain of Spi-B are phosphorylated by CKII in vitro | The CKII phosphorylation sites mapped in vitro are phosphorylated in vivo" SIGNOR-251039 Wnt proteinfamily SIGNOR-PF40 SIGNOR LRP6 protein O75581 UNIPROT "up-regulates activity" binding 9606 15578921 t Gianni "Wnt proteins bind to the frizzled receptors and lrp5/6 co-receptors, and through stabilizing the critical mediator betBeta-catenin, initiate a complex signaling cascade that plays an important role in regulating cell proliferation and differentiation." SIGNOR-131577 DUSP4 protein Q13115 UNIPROT ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR "down-regulates activity" dephosphorylation 10116 7535768 t "inferred from 70% of family members" "Dephosphorylation and Inactivation of ERKs|ERK1 phosphorylated on either threonine (ERK1*Y204F) or tyrosine alone (ERK1*T202A) was utilized as a substrate for HVH2. Threonine 202 and tyrosine 204 in ERK1 (53) correspond to threonine 183 and tyrosine 185 in ERK2 which are the activation-phosphorylation sites by MEK(14, 15, 16). ERK1*, a kinase-deficient mutant, was phosphorylated on both threonine and tyrosine by MEK2 (Fig. 3B). ERK1*T202A, having threonine 202 substituted by an alanine, was phosphorylated only on tyrosine while ERK1*Y204F, having tyrosine 204 substituted by a phenylalanine, was phosphorylated only on threonine (Fig. 3B). GST-HVH2 dephosphorylated all three ERK1* mutants (Fig. 3A), suggesting that double phosphorylations of adjacent threonine and tyrosine were not a prerequisite for HVH2 recognition. However, HVH2 dephosphorylated ERK1* and ERK1*T202A more efficiently than ERK1*Y204F (Fig. 3A), indicating that HVH2 preferred phosphotyrosine over phosphothreonine. Interestingly, MEK also phosphorylated tyrosine residues more efficiently than threonine residues of ERK" SIGNOR-269933 P2RY6 protein Q15077 UNIPROT GNAS protein Q5JWF2 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-256804 PA2G4 protein Q9UQ80 UNIPROT KLK3 protein P07288 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 16254079 t "Ectopic expression of ebp1, a member of the PA2G4 family, inhibits the proliferation and induces the differentiation of human breast and prostate cancer cell lines. Ebp1 inhibits transcription of E2F1 and androgen receptor regulated genes such as prostate specific antigen (PSA) through its interactions with histone deacetylases (HDACs)" SIGNOR-253662 NGFR protein P08138 UNIPROT MAPK10 protein P53779 UNIPROT up-regulates 9606 14699954 f amattioni "Jnk3 is expressed exclusively in the nervous system and recent evidence indicates that this jnk isoform may be required for p75ntr-mediated cell death" SIGNOR-120561 KLHL20 protein Q9Y2M5 UNIPROT ULK1 protein O75385 UNIPROT "down-regulates quantity by destabilization" binding 9606 BTO:0000007 26687681 t miannu "Cul3-KLHL20 Ubiquitin Ligase Governs the Turnover of ULK1 and VPS34 Complexes to Control Autophagy Termination. KLHL20 promotes ubiquitination of phagophore-residing VPS34 and Beclin-1" SIGNOR-272413 E2F2 protein Q14209 UNIPROT TFDP1 protein Q14186 UNIPROT "up-regulates activity" binding 10029 BTO:0000246 8832394 t 2 miannu "The transcriptionally active forms of E2F are heterodimers composed of one polypeptide encoded by the E2F gene family and one polypeptide encoded by the DP gene family.In transfected cells, DP-1 did not accumulate in the nucleus unless it was coexpressed with the heterodimeric partners E2F-1, E2F-2, or E2F-3." SIGNOR-240550 TP53 protein P04637 UNIPROT TNFRSF10B protein O14763 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 14585074 f "Nuclear p53" amattioni "Cd95l, cd95, and the trail death receptors are induced by the tumour suppressor p53" SIGNOR-113707 MAPK14 protein Q16539 UNIPROT COL1A1 protein P02452 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 22298955 f gcesareni "(tak1) and tak1 binding protein 1 (tab1) play a pivotal role as upstream sig-nal transducers by activating the mkk3-p38 mapk signaling cascade that leads to the induction of type i collagen expression by tgf-beta1." SIGNOR-192796 DCC protein P43146 UNIPROT CACNA1D protein Q01668 UNIPROT "up-regulates activity" 9606 12827203 t miannu "DCC activation by a netrin-1 gradient creates a high-level [Ca2+]i gradient by triggering LCC activity and by stimulating the cAMP–PKA pathway, which further activates LCC in the plasma membrane (PM) and Ca2+ channels in the ER." SIGNOR-268292 PTEN protein P60484 UNIPROT STAT5A protein P42229 UNIPROT down-regulates dephosphorylation 9606 20596030 t miannu "The forced expression of pten in the eol-1r cells dephosphorylated akt, erk and stat5 /eol-1r cells showed epigenetic silencing of the phosphatase and tensin homolog deleted on chromosome ten (pten) gene. Exposure of eol-1r cells to imatinib failed to dephosphorylate akt, erk and stat5, although pdgfr? Was effectively inactivated. The forced expression of pten negatively regulated these signal pathways and sensitized eol-1r cells to imatinib." SIGNOR-166481 vilanterol chemical CHEBI:75037 ChEBI ADRB2 protein P07550 UNIPROT "up-regulates activity" "chemical activation" 10030 20462258 t Luana "A series of saligenin β2 adrenoceptor agonist antedrugs having high clearance were prepared by reacting a protected saligenin oxazolidinone with protected hydroxyethoxyalkoxyalkyl bromides, followed by removal of the hydroxy-protecting group, alkylation, and final deprotection. The compounds were screened for β2, β1, and β3 agonist activity in CHO cells. | Compound 13f had high potency, selectivity, fast onset, and long duration of action in vitro and was found to have long duration in vivo" SIGNOR-257843 MCHR1 protein Q99705 UNIPROT GNAS protein Q5JWF2 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-256762 UBE3C protein Q15386 UNIPROT CAND2 protein O75155 UNIPROT "down-regulates quantity by destabilization" ubiquitination 10090 BTO:0000165 12692129 t miannu "We show that KIAA10 indeed associates with 26 S proteasomes in mammalian cells but that this interaction is likely to depend on contacts with a subunit(s) besides S2/Rpn1. Most importantly, we provide strong evidence that TIP120B (TBP-interacting protein 120B (22)) is a specific substrate that is targeted for degradation in skeletal muscle through KIAA10-catalyzed polyubiquitination." SIGNOR-271454 CHEK2 protein O96017 UNIPROT CDC25A protein P30304 UNIPROT "down-regulates quantity" phosphorylation Ser124 PALKRSHsDSLDHDI 9606 12676583 t Manara "Chk2 phosphorylates a subset of the Chk1-targeted sites of Cdc25A | Phosphorylation of serines 123, 178, 278, and 292 regulates both basal and IR-induced accelerated proteolysis of Cdc25A" SIGNOR-260835 PLK1 protein P53350 UNIPROT BRCA2 protein P51587 UNIPROT "down-regulates activity" phosphorylation Ser193 AEVDPDMsWSSSLAT 9606 BTO:0001938 12815053 t lperfetto "M phase-specific phosphorylation of brca2 by polo-like kinase 1 correlates with the dissociation of the brca2-p/caf complex.Plk1 interacts with brca2 in vivo, and mutation of ser193, ser205/206, and thr203/207 to ala in br-n1 abolished plk1 phosphorylation, suggesting that brca2 is the substrate of plk1" SIGNOR-102486 Ub:E2 complex SIGNOR-C497 SIGNOR UBE4B protein O95155 UNIPROT "up-regulates activity" ubiquitination 9606 34199813 t miannu "The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t" SIGNOR-271275 PRKCI protein P41743 UNIPROT EZR protein P15311 UNIPROT up-regulates phosphorylation Thr567 QGRDKYKtLRQIRQG 9606 BTO:0000195 18270268 t llicata "Pkciota phosphorylated ezrin on t567 in vitro, and in sf9 cells that do not activate human ezrin. we conclude that, although other molecular mechanisms contribute to ezrin activation, apically localized phosphorylation by pkciota is essential for the activation and normal distribution of ezrin at the early stages of intestinal epithelial cell differentiation." SIGNOR-160855 "AIIB/b3 integrin" complex SIGNOR-C173 SIGNOR Platelet_Adhesion phenotype SIGNOR-PH137 SIGNOR up-regulates 9606 BTO:0000132 25297919 f lperfetto "VWF binding to GPIb-IX-V induces platelet activation, converting the major integrin αIIbβ3 from a low affinity to a high affinity receptor capable of engaging the C4 domain of VWF. This last step is essential for stable adhesion" SIGNOR-261867 ABL1 protein P00519 UNIPROT PSMA7 protein O14818 UNIPROT down-regulates phosphorylation Tyr153 QTDPSGTyHAWKANA 9606 16678104 t lperfetto "Proteasome-mediated proteolysis is a primary protein degradation pathway in cells. The present study demonstrates that c-abl and arg (abl-related gene) tyrosine kinases associate with and phosphorylate the proteasome psma7 (alpha4) subunit at tyr-153. Consequently, proteasome-dependent proteolysis is compromised" SIGNOR-146585 CDC14A protein Q9UNH5 UNIPROT MAPK6 protein Q16659 UNIPROT "down-regulates quantity by destabilization" dephosphorylation Ser688 QFHSPVGsPLKSIQA 9606 20236090 t "Reciprocally, we found that the phosphatases Cdc14A and Cdc14B (Cdc is cell-division cycle) bind to ERK3 and reverse its C-terminal phosphorylation in mitosis. Importantly, alanine substitution of the four C-terminal phosphorylation sites markedly decreased the half-life of ERK3 in mitosis, thereby linking phosphorylation to the stabilization of the kinase.|In vitro phosphorylation of a series of ERK3-deletion mutants by mitotic cell extracts revealed that phosphorylation is confined to the unique C-terminal extension of the protein. Using MS analysis, we identified four novel phosphorylation sites, Ser684, Ser688, Thr698 and Ser705, located at the extreme C-terminus of ERK3." SIGNOR-248831 MAPK3 protein P27361 UNIPROT POLR2A protein P24928 UNIPROT down-regulates phosphorylation Ser1766 SPSYSPTsPSYSPTS 9606 14662762 t lperfetto "Erk1/2 are major ser-5 kinases after h2o2 treatment. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination." SIGNOR-120212 SP1 protein P08047 UNIPROT PCYT1A protein P49585 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 7227 BTO:0001677 10744779 t Luana "Sp1 and Sp3 function as transcriptional activators of the Ctpct promoter" SIGNOR-266231 GGCX protein P38435 UNIPROT GAS6 protein Q14393 UNIPROT "up-regulates activity" carboxylation 9606 31226734 t lperfetto "Thus, vitamin K acts as a cofactor for GGCX via the vitamin K cycle and exerts physiological effects through its regulation of VKDPs [29]. More than 20 VKDPs have been found. Osteocalcin promotes bone formation, and blood coagulation factors II, VII, IX, and X activate blood coagulation. Matrix Gla protein suppresses cardiovascular calcification, and brain-expressed Gas 6 promotes neural differentiation [29]. GGCX is an enzyme that converts glutamic acid (Glu) residues to Gla residues, so that the Gla-containing proteins can exert various physiological actions such as blood coagulation and bone formation." SIGNOR-265923 GRM2 protein Q14416 UNIPROT calcium(2+) smallmolecule CHEBI:29108 ChEBI "up-regulates quantity" relocalization 9606 29953871 t miannu "Ca2+ is arguably the most important second messenger in the brain because of its pivotal roles in presynaptic neurotransmitter release, postsynaptic responses, and plasticity induction. iGluRs and mGluRs can generate intracellular Ca2+ signals, albeit by different mechanisms, whose crosstalk has not been thoroughly explored (Figure 2C). iGluRs allow the influx of extracellular Ca2+ upon pore opening." SIGNOR-264933 COX5B protein P10606 UNIPROT Skeletal_muscle_differentiation phenotype SIGNOR-PH1 SIGNOR down-regulates 10090 BTO:0000165 18701479 f lperfetto "Together, these data suggest that R-cadherin expression inhibits myogenesis and induces myoblast transformation through Rac1 activation. Therefore, the properties of R-cadherin make it an attractive target for therapeutic intervention in RMS." SIGNOR-253104 RYK protein P34925 UNIPROT FZD8 protein Q9H461 UNIPROT up-regulates binding 9606 17035295 t gcesareni "Interaction between ryk and fz has been reported, suggesting that the two proteins may form a multi-receptor complex signalling through the canonical pathway" SIGNOR-150010 TFIIH complex SIGNOR-C457 SIGNOR POLR2A protein P24928 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser1951 SPGYSPTsPTYSLTS 9606 14662762 t lperfetto "Although there is some inconsistency in the literature, it is generally thought that cdk7, a component of the transcription factor (tf) iih, is a major ser-5 kinase, whereas cdk9, a component of positive transcription elongation factor (p-tef) b, is a major ser-2 kinase within cells. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination." SIGNOR-269341 S1PR1 protein P21453 UNIPROT GNAZ protein P19086 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257108 CHD2 protein O14647 UNIPROT H3-3A protein P84243 UNIPROT "up-regulates quantity" relocalization 9606 26895424 t miannu "Non-homologous end-joining (NHEJ) is the dominant DSB repair pathway in human cells, but our understanding of how it operates in chromatin is limited. Here, we define a mechanism that plays a crucial role in regulating NHEJ in chromatin. This mechanism is initiated by DNA damage-associated poly(ADP-ribose) polymerase 1 (PARP1), which recruits the chromatin remodeler CHD2 through a poly(ADP-ribose)-binding domain. CHD2 in turn triggers rapid chromatin expansion and the deposition of histone variant H3.3 at sites of DNA damage." SIGNOR-264527 TRIM31 protein Q9BZY9 UNIPROT KIF21B protein O75037 UNIPROT "up-regulates activity" binding 24086586 t "Here we show that the ubiquitin E3 ligase TRIM3, also known as BERP, interacts with KIF21B via its RBCC domain ||he E3-ligase function of TRIM3 is not involved in KIF21B degradation, however TRIM3 depletion reduces the motility of the motor. Together, our data suggest that TRIM3 is a regulator in the modulation of KIF21B motor function" SIGNOR-272479 PRKDC protein P78527 UNIPROT PRKDC protein P78527 UNIPROT "up-regulates activity" phosphorylation Thr2620 QGTLQTRtQEGSLSA -1 12186630 t lperfetto "We have identified seven in vitro autophosphorylation sites in DNA-PKcs. Six of these sites (Thr2609, Ser2612, Thr2620, Ser2624, Thr2638 and Thr2647) are clustered in a region of 38 amino acids in the central region of the protein. Five of these sites (Thr2609, Ser2612, Thr2638, Thr2647 and Ser3205) are conserved between six vertebrate species. Moreover, we show that DNA-PKcs is phosphorylated in vivo at Thr2609, Ser2612, Thr2638 and Thr2647 in okadaic acid-treated human cells. | Thus phosphorylation of DNA-PKcs at one or more of the autophosphorylation sites identified in this study is likely to be required for DNA-PKcs function." SIGNOR-249158 MAPK8 protein P45983 UNIPROT NFATC2 protein Q13469 UNIPROT down-regulates phosphorylation 9606 BTO:0000782 14517246 t gcesareni "Jnks directly phosphorylate nuclear factor of activated t-cell (nfat) transcription factors, thus antagonizing the effects of calcium-regulated signaling through the protein phosphatase calcineurin jnk directly regulated nuclear factor of activated t-cell (nfat) activation in culture and in transgenic mice containing an nfat-dependent luciferase reporter." SIGNOR-118217 SIRT1 protein Q96EB6 UNIPROT CTNNB1 protein P35222 UNIPROT "up-regulates quantity" deacetylation 10090 BTO:0002572 27776347 t "SIRT1 deacetylates β-catenin to promote its accumulation in the nucleus and thus induces the transcription of genes that block MSC adipogenesis." SIGNOR-256208 4-(trimethylammonio)butanoate smallmolecule CHEBI:16244 ChEBI carnitine smallmolecule CHEBI:17126 ChEBI "up-regulates quantity" "precursor of" 9606 11802770 t miannu "In the last step, butyrobetaine is hydroxylated on the 3-position by γ-butyrobetaine dioxygenase (BBD; EC 1.14.11.1) to yield carnitine." SIGNOR-269701 SEC24B protein O95487 UNIPROT "COPII vesicle" complex SIGNOR-C370 SIGNOR "form complex" binding 9606 BTO:0000567 30605680 t lperfetto "The Core Components of COPII Vesicles from HeLa Cells|Membrane-bound Sar1 then recruits the inner COPII coat subcomplex, the Sec23/24 heterodimer. Subsequently, together with cargo proteins recruited by the Sec24 subunit, Sar1 and Sec23/24 assemble into so-called pre-budding complexes. Finally, outer coat subcomplexes, comprising heterotetrameric Sec13/31 complexes, are recruited onto pre-budding complexes to complete the two-layered COPII coat" SIGNOR-265290 NatA complex SIGNOR-C415 SIGNOR Protein_acetylation phenotype SIGNOR-PH189 SIGNOR up-regulates 9606 21351257 f miannu "About 80% of soluble human proteins are N-terminally acetylated by 1 of 3 major Nα-terminal acetyltransferase complexes, hNatA, hNatB and hNatC, which differ in their subunit composition and substrate specificity." SIGNOR-267229 "sorafenib tosylate" chemical CHEBI:50928 ChEBI FLT4 protein P35916 UNIPROT "down-regulates activity" "chemical inhibition" -1 16757355 t miannu "Further characterization of sorafenib revealed that this molecule was a multikinase inhibitor that targeted the vascular endothelial growth factor receptor family (VEGFR-2 and VEGFR-3) and platelet-derived growth factor receptor family (PDGFR-beta and Kit), which play key roles in tumor progression and angiogenesis. The in vitro and cellular profile of sorafenib is summarized in Table I." SIGNOR-259224 CDC14B protein O60729 UNIPROT MAPK6 protein Q16659 UNIPROT down-regulates dephosphorylation Thr698 KSIQATLtPSAMKSS 9606 20236090 t lperfetto "Using ms analysis, we identified four novel phosphorylation sites, ser684, ser688, thr698 and ser705, located at the extreme c-terminus of erk3.alanine substitution of the four c-terminal phosphorylation sites markedly decreased the half-life of erk3 in mitosis, thereby linking phosphorylation to the stabilization of the kinase.we found that the phosphatases cdc14a and cdc14b (cdc is cell-division cycle) bind to erk3 and reverse its c-terminal phosphorylation in mitosis." SIGNOR-164483 AHCYL1 protein O43865 UNIPROT PAPOLB protein Q9NRJ5 UNIPROT "down-regulates activity" binding 9606 BTO:0000007 19224921 t lperfetto "Inositol 1,4,5-triphosphate receptor-binding protein released with inositol 1,4,5-triphosphate (IRBIT) associates with components of the mRNA 3' processing machinery in a phosphorylation-dependent manner and inhibits polyadenylation|In addition to CPSF, IRBIT interacted in vitro with poly(A) polymerase (PAP), which is the enzyme recruited by CPSF to elongate the poly(A) tail, and inhibited PAP activity in a phosphorylation-dependent manner." SIGNOR-268331 APOBEC3F protein Q8IUX4 UNIPROT "Clearance_of_foreign intracellular_DNA" phenotype SIGNOR-PH132 SIGNOR up-regulates 9606 29367246 f lperfetto "The apolipoprotein B mRNA editing enzyme catalytic polypeptide-like 3 (APOBEC3, or A3) family of interferon-inducible cytidine deaminases functions as antiviral restriction factors (reviewed in reference 15). Humans express seven A3 family members: A3A, A3B, A3C, A3D, A3F, A3G, and A3H (16, 17). A3A is notable in that it specifically targets and restricts foreign DNA elements. A3A binds to single-stranded DNA with a high affinity (18), mediates the catabolism of foreign DNA (19), and restricts infection of several DNA viruses, including HPV (20,–24)." SIGNOR-261327 MAPK1 protein P28482 UNIPROT AEBP1 protein Q8IUX7 UNIPROT "up-regulates activity" phosphorylation Thr621 GEPEFRYtAGIHGNE 10090 BTO:0000944 15654748 t miannu "We show that DNA binding by AEBP1 requires both the N- and C-terminal domains of AEBP1, and MAPK interaction with AEBP1 (through its N terminus) results in enhanced DNA binding. A threonine at position 623 within the C-terminal domain of AEBP1 plays an important role in DNA binding by AEBP1, because the mutation results in decreased DNA binding by AEBP1, which leads to a decrease in the transcriptional repression ability of AEBP1. We also show that in vitro phosphorylation of AEBP1 by MAPK is greatly reduced upon mutation of T623. These results suggest that MAPK regulates the transcriptional activity of AEBP1 by a novel dual mechanism, in which MAPK interaction enhances and subsequent phosphorylation decreases the DNA-binding ability of AEBP1." SIGNOR-262897 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR MASTL protein Q96GX5 UNIPROT "up-regulates activity" phosphorylation Thr194 NMMDILTtPSMAKPR 8355 22354989 t gcesareni "We propose a model in which the initiating event for Gwl activation is phosphorylation by MPF of the proline-directed sites T193 and T206 in the presumptive activation loop" SIGNOR-243403 CDH23 protein Q9H251 UNIPROT "TIP-LINK complex" complex SIGNOR-C291 SIGNOR "form complex" binding 10090 BTO:0000630 23217710 t lperfetto "The adaptor proteins harmonin and SANS, and the motor protein myosin 7a (Myo7a) bind in vitro to each other and to CDH23 (Adato et al., 2005; Bahloul et al., 2010; Boeda et al., 2002; Siemens et al., 2002) and co-localize at the upper insertion site of tip links (Grati and Kachar, 2011; Grillet et al., 2009b), suggesting that they form a protein complex important for transduction." SIGNOR-262579 PTK2B protein Q14289 UNIPROT PTK2B protein Q14289 UNIPROT up-regulates phosphorylation Tyr402 CSIESDIyAEIPDET 9606 15105428 t llicata "Overexpression of pyk2 alone led to its spontaneous activation and tyrosine phosphorylation, resulting in activation of stat5b, indicated by the reporter gfp-stat5b. These effects were completely dependent upon tyr(402), the autophosphorylation site of pyk2, which allows recruitment of src family members for further activating phosphorylations at other sites on pyk2." SIGNOR-124339 TAF10 protein Q12962 UNIPROT TFIID complex SIGNOR-C343 SIGNOR "form complex" binding 9606 27096372 t miannu "The general transcription factor IID (TFIID) plays a central role in the initiation of RNA polymerase II (Pol II)-dependent transcription by nucleating pre-initiation complex (PIC) assembly at the core promoter. TFIID comprises the TATA-binding protein (TBP) and 13 TBP-associated factors (TAF1-13), which specifically interact with a variety of core promoter DNA sequences." SIGNOR-263926 GSK3B protein P49841 UNIPROT CTNNB1 protein P35222 UNIPROT "down-regulates activity" phosphorylation Ser37 YLDSGIHsGATTTAP 9606 BTO:0000938 BTO:0000142 SIGNOR-C110 19303846 t gcesareni "DISC1 inhibits GSK3beta activity through direct physical interaction, which reduces beta-catenin phosphorylation and stabilizes beta-catenin." SIGNOR-184785 MAPK1 protein P28482 UNIPROT NUP153 protein P49790 UNIPROT unknown phosphorylation Thr388 VYFKPSLtPSGEFRK 9606 19767751 t llicata "These results indicate that phosphorylation of nup153 and nup214 by erk strongly reduces their affinity for importin-. nup153 depletion caused a strong inhibition of nuclear accumulation of gfp?importin-beta in both erk-inhibited and erk-activated cells (fig. 8b,c), indicating that nup153 is essential for the efficient importin-beta transport." SIGNOR-188127 SCF-betaTRCP complex SIGNOR-C5 SIGNOR IKBKB protein O14920 UNIPROT "down-regulates quantity by destabilization" ubiquitination 9606 BTO:0001321 20068069 t miannu "CLU-2 is a ubiquitin binding protein (UBP) that enhances proteasome activity. sCLU promotes degradation of COMMD1. sCLU interacts with the SCF-βTrCP E3 ligase complex, serving as a scaffolding chaperone to form a multimeric protein complex that facilitates COMMD1 and I-κB ubiquitination and proteasomal degradation." SIGNOR-271431 NCOA1 protein Q15788 UNIPROT PCK2 protein Q16822 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000599 16891307 f miannu "Overexpression of SRC1 and PGC1alpha by recombinant adenoviruses led to a significant up-regulation of well characterized HNF4alpha-dependent genes (ApoCIII, ApoAV, PEPCK, AldoB, OTC, and CYP7A1) and forced HepG2 cells toward a more differentiated phenotype as demonstrated by increased ureogenic rate." SIGNOR-255066 GGCX protein P38435 UNIPROT F9 protein P00740 UNIPROT "up-regulates activity" carboxylation Glu72 MEEKCSFeEAREVFE 10090 BTO:0001103 11133752 t lperfetto "The direct gamma-carboxyglutamic acid analysis and the N-terminal sequence analysis of the myotube-synthesized F.IX demonstrate efficient carboxylation at 11 of 12 γ-carboxyglutamic acid residues. |In previous work54 we have demonstrated that the γ-glutamyl carboxylase is present in skeletal muscle, but at a level only 5% to 10% of that found in the liver. This level of enzyme appears to be sufficient to provide full carboxylation of F.IX synthesized in myotubes|Glu 7, 8, 15, 17, 20, 21, 26, 27, 30, 33, and 36 are each less than 10% of the yield at the previous and subsequent cycles. Only a single γ-carboxylated residue, Gla 40, was not assessed by N-terminal sequencing." SIGNOR-263692 IL4R protein P24394 UNIPROT IL2RG protein P31785 UNIPROT up-regulates binding 9606 8266078 t gcesareni "Il-2r gamma was demonstrated to be a component of the il-4 receptor on the basis of chemical cross-linking data, the ability of il-2r gamma to augment il-4 binding affinity, and the requirement for il-2r gamma in il-4-mediated phosphorylation of insulin receptor substrate-1." SIGNOR-37362 GART protein P22102 UNIPROT N(2)-formyl-N(1)-(5-phospho-beta-D-ribosyl)glycinamide(2-) smallmolecule CHEBI:147286 ChEBI "up-regulates quantity" "chemical modification" 9606 33179964 t miannu "The second enzyme in the DNPB pathway is trifunc tional GART (TGART), whose domains and activities include: glycinamide ribonucleotide synthase (GARS) that catalyzes the ATP-dependent process that uses 5- PRA and Gly to make glycinamide ribonucleotide (GAR); glycinamide ribonucleotide transformylase (GART) that transfers the formyl group of N10-formyltetrahydrofolate to GAR, generating formylglycinamide ribonucleotide (FGAR); and aminoimidazole ribonucleotide synthase (AIRS) that converts formylglycinamidine ribonucleotide (FGAM) to aminoimidazole ribonucleotide (AIR) in an ATP-dependent manner." SIGNOR-267305 INSR protein P06213 UNIPROT PTPN1 protein P18031 UNIPROT "up-regulates activity" phosphorylation Tyr152 ISEDIKSyYTVRQLE -1 11506178 t lperfetto "Tyrosine residues 66, 152 and/or 153 of PTP1B are phosphorylated by the activated insulin receptor and are also necessary for formation of the PTP1B:insulin receptor complex| Furthermore, tyrosine phosphorylation of PTP1B by the insulin receptor tyrosine kinase increases the catalytic activity of PTP1B" SIGNOR-249368 MECOM protein Q03112 UNIPROT GATA2 protein P23769 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000565 15889140 t Luana "Evi1 directly binds to the promoter region of GATA-2 and thus enhances the GATA-2 transcription." SIGNOR-266062 CyclinD/CDK4 complex SIGNOR-C18 SIGNOR RUNX3 protein Q13761 UNIPROT down-regulates phosphorylation Ser356 SSSGGDRsPTRMLAS 9606 19351720 t lperfetto "Our findings demonstrate that the cell cycle proteins cyclin d1 and cdk4 induce runx2 and runx3 phosphorylation, ubiquitylation and proteasomal degradation." SIGNOR-216980 MAPK7 protein Q13164 UNIPROT MAP2K5 protein Q13163 UNIPROT up-regulates phosphorylation Ser142 AVSDSLPsNSLKKSS 9606 BTO:0000671 12628002 t lperfetto "Phosphorylation and activation of extracellular-signal-regulated protein kinase 5 (erk5) by mitogen-activated protein kinase kinase 5 (mkk5)activated erk5 also phosphorylated mitogen-activated protein kinase kinase 5 (mkk5) extensively at ser(129), ser(137), ser(142) and ser(149)" SIGNOR-99135 CDK1 protein P06493 UNIPROT NUP98 protein P52948 UNIPROT "down-regulates activity" phosphorylation Ser623 RDSENLAsPSEYPEN 9606 21335236 t gcesareni "We show that npc disassembly is a phosphorylation-driven process, dependent on cdk1 activity and supported by members of the nima-related kinase (nek) family. mitotic hyperphosphorylation of nup98 is accomplished by multiple kinases, including cdk1 and neks." SIGNOR-172221 "lysophosphatidic acid" smallmolecule CHEBI:132742 ChEBI LPAR5 protein Q9H1C0 UNIPROT "up-regulates activity" "chemical activation" 9606 BTO:0002524 31160049 t "Ligand-GPCR dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257532 ERBB2 protein P04626 UNIPROT SHC1 protein P29353 UNIPROT up-regulates binding 9606 10085134 t gcesareni "Shc interacts with and is an excellent substrate for erbb2 and appears to play an important role in mitogenic signaling through this receptor tyrosine kinase" SIGNOR-65579 LSM-1231 chemical CHEBI:91471 ChEBI NTRK2 protein Q16620 UNIPROT "down-regulates activity" "chemical inhibition" -1 22037378 t Luana "Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here." SIGNOR-258239 HDAC2 protein Q92769 UNIPROT HPGD protein P15428 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 10090 19010907 f miannu "We show an interaction between Snail and HDAC2 and the binding of HDAC2 to the 15-PGDH promoter. These data suggest that class I HDACs, specifically HDAC2, and the transcriptional repressor Snail play a central role in the suppression of 15-PGDH expression." SIGNOR-254236 tRNA(Ser) smallmolecule CHEBI:29179 ChEBI Ser-tRNA(Ser) smallmolecule CHEBI:29162 ChEBI "up-regulates quantity" "precursor of" 9606 24095058 t miannu "As a member of the aminoacyl-tRNA synthetase family, seryl-tRNA synthetase (SerRS) catalyzes the aminoacylation reaction that charges serine onto its cognate tRNA for protein synthesis" SIGNOR-270499 "Cullin 3-RBX1-Skp1" complex SIGNOR-C526 SIGNOR GRIK2 protein Q13002 UNIPROT "down-regulates quantity by destabilization" polyubiquitination 9534 BTO:0000298 17062563 t miannu "Here, we report that actinfilin is able to bind to GluR6, a kainate-type glutamate receptor subunit, and target GluR6 for degradation. Like many members of its protein family, actinfilin acts as a substrate adaptor, binding Cullin 3 (Cul3) and linking GluR6 to the E3 ubiquitin-ligase complex. Together our data demonstrate that actinfilin acts as a scaffold, linking GluR6 to the Cul3 ubiquitin ligase to provide a novel mechanism for kainate receptor degradation." SIGNOR-271614 PRKG1 protein Q13976 UNIPROT SF1 protein Q15637 UNIPROT "down-regulates activity" phosphorylation Ser20 PSKKRKRsRWNQDTM 10116 BTO:0000947 10449420 t lperfetto "PKG phosphorylates SF1 at Ser20, which inhibits the SF1-U2AF65 interaction leading to a block of pre-spliceosome assembly. Mutation of Ser20 to Ala or Thr also inhibits the interaction with U2AF65, indicating that Ser20 is essential for binding." SIGNOR-249018 belinostat chemical CHEBI:61076 ChEBI HDAC1 protein Q13547 UNIPROT "down-regulates activity" "chemical inhibition" -1 17868033 t Luana "Our findings suggest that hydroxamic acid-derived compounds such as TSA, NVP-LAQ824, panobinostat, ITF2357, vorinostat and belinostat act as potent pan-HDAC isoform inhibitors. A notable observation was the similarity between belinostat and vorinostat in the biochemical isoform assays; both compounds exhibit similar EC50 values in all but the HDAC8 assay." SIGNOR-257747 STK11 protein Q15831 UNIPROT SIK1 protein P57059 UNIPROT "up-regulates activity" phosphorylation Thr182 KSGEPLStWCGSPPY 9606 18946175 t miannu "Salt inducible kinase (SIK) 1, a member of the AMP-activated kinase (AMPK) family, is activated by the AMPK-activator LKB1 which phosphorylates SIK1 at Thr182." SIGNOR-262844 E2F1 protein Q01094 UNIPROT TYMS protein P04818 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000972 14618416 f miannu "To assess transactivating activity of E2F1/DP-1, we also analyzed expression of ten putative transcriptional targets of this complex in HCCs. Expression levels of TFDP1 and E2F1 correlated with those of seven transcriptional targets ( TYMS, DHFR, PCNA, RRM1, CCNE1, CDC2, and MYBL2) that play important roles in the G1/S transition, and down-regulation of TFDP1 inhibited growth of Hep3B cells." SIGNOR-253863 IL19 protein Q9UHD0 UNIPROT IL20RB protein Q6UXL0 UNIPROT up-regulates binding 9606 17208301 t gcesareni "Il-19 signals only through the type i il-20r complex." SIGNOR-151820 BCL2L11 protein O43521 UNIPROT BAX protein Q07812 UNIPROT "up-regulates activity" binding 9606 17289999 t lperfetto "Contrary to the direct-activation model, we show that Bax and Bak can mediate apoptosis without discernable association with the putative BH3-only activators (Bim, Bid, and Puma), even in cells with no Bim or Bid and reduced Puma. Our results indicate that BH3-only proteins induce apoptosis at least primarily by engaging the multiple pro-survival relatives guarding Bax and Bak" SIGNOR-152986 azelastine chemical CHEBI:2950 ChEBI HRH1 protein P35367 UNIPROT "down-regulates activity" "chemical inhibition" 10030 BTO:0000246 21381763 t Luana "Azelastine was used as a standard, with affinities (pKi) for H1 and H3 8.9 and 6.8, respectively. " SIGNOR-257894 CLU protein P10909 UNIPROT COMMD1 protein Q8N668 UNIPROT "down-regulates quantity by destabilization" binding 9606 BTO:0001321 20068069 t miannu "CLU-2 is a ubiquitin binding protein (UBP) that enhances proteasome activity. sCLU promotes degradation of COMMD1. sCLU interacts with the SCF-βTrCP E3 ligase complex, serving as a scaffolding chaperone to form a multimeric protein complex that facilitates COMMD1 and I-κB ubiquitination and proteasomal degradation." SIGNOR-271432 "all-trans-retinoic acid" smallmolecule CHEBI:15367 ChEBI HNF4G protein Q14541 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0000972 9792724 f miannu "Retinoic acid mediates down-regulation of the alpha-fetoprotein gene through decreased expression of hepatocyte nuclear factors. The levels of HNF1 and HNF4 mRNA were also decreased following RA treatment." SIGNOR-254444 ADORA2A protein P29274 UNIPROT GNAI1 protein P63096 UNIPROT "up-regulates activity" binding 9606 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257038 KIF16B protein Q96L93 UNIPROT "Plus-end directed sliding movement" phenotype SIGNOR-PH216 SIGNOR up-regulates 9606 19773780 f "In general, N-kinesins and C-kinesins drive microtubule plus end- and minus end-directed motilities, respectively, and M-kinesins depolymerize microtubules1,9 (Box 1).|Forty-five genes that encode kinesin superfamily proteins (also known as KIFs) have been discovered in the mouse and human genomes.|KIFs are molecular motors that directionally transport various cargos, including membranous organelles, protein complexes and mRNAs, along the microtubule system." SIGNOR-272527 KCNC2 protein Q96PR1 UNIPROT potassium(1+) smallmolecule CHEBI:29103 ChEBI "down-regulates quantity" relocalization 9606 11506885 t miannu "Kv3 currents are activated specifically during action potential repolarization. Analysis of the Kv3 subfamily of K+ channel subunits has lead to the discovery of a new class of neuronal voltage-gated K+ channels characterized by positively shifted voltage dependencies and very fast deactivation rates. These properties are adaptations that allow these channels to produce currents that can specifically enable fast repolarization of action potentials without compromising spike initiation or height" SIGNOR-265585 MDH2 protein P40926 UNIPROT oxaloacetate(2-) smallmolecule CHEBI:16452 ChEBI "up-regulates quantity" "chemical modification" 9606 24068518 t miannu "Malate is dehydrogenated to produce oxaloacetate by the enzyme Malate Dehydrogenase. In this reaction NAD is converted to NADH2. Oxaloacetate formed in this reaction reacts with acetyl-CoA to form citrate in order to start another round of the citric acid cycle" SIGNOR-266286 TGFB1 protein P01137 UNIPROT HBA1 protein P69905 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 8142649 f Regulation miannu "Basic fibroblast growth factor (bFGF) and transforming growth factor-beta 1 (TGF-beta) have both been shown to act on hematopoietic progenitor cells. bFGF antagonized the TGF-beta-mediated induction of hemoglobin in a dose-dependent manner, with 0.1 ng/mL bFGF inhibiting hemoglobin induction by 40% and 10 ng/mL bFGF completely abrogating hemoglobin production." SIGNOR-251798 MAPK1 protein P28482 UNIPROT RUNX1 protein Q01196 UNIPROT "up-regulates activity" phosphorylation Thr273 SPSVHPAtPISPGRA 9606 16046550 t "The effect has been demonstrated using Q01196-8" miannu "We have identified four phosphorylation sites on AML1c that are necessary for transcriptional activity of AML1c in K562 and 293T cells (27).4 Mutation of these four sites (serine 276, serine 293, serine 303, and threonine 300) to alanine abolishes transcriptional activation, whereas mutation of these sites to aspartic acid (which mimics phosphorylation) results in a hyperactive protein. The presence of these mutations results in an increase in the amount of ubiquitinated AML1c in the matrix, and increases the half-life of this insoluble AML1c. One possible model to explain these observations is that phosphorylation might be necessary for the normal process of both proteasome degradation and transcriptional activation." SIGNOR-138981 PP1 proteinfamily SIGNOR-PF54 SIGNOR IKZF1 protein Q13422 UNIPROT up-regulates dephosphorylation 9606 21750978 t lperfetto "Ikarosis dephosphorylated by protein phosphatase 1 (pp1) via interaction at a consensus pp1-binding motif/ hyperphosphorylation of ikaros promotes its degradation by the ubiquitin/proteasome pathway" SIGNOR-264663 Ub:E2 complex SIGNOR-C497 SIGNOR TRIM21 protein P19474 UNIPROT "up-regulates activity" ubiquitination 9606 34199813 t miannu "The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t" SIGNOR-271063 GRK2 protein P25098 UNIPROT CXCR2 protein P25025 UNIPROT "down-regulates activity" phosphorylation 10090 BTO:0000763 22634615 t miannu "Upon activation, GRK2 phosphorylates CXCR2 and causes receptor desensitization and internalization, leading to down-regulation of neutrophil chemotaxis" SIGNOR-260647 AURKA protein O14965 UNIPROT NDEL1 protein Q9GZM8 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser251 LTPSARIsALNIVGD 10090 17060449 t miannu "Here, we show that Aurora-A phosphorylates NDEL1 at Ser251 at the beginning of mitotic entry. Interestingly, NDEL1 phosphorylated by Aurora-A was rapidly downregulated thereafter by ubiquitination-mediated protein degradation." SIGNOR-263159 SHANK3 protein Q9BYB0 UNIPROT GRIA1 protein P42261 UNIPROT "up-regulates quantity" binding 9606 BTO:0000938 28179641 t miannu "SHANK proteins are ‘master’ scaffolding proteins that tether and organize intermediate scaffolding proteins. They are located at excitatory synapses, where they are crucial for proper synaptic development and function. SAPAP proteins subsequently bind to the PDZ domain of members of the SHANK protein family. SHANK proteins then bind to the actin cytoskeleton and to Homer protein, which in turn interacts with mGluRs. Through these extended links, PSD95, SAPAP, SHANK and Homer proteins form a quaternary complex that brings together mGluR and NMDAR complexes in the PSD (FIG. 3)." SIGNOR-264601 CyclinA2/CDK2 complex SIGNOR-C83 SIGNOR POLM protein Q9NP87 UNIPROT "down-regulates activity" phosphorylation Thr21 SGDAASStPPSTRFP -1 23933132 t miannu " In vitro kinase assays showed that the S phase-associated Cdk2/cyclin A complex was able to phosphorylate Polμ. We identified Ser12, Thr21 (located in the BRCT domain) and Ser372 (located in loop1) as the target residues. Mutation of these residues to alanine indicated that Ser372 is the main phosphorylation site.Our evidences suggest that Polμ could be regulated in vivo by phosphorylation of the BRCT domain (Ser12/Thr21) and of Ser372, affecting the function of loop1." SIGNOR-273598 MTOR protein P42345 UNIPROT EIF4EBP2 protein Q13542 UNIPROT down-regulates phosphorylation 9606 23100465 t gcesareni "Here, we show that cancer cells acquire resistance to astori by downregulating eukaryotic translation initiation factor (eif4e)-binding proteins (4e-bps-eif4ebp1, eif4ebp2)." SIGNOR-199258 SOX9 protein P48436 UNIPROT DCC protein P43146 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0003858 19745029 f miannu "Promoter analysis and transfection studies showed that the up-regulation of DCC in OA chondrocytes may be mediated by the transcription factors Sox9 and AP-2." SIGNOR-255188 CSNK2A1 protein P68400 UNIPROT SLBP protein Q14493 UNIPROT "down-regulates quantity by destabilization" phosphorylation Thr61 ERRPESFtTPEGPKP 9606 phosphorylation:Thr62 RRPESFTtPEGPKPR 18490441 t lperfetto "Phosphorylation of Thr61 is necessary for subsequent phosphorylation of Thr60 by CK2 in vitro. Inhibitors of CK2 also prevent degradation of SLBP at the end of S phase. Thus, phosphorylation of Thr61 by cyclin A/Cdk1 primes phosphorylation of Thr60 by CK2 and is responsible for initiating SLBP degradation." SIGNOR-265260 RET protein P07949 UNIPROT RET protein P07949 UNIPROT up-regulates phosphorylation Tyr1090 TNTGFPRyPNDSVYA 9606 14711813 t llicata "Mass spectrometric analysis revealed that ret tyr(806), tyr(809), tyr(900), tyr(905), tyr(981), tyr(1062), tyr(1090), and tyr(1096) were autophosphorylation sites." SIGNOR-121145 PTPN18 protein Q99952 UNIPROT ERBB2 protein P04626 UNIPROT "down-regulates quantity by destabilization" dephosphorylation Tyr1248 PTAENPEyLGLDVPV 9606 BTO:0000007 25081058 t lperfetto "PTPN18 knockdown selectively enhances the EGF-induced tyrosine phosphorylation of the HER2 Y1112, Y1196 and Y1248 sites. |Whereas the catalytic domain of PTPN18 blocks lysosomal routing and delays the degradation of HER2 by dephosphorylation of HER2 on pY(1112), the PEST domain of PTPN18 promotes K48-linked HER2 ubiquitination and its rapid destruction via the proteasome pathway and an HER2 negative feedback loop." SIGNOR-262597 ABL1 protein P00519 UNIPROT ERCC6 protein Q03468 UNIPROT "up-regulates activity" phosphorylation Tyr932 GANRVVIyDPDWNPS 9606 17626041 t Regulation miannu "N-terminal region of CSB interacts with the SH3 domain of c-Abl in vitro and in vivo. In addition, c-Abl kinase phosphorylates CSB at Tyr932. our results suggest that c-Abl interacts with and tyrosine phosphorylates CSB. This interaction may play an important role in the response to oxidative stress, resulting in activation of c-Abl, tyrosine phosphorylation of CSB and more efficient BER of oxidative DNA damage. Tyrosine-phosphorylated CSB may serve as a signal for repair proteins to localize to DNA damage and may help maintain active transcription in the nucleolus." SIGNOR-251933 CEBPA protein P49715 UNIPROT ELANE protein P08246 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0004408 19620402 f miannu "The ELA2 gene promoter is positively regulated by the direct binding of LEF-1 or C/EBPalpha, documenting the role of LEF1 in the diminished ELA2 expression." SIGNOR-253769 5-[(2,2-difluoro-1,3-benzodioxol-5-yl)methylidene]thiazolidine-2,4-dione chemical CHEBI:94690 ChEBI PIK3CG protein P48736 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-189912 N-[4-[(2-amino-3-chloro-4-pyridinyl)oxy]-3-fluorophenyl]-4-ethoxy-1-(4-fluorophenyl)-2-oxo-3-pyridinecarboxamide chemical CHEBI:91409 ChEBI AXL protein P30530 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-190401 GRIN1 protein Q05586 UNIPROT "NMDA receptor_2D" complex SIGNOR-C350 SIGNOR "form complex" binding 9606 BTO:0000938 12871085 t miannu "The NMDA receptor, a ligand-gated ion channel composed of the NR1 and NR2 subunits, is located mainly at synapses of CNS neurons. The NMDA receptor subtypes are encoded by three gene families that process mRNA transcripts to yield six distinct subunits (NR1, NR2A-2D, NR3A). Receptors are thought to be tetrameric complexes of two NR1 and two NR2 subunits" SIGNOR-264126 LARP7 protein Q4G0J3 UNIPROT HEXIM1 protein O94992 UNIPROT "down-regulates activity" binding 9606 BTO:0000567 30824372 t Monia "To investigate whether LARP7 is part of the known 7SK RNP implicated in the regulation of transcription, co‐immunoprecipitation studies were performed using the nuclear extracts of HeLa cells (Fig 3A, lanes 1–4). Antibodies against LARP7, CDK9 and HEXIM1 efficiently precipitated 7SK RNA, whereas no RNA was found in the control (Fig 3A, lower panel, lanes 1–4). Interestingly, HEXIM1, CDK9, CYCT1 and LARP7 were present in all immunopurifications, as determined by mass spectrometry of silver‐stained gels (Fig 3A; data not shown) and western blotting. In conclusion, these experiments show that LARP7 negatively regulates not only viral but also cellular POLII class genes through the 7SK P‐TEFb system." SIGNOR-261183 CSNK1A1 protein P48729 UNIPROT SNCA protein P37840 UNIPROT "down-regulates activity" phosphorylation Ser129 NEAYEMPsEEGYQDY 9606 10617630 t lperfetto "In vitro experiments and two-dimensional phosphopeptide mapping provided further evidence that serine 129 was phosphorylated by ck-1 and ck-2. Moreover, phosphorylation of serine 129 was reduced in vivo upon inhibition of ck-1 or ck-2.| together, these data may indicate that ck-1 and ck-2 are involved in the regulation of neuronal function and one may speculate that phosphorylation of alpha-synuclein could affect its binding to membranes." SIGNOR-73795 ATR protein Q13535 UNIPROT DBF4 protein Q9UBU7 UNIPROT down-regulates phosphorylation Ser502 FSTDNSGsQPKQKSD 9606 22123827 t lperfetto "Dbf4/cdc7 (dbf4-dependent kinase (ddk)) is activated at the onset of s-phase, and its kinase activity is required for dna replication initiation from each origin. We identified novel atm/atr phosphorylation sites on dbf4 and showed that atm/atr-mediated phosphorylation of dbf4 is critical for the intra-s-phase checkpoint to inhibit dna replication." SIGNOR-177805 MBP protein P02686 UNIPROT Myelination phenotype SIGNOR-PH206 SIGNOR up-regulates 31066630 f SimoneGraziosi "Myelin basic protein (MBP) is essential for the compaction of the two adjacent cytoplasmic membrane surfaces into the major dense line of myelin." SIGNOR-269230 HOXA10 protein P31260 UNIPROT PHGDH protein O43175 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 19778996 f miannu "PHGDH is expressed in both endometrial epithelial and stromal cells. HOXA10 represses endometrial PHGDH expression." SIGNOR-254468 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR SP3 protein Q02447 UNIPROT up-regulates phosphorylation 9606 17685427 t "inferred from 70% family members" gcesareni "Here, we show that sp3, which, as sp1, belongs to the gc-rich binding transcription factor family, is also phosphorylated by erk in vitro on serine 73." SIGNOR-270165 EXOSC4 protein Q9NPD3 UNIPROT Exosome_Complex complex SIGNOR-C255 SIGNOR "form complex" binding -1 24189234 t miannu "The RNA exosome is an evolutionarily conserved multi-protein complex involved in the 3' degradation of a variety of RNA transcripts. In the nucleus, the exosome participates in the maturation of structured RNAs, in the surveillance of pre-mRNAs and in the decay of a variety of noncoding transcripts. In the cytoplasm, the exosome degrades mRNAs in constitutive and regulated turnover pathways. The eukaryotic exosome, however, is composed of nine different subunits that are still somewhat related in sequence to the archaeal Rrp41-like subunits (Rrp41, Rrp46 and Mtr3), the archaeal Rrp42-like subunits (Rrp45, Rrp43 and Rrp42) and the cap proteins (Rrp4, Csl4 and Rrp40)." SIGNOR-261383 MAP2K1 protein Q02750 UNIPROT ARRB2 protein P32121 UNIPROT "up-regulates activity" phosphorylation Thr382 EFDTNYAtDDDIVFE 9606 BTO:0000007 28169830 t "Here, we show that activation of serotonin 5-HT2C receptors, which engage Erk1/2 pathway via a _-arrestin-dependent mechanism, promotes MEK-dependent _-arrestin2 phosphorylation at Thr383" SIGNOR-252027 TTF2 protein Q9UNY4 UNIPROT CDC5L protein Q99459 UNIPROT "up-regulates quantity by stabilization" binding 9606 BTO:0000567 12927788 t miannu "HLodestar/HuF2 associates with CDC5L in cell lysates and HeLa nuclear extracts. It is possible that during the cell division cycle, hLodestar/HuF2’s associates with transcription/splicing complexes in order to inhibit transcription/splicing prior to the start of mitosis and/or functions in stabilizing nuclear complexes containing splicing factors (e.g., the CDC5L complex) so that these are available for re-initiation of splicing at the end of mitosis when gene expression is re-established in cells." SIGNOR-224460 PPP1CA protein P62136 UNIPROT MECOM protein Q03112 UNIPROT "down-regulates activity" dephosphorylation Ser726 PLKMEPQsPGEVKKL 23858473 t "phosphorylation site remapping based on Fig 5" lperfetto "We also identified EVI1 phosphorylation sites by MS analysis and showed that Ser538 and Ser858 can be phosphorylated and dephosphorylated by two EVI1 interactome proteins, casein kinase II and protein phosphatase-1α. Finally, mutations that impair EVI1 phosphorylation at these sites reduced EVI1 DNA binding through its C-terminal zinc finger domain and induced cancer cell proliferation." SIGNOR-273430 domperidone chemical CHEBI:31515 ChEBI DRD2 protein P14416 UNIPROT "down-regulates activity" "chemical inhibition" 10029 BTO:0000246 1975644 t miannu "Molecular cloning and characterization of a novel dopamine receptor (D3) as a target for neuroleptics. A dopamine receptor has been characterized which differs in its pharmacology and signalling system from the D1 or D2 receptor and represents both an autoreceptor and a postsynaptic receptor. Table1. pharmacology of D2 and D3 receptors expressed in CHO cells." SIGNOR-258380 NPM1 protein P06748 UNIPROT CENPA protein P49450 UNIPROT "up-regulates activity" binding 9606 BTO:0000567 19410544 t miannu "Here we demonstrate that prenucleosomal CENP-A is complexed with histone H4, nucleophosmin 1, and HJURPA minority of NPM1 cofractionated with prenucleosomal CENP-A, consistent with only a small proportion of total NPM1 stably associated with CENP-A. The partial overlap of NPM1 and HJURP with each other supports their formation of distinct prenucleosomal complexes with CENP-A. it is also possible that NPM1 plays a non essential role in the assembly of CENP-A nucleosomes or the nucleophosmin paralogues NPM2 and NPM3 may compensate for the absence of NPM1." SIGNOR-263708 SCAF11 protein Q99590 UNIPROT PSEN1 protein P49768 UNIPROT "up-regulates activity" cleavage Asp345 EEWEAQRdSHLGPHR -1 10069390 t lperfetto "Remarkably, the caspases acting on PS1 could be subdivided in two groups. One group, containing caspase-8, -6 and -11, cleaved PS1 after residues ENDD329 and to a lesser extent after residues AQRD341. A second group consisting of caspase-3, -7 and -1 acted uniquely on AQRD341. Importantly, these two cleavage sites were also recognized by caspases in the C-terminal PS1 fragment produced by constitutive proteolysis." SIGNOR-261758 RPS6KA3 protein P51812 UNIPROT ESR1 protein P03372 UNIPROT up-regulates phosphorylation Ser167 GGRERLAsTNDKGSM 9606 BTO:0000150 19112174 t gcesareni "S6k1 regulates estrogen receptor alpha (eralpha) by phosphorylating it on serine 167, leading to transcriptional activation of eralpha." SIGNOR-182958 CDK2 protein P24941 UNIPROT MYBL2 protein P10244 UNIPROT "up-regulates activity" phosphorylation Ser452 PVKTLPFsPSQFLNF BTO:0000007 10593981 t llicata "Ten phosphorylation sites carboxyl-terminal to the DNA-binding domain were identified by this method: threonines at positions 267, 408, 497, 519, 522, and 524 and serines at positions 283, 396, 455, and 581. | Our results indicate that B-Myb can be phosphorylated in a cell-free system by both cyclin A-Cdk2 and cyclin E-Cdk2 complexes. | These data suggest that B-Myb is a target for phosphorylation by cyclin-Cdk2 and that phosphorylation of B-Myb regulates its transcriptional activity." SIGNOR-250735 KISS1R protein Q969F8 UNIPROT GNAQ protein P50148 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-256750 SENP1 protein Q9P0U3 UNIPROT HIF1A protein Q16665 UNIPROT up-regulates desumoylation 9606 17981124 t miannu "Sumo-specific protease 1 is essential for stabilization of hif1alpha during hypoxia / our results support a model in which sumoylated hif1_ is unstable but can be stabilized when sumo is removed by senp1" SIGNOR-158891 CDH20 protein Q9HBT6 UNIPROT CTNNB1 protein P35222 UNIPROT "up-regulates activity" binding 9606 21255999 t miannu "At its C-terminus, cadherin interacts with β-catenin, which dynamically associates with α-catenin, a direct binding partner of filamentous actin" SIGNOR-265859 ZNF224 protein Q9NZL3 UNIPROT ALDOA protein P04075 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 17900823 f miannu "We previously reported that ZNF224, a novel Krüppel-associated box-containing zinc-finger protein, represses aldolase A gene transcription by interacting with the KAP-1 co-repressor." SIGNOR-255627 BBC3 protein Q9BXH1 UNIPROT BCL2 protein P10415 UNIPROT "down-regulates activity" binding 9606 BTO:0001938 11463392 t lperfetto "Puma localizes to the mitochondria, interacts with bcl-2, and function to induce cytochrome c release" SIGNOR-109506 ME1 protein P48163 UNIPROT NADP(3-) smallmolecule CHEBI:58349 ChEBI "down-regulates quantity" "chemical modification" 9606 33064660 t miannu "Malic enzyme 1 (ME1) is a cytosolic protein that catalyzes the conversion of malate to pyruvate while concomitantly generating NADPH from NADP." SIGNOR-267722 PK proteinfamily SIGNOR-PF80 SIGNOR STAT3 protein P40763 UNIPROT "up-regulates activity" phosphorylation -1 22306293 t "PKM2 activates transcription of MEK5 by phosphorylating stat3 at Y705. In¬†vitro phosphorylation assays show that PKM2 is a protein kinase using PEP as a phosphate donor" SIGNOR-268149 MDFI protein Q99750 UNIPROT MYF5 protein P13349 UNIPROT "down-regulates activity" binding 10090 BTO:0000944 8797820 t 2 miannu "We demonstrate that I-mf inhibits the transactivation activity of the MyoD family and represses myogenesis. I-mf associates with MyoD family members and retains them in the cytoplasm by masking their nuclear localization signals." SIGNOR-240433 DNMT3B protein Q9UBC3 UNIPROT BAG3 protein O95817 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0001109 18413740 f lperfetto "In contrast, an increase in BAG-1, BAG-3, and BAG-4 gene expression was observed in HCT116 cells overexpressing either DNMT1 (DNMT1+) or DNMT3B (DNMT3B+)" SIGNOR-254111 UBTF protein P17480 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 10090 BTO:0002882 15169904 f miannu "Pescadillo (PES1) and the upstream binding factor (UBF1) play a role in ribosome biogenesis, which regulates cell size, an important component of cell proliferation. We have investigated the effects of PES1 and UBF1 on the growth and differentiation of cell lines derived from 32D cells, an interleukin-3 (IL-3)-dependent murine myeloid cell line. Parental 32D cells and 32D IGF-IR cells (expressing increased levels of the type 1 insulin-like growth factor I [IGF-I] receptor [IGF-IR]) do not express insulin receptor substrate 1 (IRS-1) or IRS-2. 32D IGF-IR cells differentiate when the cells are shifted from IL-3 to IGF-I. Ectopic expression of IRS-1 inhibits differentiation and transforms 32D IGF-IR cells into a tumor-forming cell line. We found that PES1 and UBF1 increased cell size and/or altered the cell cycle distribution of 32D-derived cells but failed to make them IL-3 independent. PES1 and UBF1 also failed to inhibit the differentiation program initiated by the activation of the IGF-IR, which is blocked by IRS-1. 32D IGF-IR cells expressing PES1 or UBF1 differentiate into granulocytes like their parental cells. In contrast, PES1 and UBF1 can transform mouse embryo fibroblasts that have high levels of endogenous IRS-1 and are not prone to differentiation. Our results provide a model for one of the theories of myeloid leukemia, in which both a stimulus of proliferation and a block of differentiation are required for leukemia development." SIGNOR-260077 PRKCA protein P17252 UNIPROT RAF1 protein P04049 UNIPROT down-regulates phosphorylation Ser43 FGYQRRAsDDGKLTD 9606 7935389 t gcesareni "Pka can inhibit raf-1 function directly via phosphorylation of the raf-1 kinase domain" SIGNOR-34761 FLT4 protein P35916 UNIPROT SHC1 protein P29353 UNIPROT unknown phosphorylation Tyr427 ELFDDPSyVNVQNLD 9606 9927207 t llicata "We have investigated which of the shc tyrosine residues are targeted by the vegfr3/ flt4 kinase and the role of the shc ptb and sh2 domains in this process. Our results show that y239/ y240 and y313 are simultaneously phosphorylated by the kinase, creating grb2 binding sites." SIGNOR-64190 PTPN3 protein P26045 UNIPROT VCP protein P55072 UNIPROT "down-regulates activity" dephosphorylation Tyr796 GGTGGSVyTEDNDDD 9606 BTO:0000007 10364224 t "Identification of VCP as a substrate of PTPH1in vivo.|The tyrosines (Tyr796 and Tyr805) at the C terminus of VCP have been reported to be the major sites of phosphorylation, with Tyr805 accounting for more than 90% of the tyrosine phosphorylation on the protein |The Y796F/Y805F VCP mutant was not associated with any of the PTPH1 constructs." SIGNOR-248460 YES1 protein P07947 UNIPROT YES1 protein P07947 UNIPROT "up-regulates activity" phosphorylation Tyr426 RLIEDNEyTARQGAK 9606 9794236 t lperfetto "Autophosphorylation of Src and Yes blocks their inactivation by Csk phosphorylation" SIGNOR-247014 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR AMBRA1 protein Q9C0C7 UNIPROT "up-regulates activity" phosphorylation Ser1252 QPTLPSSsPVPIPVS 9606 BTO:0000567 37584777 t "phosphorylation site remapping based on mass spec table" lperfetto "CDK1 phosphorylates AMBRA1 at T1209 and S1223. |CDK1-mediated phosphorylation primes PLK1 phosphorylation on AMBRA1|In this work, we show that AMBRA1 is sequentially phosphorylated at mitosis by CDK1 and PLK1 on multiple sites. In particular, CDK1 is responsible for the early phosphorylations on T1209 and S1223, and it promotes additional late phosphorylation events by PLK1 on AMBRA1. Altogether, these phosphorylation events are critical for proper spindle function and orientation. Indeed, phosphorylated AMBRA1 can interact with NUMA1 and is responsible for NUMA1 proper localization at the cell cortex. Moreover, we observe that loss of AMBRA1 leads to PLK1 protein stabilization and to an increase in phospho-NUMA1 levels which, in turn, contributes to spindle orientation defects." SIGNOR-272969 FOXO3 protein O43524 UNIPROT TSC22D3 protein Q99576 UNIPROT "up-regulates activity" "transcriptional regulation" 10090 15031210 t "We then characterized the human gilz promoter and showed that FoxO3 (Forkhead box class O3) binding to the Forkhead responsive elements identified in the promoter is necessary for induction of gilz expression upon IL-2 withdrawal" SIGNOR-256094 NDUFA6 protein P56556 UNIPROT "Mitochondrial respiratory chain complex I" complex SIGNOR-C277 SIGNOR "form complex" binding 30030361 t lperfetto "Thus, we now know the complete mammalian cI structure [22,23] and how the subunits are organized in six modules (N, Q, ND1, ND2, ND4 and ND5)The N-module, which is the tip of the hydrophilic arm and the last one to be incorporated [30,35], results from the assembly of NDUFV1, NDUFV2, NDUFS1 and NDUFA2 [34], to which NDUFA6, NDUFA7, NDUFA12, NDUFS4, NDUFS6 and NDUFV3 must be further associated with to complete the module [24]." SIGNOR-262157 AMPK complex SIGNOR-C15 SIGNOR CRY1 protein Q16526 UNIPROT down-regulates phosphorylation Ser71 ANLRKLNsRLFVIRG 9606 phosphorylation:Ser71 ANLRKLNsRLFVIRG 21892142 t lperfetto "Ampk was shown to regulate the stability of the core clock component cry1 though phosphorylation of cry1 ser71, which stimulates the direct binding of the fbox protein fbxl3 to cry1, targeting it for ubiquitin-mediated degradation" SIGNOR-216546 "BRCA1-BARD1 complex" complex SIGNOR-C297 SIGNOR H2AX protein P16104 UNIPROT "up-regulates activity" ubiquitination -1 12485996 t lperfetto "Strikingly, as well as H2AX, the nucleosome core histones H2A, H2B, H3 and H4 were all ubiquitylated efficiently by BRCA1/BARD1, while the linker histone H1 was not (Figure 3).| Generally, histone proteins are required for compaction of nuclear DNA into chromatin, and their modification is thought to loosen this compaction. Therefore, one might envisage that ubiquitylation of γH2AX by BRCA1/BARD1 at DNA breaks modulates local chromatin packaging to facilitate the action of DNA repair enzymes." SIGNOR-263235 Cullin4-RBX1-DDB1 complex SIGNOR-C119 SIGNOR GEN1 protein Q17RS7 UNIPROT "down-regulates quantity by destabilization" polyubiquitination 9606 BTO:0000007 31409866 t miannu "(WDR23) isoforms differentially ubiquitinate (GEN1). In the presence of the necessary components for a successful ubiquitination reaction (CUL4A-DDB1-WDR23 complex, UBE1, UBE2D1, ubiquitin, and ATP) GEN1 receives the addition of ubiquitin in a time dependent manner." SIGNOR-272263 OXGR1 protein Q96P68 UNIPROT GNA14 protein O95837 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257417 AMPK complex SIGNOR-C15 SIGNOR ULK1 protein O75385 UNIPROT up-regulates phosphorylation Ser317 SHLASPPsLGEMQQL 9606 19584320 t lperfetto "In a screen for conserved substrates of ampk, we identified ulk1 and ulk2, mammalian orthologs of the yeast protein kinase atg1, which is required for autophagy." SIGNOR-216491 PRKCA protein P17252 UNIPROT LCK protein P06239 UNIPROT unknown phosphorylation Ser42 TLLIRNGsEVRDPLV -1 8506364 t lperfetto "In vitro kinase assays show that Ser-59 can be uniquely phosphorylated by mitogen-activated protein kinase and that Ser-42 can be phosphorylated by either protein kinase A or protein kinase C." SIGNOR-248936 CDC14A protein Q9UNH5 UNIPROT IREB2 protein P48200 UNIPROT "up-regulates activity" dephosphorylation Ser157 LQKAGKLsPVKVQPK 9606 18574241 t "IRP2 Ser-157 is phosphorylated by Cdk1/cyclin B1 during G(2)/M and is dephosphorylated during mitotic exit by the phosphatase Cdc14A. Ser-157 phosphorylation during G(2)/M reduces IRP2 RNA-binding activity and increases ferritin synthesis, whereas Ser-157 dephosphorylation during mitotic exit restores IRP2 RNA-binding activity and represses ferritin synthesis." SIGNOR-248829 MAPK1 protein P28482 UNIPROT PPP2R5C protein Q13362 UNIPROT down-regulates phosphorylation Ser337 QLAKCVSsPHFQVAE 9606 16456541 t gcesareni "Iex-1 binds to b56 subunits and perk independently, enhances b56 phosphorylation by erk at a conserved ser/pro site in this complex and triggers dissociation from the catalytic subunit." SIGNOR-144313 CTNNB1 protein P35222 UNIPROT SOX2 protein P48431 UNIPROT "up-regulates activity" binding 10090 BTO:0002572 BTO:0002181 24482235 t flangone "The interaction of Beta-catenin with Tcf is important for Beta-catenin s's function in iPSCs induction. In addition, Beta-catenin interacts with Oct4, Sox2, and Klf4, respectively. In the reprogramming process, Beta-catenin further enhances expression of pluripotency-related genes." SIGNOR-242087 CDX2 protein Q99626 UNIPROT VIL1 protein P09327 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 19371634 f miannu "We concluded that cdx2 regulates intestinal villin expression through recruiting brm-type swi/snf complex to the villin promoter." SIGNOR-185486 "Class I MHC:Antigen" complex SIGNOR-C426 SIGNOR CD8A protein P01732 UNIPROT "up-regulates activity" binding 9606 21954283 t scontino "Molecular recognition of pMHCI complexes is mediated primarily by clonally distributed TCRs expressed on the surface of CTLs. The coreceptor CD8 contributes to this antigen-recognition process by binding to a largely invariant region of the MHCI molecule and by promoting intracellular signaling, the effects of which serve to enhance TCR stimuli triggered by cognate ligands." SIGNOR-267991 GSK3B protein P49841 UNIPROT NR3C1 protein P04150 UNIPROT "down-regulates activity" phosphorylation Ser404 SMRPDVSsPPSSSST 9606 18838540 t gcesareni "We found hormone-dependent GR phosphorylation on serine 404 by GSK-3beta [ ]Cells expressing a GR that is incapable of GSK-3beta phosphorylation had a redirection of the global transcriptional response to hormone, including the activation of additional signaling pathways, in part due to the altered ability of unphosphorylatable GR to recruit transcriptional cofactors CBP/p300 and the p65 (RelA) subunit of NF-kappaB" SIGNOR-181541 GABRB3 protein P28472 UNIPROT "GABA-A (a6-b3-d) receptor" complex SIGNOR-C329 SIGNOR "form complex" binding 9606 18790874 t "brain, See table 3 for identified complexes" lperfetto "The assembly of GABAA-R as heteropentamers produces complex subtype heterogeneity in structure, which is the major determinant of their pharmacological profile.|Evidence is greatly in favor of a pentameric receptor and most GABAA-R subtypes are formed from two copies of a single alpha, two copies of a single beta, and one copy of another subunit, such as gamma, delta, or epsilon." SIGNOR-263772 MAPK14 protein Q16539 UNIPROT HBP1 protein O60381 UNIPROT up-regulates phosphorylation Ser402 GFSKNCGsPGSSQLS 9606 14612426 t lperfetto "A mutation of the p38 map kinase phosphorylation site at aa 401 [(s-a)401hbp1] also triggered hbp1 protein instability. While protein stability was compromised by mutation, the specific activities of (s-a)401hbp1 and of wild-type hbp1 appeared comparable for transcriptional repression." SIGNOR-119138 lisinopril chemical CHEBI:43755 ChEBI ACE protein P12821 UNIPROT "down-regulates activity" "chemical inhibition" -1 12540854 t Monia "The structure of tACE bound to the potent inhibitor lisinopril shows that the inhibitor binds in a highly ordered (overall B-factor of 15.26 A˚ 2)" SIGNOR-261070 NTRK1 protein P04629 UNIPROT NTRK1 protein P04629 UNIPROT up-regulates phosphorylation Tyr496 HIIENPQyFSDACVH 9606 9099755 t gcesareni "In vitro studies indicate that trka autophosphorylates at tyrosines 490, 670, 674, 675, and 785" SIGNOR-47167 DRD4 protein P21917 UNIPROT GNAO1 protein P09471 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-256982 KDM6A protein O15550 UNIPROT HOXA10 protein P31260 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 24561908 t miannu "Evidence for direct involvement of UTX in regulation of HOX gene activity was demonstrated through UTX knockdown experiments in HEK293T cells in which loss of UTX induced transcriptional repression of HOXA and HOXC clusters." SIGNOR-260020 SRP19 protein P09132 UNIPROT SRP68 protein Q9UHB9 UNIPROT "up-regulates activity" binding -1 30649418 t miannu "Mammalian SRP comprises the highly base-paired SRP RNA (also referred to as 7SL RNA) of ∼300 nt and six proteins (SRP9, SRP14, SRP19, SRP54, SRP68 and SRP72) (Figure ​(Figure1A).1A). The hierarchy of protein addition always starts with the scaffolding protein SRP19 (together with SRP9/14 for the entire SRP) followed by SRP68/72 and finally by SRP54." SIGNOR-261167 KDM5D protein Q9BY66 UNIPROT H3C1 protein P68431 UNIPROT "up-regulates activity" demethylation Lys5 kQTARKST 9606 30246379 t miannu "KDM5 subfamily is capable of removing tri‐ and di‐ methyl marks from lysine 4 on histone H3 (H3K4). Depending on the methylation site, its effect on transcription can be either activating or repressing." SIGNOR-264308 Gbeta proteinfamily SIGNOR-PF4 SIGNOR POU5F1 protein Q01860 UNIPROT down-regulates phosphorylation 9606 23024368 t "inferred from 70% family members" gcesareni "Phosphorylation of this site downregulates nanog, sox2, rex1 and upregulates bmp4, gata6, ddlx5." SIGNOR-270085 IFNGR2 protein P38484 UNIPROT IFNGR2/INFGR1 complex SIGNOR-C142 SIGNOR "form complex" binding 9606 BTO:0000801 19041276 t lperfetto "The activation of this signaling pathway involves the binding of IFN-g to two IFN-g receptor (IFN-gR) subunits, made up of respective IFNgR1:IFNgR2 pairs, which dimerize upon IFN-g binding to form the IFN-gR complex. Two JAKs, JAK1and JAK2,which bind to each IFN-gR subunits, respectively through their N-terminal domains, both become activated by tyrosine phosphorylation in a JAK2-dependent process." SIGNOR-249486 "A4/b7 integrin" complex SIGNOR-C187 SIGNOR PTK2 protein Q05397 UNIPROT "up-regulates activity" 9606 15688067 f miannu "Focal adhesion kinase (FAK) is activated by growth factors and integrins during migration, and functions as a receptor-proximal regulator of cell motility. At contacts between cells and the extracellular matrix, FAK functions as an adaptor protein to recruit other focal contact proteins or their regulators, which affects the assembly or disassembly of focal contacts. Whereas it was first hypothesized that FAK might bind directly to the cytoplasmic tails of integrins, accumulated evidence supports an indirect association of FAK with integrins through binding to integrin-associated proteins such as paxillin and talin." SIGNOR-257728 OPHN1 protein O60890 UNIPROT F-actin_assembly phenotype SIGNOR-PH18 SIGNOR up-regulates 9606 BTO:0000938 12932438 f miannu "These results based on the immunodetection of the endogenous protein clearly show that OPHN1 colocalizes with F-actin in both neuronal and glial cells and suggest that OPHN-1 interacts with actin." SIGNOR-268400 ANGPT1 protein Q15389 UNIPROT MYH2 protein Q9UKX2 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 BTO:0000222 26042050 f lperfetto "Exogenous Ang-1 enhanced myogenic (MyoD and Myogenin) mRNA in differentiating myoblasts and increased myosin heavy chain protein." SIGNOR-241557 SLIT2 protein O94813 UNIPROT ROBO proteinfamily SIGNOR-PF14 SIGNOR up-regulates binding -1 16226035 t miannu "Here we describe and compare two human robo3 isoforms, robo3a and robo3b, which differ by the insertion of 26 amino acids at the n-terminus, and these forms appear to be evolutionary conserved. We investigated the bioactivity of these isoforms and show that they have different binding properties to slit." SIGNOR-268377 PRKACA protein P17612 UNIPROT DUOX1 protein Q9NRD9 UNIPROT up-regulates phosphorylation Ser1217 SHHFRRRsFRGFWLT 9606 19144650 t llicata "We analyzed the duox1 phosphorylation state with an anti-rxx(ps/pt) antibody that could potentially recognize phosphorylation on ser955 and ser1217 but not on thr1007. duox1 but not duox2 activity is stimulated by forskolin (ec50 = 0.1 _m) via protein kinase a-mediated duox1 phosphorylation on serine 955. duox1 is positively regulated by the camp-dependent protein kinase a (pka)6 cascade" SIGNOR-183445 "MLL1 complex" complex SIGNOR-C89 SIGNOR H3C1 protein P68431 UNIPROT "down-regulates activity" methylation Lys5 kQTARKST 9606 24680668 t miannu "Dimethylation of h3k4 requires a sub-complex including wrad (wdr5, rbbp5, ash2l, and dpy-30), which binds to each set1 family member forming a minimal corecomplexthat is required for multiple lysine methylation." SIGNOR-268801 TLN1 protein Q9Y490 UNIPROT ITGB6 protein P18564 UNIPROT "up-regulates activity" binding 10090 BTO:0000132 19118207 t miannu "Over the past 10 years, the binding of talin to the cytoplasmic tail of integrin-β subunits has been established to have a key role in integrin activation. Binding of the phosphotyrosinebinding (PTB)-domain-like subdomain of the protein 4.1, ezrin, radixin, moesin (FERM) domain of talin to the conserved WxxxNP(I/L)Y motif of the β-integrin tail permits additional weaker interactions between talin and the membrane-proximal region of the tail that trigger integrin activation, probably through the disruption of inhibitory interactions between α- and β-subunit cytoplasmic tails." SIGNOR-257631 MYC protein P01106 UNIPROT LDHA protein P00338 UNIPROT "up-regulates quantity" "transcriptional regulation" 10116 9192621 f "Our studies have linked c-Myc to the induction of LDH-A, whose expression increases lactate production and is necessary for c-Myc-mediated transformation" SIGNOR-259367 ASIP protein P42127 UNIPROT MC5R protein P33032 UNIPROT "down-regulates activity" binding 9606 BTO:0000142 20371771 t lperfetto "The melanocortin (MC) receptor family consists of five Gs-coupled receptors that control various physiological functions in response to four distinct agonists, adrenocorticotropic hormone (ACTH, also known as corticotrophin) and alpha, beta, and gamma melanocyte-stimulating hormone (MSH), which are derived from the proopiomelanocortin precursor protein, and two inverse agonists, agouti and agouti-related proteins" SIGNOR-268713 CHEK2 protein O96017 UNIPROT TP53 protein P04637 UNIPROT "up-regulates quantity by stabilization" phosphorylation Thr18 EPPLSQEtFSDLWKL 9606 BTO:0000776 17339337 t gcesareni "Chk1/chk2 and atm/atr also phosphorylate the effector p53, increasing its stability.We Have demonstrated that the human homologs of the checkpoint kinases, chk1 and chk2/hcds1, phosphorylate at least three dna damage-inducible phosphorylation sites in p53." SIGNOR-153483 CARM1 protein Q86X55 UNIPROT Differentiation phenotype SIGNOR-PH37 SIGNOR down-regulates 9606 BTO:0000725 24332853 f miannu "PRMT4 blocks myeloid differentiation of human hematopoietic stem/progenitor cells While PRMT4 promotes differentiation in several biological systems including T cell, adipocyte and muscle development, it blocks differentiation in the hematopoietic system, allowing HSPCs to maintain stemness. " SIGNOR-261968 Ub:E2 complex SIGNOR-C497 SIGNOR IHO1 protein Q8IYA8 UNIPROT "up-regulates activity" ubiquitination 9606 34199813 t miannu "The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t" SIGNOR-271239 AMPK complex SIGNOR-C15 SIGNOR CRTC1 protein Q6UUV9 UNIPROT down-regulates phosphorylation 9606 21331044 t lperfetto "Here we show that both ampk and calcineurin modulate longevity exclusively through post-translational modification of crtc-1, the sole c. elegans crtc. We demonstrate that crtc-1 is a direct ampk target." SIGNOR-216529 JUND protein P17535 UNIPROT FOSL1 protein P15407 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 13679379 t Luana "Members of the AP1 family distinctly regulated the fra-1 promoter. In particular, coexpression of c-Jun, Jun-D, and Fra-2 up-regulated fra-1 transcription. " SIGNOR-261603 RPS6KB1 protein P23443 UNIPROT DEPTOR protein Q8TB45 UNIPROT down-regulates phosphorylation Ser291 CGSSGYFsSSPTLSS 9606 22017876 t llicata "Deptor is phosphorylated by s6k1 and rsk1 on the degron serine residues upon serum stimulation s6k1/rsk1 and _trcp are required for ubiquitination and degradation of endogenous deptor upon mitogen stimulation." SIGNOR-176866 PIP3 smallmolecule CHEBI:16618 ChEBI AKT1 protein P31749 UNIPROT "up-regulates activity" relocalization 9606 23633519 t lperfetto "Akt is a serine-threonine protein kinase that plays important roles in cell growth, proliferation and apoptosis. It is activated after binding to phosphatidylinositol phosphates pips) with phosphate groups at positions 3,4 and 3,4,5 on the inositol ring." SIGNOR-252641 "Cullin 1-RBX1-Skp1" complex SIGNOR-C529 SIGNOR PSEN1 protein P49768 UNIPROT "down-regulates quantity by destabilization" polyubiquitination 9606 BTO:0000007 12354302 t miannu "SEL-10 interacts with presenilin 1, facilitates its ubiquitination, and alters A-beta peptide production SEL-10 protein is a homologue of yeast Cdc4, a member of the SCF (Skp1-Cdc53/CUL1-F-box protein) E2-E3 ubiquitin ligase family. In this study, we show that human SEL-10 interacts with PS1 and enhances PS1 ubiquitination, thus altering cellular levels of unprocessed PS1 and its N- and C-terminal fragments. These observations suggest that SEL-10 mediated ubiquitination of PS1-CTF and PS1-NTF leads to their degradation." SIGNOR-272601 irinotecan chemical CHEBI:80630 ChEBI TOP1MT protein Q969P6 UNIPROT "down-regulates activity" "chemical inhibition" 9606 15170677 t miannu "Irinotecan (7-ethyl-10-[4-(1-piperidino)-1-piperidino]-carbonyloxycamptothecin; CPT-11) is a widely used potent antitumor drug that inhibits mammalian DNA topoisomerase I (Topo I)" SIGNOR-259315 KIF14 protein Q15058 UNIPROT Cilium_assembly phenotype SIGNOR-PH64 SIGNOR up-regulates 9606 32348467 f miannu " We show that RNAi depletion of KIF14 specifically leads to defects in ciliogenesis and basal body (BB) biogenesis, as its absence hampers the efficiency of primary cilium formation and the dynamics of primary cilium elongation, and disrupts the localization of the distal appendage proteins SCLT1 and FBF1 and components of the IFT-B complex. " SIGNOR-266421 PROC protein P04070 UNIPROT F5 protein P12259 UNIPROT "down-regulates activity" cleavage 9606 BTO:0000131 29880919 t lperfetto "Activated protein C (APC), which cleaves and inactivates both FVIIIa and FVa, thereby shutting down both the tenase and prothrombinase complexes" SIGNOR-263528 HIF1A protein Q16665 UNIPROT Metabolism phenotype SIGNOR-PH77 SIGNOR up-regulates 9606 17415528 f "HIF-1 has been known as a major transcription factor for the induction of virtually all genes encoding glucose transporters and glycolytic enzymes, which allows hypoxic tumor cells to take up glucose more efficiently and metabolize pyruvate to lactate" SIGNOR-256591 PTEN protein P60484 UNIPROT NDRG1 protein Q92597 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 11494141 f miannu "Defects in PTEN, a tumor suppressor, have been found in cancers arising in a variety of human tissues. To elucidate the tumor-suppressive function of this gene, we have been analysing expression profiles of cancer cells after introduction of exogenous PTEN. Those experiments identified 99 candidate genes that were transcriptionally transactivated. Among them, we report here the further analyses of eight genes, EGR2/Krox-20, BPOZ, APS, HCLS1/HS1, DUSP1/MKP1, NDRG1/Drg1/RTP, NFIL3/E4BP4, and a novel gene (PINK1, PTEN-induced putative kinase)." SIGNOR-260054 MAP3K8 protein P41279 UNIPROT MAP2K2 protein P36507 UNIPROT up-regulates phosphorylation Ser226 LIDSMANsFVGTRSY 9606 BTO:0000007 15466476 t lperfetto "Cot proteins were used in an in vitro kinase assay using mek as a substrate. Samples were analyzed by western blotting. As seen in the cascade activity assay only wild-type cot was active against mekregulation of cot is of great interest to the signaling field since the cot/mek/erk pathway potentially plays a role in the etiology of inflammatory autoimmune diseases." SIGNOR-129698 PRKCB protein P05771 UNIPROT TFEB protein P19484 UNIPROT "up-regulates activity" phosphorylation Ser466 SKASSRRsSFSMEEG 10090 23599343 t "This occurs following PKCβ phosphorylation of TFEB on three serine residues located in its last 15 amino acids. This post-translational modification stabilizes and increases the activity of this transcription factor." SIGNOR-255315 CDK1 protein P06493 UNIPROT NEDD1 protein Q8NHV4 UNIPROT "up-regulates activity" phosphorylation Ser460 STSVLHSsPLNVFMG 21690413 t lperfetto "Mechanistically, we demonstrated that Cdc2-dependent phosphorylation on a γ-tubulin ring complex (γ-TuRC) recruitment protein, Nedd1/GCP-WD, at the previously uncharacterized S460 residue induces the Nedd1-Plk1 interaction" SIGNOR-272972 PRKACA protein P17612 UNIPROT NEFL protein P07196 UNIPROT "down-regulates activity" phosphorylation 9606 8019002 t miannu "Phosphorylation of neurofilament-L protein (NF-L) by the catalytic subunit of cAMP-dependent protein kinase (A-kinase) inhibits the reassembly of NF-L and disassembles filamentous NF-L." SIGNOR-252401 HUWE1 protein Q7Z6Z7 UNIPROT MFN2 protein O95140 UNIPROT "down-regulates quantity by destabilization" ubiquitination 9606 BTO:0000567 30217973 t lperfetto "AMBRA1 regulates mitophagy at two critical steps. Upon mitophagy stimulation, AMBRA1 mediates the HUWE1 E3 ubiquitin ligase translocation from cytosol to mitochondria (light blue). AMBRA1 acts as a cofactor for HUWE1 E3 ubiquitin ligase activity, favouring its binding to its substrate MFN2 (and maybe other OMM substrates) and targeting it to the proteasome" SIGNOR-272978 PRKD1 protein Q15139 UNIPROT SSH1 protein Q8WYL5 UNIPROT down-regulates phosphorylation Ser937 SNLTRSSsSDSIHSV 9606 21525957 t gcesareni "Phosphorylation of ser 402 impedes phosphatase activity of slingshot 1." SIGNOR-173437 PTPRB protein P23467 UNIPROT MET protein P08581 UNIPROT "down-regulates activity" dephosphorylation Tyr1356 YVHVNATyVNVKCVA 9606 21454675 t "Receptor-type protein tyrosine phosphatase beta (RPTP-beta) directly dephosphorylates and regulates hepatocyte growth factor receptor (HGFR/Met) function.|Expression of RPTP-β in primary human keratinocytes reduces both basal and HGF-induced Met phosphorylation at tyrosine 1356 and inhibits downstream MEK1/2 and Erk activation" SIGNOR-248440 VAMP8 protein Q9BV40 UNIPROT "STX11-VAMP8 SNARE complex" complex SIGNOR-C273 SIGNOR "form complex" binding 9606 BTO:0000132 22767500 t lperfetto "Coimmunoprecipitation experiments showed that syntaxin-11 can form SNARE complexes with both VAMP-8 and SNAP-23. " SIGNOR-261896 ITGB1 protein P05556 UNIPROT "A3/b1 integrin" complex SIGNOR-C161 SIGNOR "form complex" binding 16988024 t lperfetto "Integrins are one of the major families of cell adhesion receptors (Humphries, 2000; Hynes, 2002). All integrins are non-covalently-linked, heterodimeric molecules containing an α and a β subunit. Both subunits are type I transmembrane proteins, containing large extracellular domains and mostly short cytoplasmic domains (Springer and Wang, 2004; Arnaout et al., 2005). Mammalian genomes contain 18 α subunit and 8 β subunit genes, and to date 24 different α,β combinations have been identified at the protein level. Although some subunits only appear in a single heterodimer, twelve integrins contain the β1 subunit, and five contain αV." SIGNOR-253174 NLRX1 protein Q86UT6 UNIPROT RELA protein Q04206 UNIPROT "up-regulates activity" relocalization 9606 BTO:0002181 18219313 f Giorgia "NLRX1 synergistically potentiated ROS production induced by tumour necrosis factor alpha, Shigella infection and double-stranded RNA, resulting in amplified NF-kappaB-dependent and JUN amino-terminal kinases-dependent signalling. We observed that NLRX1-positive cells showed increased p65 translocation as early as 15 min after infection, an effect that was maintained over time." SIGNOR-260358 RIPK2 protein O43353 UNIPROT RIPK2 protein O43353 UNIPROT "up-regulates activity" phosphorylation Ser176 KWRMMSLsQSRSSKS 9606 16824733 t amattioni "In summary, our results indicate that s176 is a regulatory autophosphorylation site for rip2 and that s176 phosphorylation can be used to monitor the activation state of rip2." SIGNOR-229701 "Cullin 3-RBX1-Skp1" complex SIGNOR-C526 SIGNOR AURKB protein Q96GD4 UNIPROT "up-regulates activity" polyubiquitination 9606 BTO:0000567 17543862 t miannu "Aurora B Interacts with the Cul3 Complex during Mitosis and Is Ubiquitylated in a Cul3-Dependent Manner In Vivo and In Vitro. our results suggest that Cul3/KLHL9/KLHL13 activity is required to remove the chromosomal passenger protein Aurora B from mitotic chromosomes, and that Aurora B is ubiquitylated in vivo and in vitro in a KLHL9/13-dependent manner. We conclude that the Cul3/KLHL9/KLHL13 E3 ligase is an important cell-cycle regulator which, in addition to the anaphase-promoting complex (APC), coordinates mitotic progression and completion of cytokinesis." SIGNOR-271662 sabcomeline chemical CHEBI:134846 ChEBI CHRM2 protein P08172 UNIPROT "up-regulates activity" "chemical activation" 10116 9399977 t miannu "SB 202026 (R-(Z)-(+)-alpha-(methoxyimino)-1-azabicyclo[2.2.2] octane-3-acetonitrile) displaced [3H]-oxotremorine-M from muscarinic receptors in the rat brain with high affinity (IC50 = 14 nM), a potency similar to that of oxotremorine-M itself (IC50 = 13 nM), but exhibited low affinity for cholinergic nicotinic receptors and other neuroreceptors. In studies using cloned human muscarinic receptors, SB 202026 possessed approximately equal affinity in displacing [3H]-quinuclidinyl benzilate from all muscarinic receptor subtypes" SIGNOR-258674 "Factor FVIIa:TF" complex SIGNOR-C319 SIGNOR F5 protein P12259 UNIPROT "down-regulates activity" cleavage Arg1046 HHAPLSPrTFHPLRS -1 10026263 t lperfetto "Factor VIIa/tissue factor generates a form of factor V with unchanged specific activity, resistance to activation by thrombin, and increased sensitivity to activated protein C| In this study, we found that TF/VIIa was able to cleave multiple peptide bonds in the coagulation cofactor, factor V. SDS-PAGE analysis and sequencing indicated the factor V was cleaved at Arg679, Arg709, Arg1018, and Arg1192" SIGNOR-263645 dimethyloxalylglycine chemical CHEBI:102218 ChEBI EGLN3 protein Q9H6Z9 UNIPROT "down-regulates activity" "chemical inhibition" 9606 BTO:0000018 28900510 t lperfetto "We treated the A549 cells with the following EGLN/PHD inhibitors: dimethyloxalyglycine (DMOG), CoCl2, inhibitors of dioxygenases, and BAY 85-3494 (BAY), a specific inhibitor of EGLNs with highest potency against EGLN1." SIGNOR-261993 GPSM3 protein Q9Y4H4 UNIPROT GNAI1 protein P63096 UNIPROT "down-regulates activity" binding 9606 BTO:0000007 22843681 t lperfetto "GPSM3 acts through its two GoLoco motifs to exert GDP dissociation inhibitor activity over Galpha(i) subunits|interactions between GPSM3 and Galphai1 or Gbeta1 (20) was assayed by BRET." SIGNOR-264864 CNTN6 protein Q9UQ52 UNIPROT NOTCH proteinfamily SIGNOR-PF30 SIGNOR up-regulates relocalization 9606 BTO:0000938 15082708 t gcesareni "Here, we establish that nb-3, a member of the f3/contactin family, acts as a novel notch ligand to participate in oligodendrocyte generation. Nb-3 triggers nuclear translocation of the notch intracellular domain and promotes oligodendrogliogenesis from progenitor cells and differentiation of oligodendrocyte precursor cells via deltex1." SIGNOR-254318 GNE protein Q9Y223 UNIPROT UDP-N-acetyl-alpha-D-glucosamine smallmolecule CHEBI:16264 ChEBI "down-regulates quantity" "chemical modification" 10745088 t lperfetto "UDP-GlcNAc 2-epimerase is a bifunctional enzyme and catalyzes the first two steps of neuraminic acid synthesis in the cytosol, the conversion of UDP-N-acetylglucosamine to ManAc and the phosphorylation to ManAc-6-phosphate." SIGNOR-266073 Ub:E2 complex SIGNOR-C497 SIGNOR TRIM9 protein Q9C026 UNIPROT "up-regulates activity" ubiquitination 9606 34199813 t miannu "The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t" SIGNOR-271085 POLR1D protein P0DPB6 UNIPROT "RNA Polymerase I" complex SIGNOR-C390 SIGNOR "form complex" binding 22260999 t lperfetto "In eukaryotic cells, the RNA polymerase Pol I synthesizes the rRNA precursor, Pol II transcribes mRNAs and small non-coding RNAs (such as small nuclear RNAs), and Pol III produces tRNAs and other small RNAs. Pol I, II and II contain 14, 12 and 17 polypeptide subunits, respectively (Table 1). " SIGNOR-266146 WWTR1 protein Q9GZV5 UNIPROT TEAD2 protein Q15562 UNIPROT up-regulates binding 9606 23431053 t "YAP/TAZ mainly bind to the transcription factors TEAD1??4 to regulate genes involved in cell proliferation and cell death." gcesareni "When dephosphorylated, yap/taz enter nuclei and induce gene transcription by interacting with transcription factors tead14." SIGNOR-201382 VAV1 protein P15498 UNIPROT CBL protein P22681 UNIPROT up-regulates binding 9606 BTO:0000782 9200440 t gcesareni "Hese data imply that c-cbl is a molecular adapter that regulates the function of vav" SIGNOR-49188 RPL22L1 protein Q6P5R6 UNIPROT "60S cytosolic large ribosomal subunit" complex SIGNOR-C287 SIGNOR "form complex" binding -1 25901680 t lperfetto "Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins." SIGNOR-262498 "Blood vessel damage" stimulus SIGNOR-ST26 SIGNOR VWF protein P04275 UNIPROT up-regulates 9606 NBK559062 f lperfetto "Exposed VWF bound to collagen from vascular injury and endothelial damage adheres to the GPIb receptor on platelets to initiate signaling pathways for platelet activation, the next step in primary hemostasis. VW|VWF released by Weibel-Palade bodies or alpha-granules can enter circulation or accumulate in the subendothelial matrix binding to collagen through its A3 domain. Once exposed under high shear stress conditions in the arterial circulation, VWF can bind to platelets via its A1 domain." SIGNOR-261862 TFIIH complex SIGNOR-C457 SIGNOR POLR2A protein P24928 UNIPROT "up-regulates activity" phosphorylation Ser1668 SPSYSPTsPSYSPTS 9606 24746699 t lperfetto "After PIC formation, Pol II initiates mRNA synthesis, but productive transcription requires Pol II to escape from the PIC and transit into transcription elongation. The transition between initiation and elongation is associated with phosphorylation at the serine 5 (Ser5) residues within the hepta-peptide repeats in the C-terminal domain (CTD) of the largest Pol II subunit. Ser5 phosphorylation is mediated primarily by Kin28, the kinase subunit of the general transcription factor TFIIH" SIGNOR-269364 LAT protein O43561 UNIPROT PLCG1 protein P19174 UNIPROT "up-regulates activity" binding 9606 phosphorylation:Tyr161;Tyr200 DDYHNPGyLVVLPDS;SMESIDDyVNVPESG 11368773 t lperfetto "By substituting these tyrosine residues in LAT with phenylalanine and by utilizing phosphorylated peptides derived from these sites, we mapped the tyrosine residues in LAT required for the direct interaction and activation of Vav, p85/p110alpha and phospholipase Cgamma1 (PLCgamma1). Our results indicate that Tyr(226) and Tyr(191) are required for Vav binding, whereas Tyr(171) and Tyr(132) are necessary for association and activation of phosphoinositide 3-kinase activity and PLCgamma1 respectively." SIGNOR-246060 MAPK3 protein P27361 UNIPROT PCBP2 protein Q15366 UNIPROT "up-regulates quantity by stabilization" phosphorylation Ser189 YRPKPSSsPVIFAGG 9606 17475908 t miannu "We also identified 4 hnRNP-E2 MAPKERK1/2 phosphorylation sites and demonstrated that hnRNP-E2 is a bona fide MAPKERK1/2 substrate and that MAPKERK1/2-dependent phosphorylation of hnRNP-E2 at these amino acid residues is essential for increased hnRNP-E2 expression in BCR/ABL-expressing cells. Serine/threonine to alanine substitution abolishes hnRNP-E2 phosphorylation and markedly decreases its stability in BCR/ABL-expressing myeloid precursors. Consistent with the existence of a BCR/ABL-MAPK pathway that posttranslationally regulates hnRNP-E2 expression, sequence analysis of hnRNP-E2 revealed the presence of 4 consensus ERK phosphorylation sites (S/T-P)35,36 at amino acid residues 173, 189, 213, and 272 (Figure 2B)." SIGNOR-262915 MAPKAPK2 protein P49137 UNIPROT BAG2 protein O95816 UNIPROT up-regulates phosphorylation Ser20 GRFCRSSsMADRSSR 9606 BTO:0000567 15271996 t lperfetto "We provided definite evidence that mapkapk2 phosphorylates bag2 at ser 20 in vitro and in vivo. These results demonstrate that bag2 is a novel component of the p38 mapk signaling pathways." SIGNOR-126953 PSMD1 protein Q99460 UNIPROT "26S Proteasome" complex SIGNOR-C307 SIGNOR "form complex" binding 9606 BTO:0000007 29636472 t lperfetto "Here, we report near-atomic resolution cryo-EM structures of the activated human proteasome|The proteasome is composed of a 28-subunit barrel-shaped core particle (CP) and two 19- subunit regulatory particles (RP)5–8 capped at both sides of the CP|Human proteasomes were purified through affinity chromatography on a large scale from a stable HEK293 cell line" SIGNOR-263354 PRKCA protein P17252 UNIPROT PLD1 protein Q13393 UNIPROT up-regulates phosphorylation Ser561 PRKFSKFsLYKQLHR 9606 10441128 t gcesareni "Serine 2, threonine 147, and serine 561 were identified as phosphorylation sites of pld1 by pkcalpha in the cells." SIGNOR-69934 FFAR4 protein Q5NUL3 UNIPROT GNA14 protein O95837 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257420 CyclinA2/CDK2 complex SIGNOR-C83 SIGNOR MYBL2 protein P10244 UNIPROT up-regulates phosphorylation Thr494 TPLHRDKtPLHQKHA 9606 9840932 t lperfetto "The cell-cycle regulated transcription factor b-myb is phosphorylated by cyclin a/cdk2 at sites that enhance its transactivation properties. we show that b-myb is phosphorylated at thr447, thr490, thr497 and ser581 by cyclin a/cdk4" SIGNOR-217264 EGFR protein P00533 UNIPROT CALM1 protein P0DP23 UNIPROT down-regulates phosphorylation Tyr100 FDKDGNGyISAAELR 9606 7925415 t lperfetto "Phosphorylation of calmodulin by the epidermal-growth-factor-receptor tyrosine kinase. Phosphorylated calmodulin does not exhibit the characteristic ca2+ shift normally observed with calmodulin in electrophoretic gels, an observation that is consistent with this modification affecting the biological activity of the molecule." SIGNOR-34691 valrubicin chemical CHEBI:135876 ChEBI TOP2A protein P11388 UNIPROT "down-regulates activity" "chemical inhibition" 9606 16019763 t miannu "Valrubicin (N-trifluoroacetyladriamycin-14-valerate) is a semi-synthetic derivative of the anthracycline doxorubicin. Valrubicin inhibits the incorporation of nucleosides into nucleic acids, causing extensive chromosomal damage and cell-cycle arrest in the G2 phase. Its principal metabolites inhibit topoisomerase II, thus arresting DNA synthesis." SIGNOR-259383 CSNK1D protein P48730 UNIPROT PSEN2 protein P49810 UNIPROT "up-regulates activity" phosphorylation Ser327 DPEMEEDsYDSFGEP -1 9558331 t llicata "In vitro the large hydrophilic loop of PS-2 between transmembrane domains 6 and 7 can be phosphorylated by casein kinase-1 (CK-1) and CK-2, but not by PKA or PKC. Quantitative analysis of in vitro phosphorylation demonstrates the presence of two phosphorylation sites for CK-1 and a single site for CK-2. A deletion analysis revealed that the CTF of PS-2 is phosphorylated in vivo within an acidic sequence containing three potential phosphorylation sites for CKs (serines 327, 330, and 335). These data suggest that CK type protein kinases phosphorylate the CTF of PS-2 within its hydrophilic loop domain in vivo. Interestingly, the potential phosphorylation sites are located directly adjacent to the recently identified caspase cleavage sites." SIGNOR-250800 Ubiquitinated-Viral_Protein complex SIGNOR-C427 SIGNOR "26S Proteasome" complex SIGNOR-C307 SIGNOR "up-regulates activity" binding 9606 15571818 t scontino "The proteasome system is the central proteolytic system of the eukaryotic cell [1] and plays an important role in the generation of MHC-class I peptides. The enzyme complex responsible for the selectivity of intracellular protein degradation is the 26S proteasome that degrades poly-ubiquitinated substrates." SIGNOR-267767 3-[4-[4-[2-[3-[(dimethylamino)methyl]phenyl]-1H-pyrrolo[2,3-b]pyridin-4-yl]-1-ethyl-3-pyrazolyl]phenyl]-1,1-dimethylurea chemical CHEBI:91362 ChEBI AURKA protein O14965 UNIPROT "down-regulates activity" "chemical inhibition" 9606 19567821 t miannu "The protein kinases, Aurora A, B, and C have critical roles in the regulation of mitosis and are frequently overexpressed or amplified in human tumors. GSK1070916, is a novel ATP competitive inhibitor that is highly potent and selective for Aurora B/C kinases." SIGNOR-262225 SRC protein P12931 UNIPROT ARAF protein P10398 UNIPROT "up-regulates activity" phosphorylation Tyr302 GYRDSGYyWEVPPSE 9534 9020159 t lperfetto "A-raf behaves like raf-1, being weakly activated by oncogenic ras more strongly activated by oncogenic src, and these signals synergize to give maximal activation" SIGNOR-236459 BDKRB2 protein P30411 UNIPROT GNAI3 protein P08754 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-256838 MAGOH protein P61326 UNIPROT "Exon junction complex" complex SIGNOR-C369 SIGNOR "form complex" binding -1 16923391 t miannu "The EJC is deposited onto mRNA during splicing and is transported to the cytoplasm where it influences translation, surveillance, and localization of the spliced mRNA. The complex is formed by the association of four proteins (eIF4AIII, Barentsz [Btz], Mago, and Y14), mRNA, and ATP." SIGNOR-265243 Ub:E2 complex SIGNOR-C497 SIGNOR TRIM56 protein Q9BRZ2 UNIPROT "up-regulates activity" ubiquitination 9606 34199813 t miannu "The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t" SIGNOR-270961 PLK3 protein Q9H4B4 UNIPROT CDC25C protein P30307 UNIPROT unknown phosphorylation Ser216 SGLYRSPsMPENLNR -1 10557092 t lperfetto "The physical association and phosphorylation of Cdc25C protein phosphatase by Prk. | Further studies reveal that His6-Prk phosphorylates Cdc25C on serine216, a residue also phosphorylated by Chk1 and Chk2. Together, these observations strongly suggest that Prk's role in mitosis is at least partly mediated through direct regulation of Cdc25C." SIGNOR-249030 PRKCB protein P05771 UNIPROT CD5 protein P06127 UNIPROT unknown phosphorylation Thr436 FHRNHTAtVRSHAEN 9606 BTO:0000661 11123317 t lperfetto "Here, we present a selective mutagenesis analysis of two conserved threonine residues (T410 and T412) located at the membrane-proximal cytoplasmic region of CD5. These residues are contained within consensus phosphorylation motifs for protein kinase C and are shown here to be critical for in vivo protein kinase C-mediated phosphorylation of CD5. " SIGNOR-249075 PRKDC protein P78527 UNIPROT PRKDC protein P78527 UNIPROT down-regulates phosphorylation Thr3950 GHAFGSAtQFLPVPE 9606 17189255 t gcesareni "Ir-induced dna-pkcs phosphorylation at thr-2609 and ser-2056, however, exhibits distinct kinetics indicating that they are differentially regulated. Although dna-pkcs autophosphorylates itself at ser-2056 after ir, we have reported here that atm mediates dna-pkcs phosphorylation at thr-2609 as well as at the adjacent (s/t)q motifs within the thr-2609 cluster." SIGNOR-151453 Degranulation phenotype SIGNOR-PH92 SIGNOR IL5 protein P05113 UNIPROT "up-regulates quantity" 9606 BTO:0000830 17259966 f apalma "The array of mediators released by human mast cells is enormous and explains how mast cells can be involved in so many different physiological and pathophysiological functions. Of particular relevance [...] cytokines, such as IL-3 -basophil recruitment and activation-, IL-5 -eosinophil recruitment and activation- and IL-13 -induction of IgE synthesis by B cells." SIGNOR-255346 PTPN12 protein Q05209 UNIPROT INSR protein P06213 UNIPROT down-regulates dephosphorylation Tyr999 YASSNPEyLSASDVF 9606 BTO:0000567 BTO:0000887;BTO:0001103 8454633 t gcesareni "Autophosphorylated on tyrosine residues in response to insulin. Dephosphorylated by ptpreand ptpn1 at tyr-999, tyr-1185, tyr-1189 and tyr-1190." SIGNOR-39159 "Vps34 Complex I" complex SIGNOR-C242 SIGNOR Autophagy phenotype SIGNOR-PH31 SIGNOR up-regulates 30397185 f lperfetto "PtdIns3P recruits specific recognition modules that are common in protein-sorting pathways, such as autophagy and endocytic sorting. It is best characterized in two heterotetramers, complexes I and II. Complex I is composed of VPS34, VPS15, Beclin 1, and autophagy-related gene (ATG)14L, whereas complex II replaces ATG14L with UVRAG. |Complexes I and II are critical for early events in autophagy and endocytic sorting, respectively." SIGNOR-260325 NUP85 protein Q9BW27 UNIPROT NPC complex SIGNOR-C263 SIGNOR "form complex" binding 27016207 t lperfetto "The protein inventory of the NPC has been studied for a very diverse set of eukaryotes, including trypanosomes, fungi, plants, animals, and humans [4], [5], [6], [7], [8], [9]. In all cases, about 30 different Nups were found (Fig. 2)." SIGNOR-262093 SP1 protein P08047 UNIPROT CADM1 protein Q9BY67 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 18794147 f lperfetto "Treatment with mithramycin A, an inhibitor of Sp1 or Sp3 binding, resulted in reduction of Cadm1 gene expression, therefore suggesting a potential role of Sp1/Sp3 in Cadm1 regulation." SIGNOR-268958 PRKCA protein P17252 UNIPROT KIT protein P10721 UNIPROT "down-regulates activity" phosphorylation Ser741 TKADKRRsVRIGSYI 9823 BTO:0004007 7539802 t lperfetto "We present here the identification of the major phosphorylation sites for PKC in Kit/SCFR. Two serine residues in the kinase insert, Ser-741 and Ser-746, are PKC-dependent phosphorylation sites in vivo and account for all phosphorylation by PKC in vitro. | Two additional serine residues, Ser-821 close to the major tyrosine autophosphorylation site in the kinase domain and Ser-959 in the carboxyl terminus are SCF-stimulated PKC-dependent phosphorylation sites. | Furthermore, the kinase activity of Kit/SCFR(S741A/S746A) toward an exogenous substrate was increased, which was reflected as a decreased Km and an increased Vmax, in accordance with the negative regulatory role of PKC on Kit/SCFR signaling." SIGNOR-248898 MAPK8IP1 protein Q9UQF2 UNIPROT MAPK8 protein P45983 UNIPROT down-regulates binding 9606 10490659 t "JNK bound to an NH2-terminal reagion of JIP1 (residues 283 to 660)." gcesareni "These experiments demonstrated that 10 different jnk isoforms bound to both jip proteins." SIGNOR-70851 HIF1A protein Q16665 UNIPROT KDM5A protein P29375 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 32938217 t SaraGualdi "To this end, we confirm that KDM3A, KDM4B, KDM4C, KDM5B, KDM5C, and KDM62 are direct targets of HIF-1a while extent the list of known targets to KDM2A, KDM2B, KDM4D, KDM5A, and KDM6A. The results demonstrated that majority of the KDMs were similarly induced (KDM2A, KDM2B, KDM3A, KDM4B, KDM4C, KDM4D, KDM5A, KDM5B, KDM5C, KDM6B, and KDM7A) or repressed (KDM NO66 and KDM1A) by both HIF-1a and HIF-2a." SIGNOR-271565 CHUK protein O15111 UNIPROT NFKB1 protein P19838 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser932 CDSGVETsFRKLSFT 10090 BTO:0000944 SIGNOR-C14 SIGNOR-C13 11297557 t lperfetto "The i b kinase (ikk) complex rapidly phosphorylates nf- b1 p105 on serine 927 in the pest region romashkova et al. demonstrated that akt binds to and activates inhibitor of kappa b kinase-alfa (ikkalfa), which in turn phosphorylates and thereby promotes the degradation of the inhibitory cofactor of nf-kb, i-kb the scf-betatrcp complex is responsible for the ubiquitination of p100 and p105 following their phosphorylation by ikk." SIGNOR-235442 CAPN1 protein P07384 UNIPROT CDK5/CDK5R1 complex SIGNOR-C144 SIGNOR "up-regulates activity" cleavage 9606 BTO:0000590 25969760 t lperfetto "Calpains also modulate the activity of CDK5. Physiologically, CDK 5 is activated by p35 and its cleaved product p25. The latter has a longer half life than p35 and therefore it is a more potent activator of CDK5. The cleavage of p35 to p25 is mediated by calpain" SIGNOR-251581 SP1 protein P08047 UNIPROT SLC19A1 protein P41440 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000599 15652157 f "Collectively, these results identify transcriptionally important regions in the hRFC-C minimal promoter that include a GC-box and CCAAT-box, and suggest that cooperative interactions between Sp1 and C/EBP beta are essential for hRFC-C transactivation." SIGNOR-254064 CSNK1D protein P48730 UNIPROT PSEN2 protein P49810 UNIPROT "up-regulates activity" phosphorylation Ser335 YDSFGEPsYPEVFEP -1 9558331 t llicata "In vitro the large hydrophilic loop of PS-2 between transmembrane domains 6 and 7 can be phosphorylated by casein kinase-1 (CK-1) and CK-2, but not by PKA or PKC. Quantitative analysis of in vitro phosphorylation demonstrates the presence of two phosphorylation sites for CK-1 and a single site for CK-2. A deletion analysis revealed that the CTF of PS-2 is phosphorylated in vivo within an acidic sequence containing three potential phosphorylation sites for CKs (serines 327, 330, and 335). These data suggest that CK type protein kinases phosphorylate the CTF of PS-2 within its hydrophilic loop domain in vivo. Interestingly, the potential phosphorylation sites are located directly adjacent to the recently identified caspase cleavage sites." SIGNOR-250802 LRFN5 protein Q96NI6 UNIPROT PTPRS protein Q13332 UNIPROT "up-regulates activity" binding 9606 27225731 t miannu "SALM5 trans-synaptically interacts with LAR-RPTPs in a splicing-dependent manner to regulate synapse development. we identified LAR-RPTPs as novel ligands of SALM5 that mediates SALM5-dependent presynaptic differentiation in a splicing-dependent manner. Our data indicate that SALM5 interacts with all three known LAR-RPTPs—LAR, PTPδ, and PTPσ (Fig. 1)." SIGNOR-264088 MFF protein Q9GZY8 UNIPROT Mitochondrial_fission phenotype SIGNOR-PH143 SIGNOR up-regulates 9606 33610749 f lperfetto "These proteins include the classical mitochondrial fusion (MFN1, MFN2, and OPA1) and fission proteins (DRP1, MFF, FIS1, etc.) as well as several other proteins that are directly or indirectly involved in these processes (e.g. YME1L, OMA1, INF2, GDAP1, MIC13, etc." SIGNOR-272983 EZH2 protein Q15910 UNIPROT SUZ12/EZH2 complex SIGNOR-C77 SIGNOR "form complex" binding 9606 16712789 t miannu "Suz12 is a polycomb group protein that forms polycomb repressive complexes (prc2/3) together with eed and histone methyltransferase ezh2." SIGNOR-146758 OPA3 protein Q9H6K4 UNIPROT Mitochondrial_fission phenotype SIGNOR-PH143 SIGNOR up-regulates 9606 20372962 f lperfetto "Optic atrophy 3 as a protein of the mitochondrial outer membrane induces mitochondrial fragmentation|Together, these results indicate that OPA3, as an integral MOM protein, has a crucial role in mitochondrial fission, and provides a direct link between mitochondrial morphology and optic atrophy." SIGNOR-272988 MSL1 protein Q68DK7 UNIPROT "MSL acetyltransferase" complex SIGNOR-C344 SIGNOR "form complex" binding 9606 BTO:0000567 16227571 t miannu "We describe a stable, multisubunit human histone acetyltransferase complex (hMSL) that contains homologs of the Drosophila dosage compensation proteins MOF, MSL1, MSL2, and MSL3. This complex shows strong specificity for histone H4 lysine 16 in chromatin in vitro, and RNA interference-mediated knockdown experiments reveal that it is responsible for the majority of H4 acetylation at lysine 16 in the cell." SIGNOR-263942 CHUK protein O15111 UNIPROT CREBBP protein Q92793 UNIPROT up-regulates phosphorylation Ser1386 FVDSGEMsESFPYRT 9606 BTO:0000551 17434128 t lperfetto "Phosphorylation of cbp by ikkalpha promotes cell growth by switching the binding preference of cbp from p53 to nf-kappabhere, we show that ikkalpha phosphorylates cbp at serine 1382 and serine 1386 and consequently increases cbp's hat and transcriptional activities" SIGNOR-154333 "AP-1/clathrin vescicle" complex SIGNOR-C251 SIGNOR oligopeptide smallmolecule CHEBI:25676 ChEBI "up-regulates quantity" relocalization 9606 25720354 t scontino "APCs cell surface receptors facilitate antigen entry into antigen-processing compartments through clathrin-mediated endocytosis. It is in these compartments that internalized antigen proteolysis and peptide–MHC class II complex formation takes place." SIGNOR-267860 Ub:E2 complex SIGNOR-C497 SIGNOR RNF133 protein Q8WVZ7 UNIPROT "up-regulates activity" ubiquitination 9606 34199813 t miannu "The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t" SIGNOR-271205 PPARGC1A protein Q9UBK2 UNIPROT NFKB1 protein P19838 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 10090 BTO:0001103 SIGNOR-C13 20404331 f lperfetto "In mouse muscles, overexpression of PGC-1beta (like PGC-1alpha) inhibited denervation atrophy, ubiquitin ligase induction, and transcription by NFkappaB" SIGNOR-217969 nintedanib chemical CHEBI:85164 ChEBI FGFR1 protein P11362 UNIPROT "down-regulates activity" "chemical inhibition" -1 18559524 t Luana "In this report, we describe the preclinical profile of BIBF 1120, a combined VEGFR, FGFR, and PDGFR inhibitor currently entering phase III clinical studies in non–small cell lung carcinoma and other cancers." SIGNOR-257804 Gbeta proteinfamily SIGNOR-PF4 SIGNOR MED1 protein Q15648 UNIPROT up-regulates phosphorylation 9606 12356758 t "inferred from 70% family members" lperfetto "Phosphorylation of transcriptional coactivator peroxisome proliferator-activated receptor (ppar)-binding protein (pbp). Stimulation of transcriptional regulation by mitogen-activated protein kinase" SIGNOR-270106 POLR3A protein O14802 UNIPROT Viral_dsRNA stimulus SIGNOR-ST21 SIGNOR up-regulates 9606 19631370 t miannu "Here we show that the cytosolic poly(dA-dT) DNA is converted into 5′-ppp RNA to induce IFN-β through the RIG-I pathway. Biochemical purification led to the identification of DNA-dependent RNA polymerase III (Pol-III) as the enzyme responsible for synthesizing 5′-ppp RNA from the poly(dA-dT) template. Inhibition of RNA Pol-III prevents IFN-β induction by transfection of DNA or infection with DNA viruses." SIGNOR-265563 mTORC1 complex SIGNOR-C3 SIGNOR PIP4K2C protein Q8TBX8 UNIPROT "up-regulates quantity" phosphorylation Ser324 GPPALVGsYGTSPEG 9606 BTO:0000567 25372051 t miannu " PIP4kγ was phosphorylated by mTORC1 and associated with the complex. Phosphorylated PIP4kγ was enriched in light microsomal vesicles, whereas the unphosphorylated form was enriched in heavy microsomal vesicles associated with the Golgi. " SIGNOR-273680 mTORC1 complex SIGNOR-C3 SIGNOR PIP4K2C protein Q8TBX8 UNIPROT "up-regulates quantity" phosphorylation Ser328 LVGSYGTsPEGIGGY 9606 BTO:0000567 25372051 t miannu " PIP4kγ was phosphorylated by mTORC1 and associated with the complex. Phosphorylated PIP4kγ was enriched in light microsomal vesicles, whereas the unphosphorylated form was enriched in heavy microsomal vesicles associated with the Golgi. " SIGNOR-273681 RUBCNL protein Q9H714 UNIPROT "HOPS tethering complex" complex SIGNOR-C549 SIGNOR "up-regulates activity" binding 9606 BTO:0000007 30704899 t miannu "Under nutrient-rich conditions, mTORC1 phosphorylates Pacer at serine157 to disrupt the association of Pacer with Stx17 and the HOPS complex and thus abolishes Pacer-mediated autophagosome maturation. These results demonstrate that mTORC1-mediated Pacer phosphorylation at S157 inhibits autophagosome maturation by disrupting the association of Pacer with Stx17 and the HOPS complex" SIGNOR-273685 JAK2 protein O60674 UNIPROT JAK2 protein O60674 UNIPROT up-regulates phosphorylation Tyr868 GSVEMCRyDPLQDNT 9606 BTO:0000007 20304997 t lperfetto "Tyrosines 868, 966, and 972 in the kinase domain of jak2 are autophosphorylated and required for maximal jak2 kinase activity" SIGNOR-236298 CXCL10 protein P02778 UNIPROT Immune_response phenotype SIGNOR-PH17 SIGNOR up-regulates 9606 32283152 f miannu "High levels of expression of IL-1B, IFN-γ, IP-10, and monocyte chemoattractant protein 1 (MCP-1) have been detected in patients with COVID-19. These inflammatory cytokines may activate the T-helper type 1 (Th1) cell response. Th1 activation is a key event in the activation of specific immunity." SIGNOR-261025 "Multiaminoacyl-tRNA synthetase" complex SIGNOR-C472 SIGNOR Lys-tRNA(Lys) smallmolecule CHEBI:16047 ChEBI "up-regulates quantity" "chemical modification" 9606 28271488 t miannu "Aminoacyl-tRNA synthetases (AARSs) are essential enzymes that specifically aminoacylate one tRNA molecule by the cognate amino acid. In mammals, nine synthetases, those specific for amino acids Arg, Asp, Gln, Glu, Ile, Leu, Lys, Met and Pro, associate into a multi-aminoacyl-tRNA synthetase complex, an association which is believed to play a key role in the cellular organization of translation, but also in the regulation of the translational and nontranslational functions of these enzymes." SIGNOR-270406 olanzapine chemical CHEBI:7735 ChEBI HTR2A protein P28223 UNIPROT "down-regulates activity" "chemical inhibition" 10090 BTO:0000331 8935801 t miannu "Risperidone and its active metabolite 9-OH-risperidone were compared to reference antipsychotic drugs (haloperidol, pipamperone, fluspirilene, clozapine, zotepine) and compounds under development (olanzapine, seroquel, sertindole, ORG-5222, ziprasidone) for in vitro binding to neurotransmitter receptors in brain tissue and on membranes of recombinant cells expressing cloned human receptors and for in vivo occupancy of neurotransmitter receptors in rat and guinea-pig brain following acute treatment (2 h., s.c.). The binding affinities of the compounds for various neurotransmitter receptors were measured using membrane preparations of animal brain regions and of recombinant cells expressing cloned, mostly human receptors. Receptors, tissues and cells are indicated in Table I; results are shown in Table 4A-B." SIGNOR-258506 CDK7 protein P50613 UNIPROT TP53 protein P04637 UNIPROT up-regulates phosphorylation Ser371 AHSSHLKsKKGQSTS 9606 9315650 t llicata "The cdk7-cych-p36 complex of transcription factor iih phosphorylates p53, enhancing its sequence-specific dna binding activity in vitro. serines 371, 376, 378, and 392 may be the potential sites for this kinase." SIGNOR-51280 SYK protein P43405 UNIPROT GCSAM protein Q8N6F7 UNIPROT "up-regulates activity" phosphorylation Tyr106 SGNSAEEyYENVPCK -1 31362927 t miannu "Herein, we demonstrate phosphorylation of HGAL by Syk and Lyn kinases at tyrosines Y80, Y86, Y106Y107, Y128, and Y148.  Y148 (in black) was already phosphorylated before the addition of kinases. We demonstrate that Grb2 facilitates HGAL and Syk binding following BCR stimulation but does not affect the HGAL-mediated increase in Syk kinase activity. Previous studies showed that Grb2 inhibits BCR signaling by decreasing the activation of Syk by Lyn.11 Thus, while HGAL and Grb2 oppositely affect Syk kinase activity, this is not due to direct Grb2 effects on HGAL-mediated Syk kinase activation." SIGNOR-273570 VPS11 protein Q9H270 UNIPROT "HOPS tethering complex" complex SIGNOR-C549 SIGNOR "form complex" binding 9606 23351085 t miannu "The two Vps-C complexes CORVET (class C core vacuole/endosome tethering) and HOPS (homotypic fusion and vacuole protein sorting) perform diverse biochemical functions in endocytosis: they tether membranes, interact with Rab GTPases, activate and proof-read SNARE assembly to drive membrane fusion, and possibly attach endosomes to the cytoskeleton. The core subunits Vps11, Vps16 and Vps18 present the SNARE-interacting Vps33 subunit on one side and bind the Rab GTPase interaction module through Vps3/Vps8 (in CORVET) or Vps39/Vps41 (in HOPS) on the other side (Fig. 3A) The core subunits Vps11, Vps16 and Vps18 present the SNARE-interacting Vps33 subunit on one side and bind the Rab GTPase interaction module through Vps3/Vps8 (in CORVET) or Vps39/Vps41 (in HOPS) on the other side (Fig. 3A)" SIGNOR-273686 MARCHF9 protein Q86YJ5 UNIPROT IGHD protein P01880 UNIPROT "down-regulates quantity by destabilization" ubiquitination 9606 BTO:0001522 19457934 t miannu "MARCH9, a member of the RING-CH family of transmembrane E3 ubiquitin ligases, down-regulates CD4, major histocompatibility complex-I (MHC), and ICAM-1 in lymphoid cells. To identify novel MARCH9 substrates, we used high throughput flow cytometry and quantitative mass spectrometry by stable isotope labeling by amino acids in cell culture (SILAC) to determine the differential expression of plasma membrane proteins in a MARCH9-expressing B cell line. This combined approach identified 13 potential new MARCH9 targets. " SIGNOR-271542 PTAFR protein P25105 UNIPROT GNAI3 protein P08754 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257174 POMC protein P01189 UNIPROT MC4R protein P32245 UNIPROT "up-regulates activity" binding 9606 20694162 t miannu "α-MSH can activate both melanocortin 4 receptors (MC4R) and melanocortin 1 receptors (MC1R)" SIGNOR-252373 PRKDC protein P78527 UNIPROT RPA2 protein P15927 UNIPROT "down-regulates activity" phosphorylation Ser12 GFESYGSsSYGGAGG -1 9295339 t lperfetto "We showed previously that UV irradiation increases phosphorylation of the p34 subunit of human replication protein A (RPA) and that this hyperphosphorylation correlated with loss of activity of the DNA replication complex. | we detected phosphorylation of the RPA complex by DNA-PK on RPA-p34 sites Ser-23, Ser-29, and Ser-11, -12, or -13" SIGNOR-248981 VPS16 protein Q9H269 UNIPROT "HOPS tethering complex" complex SIGNOR-C549 SIGNOR "form complex" binding 9606 23351085 t miannu "The two Vps-C complexes CORVET (class C core vacuole/endosome tethering) and HOPS (homotypic fusion and vacuole protein sorting) perform diverse biochemical functions in endocytosis: they tether membranes, interact with Rab GTPases, activate and proof-read SNARE assembly to drive membrane fusion, and possibly attach endosomes to the cytoskeleton. The core subunits Vps11, Vps16 and Vps18 present the SNARE-interacting Vps33 subunit on one side and bind the Rab GTPase interaction module through Vps3/Vps8 (in CORVET) or Vps39/Vps41 (in HOPS) on the other side (Fig. 3A) The core subunits Vps11, Vps16 and Vps18 present the SNARE-interacting Vps33 subunit on one side and bind the Rab GTPase interaction module through Vps3/Vps8 (in CORVET) or Vps39/Vps41 (in HOPS) on the other side (Fig. 3A)" SIGNOR-273687 VPS18 protein Q9P253 UNIPROT "HOPS tethering complex" complex SIGNOR-C549 SIGNOR "form complex" binding 9606 23351085 t miannu "The two Vps-C complexes CORVET (class C core vacuole/endosome tethering) and HOPS (homotypic fusion and vacuole protein sorting) perform diverse biochemical functions in endocytosis: they tether membranes, interact with Rab GTPases, activate and proof-read SNARE assembly to drive membrane fusion, and possibly attach endosomes to the cytoskeleton. The core subunits Vps11, Vps16 and Vps18 present the SNARE-interacting Vps33 subunit on one side and bind the Rab GTPase interaction module through Vps3/Vps8 (in CORVET) or Vps39/Vps41 (in HOPS) on the other side (Fig. 3A) The core subunits Vps11, Vps16 and Vps18 present the SNARE-interacting Vps33 subunit on one side and bind the Rab GTPase interaction module through Vps3/Vps8 (in CORVET) or Vps39/Vps41 (in HOPS) on the other side (Fig. 3A)" SIGNOR-273688 VPS39 protein Q96JC1 UNIPROT "HOPS tethering complex" complex SIGNOR-C549 SIGNOR "form complex" binding 9606 23351085 t miannu "The two Vps-C complexes CORVET (class C core vacuole/endosome tethering) and HOPS (homotypic fusion and vacuole protein sorting) perform diverse biochemical functions in endocytosis: they tether membranes, interact with Rab GTPases, activate and proof-read SNARE assembly to drive membrane fusion, and possibly attach endosomes to the cytoskeleton. The core subunits Vps11, Vps16 and Vps18 present the SNARE-interacting Vps33 subunit on one side and bind the Rab GTPase interaction module through Vps3/Vps8 (in CORVET) or Vps39/Vps41 (in HOPS) on the other side (Fig. 3A) The core subunits Vps11, Vps16 and Vps18 present the SNARE-interacting Vps33 subunit on one side and bind the Rab GTPase interaction module through Vps3/Vps8 (in CORVET) or Vps39/Vps41 (in HOPS) on the other side (Fig. 3A)" SIGNOR-273690 MAPK1 protein P28482 UNIPROT AHNAK protein Q09666 UNIPROT unknown phosphorylation Thr5794 REFSGPStPTGTLEF 10090 BTO:0000944 22028470 t miannu "We have optimized a chemical genetic system using analog-sensitive ERK2, a form of ERK2 engineered to use an analog of adenosine 5'-triphosphate (ATP), to tag and isolate ERK2 substrates in vitro. This approach identified 80 proteins phosphorylated by ERK2, 13 of which are known ERK2 substrates. With this improved methodology, we detected 98 sites directly phosphorylated by ERK2 on 80 proteins from NIH 3T3-L1 fibroblasts. Thirteen of these proteins are known substrates and the rest represent previously unknown kinase/substrate interactions. (table1)" SIGNOR-262767 STK38L protein Q9Y2H1 UNIPROT ULK1 protein O75385 UNIPROT "down-regulates quantity" phosphorylation Ser495 GVLARKMsLGGGRPY 10090 35670107 t "STK38L ubiquitination promotes its activation and phosphorylation of ULK1 at Ser495, rendering ULK1 in a permissive state for TRIM27-mediated hyper-ubiquitination" SIGNOR-270348 SMAD2/SMAD4 complex SIGNOR-C8 SIGNOR SP1 protein P08047 UNIPROT "up-regulates activity" binding 9606 BTO:0000552 11013220 t irozzo "TGF-β induces the formation and nuclear translocation of a trimeric Smad complex, which in this case is likely to consist of one monomer each of Smad2, Smad3 and Smad4. Smad2 and Smad4 associate directly with Sp1 and co-activate the transcriptional activity of Sp1." SIGNOR-256288 VPS33A protein Q96AX1 UNIPROT "HOPS tethering complex" complex SIGNOR-C549 SIGNOR "form complex" binding 9606 23351085 t miannu "The two Vps-C complexes CORVET (class C core vacuole/endosome tethering) and HOPS (homotypic fusion and vacuole protein sorting) perform diverse biochemical functions in endocytosis: they tether membranes, interact with Rab GTPases, activate and proof-read SNARE assembly to drive membrane fusion, and possibly attach endosomes to the cytoskeleton. The core subunits Vps11, Vps16 and Vps18 present the SNARE-interacting Vps33 subunit on one side and bind the Rab GTPase interaction module through Vps3/Vps8 (in CORVET) or Vps39/Vps41 (in HOPS) on the other side (Fig. 3A) The core subunits Vps11, Vps16 and Vps18 present the SNARE-interacting Vps33 subunit on one side and bind the Rab GTPase interaction module through Vps3/Vps8 (in CORVET) or Vps39/Vps41 (in HOPS) on the other side (Fig. 3A)" SIGNOR-273691 "HOPS tethering complex" complex SIGNOR-C549 SIGNOR SNARE_complex complex SIGNOR-C346 SIGNOR "up-regulates activity" binding 9606 23351085 t miannu "The two Vps-C complexes CORVET (class C core vacuole/endosome tethering) and HOPS (homotypic fusion and vacuole protein sorting) perform diverse biochemical functions in endocytosis: they tether membranes, interact with Rab GTPases, activate and proof-read SNARE assembly to drive membrane fusion, and possibly attach endosomes to the cytoskeleton. The core subunits Vps11, Vps16 and Vps18 present the SNARE-interacting Vps33 subunit on one side and bind the Rab GTPase interaction module through Vps3/Vps8 (in CORVET) or Vps39/Vps41 (in HOPS) on the other side (Fig. 3A) The core subunits Vps11, Vps16 and Vps18 present the SNARE-interacting Vps33 subunit on one side and bind the Rab GTPase interaction module through Vps3/Vps8 (in CORVET) or Vps39/Vps41 (in HOPS) on the other side (Fig. 3A)" SIGNOR-273692 UBE4B protein O95155 UNIPROT TP53 protein P04637 UNIPROT "down-regulates quantity by destabilization" polyubiquitination 9606 BTO:0002552 21317885 t miannu "We show that ubiquitination factor E4B (UBE4B), an E3 and E4 ubiquitin ligase, physically interacts with p53 and Hdm2 (also known as Mdm2 in mice). UBE4B promotes p53 polyubiquitination and degradation and inhibits p53-dependent transactivation and apoptosis. " SIGNOR-271907 CSNK2A1 protein P68400 UNIPROT DDIT3 protein P35638 UNIPROT "down-regulates activity" phosphorylation Ser15 FSFGTLSsWELEAWY 9606 BTO:0000567 12876286 t llicata "CHOP transcription factor phosphorylation by casein kinase 2 inhibits transcriptional activation. | The serine to alanine substituted site CHOP mutant was not phosphorylated by CK2, indicating that serines 14–15 and 30–31 of CHOP are the CK2 phosphoacceptor sites" SIGNOR-250851 VPS16 protein Q9H269 UNIPROT "CORVET tethering complex" complex SIGNOR-C550 SIGNOR "form complex" binding 9606 23351085 t miannu "The two Vps-C complexes CORVET (class C core vacuole/endosome tethering) and HOPS (homotypic fusion and vacuole protein sorting) perform diverse biochemical functions in endocytosis: they tether membranes, interact with Rab GTPases, activate and proof-read SNARE assembly to drive membrane fusion, and possibly attach endosomes to the cytoskeleton. The core subunits Vps11, Vps16 and Vps18 present the SNARE-interacting Vps33 subunit on one side and bind the Rab GTPase interaction module through Vps3/Vps8 (in CORVET) or Vps39/Vps41 (in HOPS) on the other side (Fig. 3A) The core subunits Vps11, Vps16 and Vps18 present the SNARE-interacting Vps33 subunit on one side and bind the Rab GTPase interaction module through Vps3/Vps8 (in CORVET) or Vps39/Vps41 (in HOPS) on the other side (Fig. 3A)" SIGNOR-273696 VPS33A protein Q96AX1 UNIPROT "CORVET tethering complex" complex SIGNOR-C550 SIGNOR "form complex" binding 9606 23351085 t miannu "The two Vps-C complexes CORVET (class C core vacuole/endosome tethering) and HOPS (homotypic fusion and vacuole protein sorting) perform diverse biochemical functions in endocytosis: they tether membranes, interact with Rab GTPases, activate and proof-read SNARE assembly to drive membrane fusion, and possibly attach endosomes to the cytoskeleton. The core subunits Vps11, Vps16 and Vps18 present the SNARE-interacting Vps33 subunit on one side and bind the Rab GTPase interaction module through Vps3/Vps8 (in CORVET) or Vps39/Vps41 (in HOPS) on the other side (Fig. 3A) The core subunits Vps11, Vps16 and Vps18 present the SNARE-interacting Vps33 subunit on one side and bind the Rab GTPase interaction module through Vps3/Vps8 (in CORVET) or Vps39/Vps41 (in HOPS) on the other side (Fig. 3A)" SIGNOR-273697 FZD5 protein Q13467 UNIPROT LRP6 protein O75581 UNIPROT "up-regulates activity" binding 9606 18077588 t areggio "Here we show that both Fz and Dvl functions are critical for Wnt-induced Lrp6 phosphorylation through Fz-Lrp6 interaction." SIGNOR-258966 BCL2L11 protein O43521 UNIPROT BAX protein Q07812 UNIPROT "up-regulates activity" binding 10090 12242151 t lperfetto "We find short peptides representing the alpha-helical BH3 domains of BID or BIM are capable of inducing oligomerization of BAK and BAX to release cytochrome c." SIGNOR-92939 CSNK2A1 protein P68400 UNIPROT CDH1 protein P12830 UNIPROT "up-regulates activity" phosphorylation Ser851 SLSSLNSsESDKDQD 10090 BTO:0000944 10671552 t llicata "Casein kinase II phosphorylation of E-cadherin increases E-cadherin/beta-catenin interaction and strengthens cell-cell adhesion. | Under these conditions, phosphorylation of the E-cadherin double mutant S853A/S855A was reduced by 25% as compared with wt E-cadherin. | Expression of the E-cadherin double mutant S853A/S855A in NIH3T3 cells expressing Wnt-1 reduces cell-cell adhesion." SIGNOR-250840 BLOC-2 complex SIGNOR-C252 SIGNOR KIF13A protein Q9H1H9 UNIPROT "up-regulates activity" binding 9606 30404817 t lperfetto "Recycling endosomes (REs) are transient endosomal tubular intermediates of early/sorting endosomes (E/SEs) that function in cargo recycling to the cell surface and deliver the cell type-specific cargo to lysosome-related organelles such as melanosomes in melanocytes.|Taken together, these findings suggest that Rab22A promotes the assembly of a BLOC-1-BLOC-2-KIF13A complex on E/SEs to generate REs that maintain cellular and organelle homeostasis." SIGNOR-260702 PDK2 protein Q15119 UNIPROT PDHA1 protein P08559 UNIPROT "down-regulates activity" phosphorylation Ser293 TYRYHGHsMSDPGVS -1 11485553 t lperfetto "Here we report that the four isoenzymes of protein kinase responsible for the phosphorylation and inactivation of pyruvate dehydrogenase (pdk1, pdk2, pdk3 and pdk4) differ in their abilities to phosphorylate the enzyme. Pdk1 can phosphorylate all three sites (s232, s293, s300), whereas pdk2, pdk3 and pdk4 each phosphorylate only s232 and s293." SIGNOR-109563 MAPK1 protein P28482 UNIPROT PTPN7 protein P35236 UNIPROT "up-regulates activity" phosphorylation Thr66 EPICSVNtPREVTLH -1 16226275 t lperfetto "First, Erk phosphorylates HePTP at residues Thr45 and Ser72. Second, HePTP dephosphorylates Erk at PTyr185.|" SIGNOR-249437 VPS18 protein Q9P253 UNIPROT "CORVET tethering complex" complex SIGNOR-C550 SIGNOR "form complex" binding 9606 23351085 t miannu "The two Vps-C complexes CORVET (class C core vacuole/endosome tethering) and HOPS (homotypic fusion and vacuole protein sorting) perform diverse biochemical functions in endocytosis: they tether membranes, interact with Rab GTPases, activate and proof-read SNARE assembly to drive membrane fusion, and possibly attach endosomes to the cytoskeleton. The core subunits Vps11, Vps16 and Vps18 present the SNARE-interacting Vps33 subunit on one side and bind the Rab GTPase interaction module through Vps3/Vps8 (in CORVET) or Vps39/Vps41 (in HOPS) on the other side (Fig. 3A) The core subunits Vps11, Vps16 and Vps18 present the SNARE-interacting Vps33 subunit on one side and bind the Rab GTPase interaction module through Vps3/Vps8 (in CORVET) or Vps39/Vps41 (in HOPS) on the other side (Fig. 3A)" SIGNOR-273698 PCDHA10 protein Q9Y5I2 UNIPROT PCDHGA9 protein Q9Y5G4 UNIPROT "up-regulates activity" binding 9606 BTO:0000227 16697637 t miannu "The clustered protocadherins comprise the largest subfamily of the cadherin superfamily and are predominantly expressed in the nervous system. Pcdh-alpha proteins interact with beta1-integrin to promote cell adhesion. They also form oligomers with Pcdh-gamma proteins at the same membrane sites." SIGNOR-265700 "CORVET tethering complex" complex SIGNOR-C550 SIGNOR SNARE_complex complex SIGNOR-C346 SIGNOR "up-regulates activity" binding 9606 23351085 t miannu "The two Vps-C complexes CORVET (class C core vacuole/endosome tethering) and HOPS (homotypic fusion and vacuole protein sorting) perform diverse biochemical functions in endocytosis: they tether membranes, interact with Rab GTPases, activate and proof-read SNARE assembly to drive membrane fusion, and possibly attach endosomes to the cytoskeleton. The core subunits Vps11, Vps16 and Vps18 present the SNARE-interacting Vps33 subunit on one side and bind the Rab GTPase interaction module through Vps3/Vps8 (in CORVET) or Vps39/Vps41 (in HOPS) on the other side (Fig. 3A) The core subunits Vps11, Vps16 and Vps18 present the SNARE-interacting Vps33 subunit on one side and bind the Rab GTPase interaction module through Vps3/Vps8 (in CORVET) or Vps39/Vps41 (in HOPS) on the other side (Fig. 3A)" SIGNOR-273699 MTOR protein P42345 UNIPROT RPTOR protein Q8N122 UNIPROT "up-regulates activity" phosphorylation Ser863 LTQSAPAsPTNKGVH 9606 BTO:0000007 SIGNOR-C3 SIGNOR-C3 19864431 t lperfetto "Our data that insulin-stimulated raptor ser863 phosphorylation requires kinase-active mtorc1 and displays rapamycin sensitivity in intact cells, together with the data of wang et al. (67) that mtor phosphorylates raptor ser863 in vitro, strongly suggest that mtor itself mediates raptor ser863 phosphorylation. / strikingly, raptor ser863 phosphorylation is absolutely required for raptor ser859 and ser855 phosphorylation. These data suggest that mtorc1 activation leads to raptor multisite phosphorylation and that raptor ser863 phosphorylation functions as a master biochemical switch that modulates hierarchical raptor phosphorylation" SIGNOR-188924 MAPK3 protein P27361 UNIPROT ATF2 protein P15336 UNIPROT up-regulates phosphorylation Thr71 IVADQTPtPTRFLKN 9606 20068231 t gcesareni "Phosphorylation of thr-69 by mapk14 and mapk11, and at thr-71 by mapk1/erk2, mapk3/erk1, mapk11, mapk12 and mapk14 in response to external stimulus like insulin causes increased transcriptional activity." SIGNOR-163258 CDK1 protein P06493 UNIPROT NPM1 protein P06748 UNIPROT unknown phosphorylation Ser70 EAMNYEGsPIKVTLA 9606 19933706 t gcesareni "Simultaneous inactivation of two cdk phosphorylation sites at ser10 and ser70 (npm-aa) induced g(2)/m cell cycle arrest, phosphorylation of cdk1 at tyr15 (cdc2(tyr15)) and increased cytoplasmic accumulation of cdc25c." SIGNOR-161801 TBL1X protein O60907 UNIPROT SCF(TBL1) complex SIGNOR-C533 SIGNOR "form complex" binding 9606 BTO:0000007 20181957 t miannu "Upon UV-induced DNA damage, beta-catenin is recruited for polyubiquitination and subsequent proteasomal degradation by a unique, p53-induced SCF-like complex (SCF(TBL1)), comprised of Siah-1, Siah-1-interacting protein (SIP), Skp1, transducin beta-like 1 (TBL1), and adenomatous polyposis coli (APC). " SIGNOR-271948 SHH protein Q15465 UNIPROT CP protein P00450 UNIPROT down-regulates binding 9606 BTO:0001253 9811851 t gcesareni "Binding of sonic hedgehog (shh) to patched (ptc) relieves the latter's tonic smoothened (smo), a receptor that spans the cell membrane seven times. Ptch exists in vertebrates as two isoforms, ptch1 and ptch2, which seem to be equivalent in terms of binding the three hh isoforms." SIGNOR-61549 ADCY7 protein P51828 UNIPROT "3',5'-cyclic AMP" smallmolecule CHEBI:17489 ChEBI "up-regulates quantity" "chemical modification" 9606 15385642 t miannu "Adenylyl cyclases (AC), a family of enzymes that catalyze the synthesis of cyclic AMP, are critical regulators of cellular functions." SIGNOR-265007 ARHGAP35 protein Q9NRY4 UNIPROT RHOA protein P61586 UNIPROT "down-regulates activity" "gtpase-activating protein" 9606 BTO:0000007 32203420 t Luana "We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2)." SIGNOR-260492 CAST protein P20810 UNIPROT CAPN3 protein P20807 UNIPROT "down-regulates activity" binding 9606 BTO:0000590 25969760 t lperfetto "In addition to Ca2+, calpastatin has a key role in the regulation of calpain. Calpastatin, a heat-stable protein ranging from ~70 to ~140 kDa of apparent molecular weight depending on the cell type, is considered a specific endogenous inhibitor of calpains|The calpastatin molecule contains four inhibitory units [75–77]. Each of these units binds to one calpain molecule [75–77]. Therefore, the ratio calpain/calpastatin plays a key role in the regulation of calpain activity [78–80]. The inhibitory effect of calpastatin requires Ca2+-dependent high-affinity binding to three sites of calpain" SIGNOR-251603 IRAK1 protein P51617 UNIPROT PELI3 protein Q8N2H9 UNIPROT up-regulates phosphorylation 9606 17997719 t gcesareni "Pellino3 physically interacts with il-1r-associated kinase-1, tnf receptor-associated factor-6, tgf-beta-activated kinase-1, and nf-kappab-inducing kinase in an il-1-dependent manner in the present study, we demonstrate that irak1 and irak4 phosphorylate pellino isoforms in vitro and that phosphorylation greatly enhances pellino's e3 ubiquitin ligase activity." SIGNOR-159052 GAS2L1 protein Q99501 UNIPROT F-actin_assembly phenotype SIGNOR-PH18 SIGNOR up-regulates 9606 24706950 f miannu "Previous work has shown that members of the growth-arrest-specific 2 (GAS2) family mediate the crosstalk between filamentous actin (F-actin) and MTs, but the molecular basis of this process remained unclear. By using fluorescence microscopy, we demonstrate that three members of this family, GAS2-like 1, GAS2-like 2 and GAS2-like 3 (G2L1, G2L2 and G2L3, also known as GAS2L1, GAS2L2 and GAS2L3, respectively) are differentially involved in mediating the crosstalk between F-actin and MTs. " SIGNOR-273700 GAS2 protein O43903 UNIPROT F-actin_assembly phenotype SIGNOR-PH18 SIGNOR up-regulates 9606 24706950 f miannu "Previous work has shown that members of the growth-arrest-specific 2 (GAS2) family mediate the crosstalk between filamentous actin (F-actin) and MTs, but the molecular basis of this process remained unclear. By using fluorescence microscopy, we demonstrate that three members of this family, GAS2-like 1, GAS2-like 2 and GAS2-like 3 (G2L1, G2L2 and G2L3, also known as GAS2L1, GAS2L2 and GAS2L3, respectively) are differentially involved in mediating the crosstalk between F-actin and MTs. " SIGNOR-273701 CSNK1E protein P49674 UNIPROT CDH1 protein P12830 UNIPROT "down-regulates activity" phosphorylation Ser844 GSGSEAAsLSSLNSS 17353278 t lperfetto "Casein kinase 1 is a novel negative regulator of E-cadherin-based cell-cell contacts|CK1 colocalizes with E-cadherin and phosphorylates the cytoplasmic domain of E-cadherin in vitro and in a cell culture system. We show that the major CK1 phosphorylation site of E-cadherin is serine 846" SIGNOR-274047 PAK1 protein Q13153 UNIPROT SORT1 protein Q99523 UNIPROT "down-regulates activity" phosphorylation Ser793 RFLVHRYsVLQQHAE 9606 BTO:0000007 31767632 t miannu "PAKs specifically phosphorylate Ser15 of the sortilin-cd and alter its trafficking. It can be concluded that PAK1-3 may indeed instigate the phosphorylation of sortilin and that they target a single serine residue (Ser15) located in the kinase domain-binding site of the sortilin-cd. Full-length sortilins with the serine at position 793 (residue 15 in the cytoplasmic domain) (for the sequence, see Fig. 2). Phosphorylation (Ser15) downregulates the sortilin–AP-1 interaction." SIGNOR-273718 ATM protein Q13315 UNIPROT TAOK1 protein Q7L7X3 UNIPROT up-regulates phosphorylation Thr785 SINEMLStQALRLDE 9606 17396146 t gcesareni "The dna damage kinase ataxia telangiectasia mutated (atm) phosphorylates taos in vitro;radiation induces phosphorylation of tao on a consensus site for phosphorylation by the atmprotein kinase in cells." SIGNOR-154175 CDK1 protein P06493 UNIPROT RUNX1 protein Q01196 UNIPROT up-regulates phosphorylation Ser21 TPPSTALsPGKMSEA 9606 SIGNOR-C17 21059642 t "The effect has been demonstrated using Q01196-8" gcesareni "Phosphorylation of runx1 on ser-303 by cdks leads its ubiquitin-mediated degradation during g2/m (19). We developed additional evidence that cdks phosphorylate ser-303 and found that ser-48 and ser-424 are also substrates of cdk1/cyclin b and cdk6/cyclin d3. Moreover, we demonstrated that phosphorylation of ser-48, ser-303, and ser-424 strengthens the ability of runx1 to activate transcription and to stimulate proliferation of the ba/f3 hematopoietic cell line (20)." SIGNOR-169318 clotrimazole chemical CHEBI:3764 ChEBI KCNN4 protein O15554 UNIPROT "down-regulates activity" "chemical inhibition" 9606 BTO:0000007 9730970 t miannu "IK was blocked by the classical inhibitors of the Gardos channel charybdotoxin (IC50 28 nM) and clotrimazole (IC50 153 nM) as well as by nitrendipine (IC50 27 nM), Stichodactyla toxin (IC50 291 nM), margatoxin (IC50 459 nM), miconazole (IC50 785 nM), econazole (IC50 2.4 microM), and cetiedil (IC50 79 microM). Finally, 1-ethyl-2-benzimidazolinone, an opener of the T84 cell IK channel, activated hIK with an EC50 of 74 microM." SIGNOR-258832 NLGN1 protein Q8N2Q7 UNIPROT NRXN1 protein P58400 UNIPROT "up-regulates activity" binding 9606 BTO:0000938 18923512 t brain lperfetto "Pre- and postsynaptic plasma membranes are always precisely aligned, and are separated by a synaptic cleft of ~20 nm. The cleft contains an undefined proteinaceous material in the middle, and is presumably bridged by synaptic cell-adhesion molecules such as Nrxns and Nlgns that align the pre- and postsynaptic elements and mediate trans-synaptic signaling.|Nlgns bind to both alpha- and beta-Nrxns with nanomolar affinities; binding involves the sixth LNS-domain of alpha-Nrxns which corresponds to the only LNS-domain of beta-Nrxns52. The binding affinities differ characteristically between various pairs of Nlgns and Nrxns, and are controlled by alternative splicing of both Nrxns and Nlgns (Figure 1c)" SIGNOR-264149 MAPKAPK2 protein P49137 UNIPROT HSPB1 protein P04792 UNIPROT down-regulates phosphorylation Ser15 FSLLRGPsWDPFRDW 9606 20626350 t "10383393: We demonstrate that both phosphorylated sHsps and the triple mutant Hsp27-S15D,S78D,S82D show significantly decreased abilities to act as molecular chaperones suppressing thermal denaturation and facilitating refolding of citrate synthase in vitro." gcesareni "Notably mk2 is well known to play an important role in actin filament remodellng by phosphorylating hsp27." SIGNOR-166629 PAK3 protein O75914 UNIPROT SORT1 protein Q99523 UNIPROT "down-regulates activity" phosphorylation Ser793 RFLVHRYsVLQQHAE 9606 BTO:0000007 31767632 t miannu "PAKs specifically phosphorylate Ser15 of the sortilin-cd and alter its trafficking. It can be concluded that PAK1-3 may indeed instigate the phosphorylation of sortilin and that they target a single serine residue (Ser15) located in the kinase domain-binding site of the sortilin-cd. Full-length sortilins with the serine at position 793 (residue 15 in the cytoplasmic domain) (for the sequence, see Fig. 2). Phosphorylation (Ser15) downregulates the sortilin–AP-1 interaction." SIGNOR-273719 SORT1 protein Q99523 UNIPROT APOE protein P02649 UNIPROT "up-regulates quantity" binding 10029 BTO:0000246 23283348 t miannu "Here, we identified the pro-neurotrophin receptor sortilin as major endocytic pathway for clearance of APOE/Aβ complexes in neurons. Sortilin binds APOE with high affinity. Lack of receptor expression in mice results in accumulation of APOE and of Aβ in the brain and in aggravated plaque burden. Sortilin interacts with all human APOE isoforms." SIGNOR-273721 SORT1 protein Q99523 UNIPROT APOA1 protein P02647 UNIPROT "up-regulates quantity" binding 10029 BTO:0000246 23283348 t miannu "Here, we identified the pro-neurotrophin receptor sortilin as major endocytic pathway for clearance of APOE/Aβ complexes in neurons. Sortilin binds APOE with high affinity. Lack of receptor expression in mice results in accumulation of APOE and of Aβ in the brain and in aggravated plaque burden. Sortilin interacts with all human APOE isoforms." SIGNOR-273722 SRC protein P12931 UNIPROT CDH1 protein P12830 UNIPROT "down-regulates quantity by destabilization" phosphorylation Tyr797 TLMSVPRyLPRPANP 31286874 t lperfetto "Activated c-Src phosphorylated E-cadherin at the tyrosine 797 site to initiate RNF43-mediated E-cadherin ubiquitination at lysine 816 and subsequent degradation" SIGNOR-274048 NEK3 protein P51956 UNIPROT SNAP29 protein O95721 UNIPROT "up-regulates activity" phosphorylation Ser105 MDQDLKIsQKHINSI 9606 BTO:0000007 29454964 t miannu "In the present study, we show that NEK3 (NIMA-never in mitosis gene A-related kinase 3)-mediated serine 105 (S105) phosphorylation of SNAP29 directs its membrane association, without which cells present defective focal adhesion formation, impaired Golgi structure and attenuated cellular recycling. Our results highlight the importance of NEK3-mediated S105 phosphorylation of SNAP29 for its membrane localization and for membrane fusion dependent processes." SIGNOR-273708 PLK1 protein P53350 UNIPROT SVIL protein O95425 UNIPROT "up-regulates activity" phosphorylation Ser238 SFSGRDSsFTEVPRS 9606 BTO:0000007 23750008 t miannu "PLK1 phosphorylates Ser238 of SVIL, which can promote the localization of SVIL to the central spindle and association with PRC1. Expression of a PLK1 phosphorylation site mutant, S238A-SVIL, inhibited myosin II activation at the equatorial cortex and induced aberrant furrowing. " SIGNOR-273729 QRICH1 protein Q2TAL8 UNIPROT VARS1 protein P26640 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 33384352 t miannu "QRICH1 promotes the expression of translation-related genes. our combined ChIP-seq and RNA-seq analyses identified that QRICH1 and ATF4 were enriched at the promoters of these specific tRNA synthetases, and that ER stress positively regulated their transcription (Fig. 4I). Together, these findings suggest that QRICH1 and ATF4 modulate tRNA metabolic processes to promote secreted protein synthesis during ER stress." SIGNOR-269408 "RFX complex" complex SIGNOR-C104 SIGNOR HLA-DMB protein P28068 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" -1 11258423 f "The RFX complex is comprised of three proteins – RFX5, RFXB, and RFXAP – all of which are required for expression of MHCII genes|In our current studies, we have utilized electrophoretic mobility shift assays to characterize the DNA binding of the RFX5(1–330)2•RFXAP•RFXB complex to the proximal regulatory region from the HLA-DRα gene to gain insight into the DNA binding properties of the RFX complex" SIGNOR-253999 ING1 protein Q9UK53 UNIPROT AFP protein P02771 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0000599 14522900 f miannu " In this study, we found that a subset of ING family members strongly repressed human alpha-fetoprotein (AFP) promoter activity but stimulated the p21(WAF1) promoter in parallel experiments in the same cell type, similar to the effects of p53. Both ING1 and p53 were able to suppress AFP transcription and cause p21 induction; hSIR2, a negative regulator of the p53 protein, showed the opposite effects on the AFP promoter and, like HDAC1, repressed p21 promoter activity." SIGNOR-254480 MAPK3 protein P27361 UNIPROT ESR1 protein P03372 UNIPROT up-regulates phosphorylation Ser104 FPPLNSVsPSPLMLL 9606 18372406 t gcesareni "In several estrogen response element-containing genes, the s118a mutation strongly reduced induction by e(2), and u0126 did not further reduce expression. Here, we show that serines 104 (s104) and 106 (s106) are also phosphorylated by mapk in vitro and upon stimulation of mapk activity in vivo.Phosphorylation at serines 104 and 106 by erk1/2 mapk is important for estrogen receptor-alpha activity" SIGNOR-178141 PLK1 protein P53350 UNIPROT WDCP protein Q9H6R7 UNIPROT "up-regulates activity" phosphorylation Ser686 RSDVFRDsFSHSPGA 9606 BTO:0000007 30297404 t miannu "PLK1 Phosphorylates MMAP to Promote Its Interaction with KIF2A and MRE11. we performed in vitro kinase assays followed by mass spectrometry and found that two sites (S686 and S695) in this cluster were phosphorylated. Thus, all of these results are in agreement that this cluster is phosphorylated by PLK1." SIGNOR-273730 PLK1 protein P53350 UNIPROT WDCP protein Q9H6R7 UNIPROT "up-regulates activity" phosphorylation Ser695 SHSPGAVsSLKVFTG 9606 BTO:0000007 30297404 t miannu "PLK1 Phosphorylates MMAP to Promote Its Interaction with KIF2A and MRE11. we performed in vitro kinase assays followed by mass spectrometry and found that two sites (S686 and S695) in this cluster were phosphorylated. Thus, all of these results are in agreement that this cluster is phosphorylated by PLK1." SIGNOR-273731 PRKAA1 protein Q13131 UNIPROT GSR protein P00390 UNIPROT "up-regulates activity" phosphorylation Thr507 TKADFDNtVAIHPTS 9606 BTO:0001890 31530934 t miannu "Mechanistically, AMPKα1 regulate the glutathione reductase (GSR) phosphorylation possibly through residue Thr507 which enhances its activity. " SIGNOR-273734 AMPK complex SIGNOR-C15 SIGNOR KCNA5 protein P22460 UNIPROT "down-regulates activity" phosphorylation Ser592 KCNVKAKsNVDLRRS 9606 BTO:0000007 30279167 t miannu "Thus, AMPK directly phosphorylates the α subunit of KV1.5 at Ser592 and, to a lesser extent, at Ser559. " SIGNOR-273735 AMPK complex SIGNOR-C15 SIGNOR KCNA5 protein P22460 UNIPROT "down-regulates activity" phosphorylation Ser559 VQRKVSGsRGSFCKA 9606 BTO:0000007 30279167 t miannu "Thus, AMPK directly phosphorylates the α subunit of KV1.5 at Ser592 and, to a lesser extent, at Ser559. " SIGNOR-273736 APC-c complex SIGNOR-C150 SIGNOR CLSPN protein Q9HAW4 UNIPROT "down-regulates quantity by destabilization" ubiquitination 18662541 t lperfetto "Claspin Is Degraded in G0 and G1 via the APC/CCdh1 Ubiquitin Ligase" SIGNOR-274056 USP28 protein Q96RU2 UNIPROT CDH1 protein P12830 UNIPROT "up-regulates quantity by stabilization" deubiquitination 18662541 t lperfetto "Usp28 deubiquitylates and consequently stabilizes Claspin in response to DNA damage" SIGNOR-274057 CDH1 protein P12830 UNIPROT APC-c complex SIGNOR-C150 SIGNOR "up-regulates activity" binding 18662541 t lperfetto "In early mitosis, APC/C is activated through binding to Cdc20, and in late M, Cdc20 is replaced by Cdh1, the second activator of APC/C." SIGNOR-274058 AMPK complex SIGNOR-C15 SIGNOR PAQR3 protein Q6TCH7 UNIPROT "up-regulates activity" phosphorylation Thr32 PRGIRLYtYEQIPGS 9606 BTO:0000007 26834238 t miannu "Firstly, PAQR3 functions as a scaffold protein that facilitates the formation of ATG14L- but not UVRAG-linked VPS34 complex, leading to elevated capacity of PI(3)P generation ahead of starvation signals. Secondly, AMPK phosphorylates PAQR3 at threonine 32 and switches on PI(3)P production to initiate autophagosome formation swiftly after glucose starvation. " SIGNOR-273737 POU5F1 protein Q01860 UNIPROT BMP4 protein P12644 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0001086 17068183 f miannu "To enhance our understanding of the molecular basis of this differentiation event in humans, we used a functional genomics approach involving RNA interference-mediated suppression of OCT4 function in a human ESC line and analysis of the resulting transcriptional profiles to identify OCT4-dependent genes in human cells. We detected altered expression of >1,000 genes, including targets regulated directly by OCT4 either positively (NANOG, SOX2, REX1, LEFTB, LEFTA/EBAF DPPA4, THY1, and TDGF1) or negatively (CDX2, EOMES, BMP4, TBX18, Brachyury [T], DKK1, HLX1, GATA6, ID2, and DLX5), as well as targets for the OCT4-associated stem cell regulators SOX2 and NANOG." SIGNOR-254932 HTR4 protein Q13639 UNIPROT GNA14 protein O95837 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257416 ERBB3 protein P21860 UNIPROT PIK3CA protein P42336 UNIPROT up-regulates binding 9606 16729043 t gcesareni "Pi3k is the sole binding partner to six tyrosines of erbb3 and one in erbb4." SIGNOR-146861 LYN protein P07948 UNIPROT CDKN1B protein P46527 UNIPROT down-regulates phosphorylation Tyr88 KGSLPEFyYRPPRPP 9606 21423214 t gcesareni "We previously reported that y88 phosphorylation of p27(kip1) by oncogenic tyrosine kinases impairs p27(kip1)-mediated cdk inhibition, and initiates its ubiquitin-dependent proteasomal degradation." SIGNOR-172904 ANXA3 protein P12429 UNIPROT NFKBIA protein P25963 UNIPROT "up-regulates activity" 9606 BTO:0000018 27995049 f miannu "We also investigated the potential regulation of cancer-associated signaling pathways by Anxa3 through screening for the altered expression of some common signaling molecules after Anxa3 downregulation. Decreased phosphorylation of MEK1/2, ERK1/2, Akt, and IκBα was detected after downregulating Anxa3 expression in A549 cells." SIGNOR-262213 FAM83G protein A6ND36 UNIPROT CSNK1A1 protein P48729 UNIPROT "up-regulates quantity" binding 9606 BTO:0000007 29789297 t miannu "We identified members of the FAM83 family of proteins as partners of CK1 in cells. All eight members of the FAM83 family (FAM83A–H) interacted with the α and α-like isoforms of CK1; FAM83A, -B, -E, and -H also interacted with the δ and ε isoforms of CK1. The intrinsic catalytic activity of CK1 is not affected by or required for the association of CK1 with FAM83 proteins. Our findings imply that the DUF1669 domains of FAM83 proteins anchor CK1 α, α-like, δ, and ε isoforms in specific subcellular compartments and potentially mediate their association with substrates." SIGNOR-273745 FAM83B protein Q5T0W9 UNIPROT CSNK1A1 protein P48729 UNIPROT "up-regulates quantity" binding 9606 BTO:0000007 29789297 t miannu "We identified members of the FAM83 family of proteins as partners of CK1 in cells. All eight members of the FAM83 family (FAM83A–H) interacted with the α and α-like isoforms of CK1; FAM83A, -B, -E, and -H also interacted with the δ and ε isoforms of CK1. The intrinsic catalytic activity of CK1 is not affected by or required for the association of CK1 with FAM83 proteins. Our findings imply that the DUF1669 domains of FAM83 proteins anchor CK1 α, α-like, δ, and ε isoforms in specific subcellular compartments and potentially mediate their association with substrates." SIGNOR-273746 FAM83H protein Q6ZRV2 UNIPROT CSNK1A1 protein P48729 UNIPROT "up-regulates quantity" binding 9606 BTO:0000007 29789297 t miannu "We identified members of the FAM83 family of proteins as partners of CK1 in cells. All eight members of the FAM83 family (FAM83A–H) interacted with the α and α-like isoforms of CK1; FAM83A, -B, -E, and -H also interacted with the δ and ε isoforms of CK1. The intrinsic catalytic activity of CK1 is not affected by or required for the association of CK1 with FAM83 proteins. Our findings imply that the DUF1669 domains of FAM83 proteins anchor CK1 α, α-like, δ, and ε isoforms in specific subcellular compartments and potentially mediate their association with substrates." SIGNOR-273747 FAM83F protein Q8NEG4 UNIPROT CSNK1A1 protein P48729 UNIPROT "up-regulates quantity" binding 9606 BTO:0000007 29789297 t miannu "We identified members of the FAM83 family of proteins as partners of CK1 in cells. All eight members of the FAM83 family (FAM83A–H) interacted with the α and α-like isoforms of CK1; FAM83A, -B, -E, and -H also interacted with the δ and ε isoforms of CK1. The intrinsic catalytic activity of CK1 is not affected by or required for the association of CK1 with FAM83 proteins. Our findings imply that the DUF1669 domains of FAM83 proteins anchor CK1 α, α-like, δ, and ε isoforms in specific subcellular compartments and potentially mediate their association with substrates." SIGNOR-273751 CSNK2A2 protein P19784 UNIPROT NOL3 protein O60936 UNIPROT "up-regulates activity" phosphorylation Thr149 SEAVQSGtPEEPEPE 9606 12191471 t miannu "Phosphorylation of ARC at T149 Is Required for Its Antiapoptotic Effect. Here we report that the function of ARC is regulated by protein kinase CK2. ARC at threonine 149 is phosphorylated by CK2. This phosphorylation targets ARC to mitochondria. ARC is able to bind to caspase-8 only when it is localized to mitochondria but not to the cytoplasm." SIGNOR-262836 SRC protein P12931 UNIPROT DAB1 protein O75553 UNIPROT "up-regulates activity" phosphorylation Tyr185 KQCEQAVyQTILEED 10090 BTO:0000938 11279201 t lperfetto "Dab1 is rapidly phosphorylated when neurons isolated from embryonic brains are stimulated with Reelin, and several tyrosines have been implicated in this response. Mice with phenylalanine substitutions of all five tyrosines (Tyr(185), Tyr(198), Tyr(200), Tyr(220), and Tyr(232)) exhibit a reeler phenotype, implying that tyrosine phosphorylation is critical for Dab1 function. Here we report that, although Src can phosphorylate all five tyrosines in vitro, Tyr(198) and Tyr(220) represent the major sites of Reelin-induced Dab1 phosphorylation in embryonic neurons." SIGNOR-247072 TRAF6 protein Q9Y4K3 UNIPROT TAB2 protein Q9NYJ8 UNIPROT "up-regulates activity" binding 9606 25290089 t lperfetto "The irak1/traf6 complex can also activate jnk and p38 signalling through assembly of a catalytically active tab2-tab3-tak1 complex." SIGNOR-205458 SAV1 protein Q9H4B6 UNIPROT STK3/4 proteinfamily SIGNOR-PF41 SIGNOR "up-regulates activity" binding 9606 BTO:0000007 19212654 t miannu "The human WW45 protein enhances MST1-mediated apoptosis in vivo In this model, hWW45 binds both MST1 and LATS through its coiled-coil domains and WW domains, respectively, and facilitates the phosphorylation of LATS by MST1. This model could explain the enhanced apoptotic efficacy of MST1 with the over-expression of hWW45 and the attenuated MST1-induced apoptosis with the down-regulation of endogenous hWW45." SIGNOR-263661 ALK protein Q9UM73 UNIPROT STAT3 protein P40763 UNIPROT up-regulates binding 9606 BTO:0000785 14968112 t gcesareni "Npm-alk has been shown to activate signal transducer and activator of transcription (stat) 3, a transcriptional regulator of cyclin d3.Proteins that interact with alk tyrosine kinase play important roles in mediating downstream cellular signals. Previously reported proteins in the alk signal pathway were identified including pi3-k, jak2, jak3, stat3, grb2, irs, and plcgamma1." SIGNOR-122085 PRKD1 protein Q15139 UNIPROT ARFIP1 protein P53367 UNIPROT up-regulates phosphorylation Ser132 LELVRKWsLNTYKCT 9606 23695357 t lperfetto "We report that arfaptins contain an amphipathic helix (ah) preceding the bar domain, which is essential for their binding to phosphatidylinositol 4-phosphate (pi(4)p)-containing liposomes and the tgn of mammalian cells. The binding of arfaptin1, but not arfaptin2, to pi(4)p is regulated by protein kinase d (pkd) mediated phosphorylation at ser100 within the ah. We also found that only arfaptin1 is required for the pkd-dependent trafficking of chromogranin a by the regulated secretory pathway." SIGNOR-202101 WNT7B protein P56706 UNIPROT LRP5 protein O75197 UNIPROT up-regulates binding 9606 15923619 t flangone "These studies point to an important interaction between wnt7b, lrp5, and fzd1 and fzd10." SIGNOR-137937 FAM83C protein Q9BQN1 UNIPROT CSNK1A1 protein P48729 UNIPROT "up-regulates quantity" binding 9606 BTO:0000007 29789297 t miannu "We identified members of the FAM83 family of proteins as partners of CK1 in cells. All eight members of the FAM83 family (FAM83A–H) interacted with the α and α-like isoforms of CK1; FAM83A, -B, -E, and -H also interacted with the δ and ε isoforms of CK1. The intrinsic catalytic activity of CK1 is not affected by or required for the association of CK1 with FAM83 proteins. Our findings imply that the DUF1669 domains of FAM83 proteins anchor CK1 α, α-like, δ, and ε isoforms in specific subcellular compartments and potentially mediate their association with substrates." SIGNOR-273752 JUN protein P05412 UNIPROT FOSL1 protein P15407 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0004603 13679379 t Luana "Members of the AP1 family distinctly regulated the fra-1 promoter. In particular, coexpression of c-Jun, Jun-D, and Fra-2 up-regulated fra-1 transcription. " SIGNOR-261604 miR-132 mirna URS00001F4E81_9606 RNAcentral MECP2 protein P51608 UNIPROT "down-regulates quantity by repression" "post transcriptional regulation" 10090 23132946 f irozzo "In human leukemic cells with MLL rearrangements (e.g., MONOMAC-6 and THP-1 cells), we found that ectopic expression of miR-495 could significantly inhibit cell growth/proliferation and increase apoptosis while decreasing cell viability." SIGNOR-255884 PRKG1 protein Q13976 UNIPROT VASP protein P50552 UNIPROT down-regulates phosphorylation Thr278 LARRRKAtQVGEKTP 9606 12576312 t lperfetto "Vasodilator-stimulated phosphoprotein activation of serum-response element-dependent transcription occurs downstream of rhoa and is inhibited by cgmp-dependent protein kinase phosphorylation. Three phosphorylation sites have been identified in vasp: ser157, ser239, and thr278, all of which can be phosphorylated by either pka or pkg in vitro" SIGNOR-98139 MELK protein Q14680 UNIPROT MELK protein Q14680 UNIPROT up-regulates phosphorylation Ser505 SPERRCRsVELDLNQ 9606 16216881 t lperfetto "We have mapped no less than 16 autophosphorylation sites including serines, threonines, and a tyrosine residue and show that the phosphorylation of thr167 and ser171 is required for the activation of melk.We have not yet explored the role of autophosphorylation of nine residues in the c-terminal, autoinhibitory domain (fig. 4c). An enticing hypothesis is that these autophosphorylations decrease the inhibitory potency of this domain and thereby contribute to the activation of the kinase." SIGNOR-141014 ETV6 protein P41212 UNIPROT HBB protein P68871 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 15958056 f "Regulation of expression" miannu "Upon erythropoietin exposure, overexpressed TEL stimulated hemoglobin synthesis" SIGNOR-251793 NRXN3 protein Q9Y4C0 UNIPROT NLGN2 protein Q8NFZ4 UNIPROT "up-regulates activity" binding 9606 BTO:0000142 22626547 t miannu "The neurexin–NL2 interaction is sufficient to induce GABAergic differentiation and clustering of GABAARs at postsynaptic sites" SIGNOR-265457 U2AF1 protein Q01081 UNIPROT TP53 protein P04637 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 31144421 f miannu " Our results further showed that knockdown of U2AF1 significantly Western blot analysis revealed an increase in the protein levels of downstream targets of p53 following U2AF1 knockdown. The data further showed that depletion of U2AF1 altered alternatively spliced apoptosis-associated gene transcripts in CFU-E cells. Our findings elucidate the role of U2AF1 in human erythropoiesis and reveal the underlying mechanisms." SIGNOR-261512 FAM83B protein Q5T0W9 UNIPROT CSNK1A1L protein Q8N752 UNIPROT "up-regulates quantity" binding 9606 BTO:0000007 29789297 t miannu "We identified members of the FAM83 family of proteins as partners of CK1 in cells. All eight members of the FAM83 family (FAM83A–H) interacted with the α and α-like isoforms of CK1; FAM83A, -B, -E, and -H also interacted with the δ and ε isoforms of CK1. The intrinsic catalytic activity of CK1 is not affected by or required for the association of CK1 with FAM83 proteins. Our findings imply that the DUF1669 domains of FAM83 proteins anchor CK1 α, α-like, δ, and ε isoforms in specific subcellular compartments and potentially mediate their association with substrates." SIGNOR-273754 FAM83H protein Q6ZRV2 UNIPROT CSNK1A1L protein Q8N752 UNIPROT "up-regulates quantity" binding 9606 BTO:0000007 29789297 t miannu "We identified members of the FAM83 family of proteins as partners of CK1 in cells. All eight members of the FAM83 family (FAM83A–H) interacted with the α and α-like isoforms of CK1; FAM83A, -B, -E, and -H also interacted with the δ and ε isoforms of CK1. The intrinsic catalytic activity of CK1 is not affected by or required for the association of CK1 with FAM83 proteins. Our findings imply that the DUF1669 domains of FAM83 proteins anchor CK1 α, α-like, δ, and ε isoforms in specific subcellular compartments and potentially mediate their association with substrates." SIGNOR-273755 AKT proteinfamily SIGNOR-PF24 SIGNOR AR protein P10275 UNIPROT "down-regulates activity" phosphorylation Ser792 CVRMRHLsQEFGWLQ 9534 BTO:0001538 11404460 t lperfetto "Akt suppresses androgen-induced apoptosis by phosphorylating and inhibiting androgen receptor. Here, we demonstrate that akt phosphorylates the androgen receptor (ar) at ser-210 and ser-790" SIGNOR-244136 POLD3 protein Q15054 UNIPROT "DNA polymerase delta" complex SIGNOR-C376 SIGNOR "form complex" binding -1 12403614 t lperfetto "Reconstitution and characterization of the human DNA polymerase delta four-subunit holoenzyme." SIGNOR-265515 PRKCD protein Q05655 UNIPROT SRC protein P12931 UNIPROT "up-regulates activity" phosphorylation Ser12 KSKPKDAsQRRRSLE 9606 BTO:0001938 18069897 t gcesareni "We conclude that treatment with either UV or PMA induces the phosphorylation of the PKC site Ser12 on c-SRC and that this specific phosphorylation event is significantly diminished in cells overexpressing PR55" SIGNOR-247974 CSNK2A1 protein P68400 UNIPROT α-Catenin proteinfamily SIGNOR-PF72 SIGNOR "down-regulates activity" phosphorylation 9606 BTO:0000527 19941816 t miannu "We demonstrate here that egfr activation results in disruption of the complex of beta-catenin and alpha-catenin, thereby abrogating the inhibitory effect of alpha-catenin on beta-catenin transactivation via ck2alpha-dependent phosphorylation of alpha-catenin at s641." SIGNOR-265822 KLF4 protein O43474 UNIPROT NPNT protein Q6UXI9 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0005787 BTO:0001103 23612709 f miannu "The MEK5-dependent activation of ERK5 promotes binding of the transcription factor SP1 to the promoter of the genes encoding the transcription factors Klf2 and Klf4, leading to their increased abundance. Subsequently, Klf2 and Klf4 bind to the Npnt promoter and induce the production of nephronectin during myoblast fusion" SIGNOR-255457 UBE3A protein Q05086 UNIPROT PSMD4 protein P55036 UNIPROT "down-regulates quantity by destabilization" polyubiquitination Lys122 SPVEDNEkDLVKLAK -1 19240029 t miannu "S5a/Rpn10 is a ubiquitin (Ub)-binding protein that is a subunit of the 26S proteasome but also exists free in the cytosol. It binds poly-Ub chains through its two Ub-interacting motifs (UIMs). We discovered that, unlike typical substrates of Ub ligases (E3s), S5a can be ubiquitinated by all E3s tested including multimeric and monomeric Ring finger E3s (MuRF1, Siah2, Parkin, APC, and SCF(betaTRCP1)), the U-box E3, CHIP, and HECT domain E3s (E6AP and Nedd4) when assayed with UbcH5 or related Ub-conjugating enzymes.The short half-life of S5a presumably is because of the presence of the UIM domain and reflects the ubiquitination of free S5a by many E3s. Surprisingly, the same four Lys residues on S5a, Lys-74, Lys-122, Lys-262, and Lys-365 were ubiquitinated by MuRF1 and E6AP (Fig. 10). Two additional Lys residues (Lys-126 and -135) were ubiquitinated by E6AP." SIGNOR-272743 GNAI1 protein P63096 UNIPROT "3',5'-cyclic AMP" smallmolecule CHEBI:17489 ChEBI down-regulates 9606 23994464 f apalma "The G alpha I subunit inhibits adenylyl cyclase activity and therefore reduces cytoplasmic cAMP levels" SIGNOR-255008 FAM83F protein Q8NEG4 UNIPROT CSNK1A1L protein Q8N752 UNIPROT "up-regulates quantity" binding 9606 BTO:0000007 29789297 t miannu "We identified members of the FAM83 family of proteins as partners of CK1 in cells. All eight members of the FAM83 family (FAM83A–H) interacted with the α and α-like isoforms of CK1; FAM83A, -B, -E, and -H also interacted with the δ and ε isoforms of CK1. The intrinsic catalytic activity of CK1 is not affected by or required for the association of CK1 with FAM83 proteins. Our findings imply that the DUF1669 domains of FAM83 proteins anchor CK1 α, α-like, δ, and ε isoforms in specific subcellular compartments and potentially mediate their association with substrates." SIGNOR-273759 FAM83C protein Q9BQN1 UNIPROT CSNK1A1L protein Q8N752 UNIPROT "up-regulates quantity" binding 9606 BTO:0000007 29789297 t miannu "We identified members of the FAM83 family of proteins as partners of CK1 in cells. All eight members of the FAM83 family (FAM83A–H) interacted with the α and α-like isoforms of CK1; FAM83A, -B, -E, and -H also interacted with the δ and ε isoforms of CK1. The intrinsic catalytic activity of CK1 is not affected by or required for the association of CK1 with FAM83 proteins. Our findings imply that the DUF1669 domains of FAM83 proteins anchor CK1 α, α-like, δ, and ε isoforms in specific subcellular compartments and potentially mediate their association with substrates." SIGNOR-273760 lapatinib chemical CHEBI:49603 ChEBI EGFR protein P00533 UNIPROT down-regulates "chemical inhibition" 9606 BTO:0000150 17892419 t gcesareni "Recently, lapatinib, a small molecule dual inhibitor of both her2 and egf receptors, has been developed to expand the options for treating her-positive breast cancer." SIGNOR-157867 PTPN11 protein Q06124 UNIPROT ERBB2 protein P04626 UNIPROT down-regulates dephosphorylation Tyr1023 DLVDAEEyLVPQQGF -1 32024694 t lperfetto "...which in turn suggests the importance SHP2 dephosphorylation of pTyr992 in EGFR and pTyr1023 in HER2 to mediate signaling.|More specifically, we show that acidic residues N-terminal to the substrate pTyr in EGFR and HER2 mediate specific binding by the SHP2 active site, leading to blockade of RasGAP binding and optimal signaling by the two receptors." SIGNOR-262957 MAPK1 protein P28482 UNIPROT NCOA1 protein Q15788 UNIPROT up-regulates phosphorylation Thr1179 NYGTNPGtPPASTSP 9606 10660621 t lperfetto "Furthermore, erk-2 phosphorylated threonine 1179 and serine 1185 (and to a lesser extent, serine 395) in vitro, suggesting the importance of this pathway for src-1 regulation. Treatment of cells expressing src-1 with epidermal growth factor enhanced the ligand-dependent, progesterone receptor-mediated activation of a target reporter gene." SIGNOR-74880 TFIID complex SIGNOR-C343 SIGNOR POLR2A protein P24928 UNIPROT "up-regulates activity" binding 9606 27096372 t miannu "Our structures suggest that a primary function of TFIID during PIC assembly is the proper positioning of TBP on the upstream promoter, which ultimately determines the placement of Pol II relative to the TSS. The structures presented here offer a structural framework for understanding the complex mechanism underlying TFIID function, shedding new light into the overlapping roles of TFIID as both a coactivator and a general platform for PIC assembly in the coordination of transcription initiation." SIGNOR-263934 "pyridoxal 5'-phosphate(2-)" smallmolecule CHEBI:597326 ChEBI PSAT1 protein Q9Y617 UNIPROT "up-regulates activity" "chemical activation" 3702 30034403 t lperfetto "Phosphoserine aminotransferase (PSAT) is a pyridoxal 5′-phosphate (PLP)-dependent enzyme that catalyzes the conversion of 3-phosphohydroxypyruvate (3-PHP) to 3-phosphoserine (PSer) in an L-glutamate (Glu)-linked reversible transamination reaction." SIGNOR-268561 FAM83A protein Q86UY5 UNIPROT CSNK1E protein P49674 UNIPROT "up-regulates quantity" binding 9606 BTO:0000007 29789297 t miannu "We identified members of the FAM83 family of proteins as partners of CK1 in cells. All eight members of the FAM83 family (FAM83A–H) interacted with the α and α-like isoforms of CK1; FAM83A, -B, -E, and -H also interacted with the δ and ε isoforms of CK1. The intrinsic catalytic activity of CK1 is not affected by or required for the association of CK1 with FAM83 proteins. Our findings imply that the DUF1669 domains of FAM83 proteins anchor CK1 α, α-like, δ, and ε isoforms in specific subcellular compartments and potentially mediate their association with substrates." SIGNOR-273761 FAM83B protein Q5T0W9 UNIPROT CSNK1E protein P49674 UNIPROT "up-regulates quantity" binding 9606 BTO:0000007 29789297 t miannu "We identified members of the FAM83 family of proteins as partners of CK1 in cells. All eight members of the FAM83 family (FAM83A–H) interacted with the α and α-like isoforms of CK1; FAM83A, -B, -E, and -H also interacted with the δ and ε isoforms of CK1. The intrinsic catalytic activity of CK1 is not affected by or required for the association of CK1 with FAM83 proteins. Our findings imply that the DUF1669 domains of FAM83 proteins anchor CK1 α, α-like, δ, and ε isoforms in specific subcellular compartments and potentially mediate their association with substrates." SIGNOR-273762 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR SHC4 protein Q6S5L8 UNIPROT "down-regulates activity" phosphorylation Thr159 GHRATALtPDSCPLP -1 31121283 t done miannu "The luminescence obtained in the kinase assay with FLAG-ShcD as substrate was significantly different to that with FLAG peptide suggesting that ShcD is a direct substrate of ERK (Fig. 2C).Furthermore, Thr159 was mutated to either alanine (A) or glutamic acid (E) to study whether the threonine phosphorylation state influences the ShcD/ERK interaction. Introducing the T159E mutation obliterated the ShcD/ERK interaction." SIGNOR-273669 CCL2 protein P13500 UNIPROT CCR4 protein P51679 UNIPROT "up-regulates activity" binding 9606 17160712 t gcesareni "CCR2 and CCR4 are two cell surface receptors that bind CCL2" SIGNOR-237555 FAM83E protein Q2M2I3 UNIPROT CSNK1D protein P48730 UNIPROT "up-regulates quantity" binding 9606 BTO:0000007 29789297 t miannu "We identified members of the FAM83 family of proteins as partners of CK1 in cells. All eight members of the FAM83 family (FAM83A–H) interacted with the α and α-like isoforms of CK1; FAM83A, -B, -E, and -H also interacted with the δ and ε isoforms of CK1. The intrinsic catalytic activity of CK1 is not affected by or required for the association of CK1 with FAM83 proteins. Our findings imply that the DUF1669 domains of FAM83 proteins anchor CK1 α, α-like, δ, and ε isoforms in specific subcellular compartments and potentially mediate their association with substrates." SIGNOR-273767 Monobutylphthalate chemical CHEBI:88522 ChEBI AHR protein P35869 UNIPROT "up-regulates activity" "chemical activation" -1 25081364 t miannu "BBP affected hepatocellular carcinoma progression through the aryl hydrocarbon receptor (AhR) and that benzyl butyl phthalate (BBP) stimulated AhR at the cell surface, which then interacted with G proteins and triggered a downstream signaling cascade. BBP activated AhR through a nongenomic action involving G-protein signaling rather than the classical genomic AhR action." SIGNOR-268791 IL9 protein P15248 UNIPROT IL2RG protein P31785 UNIPROT up-regulates binding 9606 11418623 t gcesareni "The common gamma-chain (gamma(c)) is an indispensable subunit of the functional receptor complexes for il-4, il-7, il-9, and il-15 as well as il-2. Here we show that the gamma(c) is also shared with the il-21r complex" SIGNOR-108867 CDK1 protein P06493 UNIPROT CDC16 protein Q13042 UNIPROT up-regulates phosphorylation Ser560 KTLKNIIsPPWDFRE 9606 14657031 t lperfetto "Apc activation is thought to depend on apc phosphorylation and cdc20 binding. We have identified 43 phospho_sites on apc of which at least 34 are mitosis specific. Of these, 32 sites are clustered in parts of apc1 and the tetratricopeptide repeat (tpr) subunits cdc27, cdc16, cdc23 and apc7. In vitro, at least 15 of the mitotic phospho_sites can be generated by cyclin_dependent kinase 1 (cdk1), and 3 by polo_like kinase 1 (plk1). Apc phosphorylation by cdk1, but not by plk1, is sufficient for increased cdc20 binding and apc activation" SIGNOR-119762 DLK1 protein P80370 UNIPROT SOX9 protein P48436 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 19254573 f fspada "Pref-1 inhibits adipocyte differentiation through upregulating sox9 expression." SIGNOR-184277 CDK3 protein Q00526 UNIPROT MECOM protein Q03112 UNIPROT "up-regulates activity" phosphorylation Ser624 KMFKDKVsPLQNLAS 33082307 t lperfetto "The motif harbouring S436 is a target of CDK2 and CDK3 kinases, which interacted with EVI1-WT. The methyltransferase DNMT3A bound preferentially to EVI1-WT compared with EVI1-S436A, and a hypomethylated cell population associated by EVI1-WT expression in murine haematopoietic progenitors is not maintained with EVI1-S436A." SIGNOR-273431 TGFB1 protein P01137 UNIPROT SKP2 protein Q13309 UNIPROT down-regulates 9606 21212736 f gcesareni "Skp2, a f-box protein that determines the substrate specificity for scf ubiquitin ligase, has recently been demonstrated to be degraded by cdh1/apc in response to tgfbeta signaling." SIGNOR-171013 SYK protein P43405 UNIPROT GCSAM protein Q8N6F7 UNIPROT "up-regulates activity" phosphorylation Tyr80 QDNVDQTySEELCYT -1 31362927 t miannu "Herein, we demonstrate phosphorylation of HGAL by Syk and Lyn kinases at tyrosines Y80, Y86, Y106Y107, Y128, and Y148.  Y148 (in black) was already phosphorylated before the addition of kinases. We demonstrate that Grb2 facilitates HGAL and Syk binding following BCR stimulation but does not affect the HGAL-mediated increase in Syk kinase activity. Previous studies showed that Grb2 inhibits BCR signaling by decreasing the activation of Syk by Lyn.11 Thus, while HGAL and Grb2 oppositely affect Syk kinase activity, this is not due to direct Grb2 effects on HGAL-mediated Syk kinase activation." SIGNOR-273572 FAM83H protein Q6ZRV2 UNIPROT CSNK1D protein P48730 UNIPROT "up-regulates quantity" binding 9606 BTO:0000007 29789297 t miannu "We identified members of the FAM83 family of proteins as partners of CK1 in cells. All eight members of the FAM83 family (FAM83A–H) interacted with the α and α-like isoforms of CK1; FAM83A, -B, -E, and -H also interacted with the δ and ε isoforms of CK1. The intrinsic catalytic activity of CK1 is not affected by or required for the association of CK1 with FAM83 proteins. Our findings imply that the DUF1669 domains of FAM83 proteins anchor CK1 α, α-like, δ, and ε isoforms in specific subcellular compartments and potentially mediate their association with substrates." SIGNOR-273768 XAV939 chemical CHEBI:62878 ChEBI AXIN1 protein O15169 UNIPROT up-regulates 9606 19759537 f gcesareni "Using a quantitative chemical proteomic approach, we discovered that xav939 stabilizes axin by inhibiting the poly-adp-ribosylating enzymes tankyrase 1 and tankyrase 2" SIGNOR-188045 LCK protein P06239 UNIPROT CCDC50 protein Q8IVM0 UNIPROT "down-regulates activity" phosphorylation Tyr304 SSHKGFHyKH 9606 BTO:0000567 19059208 t miannu "We found that Ymer was considerably phosphorylated on tyrosine residues also via Src family kinases such as Lck. A luciferase reporter assay showed that mutation of tyrosines on Ymer (YmerY217/279/304F) results in loss of the inhibitory activity for NF-kappaB signaling." SIGNOR-262855 SLC2A1 protein P11166 UNIPROT glucose chemical CHEBI:17234 ChEBI "up-regulates quantity" relocalization 9606 23506862 t miannu "GLUT1 plays a critical role in cerebral glucose uptake as the major GLUT isoform expressed in brain endothelial cells." SIGNOR-267460 SYK protein P43405 UNIPROT GCSAM protein Q8N6F7 UNIPROT "up-regulates activity" phosphorylation Tyr128 LGGTETEySLLHMPS -1 31362927 t miannu "Herein, we demonstrate phosphorylation of HGAL by Syk and Lyn kinases at tyrosines Y80, Y86, Y106Y107, Y128, and Y148.  Y148 (in black) was already phosphorylated before the addition of kinases. We demonstrate that Grb2 facilitates HGAL and Syk binding following BCR stimulation but does not affect the HGAL-mediated increase in Syk kinase activity. Previous studies showed that Grb2 inhibits BCR signaling by decreasing the activation of Syk by Lyn.11 Thus, while HGAL and Grb2 oppositely affect Syk kinase activity, this is not due to direct Grb2 effects on HGAL-mediated Syk kinase activation." SIGNOR-273573 IKBKB protein O14920 UNIPROT CYLD protein Q9NQC7 UNIPROT "down-regulates activity" phosphorylation Ser418 TTENRFHsLPFSLTK 9606 BTO:0000938 24614225 t lperfetto "Thus, serine 418 is phosphorylated in vivo.Cyld phosphorylation may serve as a mechanism to inactivate its traf2 deubiquitination activity." SIGNOR-204716 FUS protein P35637 UNIPROT DHX9 protein Q08211 UNIPROT "down-regulates activity" relocalization 9606 BTO:0000793 27460707 t "P35637:p.Pro525Leu (mutation causing interaction)" "We found that ALS mutants of FUS co-localized with Caprin-1, DDX3X, and DHX9 in cytoplasmic inclusions that could lead to the mis-regulation of their respective pathways, providing further clues to the mechanism of ALS pathogenesis.|FUS interacting proteins were sequestered into the cytoplasmic mutant FUS inclusions that could lead to their mis-regulation or loss of function, contributing to ALS pathogenesis. | We also demonstrated the co-localization of DHX9, DDX3X and Caprin-1 with cytoplasmic EGFP-P525L mutant FUS inclusions in primary cortical neurons" SIGNOR-262810 USP21 protein Q9UK80 UNIPROT STING1 protein Q86WV6 UNIPROT "down-regulates activity" deubiquitination 9606 BTO:0000567 28254948 t done miannu "In this study, we found that USP21 is an important deubiquitinating enzyme for STING and that it negatively regulates the DNA virus-induced production of type I interferons by hydrolyzing K27/63-linked polyubiquitin chain on STING. HSV-1 infection recruited USP21 to STING at late stage by p38-mediated phosphorylation of USP21 at Ser538. I" SIGNOR-273671 CSNK1A1 protein P48729 UNIPROT SQSTM1 protein Q13501 UNIPROT "up-regulates activity" phosphorylation Ser349 SSKEVDPsTGELQSL 10090 37723657 t miannu "Mechanistically, CSNK1A1 interacted with STING1 upon the CGAS-STING1 pathway activation and promoted STING1 autophagic degradation by enhancing the phosphorylation of SQSTM1/p62 at serine 351 (serine 349 in human), which was critical for SQSTM1-mediated STING1 autophagic degradation." SIGNOR-273769 STK35 protein Q8TDR2 UNIPROT STK35/PDIK1L complex SIGNOR-C552 SIGNOR "form complex" binding 9606 BTO:0002181 35021089 t miannu "Through mass spectrometry analysis of affinity-purified complexes, we identify the kinase paralogs STK35 and PDIK1L as binding partners and substrates of the SCP4 phosphatase domain. We show that STK35 and PDIK1L function catalytically and redundantly in the same pathway as SCP4 to maintain AML proliferation and to support amino acid biosynthesis and transport." SIGNOR-273770 PDIK1L protein Q8N165 UNIPROT STK35/PDIK1L complex SIGNOR-C552 SIGNOR "form complex" binding 9606 BTO:0002181 35021089 t miannu "Through mass spectrometry analysis of affinity-purified complexes, we identify the kinase paralogs STK35 and PDIK1L as binding partners and substrates of the SCP4 phosphatase domain. We show that STK35 and PDIK1L function catalytically and redundantly in the same pathway as SCP4 to maintain AML proliferation and to support amino acid biosynthesis and transport." SIGNOR-273771 FH protein P07954 UNIPROT ATF2 protein P15336 UNIPROT "up-regulates activity" binding -1 28628081 t miannu "Glucose deficiency induces AMPK activation, which phosphorylates FH at Ser75 and promotes its binding to ATF2 and the enrichment of the FH–ATF2 complex on the promoter regions of ATF2-targeted genes." SIGNOR-266314 MAPK1 protein P28482 UNIPROT SMAD2 protein Q15796 UNIPROT up-regulates phosphorylation Ser245 NQSMDTGsPAELSPT 9606 BTO:0000763 12193595 t gcesareni "We show that phosphorylation of smad2, a mediator of the activin/transforming growth factor-beta signal, by activated extracellular signal-regulated kinase 1 (erk1) increases the amount of smad2 protein and leads to enhanced transcriptional activity." SIGNOR-91714 ADORA2A protein P29274 UNIPROT GNAL protein P38405 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-256909 ABL1 protein P00519 UNIPROT WRN protein Q14191 UNIPROT up-regulates phosphorylation 9606 BTO:0000567;BTO:0001271 12944467 t gcesareni "We thus hypothesized that wrn may interact with the abl tyrosine kinase in the dna damage response. Here, we provide evidence for a functional and physical interaction between wrn and c-abl, including wrn relocalization in response to dna damage, suggesting that this protein-protein interaction participates in a shared pathway of genome surveillance." SIGNOR-86497 ATM protein Q13315 UNIPROT CCAR2 protein Q8N163 UNIPROT "up-regulates activity" phosphorylation Thr454 AAEAAPPtQEAQGET 9606 22735644 t lperfetto " Here, we report that, in human cell lines, DNA damage triggered the phosphorylation of DBC1 on Thr454 by ATM (ataxia telangiectasia-mutated) and ATR (ataxia telangiectasia and Rad3-related) kinases. Phosphorylated DBC1 bound to and inhibited SIRT1, resulting in the dissociation of the SIRT1-p53 complex and stimulating p53 acetylation and p53-dependent cell death. " SIGNOR-267661 Varespladib chemical CID:155815 PUBCHEM PLA2G1B protein P04054 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-207633 CTDSPL2 protein Q05D32 UNIPROT STK35/PDIK1L complex SIGNOR-C552 SIGNOR "up-regulates quantity by stabilization" dephosphorylation 9606 BTO:0002181 35021089 t miannu "Through mass spectrometry analysis of affinity-purified complexes, we identify the kinase paralogs STK35 and PDIK1L as binding partners and substrates of the SCP4 phosphatase domain. We show that STK35 and PDIK1L function catalytically and redundantly in the same pathway as SCP4 to maintain AML proliferation and to support amino acid biosynthesis and transport.We provide evidence that SCP4 regulates STK35/PDIK1L through two distinct mechanisms: catalytic removal of inhibitory phosphorylation and by promoting kinase stability." SIGNOR-273772 CTDSPL2 protein Q05D32 UNIPROT PDIK1L protein Q8N165 UNIPROT "up-regulates quantity by stabilization" dephosphorylation Ser216 SVNKCFLsTACGTDF 9606 BTO:0002181 35021089 t miannu " We found that peptides corresponding to phosphoserines 194 and 216 of PDIK1L (S385 and S413 of STK35) were efficiently dephosphorylated by SCP4, whereas no activity was detected for the other two phosphopeptides (Figure 6D)." SIGNOR-273774 CTDSPL2 protein Q05D32 UNIPROT STK35 protein Q8TDR2 UNIPROT "up-regulates quantity by stabilization" dephosphorylation Ser385 KVADFGLsKVCAGLA 9606 BTO:0002181 35021089 t miannu " We found that peptides corresponding to phosphoserines 194 and 216 of PDIK1L (S385 and S413 of STK35) were efficiently dephosphorylated by SCP4, whereas no activity was detected for the other two phosphopeptides (Figure 6D)." SIGNOR-273775 CTDSPL2 protein Q05D32 UNIPROT STK35 protein Q8TDR2 UNIPROT "up-regulates quantity by stabilization" dephosphorylation Ser413 NVNKYWLsSACGSDF 9606 BTO:0002181 35021089 t miannu " We found that peptides corresponding to phosphoserines 194 and 216 of PDIK1L (S385 and S413 of STK35) were efficiently dephosphorylated by SCP4, whereas no activity was detected for the other two phosphopeptides (Figure 6D)." SIGNOR-273776 "CENP-A nucleosome" complex SIGNOR-C321 SIGNOR Centromere_assembly phenotype SIGNOR-PH154 SIGNOR up-regulates 9606 BTO:0000567 20566683 f miannu "Centromeres contain specialized nucleosomes in which histone H3 is replaced by the histone variant centromere protein A (CENP-A). CENP-A nucleosomes are thought to act as an epigenetic mark that specifies centromere identity." SIGNOR-263704 ESRRA protein P11474 UNIPROT NR2F6 protein P10588 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0000156 15955695 f miannu "In cancer tissue, the expression levels of EAR-2, COUP-TF1, EARgamma, Snail, and Slug decrease, and aromatase expression is then up-regulated through the binding of ERRalpha to S1 and the binding of CREB1 or related factors to CREaro." SIGNOR-253796 CDX2 protein Q99626 UNIPROT UGT1A10 protein Q9HAW8 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000195 15044625 t "Using gel shift and functional assays, HNF1alpha was demonstrated to bind to and activate the UGT1A8, -1A9, and -1A10 promoters. In contrast, Cdx2 bound to and activated the UGT1A8 and -1A10 promoters but could not activate the UGT1A9 promoter." SIGNOR-253968 PKA proteinfamily SIGNOR-PF17 SIGNOR KCNA4 protein P22459 UNIPROT "down-regulates activity" phosphorylation Thr601 LKKFRSStSSSLGDK 9606 BTO:0000007 15955806 t done miannu " In GIP receptor-expressing HEK293 cells, GIP reduced A-type peak ionic current amplitude of K(V)1.4 via activation of protein kinase A (PKA). Using mutant forms of K(V)1.4 with Ala-Ser/Thr substitutions in a potential PKA phosphorylation site, C-terminal phosphorylation was shown to be linked to GIP-mediated current amplitude decreases." SIGNOR-273778 PKA proteinfamily SIGNOR-PF17 SIGNOR KCNJ2 protein P63252 UNIPROT "down-regulates activity" phosphorylation Ser425 PRPLRREsEI -1 19843922 t done miannu "KCNJ2 encodes Kir2.1, a pore-forming subunit of the cardiac inward rectifier current, I(K1). This PKA-simulated catecholaminergic stimulation caused marked reduction of outward I(K1) compared with Kir2.1-WT. PKA-induced reduction in I(K1) was eliminated by mutating the phosphorylation site at serine 425 (S425N)." SIGNOR-273779 PKC proteinfamily SIGNOR-PF53 SIGNOR KLHL3 protein Q9UH77 UNIPROT "up-regulates quantity by stabilization" phosphorylation Ser433 PMNTRRSsVGVGVVE 9534 BTO:0000298 25313067 t done miannu "We show that KLHL3 is phosphorylated at serine 433 in the Kelch domain (a site frequently mutated in hypertension with hyperkalemia) by protein kinase C in cultured cells and that this phosphorylation prevents WNK4 binding and degradation." SIGNOR-273780 PRKACA protein P17612 UNIPROT MORC2 protein Q9Y6X9 UNIPROT "up-regulates quantity by stabilization" phosphorylation Thr582 LEALQKTtPIRSQAD 9606 BTO:0000007 32401166 t done miannu "Mechanistically, GPER1 activates PRKACA (protein kinase cAMP-activated catalytic subunit alpha), which in turn phosphorylates MORC2 at threonine 582 (T582). Phosphorylated MORC2 decreases its interaction with HSPA8 (heat shock protein family A [Hsp70] member 8) and LAMP2A (lysosomal associated membrane protein 2A), two core components of the chaperone-mediated autophagy (CMA) machinery, thus protecting MORC2 from lysosomal degradation by CMA." SIGNOR-273781 PKA proteinfamily SIGNOR-PF17 SIGNOR NKD2 protein Q969F2 UNIPROT "up-regulates quantity by stabilization" phosphorylation Ser223 SAHVRRPsTDPQPCS 9606 BTO:0000007 30941853 t done miannu "VIP and PGE2 rapidly activate protein kinase A (PKA) that then phosphorylates NKD2 at Ser-223, a process that is facilitated by the molecular scaffold A-kinase anchoring protein 12 (AKAP12). This phosphorylation stabilized NKD2, ensuring efficient cell-surface delivery of TGFα and increased EGFR activation." SIGNOR-273782 PKA proteinfamily SIGNOR-PF17 SIGNOR PDE8A protein O60658 UNIPROT "up-regulates activity" phosphorylation Ser359 HKDRRKGsLDVKAVA 9606 BTO:0000567 22673573 t done miannu " We show that under elevated cAMP conditions, PKA acts to phosphorylate PDE8A on serine 359 and this action serves to enhance the activity of the enzyme. " SIGNOR-273783 CUL5 protein Q93034 UNIPROT ARIH2 protein O95376 UNIPROT "up-regulates activity" binding 9606 BTO:0000007 24076655 t miannu "Here, we provide evidence that Ariadne RBR E3 ubiquitin ligases such as TRIAD1 and HHARI can bind and be activated by CRL complexes. Whereas TRIAD1 specifically associates with CUL5–RBX2, HHARI is more promiscuous towards cullin types and associates with RBX1-associated cullins 1, 2, 3, and 4A. Interestingly, both TRIAD1 and HHARI show a strong preference for binding the neddylated form of the cullin. Our data suggest a novel function of NEDD8 in directing specific CRLs to Ariadne RBR ligases, which in turn exert influence on the levels of their cognate neddylated cullin." SIGNOR-268843 PML-RARalpha "fusion protein" SIGNOR-FP2 SIGNOR Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 BTO:0001412 8394219 f "We expressed the PML-RARa protein in U937 myeloid precursor cells and showed that they lost the capacity to differentiate under the action of different stimuli (vitamin Ds and transforming growth factor pl), acquired enhanced sensitivity to retinoic acid, and exhibited a higher growth rate consequent to diminished apoptotic cell death." SIGNOR-255722 MAP2K4 protein P45985 UNIPROT MAPK10 protein P53779 UNIPROT up-regulates phosphorylation 9606 11062067 t "Phosphorylation of a threonine and a tyrosine residue in a Thr-Pro-Tyr motif." gcesareni "A map kinase kinase kinase (mapkkk), termed ask1, was identified that activated two different subs of map kinase kinases (mapkk), sek1 (or mkk4) and mkk3/mapkk6 (or mkk6), which in turn activated stress-activated protein kinase (sapk, also known as jnk;c-jun amino-terminal kinase) and p38 subs of map kinases, respectively. Here we report that mkk4 shows a striking preference for the tyrosine residue (tyr-185), and mkk7 a striking preference for the threonine residue (thr-183) in three sapk1/jnk1 isoforms tested (jnk1 alpha 1, jnk2 alpha 2 and jnk3 alpha 1)." SIGNOR-83721 PLK1 protein P53350 UNIPROT CLSPN protein Q9HAW4 UNIPROT down-regulates phosphorylation Ser30 EADSPSDsGQGSYET 9606 16885021 t gcesareni "We show that claspin, an adaptor protein required for chk1 activation, becomes degraded at the onset of mitosis. Claspin degradation was triggered by its interaction with, and ubiquitylation by, the scfbtrcp ubiquitin ligase. This interaction was phosphorylation dependent and required the activity of the plk1 kinase" SIGNOR-148442 PKA proteinfamily SIGNOR-PF17 SIGNOR SEC14L2 protein O76054 UNIPROT "up-regulates activity" phosphorylation Ser289 VQISRGSsHQVEYEI -1 15680919 t done miannu " Thus, phosphorylation of SPF at Ser-289 appears necessary for maximal stimulation of squalene monooxygenase activity in vitro and absolutely required for the stimulation of cholesterol synthesis in cell culture. the 2.3-fold activation of SPF by PKA was reduced by 60% in the S289A mutant, indicating that phosphorylation of this site contributes to the activation of SPF." SIGNOR-273788 PKA proteinfamily SIGNOR-PF17 SIGNOR TRPC5 protein Q9UL62 UNIPROT "down-regulates activity" phosphorylation Ser796 GARAKSKsVSFNLGC 9606 BTO:0000007 21734191 t done miannu "Together, these results suggest that TRPC5 is directly phosphorylated by G(s)/cAMP/PKA at positions S794 and S796. These inhibitory effects were blocked by the protein kinase A (PKA) inhibitors, KT-5720 and H-89, as well as by two point mutations at consensus PKA phosphorylation sites on TRPC5 (S794A and S796A)." SIGNOR-273789 TAC1 protein P20366 UNIPROT TACR2 protein P21452 UNIPROT up-regulates binding 9606 8925404 t gcesareni "The mammalian tachykinins include substance p, neurokinin a and neurokinin b, which exert their effects by binding to specific receptors. These tachykinin receptors are divided into three types, designated nk1, nk2 and nk3, respectively. The interaction of tachykinin with its receptor activates gq, which in turn activates phospholipase c to break down phosphatidyl inositol bisphosphate into inositol trisphosphate (ip3) and diacylglycerol (dag)." SIGNOR-44773 CENPL protein Q8N0S6 UNIPROT "CCAN complex" complex SIGNOR-C365 SIGNOR "form complex" binding 9606 BTO:0000567 18007590 t lperfetto "CENP-A NAC/CAD components have been subdivided into either NAC proteins (nucleosome-associated complex; CENP-C, CENP-H, CENP-50CENP−U, CENP-M, CENP-T and Chl4RCENP−N) or CAD proteins (CENP-A Distal; CENP-I, Mcm21RCENP−O, Fta1RCENP−L, Sim4RCENP−K, CENP-P, CENP-Q, CENP-R and CENP-S)." SIGNOR-265199 PRDM1 protein O75626 UNIPROT CIITA protein P33076 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0000776 12626569 f miannu "The positive regulatory domain i binding factor 1 (prdi-bf1 or blimp-1) protein represses the transcription of specific target genes, including c-myc, the mhc class ii trans-activator, pax-5, and cd23b" SIGNOR-99116 CREB5 protein Q02930 UNIPROT DGKG protein P49619 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 21132541 f miannu "Our result verified CREB5 biological regulation module in the upstream of frontal cortex of HIVE-control patients (MAPKAPK3 activation; DGKG, LY96, TNFRSF11B inhibition) and downstream (ATP6V0E1, CFB, DGKG, MX1, TGFBR3 activation; LGALS3BP, RASGRP3, RDX, STAT1 inhibition)," SIGNOR-253804 NOD2 protein Q9HC29 UNIPROT ATG16L1 protein Q676U5 UNIPROT "up-regulates activity" binding 9606 BTO:0000567 19898471 t miannu "By a mechanism independent of the adaptor RIP2 and transcription factor NF-kappaB, Nod1 and Nod2 recruited the autophagy protein ATG16L1 to the plasma membrane at the bacterial entry site. Our results link bacterial sensing by Nod proteins to the induction of autophagy and provide a functional link between Nod2 and ATG16L1, which are encoded by two of the most important genes associated with Crohn's disease." SIGNOR-252405 FLT3 protein P36888 UNIPROT FLT3 protein P36888 UNIPROT unknown phosphorylation Tyr726 KEHNFSFyPTFQSHP 10090 BTO:0001516 16627759 t lperfetto "In vitro mapping of FLT3 autophosphorylation sites|Tryptic peptides covering more than 80% of the FLT3 kinase domain were recovered, and 5 tyrosine residues (Y591, Y726, Y842, Y955, and Y969) within this region were phosphorylated." SIGNOR-271922 P2RY10 protein O00398 UNIPROT GNA14 protein O95837 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-257213 PKA proteinfamily SIGNOR-PF17 SIGNOR TRPC5 protein Q9UL62 UNIPROT "down-regulates activity" phosphorylation Ser794 SGGARAKsKSVSFNL 9606 BTO:0000007 21734191 t done miannu "Together, these results suggest that TRPC5 is directly phosphorylated by G(s)/cAMP/PKA at positions S794 and S796. These inhibitory effects were blocked by the protein kinase A (PKA) inhibitors, KT-5720 and H-89, as well as by two point mutations at consensus PKA phosphorylation sites on TRPC5 (S794A and S796A)." SIGNOR-273790 CDK2 protein P24941 UNIPROT PP1 proteinfamily SIGNOR-PF54 SIGNOR "down-regulates activity" phosphorylation 9606 12202491 t lperfetto "Both of these pp1 isoforms contain an arg-pro-ile/val-thr-pro-pro-arg sequence near the c terminus, a known site of phosphorylation by cdc/cdk kinases, and phosphorylation attenuates phosphatase activity" SIGNOR-264650 SCN11A protein Q9UI33 UNIPROT Action_potential phenotype SIGNOR-PH82 SIGNOR up-regulates 9606 26043074 f miannu "The expression of voltage-gated sodium channels (NaVs) is a key feature for initiation and conduction of action potentials in excitable tissues and cells such as cardiac and skeletal muscle and neurons." SIGNOR-253453 SYK protein P43405 UNIPROT GCSAM protein Q8N6F7 UNIPROT "up-regulates activity" phosphorylation Tyr86 TYSEELCyTLINHRV -1 31362927 t miannu "Herein, we demonstrate phosphorylation of HGAL by Syk and Lyn kinases at tyrosines Y80, Y86, Y106Y107, Y128, and Y148.  Y148 (in black) was already phosphorylated before the addition of kinases. We demonstrate that Grb2 facilitates HGAL and Syk binding following BCR stimulation but does not affect the HGAL-mediated increase in Syk kinase activity. Previous studies showed that Grb2 inhibits BCR signaling by decreasing the activation of Syk by Lyn.11 Thus, while HGAL and Grb2 oppositely affect Syk kinase activity, this is not due to direct Grb2 effects on HGAL-mediated Syk kinase activation." SIGNOR-273574 Monobutylphthalate chemical CHEBI:88522 ChEBI PPARG protein P37231 UNIPROT "up-regulates activity" "chemical activation" 9606 BTO:0000816 16326050 t miannu "Mono(2-ethylhexyl)phthalate and mono-n-butyl phthalate activation of peroxisome proliferator activated-receptors alpha and gamma in breast" SIGNOR-268752 "Caspase 3 complex" complex SIGNOR-C221 SIGNOR ACIN1 protein Q9UKV3 UNIPROT up-regulates cleavage 9606 10490026 t amattioni "Induces apoptotic chromatin condensation after activation by casp3" SIGNOR-256449 PAX3 protein P23760 UNIPROT PITX2 protein Q99697 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 21143873 f gcesareni "Pitx genes, such as pitx2, which is positively regulated by pax3, have been implicated in myogenesis." SIGNOR-170343 PRKACA protein P17612 UNIPROT TRPM8 protein Q7Z2W7 UNIPROT "up-regulates activity" phosphorylation Thr17 MRNRRNDtLDSTRTL 9606 BTO:0000007 20110357 t done miannu "Using specific pharmacological and molecular tools combined with patch-clamp current recordings, we found that in heterologously expressed HEK-293 (human embryonic kidney) cells, TRPM8 channel is inhibited by the G(i) protein/adenylate cyclase (AC)/cAMP/protein kinase A (PKA) signaling cascade. We further identified the TRPM8 S9 and T17 as two key PKA phosphorylation sites regulating TRPM8 channel activity. the intracellular serine/threonine protein phosphatase 2A (PP2A) dephosphorylates TRPM8 Ser-9 and Thr-17 inhibiting the channel activity." SIGNOR-273791 CHEK2 protein O96017 UNIPROT RASGRF1 protein Q13972 UNIPROT down-regulates phosphorylation Ser287 PITHDDVsSIFLNSE 9606 17110335 t miannu "During interphase, cdc25 is inhibited by ser287 phosphorylation (xenopus cdc25;ser 216 in human cdc25c) and this inhibitory phosphorylation is maintained by dna-responsive checkpoints / s287 is targeted by many kinases, including chk1, chk2, ctak-1, pka, p38 and mapkap kinase-2 suggesting that phosphorylation of this site may integrate multiple signaling inputs." SIGNOR-150843 PTPRJ protein Q12913 UNIPROT RET protein P07949 UNIPROT down-regulates dephosphorylation Tyr905 DVYEEDSyVKRSQGR 9606 16778204 t gcesareni "Ptprj expression induces dephosphorylation of the ret(c634r) and, probably via an indirect mechanism, ret/ptc1 oncoproteins on two key ret autophosphorylation sites (tyr1062 and tyr905). in line with this finding, adoptive ptprj expression reduced the oncogenic activity of ret" SIGNOR-147165 CyclinA2/CDK2 complex SIGNOR-C83 SIGNOR SLBP protein Q14493 UNIPROT "down-regulates quantity by destabilization" phosphorylation Thr62 RRPESFTtPEGPKPR 9606 BTO:0000567 18490441 t lperfetto "Phosphorylation of threonine 61 by cyclin a/Cdk1 triggers degradation of stem-loop binding protein at the end of S phase" SIGNOR-265259 STXBP1 protein P61764 UNIPROT SNARE_complex complex SIGNOR-C346 SIGNOR "up-regulates activity" "transcriptional regulation" 9606 BTO:0000938 30267828 t miannu "In neuronal exocytosis, Munc18-1 (aSM-protein) and Munc13-1/2 (similar to CATCHRs) arethe relevant proteins responsible for SNARE-complex formation. Munc18-1 associates with syntaxin-1 in its‘closed’ conformation, i.e. with the regulatory Habc-domain folded against the SNARE (H3-)-domain. Opening-up of syntaxin is catalyzed by the Mun-domainwithin Munc13-1/2 and allows assembly with the partnerSNARE SNAP-25 and possibly VAMP2." SIGNOR-263970 CD19 protein P15391 UNIPROT PI3K complex SIGNOR-C156 SIGNOR "up-regulates activity" binding 10090 BTO:0000899 10201980 t lperfetto "Phosphorylation of CD19 Y484 and Y515, and linked activation of phosphatidylinositol 3-kinase, are required for B cell antigen receptor-mediated activation of Bruton's tyrosine kinase." SIGNOR-252669 CHRM2 protein P08172 UNIPROT GNAI3 protein P08754 UNIPROT "up-regulates activity" binding 9606 BTO:0002524 31160049 t "GPCR-Ga dataset" Luana "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-256828 RNF31 protein Q96EP0 UNIPROT IKBKG protein Q9Y6K9 UNIPROT "up-regulates activity" polyubiquitination 9606 BTO:0000007 24469399 t miannu "Involvement of Gln271 and Asp275 of NEMO in LUBAC-mediated linear polyubiquitination.vHOIP NZF1 also recognizes NEMO, and this recognition is involved in linear polyubiquitination of NEMO. Linear chains conjugated to NEMO are recognized by NEMO in trans on another IKK complex, thereby inducing multimerization of the IKK complex and trans autophosphorylation of IKK2." SIGNOR-272052 SGK1 protein O00141 UNIPROT FOXO3 protein O43524 UNIPROT "down-regulates activity" phosphorylation Ser315 DFRSRTNsNASTVSG 9606 11154281 t lperfetto "We show here that sgk1, like akt, promotes cell survival and that it does so in part by phosphorylating and inactivating fkhrl1. However, sgk and akt display differences with respect to the efficacy with which they phosphorylate the three regulatory sites on fkhrl1. While both kinases can phosphorylate thr-32, sgk displays a marked preference for ser-315 whereas akt favors ser-253." SIGNOR-236607 SP1 protein P08047 UNIPROT CACNA1G protein O43497 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 23868804 t miannu "Consistent with this, Sp1 over-expression enhanced promoter activity while siRNA-mediated Sp1 silencing significantly decreased the level of CaV 3.1 protein and reduced the amplitude of whole-cell T-type Ca(2+) currents expressed in the N1E-115 cells. These results provide new insights into the molecular mechanisms that control CaV 3.1 channel expression." SIGNOR-264034 EEF1A2 protein Q05639 UNIPROT Ser-tRNA(Ser) smallmolecule CHEBI:29162 ChEBI up-regulates relocalization 9606 23699257 t lperfetto "During protein synthesis, eEF1A binds to and delivers aminoacylated tRNAs (aa-tRNAs) to the elongating ribosome (Fig. 1). GTP bound to eEF1A is hydrolyzed upon codon-anticodon match between an aa-tRNA in the A site of the ribosome and mRNA bound to the ribosome." SIGNOR-269535 UBE3A protein Q05086 UNIPROT SCRIB protein Q14160 UNIPROT "down-regulates quantity by destabilization" polyubiquitination -1 11027293 t miannu "Human scribble (Vartul) is targeted for ubiquitin-mediated degradation by the high-risk papillomavirus E6 proteins and the E6AP ubiquitin-protein ligase" SIGNOR-272573 ARAP3 protein Q8WWN8 UNIPROT CDC42 protein P60953 UNIPROT "down-regulates activity" "gtpase-activating protein" 9606 BTO:0000007 32203420 t Luana "We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2)." SIGNOR-260457 PRKCA protein P17252 UNIPROT FMNL2 protein Q96PY5 UNIPROT "up-regulates activity" phosphorylation Ser1072 ARTAKRGsRFFCEPV -1 26256210 t done miannu "PKCα associates with and phosphorylates FMNL2 at S1072 within its Diaphanous autoregulatory region, leading to the release of formin autoinhibition." SIGNOR-273796 PRKCB protein P05771 UNIPROT ICOSLG protein O75144 UNIPROT "up-regulates activity" phosphorylation Ser285 RDRCLQHsYAGAWAV 9606 BTO:0000567 24837102 t done miannu "PKCα and PKCβ are required for phosphorylation of ICOSL and ICOSL-mediated cytokine induction " SIGNOR-273797 SYK protein P43405 UNIPROT LAT2 protein Q9GZY6 UNIPROT "up-regulates activity" phosphorylation Tyr193 EDEESEDyQNSASIH 10090 BTO:0001930 14722116 t miannu "Our results indicated that human LAB was primarily phosphorylated on three membrane-distal tyrosines, Tyr(136), Tyr(193), and Tyr(233). Mutation of these three tyrosines abolished Grb2 binding and LAB function. Our data suggested that these tyrosines are the most important tyrosines for LAB function.The dramatic reduction in phosphorylation of the LAB Y233F mutant suggested that Tyr233 is a primary target of the Syk family kinases." SIGNOR-273575 PRKDC protein P78527 UNIPROT RPA2 protein P15927 UNIPROT "down-regulates activity" phosphorylation Ser11 SGFESYGsSSYGGAG -1 9295339 t lperfetto "We showed previously that UV irradiation increases phosphorylation of the p34 subunit of human replication protein A (RPA) and that this hyperphosphorylation correlated with loss of activity of the DNA replication complex. | we detected phosphorylation of the RPA complex by DNA-PK on RPA-p34 sites Ser-23, Ser-29, and Ser-11, -12, or -13" SIGNOR-248980 "beta-D-fructofuranose 2,6-bisphosphate" smallmolecule CHEBI:28602 ChEBI PFKL protein P17858 UNIPROT "up-regulates activity" binding 9606 19454274 t "The PFKFB enzymes synthesize fructose-2,6-bisphosphate (F2,6BP) which allosterically activates 6-phosphofructo-1-kinase (PFK-1), a rate-limiting enzyme and essential control point in the glycolytic pathway. PFK-1 is inhibited by ATP when energy stores are abundant and F2,6BP can override this inhibition and enhance glucose uptake and glycolytic flux" SIGNOR-267266 RIMBP2 protein O15034 UNIPROT RIMS3 protein Q9UJD0 UNIPROT "down-regulates activity" binding 10116 BTO:0001009 11988172 t miannu "SH3 domains of RBPs interact with RIMs. The enhancement of depolarization-induced secretion in PC12 cells by fusion proteins that suppress the associations of RBPs with RIMs and α1 suggests that RBPs may repress RIMs, either directly or through associated proteins." SIGNOR-264371 PRKCA protein P17252 UNIPROT ICOSLG protein O75144 UNIPROT "up-regulates activity" phosphorylation Ser285 RDRCLQHsYAGAWAV 9606 BTO:0000567 24837102 t done miannu "PKCα and PKCβ are required for phosphorylation of ICOSL and ICOSL-mediated cytokine induction. Therefore, S285 is required for PKC substrate (serine) phosphorylation of ICOSL, and each of the upstream arginines is similarly required for this phosphorylation." SIGNOR-273798 MAPK3 protein P27361 UNIPROT RPS6KA3 protein P51812 UNIPROT up-regulates phosphorylation Thr577 AENGLLMtPCYTANF 9606 10980595 t llicata "We have generated two monoclonal antibodies that recognize two phosphorylated sites, p-ser227 and p-thr577, in the n- and c-terminal kinase domains of rsk2, respectively. phosphorylation and activation of rsk2 by uv light involves the erk pathway" SIGNOR-81464 SCF-betaTRCP complex SIGNOR-C5 SIGNOR ATF4 protein P18848 UNIPROT "down-regulates quantity by destabilization" polyubiquitination 9606 BTO:0000567 11238952 t miannu "Here we show that the F-box protein betaTrCP, the receptor component of the SCF E3 ubiquitin ligase responsible for IkappaBalpha and beta-catenin degradation, is colocalized in the nucleus with ATF4, a member of the ATF-CREB bZIP family of transcription factors, and controls its stability. ATF4 ubiquitination in HeLa cells is enhanced in the presence of betaTrCP." SIGNOR-272580 SRC protein P12931 UNIPROT PANX1 protein Q96RD7 UNIPROT "up-regulates activity" phosphorylation Tyr199 KYPIVEQyLKTKKNS 9606 BTO:0005101 30814251 t done miannu "We report herein that the YLK motif is contained within an SRC homology 2 domain and is directly phosphorylated by SRC proto-oncogene, nonreceptor tyrosine kinase (SRC) at Tyr198. Using a PANX1 Tyr198-specific antibody, SFK inhibitors, SRC knockdown, temperature-dependent SRC cells, and kinase assays, we found that PANX1-mediated ATP release and vasoconstriction involves constitutive phosphorylation of PANX1 Tyr198 by SRC." SIGNOR-273806 SRC protein P12931 UNIPROT PKP3 protein Q9Y446 UNIPROT "up-regulates activity" phosphorylation Tyr195 PGGLDDRySLVSEQL 9606 BTO:0000552 25501895 t done miannu "We have discovered that reactive oxygen species (ROS) trigger the c-Src kinase-mediated tyrosine (Tyr)-195 phosphorylation of PKP3. This modification is associated with a change in the subcellular distribution of the protein. Specifically, PKP3 bearing phospho-Tyr-195 is released from the desmosomes, suggesting that phospho-Tyr-195 is relevant for the control of desmosome disassembly and function, at least in cells exposed to ROS. " SIGNOR-273807 PLEKHG2 protein Q9H7P9 UNIPROT PIK3R3 protein Q92569 UNIPROT "up-regulates activity" binding 9606 BTO:0000007 24378532 t done miannu "Through deletion and base substitution mutagenesis we have identified Tyr489 of PLEKHG2 as the site phosphorylated by cSrc.The interaction between PLEKHG2 and the full-length of PIK3R3, but not ABL1, occurs in a tyrosine-phosphorylation-dependent manner." SIGNOR-273809 AKT1 protein P31749 UNIPROT KDM5A protein P29375 UNIPROT "up-regulates activity" phosphorylation Ser1255 CLTERAMsWQDRARQ -1 27292631 t miannu "We immunoprecipitated ectopically expressed wild-type KDM5A or KDM5Amut5A and performed an in vitro kinase assay using recombinant AKT1 in the presence or absence of AKT inhibition.Wild-type KDM5A is phosphorylated by AKT1 and this modification is sensitive to AKT inhibition, whereas KDM5Amut5A is not phosphorylated in the presence of AKT1 (Figure 3C).These results suggest that AKT-mediated KDM5A phosphorylation enhances KDM5A promoter recruitment." SIGNOR-274059 NFATC1 protein O95644 UNIPROT IL4 protein P05112 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 8668213 t lperfetto "Recombinant NFAT1 can mediate transcription of the interleukin-2, interleukin-4, tumor necrosis factor alpha, and granulocyte-macrophage colony-stimulating factor promoters in T cells, suggesting that NFAT1 contributes to the CsA-sensitive transcription of these genes during the immune response." SIGNOR-254498 ZBTB16 protein Q05516 UNIPROT RSAD2 protein Q8WXG1 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0003846 19523849 t lperfetto "Promoter regions from the PLZF-regulated transcripts Rsad2 and Ifit2 were fused to luciferase and activity was measured after IFN treatment. Overexpression of PLZF in RCC1 or ACHN cells produced a dose-dependent induction of the reporter promoters. " SIGNOR-261023 TP53 protein P04637 UNIPROT PMS2 protein P54278 UNIPROT "up-regulates quantity" "transcriptional regulation" 9606 15781865 t ".... numerous potentially novel targets, including the DNA mismatch repair genes MLH1 and PMS2. Both of these genes were determined to be responsive to DNA damage and p53 activation in normal human fibroblasts, and have p53-response elements within their first intron." SIGNOR-257604 CDK9 protein P50750 UNIPROT SMAD3 protein P84022 UNIPROT down-regulates phosphorylation Ser213 NLSPNPMsPAHNNLD 9606 19914161 t lpetrilli "Similarly, tgf-?-Induced and cdk8/9-mediated phosphorylation of smad3 at threonine 179 (t179) is important for binding of the nedd4l e3 ubiquitin ligase, which accelerates smad3 turnover;cdk8 and cyclint-cdk9 showed a preference for s206 and s214 but also phosphorylated s186 and s195 in the case of smad1;and t179, s208 and s213 in the case of smad3." SIGNOR-161585 MAP2K4 protein P45985 UNIPROT MAPK9 protein P45984 UNIPROT up-regulates phosphorylation Tyr185 TNFMMTPyVVTRYYR 9606 BTO:0000149;BTO:0001129 22730327 t gcesareni "Mkk4, which activates p38gamma, p38delta, and jnk2 to phosphorylate p53 on ser-33 and cause a transient g(1) arrest. A map kinase kinase kinase (mapkkk), termed ask1, was identified that activated two different subs of map kinase kinases (mapkk), sek1 (or mkk4) and mkk3/mapkk6 (or mkk6), which in turn activated stress-activated protein kinase (sapk, also known as jnk;c-jun amino-terminal kinase) here we report that mkk4 shows a striking preference for the tyrosine residue (tyr-185), and mkk7 a striking preference for the threonine residue (thr-183) in three sapk1/jnk1 isoforms tested (jnk1 alpha 1, jnk2 alpha 2 and jnk3 alpha 1)" SIGNOR-197998 WNT3A protein P56704 UNIPROT FBN1 protein P35555 UNIPROT "up-regulates quantity by stabilization" 10090 17943183 f Regulation miannu "Wnt3a markedly stimulated matrix assembly of microfibrillar proteins, including Fbn-1, by cultured fibroblasts, suggesting that Wnts contribute to increased microfibrillar matrices in Tsk skin.Wnt3a stimulates Fbn-1 matrix formation." SIGNOR-251894 AKT1 protein P31749 UNIPROT KDM5A protein P29375 UNIPROT "up-regulates activity" phosphorylation Ser225 TRRVKTQsESGDVSR -1 27292631 t miannu "We immunoprecipitated ectopically expressed wild-type KDM5A or KDM5Amut5A and performed an in vitro kinase assay using recombinant AKT1 in the presence or absence of AKT inhibition.Wild-type KDM5A is phosphorylated by AKT1 and this modification is sensitive to AKT inhibition, whereas KDM5Amut5A is not phosphorylated in the presence of AKT1 (Figure 3C).These results suggest that AKT-mediated KDM5A phosphorylation enhances KDM5A promoter recruitment." SIGNOR-274060 TBK1 protein Q9UHD2 UNIPROT STX17 protein P56962 UNIPROT "up-regulates activity" phosphorylation Ser202 SQQEKIDsIADHVNS 9606 BTO:0000007 30827897 t done miannu "Stx17 is phosphorylated by TBK1 whereby phospho-Stx17 controls the formation of the ATG13+FIP200+ mammalian pre-autophagosomal structure (mPAS) in response to induction of autophagy. TBK1 phosphorylates Stx17 at S202." SIGNOR-273812 DUSP6 protein Q16828 UNIPROT ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR down-regulates dephosphorylation 9606 12840032 t "inferred from 70% of family members" gcesareni "P-erk1/2 proteins were efficiently dephosphorylated in vitro by protein phosphatases 1 and 2a (pp1/2a) and mapk phosphatase 3 (mkp3)." SIGNOR-269926 TBK1 protein Q9UHD2 UNIPROT SIKE1 protein Q9BRV8 UNIPROT "up-regulates quantity" phosphorylation Ser133 PVLKAHQsHSAEIES 9606 BTO:0000007 23649622 t done miannu "TBK1 phosphorylates SIKE on six serine residues that mimic the IRF3 phosphorylation sequence.Serines are listed from left to right: 133, 185, 187, 188, 190, and 198." SIGNOR-273815 FBXO7 protein Q9Y3I1 UNIPROT DLGAP5 protein Q15398 UNIPROT "down-regulates quantity by destabilization" binding 9606 BTO:0000007 15145941 t miannu "We show here that Fbx7, an F-box protein without WD repeats and leucine-rich repeats, is required for the proteasome-mediated proteolysis of the hepatoma up-regulated protein (HURP).Thus, Fbx7 is a functional adaptor of the SCF complex with a proline-rich region as the substrate-binding module. Depletion of Fbx7 by small interfering RNA leads to depression of HURP ubiquitination and accumulation of HURP abundance. In the SCFFbx7 complex, Fbx7 recruits HURP through its C-terminal proline-rich region in a Cdk1-cyclin B-phosphorylation dependent manner." SIGNOR-271506 "SWI/SNF complex" complex SIGNOR-C92 SIGNOR CCND1 protein P24385 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 12138206 f irozzo "INI1/hSNF5 is a component of the ATP-dependent chromatin remodeling hSWI/SNF complex [.]. Our data suggest that one of the mechanisms by which INI1/hSNF5 exerts its tumor suppressor function is by mediating the cell cycle arrest due to the direct recruitment of HDAC activity to the cyclin D1 promoter thereby causing its repression and G(0)-G(1) arrest. These results together indicate that cyclin D1 is a direct target for repression by INI1/hSNF5." SIGNOR-256293 F2 protein P00734 UNIPROT F2R protein P25116 UNIPROT "down-regulates activity" cleavage Phe43 ATLDPRSfLLRNPND -1 10978167 t lperfetto "PAR1E and PAR2E (10 microM) were incubated in the presence of the different proteases | The enzymes were used at the following concentrations: 0.5 unit/mL thrombin, 2.5 nM trypsin, 20 nM plasmin, 20 nM cathepsin G, 20 nM elastase, 20 nM proteinase 3, and 2 units/mL calpain I and II|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus.|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus.|Plasmin, calpain and leukocyte elastase, cathepsin G, and proteinase 3 cleaved at multiple sites and would be expected to disable PAR1 by cleaving COOH-terminal to the activation site." SIGNOR-263570 TBK1 protein Q9UHD2 UNIPROT SIKE1 protein Q9BRV8 UNIPROT "up-regulates quantity" phosphorylation Ser188 RELLSISsESLQARK 9606 BTO:0000007 23649622 t done miannu "TBK1 phosphorylates SIKE on six serine residues that mimic the IRF3 phosphorylation sequence.Serines are listed from left to right: 133, 185, 187, 188, 190, and 198." SIGNOR-273816 TBK1 protein Q9UHD2 UNIPROT SIKE1 protein Q9BRV8 UNIPROT "up-regulates quantity" phosphorylation Ser190 LLSISSEsLQARKEN 9606 BTO:0000007 23649622 t done miannu "TBK1 phosphorylates SIKE on six serine residues that mimic the IRF3 phosphorylation sequence.Serines are listed from left to right: 133, 185, 187, 188, 190, and 198." SIGNOR-273817 TBK1 protein Q9UHD2 UNIPROT SIKE1 protein Q9BRV8 UNIPROT "up-regulates quantity" phosphorylation Ser198 LQARKENsMDTASQA 9606 BTO:0000007 23649622 t done miannu "TBK1 phosphorylates SIKE on six serine residues that mimic the IRF3 phosphorylation sequence.Serines are listed from left to right: 133, 185, 187, 188, 190, and 198." SIGNOR-273818 MRPS10 protein P82664 UNIPROT "28S mitochondrial small ribosomal subunit" complex SIGNOR-C266 SIGNOR "form complex" binding 9606 25838379 t miannu "The mammalian mitochondrial ribosome (mitoribosome) has a highly protein-rich composition with a small sedimentation coefficient of 55 S, consisting of 39 S large and 28 S small subunits. . We report here the identification of 28 S small subunit proteins." SIGNOR-267731 PIK3CA protein P42336 UNIPROT PI3K complex SIGNOR-C156 SIGNOR "form complex" binding 9606 19805105 t miannu "Phosphoinositol 3- kinase alpha (PI3Kα) is a heterodimeric enzyme formed by a catalytic subunit (p110α, encoded by PIK3CA) and one of several regulatory subunits (a major one being p85α, encoded by PI3KR1)." SIGNOR-255299 SDCBP protein O00560 UNIPROT SOX4 protein Q06945 UNIPROT "up-regulates activity" binding 10090 BTO:0003104 11498591 t miannu "Sox4 activation by IL-5R_ appears to be direct, with syntenin functioning as an adaptor molecule. Syntenin mediates IL-5–induced Sox4 activation." SIGNOR-223089 SRC protein P12931 UNIPROT VAMP7 protein P51809 UNIPROT "up-regulates activity" phosphorylation Tyr45 SENNKLTySHGNYLF 9534 BTO:0000298 23471971 t done miannu "We found that TI-VAMP is phosphorylated in vitro by c-Src kinase on tyrosine 45 of the Longin domain.Mimicking tyrosine 45 phosphorylation activates both t-SNARE binding and exocytosis of TI-VAMP." SIGNOR-273819 "Cullin 1-RBX1-Skp1" complex SIGNOR-C529 SIGNOR CCND1 protein P24385 UNIPROT "down-regulates quantity by destabilization" polyubiquitination 9606 BTO:0001109 phosphorylation:Thr286 EEVDLACtPTDVRDV 17205132 t miannu "FBXW8 associates with CUL1 or CUL7 and forms a complex with SKP1 and RBX1. We next investigated whether in vitro ubiquitination of cyclin D1 through the SCF-like (SCFL) complex FBXW8 (SKP1-CUL7-FBXW8-RBX1/SCFLFBXW8) requires phosphorylation of cyclin D1 at Thr286 (Fig. 3F). Polyubiquitination through SCFLFBXW8 was dramatically reduced by the depletion of ERK2 (lane 2). Furthermore, cyclin D1 polyubiquitination was largely prevented by the alanine-for-Thr286 substitution (T286A, lane 3), suggesting that phosphorylation of cyclin D1 at Thr286 is necessary for ubiquitination by SCFLFBXW8." SIGNOR-271634 PKN1 protein Q16512 UNIPROT ARHGEF2 protein Q92974 UNIPROT down-regulates phosphorylation Ser886 PVDPRRRsLPAGDAL 9606 14970201 t lperfetto "Here we identify a region in the carboxyl terminus of gef-h1 that is important for suppression of its guanine nucleotide exchange activity by microtubules. This portion of the protein includes a coiled-coil motif, a proline-rich motif that may interact with src homology 3 domain-containing proteins, and a potential binding site for 14-3-3 proteins. We show that phosphorylation of gef-h1 at ser(885) by pak1 induces 14-3-3 binding to the exchange factor and relocation of 14-3-3 to microtubules." SIGNOR-122191 SRC protein P12931 UNIPROT CTTN protein Q14247 UNIPROT down-regulates phosphorylation Tyr470 AYATEAVyESAEAPG 9606 12601080 t lperfetto "Cortactin was first identified as a substrate of v-src (46) that mediates in vitro phosphorylation of residues tyr-421, tyr-466, and tyr-482 at the c terminus of the murine ortholog (47). Phosphorylation of these residues attenuates the f-actin cross-linking activity" SIGNOR-98716 LRRK2 protein Q5S007 UNIPROT SH3GL1 protein Q99961 UNIPROT down-regulates phosphorylation 9606 22998870 t miannu "We show that lrrk2 affects synaptic endocytosis by phosphorylating endoa at s75, a residue in the bar domain / our work uncovers a regulatory mechanism that indicates that reduced lrrk2 kinase activity facilitates endoa membrane association, while increased kinase activity inhibits membrane association." SIGNOR-192068 AMPK complex SIGNOR-C15 SIGNOR ULK1 protein O75385 UNIPROT up-regulates phosphorylation 9606 21460634 t lperfetto "Ampk and ulk1 interact and that the latter is phosphorylated by ampk. This phosphorylation leads to the direct activation of ulk1 by ampk bypassing mtor-inhibition." SIGNOR-216464 GLE1 protein Q53GS7 UNIPROT NPC complex SIGNOR-C263 SIGNOR "form complex" binding 27016207 t lperfetto "The protein inventory of the NPC has been studied for a very diverse set of eukaryotes, including trypanosomes, fungi, plants, animals, and humans [4], [5], [6], [7], [8], [9]. In all cases, about 30 different Nups were found (Fig. 2)." SIGNOR-262096 KDM2B protein Q8NHM5 UNIPROT "Noncanonical PRC1" complex SIGNOR-C151 SIGNOR "up-regulates activity" binding 10090 BTO:0000011 25533466 t miannu "We show that FBXL10/KDM2B is an anti-adipogenic factor that is up-regulated during the early phase of 3T3-L1 preadipocyte differentiation and in adipose tissue in a diet-induced model of obesity. Interestingly, inhibition of adipogenesis does not require the JmjC demethylase domain of FBXL10, but it does require the F-box and leucine-rich repeat domains, which we show recruit a noncanonical polycomb repressive complex 1 (PRC1) containing RING1B, SKP1, PCGF1, and BCOR." SIGNOR-252247 CDK2 protein P24941 UNIPROT SMAD3 protein P84022 UNIPROT "down-regulates activity" phosphorylation Ser213 NLSPNPMsPAHNNLD 9606 15241418 t lperfetto "We have mapped CDK4 and CDK2 phosphorylation sites to Thr 8, Thr 178 and Ser 212 in Smad3. Mutation of the CDK phosphorylation sites increases Smad3 transcriptional activity" SIGNOR-232134 NDN protein Q99608 UNIPROT EID1 protein Q9Y6B2 UNIPROT "up-regulates activity" binding 10090 BTO:0000165 18557765 t llicata "The Prader-Willi syndrome protein necdin interacts with the E1A-like inhibitor of differentiation EID-1 and promotes myoblast differentiation." SIGNOR-237614 2-[(4S)-6-(4-chlorophenyl)-8-methoxy-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-4-yl]-N-ethylacetamide chemical CHEBI:95082 ChEBI BRD4 protein O60885 UNIPROT "down-regulates activity" "chemical inhibition" -1 24015967 t Gianni "This paper describes the discovery and structure-activity relationships (SAR) of potent benzodiazepine inhibitors that disrupt the function of the BET family of bromodomains (BRD2, BRD3, and BRD4). This work has yielded a potent, selective compound I-BET762 that is now under evaluation" SIGNOR-262204 WWTR1 protein Q9GZV5 UNIPROT SMAD3 protein P84022 UNIPROT up-regulates binding 9606 21084559 t gcesareni "Taz has been shown to interact with smad2 and smad3 through its coiled-coil region, and to be important in maintaining the nuclear localization of smad2 and smad3 as well as the expression of their target genes in response to tgf-b signaling and, thus, in the maintenance of human esc self-renewal." SIGNOR-169841 AMPK complex SIGNOR-C15 SIGNOR ULK1 protein O75385 UNIPROT up-regulates phosphorylation Ser556 GLGCRLHsAPNLSDL 9606 19584320 t lperfetto "In a screen for conserved substrates of ampk, we identified ulk1 and ulk2, mammalian orthologs of the yeast protein kinase atg1, which is required for autophagy." SIGNOR-216495 NLK protein Q9UBE8 UNIPROT LEF1 protein Q9UJU2 UNIPROT down-regulates phosphorylation Thr155 SHAVHPLtPLITYSD 9606 12556497 t gcesareni "Regulation of lymphoid enhancer factor 1/t-cell factor by mitogen-activated protein kinase-related nemo-like kinase-dependent phosphorylation in wnt/beta-catenin signaling.Nlk phosphorylates lef-1/tcf on two serine/threonine residues located in its central region. Mutation of both residues to alanine enhanced lef-1 transcriptional activity and rendered it resistant to inhibition by nlk." SIGNOR-97812 SREBF2 protein Q12772 UNIPROT SQLE protein Q14534 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000759 31848472 t miannu "The processed SREBP2, designated nuclear SREBP2 (nSREBP2), then enters the nucleus as a homodimer, binds to the sterol regulatory element (SRE) sequence in the promoters of target genes, including HMGCR and SQLE (encoding squalene monooxygenase), and upregulates their transcription" SIGNOR-265162 CDK1 protein P06493 UNIPROT NPM1 protein P06748 UNIPROT "down-regulates activity" phosphorylation Thr237 KQEKTPKtPKGPSSV 9606 SIGNOR-C17 12058066 t gcesareni "Both subtypes of B23 proteins were phosphorylated during mitosis by cyclin B/cdc2. The RNA binding activity of B23.1 was repressed through cyclin B/cdc2-mediated phosphorylation at specific sites in B23. Thus, the RNA binding activity of B23.1 is stringently modulated by its phosphorylation and subtype association." SIGNOR-89601 FBXL2 protein Q9UKC9 UNIPROT PIK3R2 protein O00459 UNIPROT "down-regulates quantity by destabilization" binding 9606 BTO:0000007 23604317 t miannu "FBXL2 binds p85α and p85β. p85β is targeted for ubiquitylation and degradation by SCF FBXL2." SIGNOR-272111 RIPK3 protein Q9Y572 UNIPROT MLKL protein Q8NB16 UNIPROT "up-regulates activity" phosphorylation Ser360 RKTQTSMsLGTTREK 10090 24012422 t gianni "MLKL comprises a four-helical bundle tethered to the pseudokinase domain, which contains an unusual pseudoactive site. Although the pseudokinase domain binds ATP, it is catalytically inactive and its essential nonenzymatic role in necroptotic signaling is induced by receptor-interacting serine-threonine kinase 3 (RIPK3)-mediated phosphorylation.[...]S345, S347, and T349 in the MLKL activation loop were phosphorylated by RIPK3 in in vitro kinase assays" SIGNOR-266428 CDK9 protein P50750 UNIPROT POLR2A protein P24928 UNIPROT up-regulates phosphorylation Ser1889 SPTTPKYsPTSPTYS 9606 24385927 t lperfetto "Cyclin-dependent kinase 9 (cdk9) promotes elongation by rna polymerase ii (rnapii), mrna processing, and co-transcriptional histone modification. Cdk9 phosphorylates multiple targets, including the conserved rnapii elongation factor spt5 and rnapii itself. Cellular kinase cdk9 phosphorylates serine-2 in the c-terminal domain (ctd) of rnap ii" SIGNOR-203580 TACSTD2 protein P09758 UNIPROT CLDN7 protein O95471 UNIPROT "up-regulates quantity" binding 9606 BTO:0001109 31177095 t done miannu "In summary, our findings provide evidence that Trop-2 is phosphorylated at Ser-322 by PKCα/δ and that this phosphorylation enhances cell motility and decreases claudin-7 localization to cellular borders." SIGNOR-273822 palmitoyl-CoA smallmolecule CHEBI:15525 ChEBI 3-hydroxyoctadecanoyl-CoA smallmolecule CHEBI:50583 ChEBI "up-regulates quantity" "precursor of" 9606 31616255 t miannu "The ELOVL family of enzymes in mammals is comprised of seven members that all reside in the endoplasmic reticulum (ER) and are thought to form a multimeric complex. Together, the ELOVL family is responsible for the elongation of saturated and unsaturated fatty acids.Fatty acid elongation occurs by cycling through a four step process (condensation, reduction, dehydration, and reduction), with two carbon atoms added through each cycle." SIGNOR-267883 PRKCA protein P17252 UNIPROT UGT1A3 protein P35503 UNIPROT "up-regulates activity" phosphorylation Ser43 IDGSHWLsMREVLRE -1 26094731 t done miannu "Curcumin and calphostin C suppressed the activity and phosphorylation of recombinant UGT1A3 expressed in Sf9 cells. These results indicate that UGT1A3 undergoes phosphorylation, which is required for its catalytic activity. Calphostin C is a highly specific protein kinase C (PKC) inhibitor, so three predicted PKC phosphorylation sites in UGT1A3 were examined. In conclusion, phosphorylation plays an important role in UGT1A3 activity, and the serine at site 43 in UGT1A3 is most likely a phosphorylation site." SIGNOR-273823 ABL1 protein P00519 UNIPROT CRK protein P46108 UNIPROT "down-regulates activity" phosphorylation Tyr221 GGPEPGPyAQPSVNT 9606 21779437 t lperfetto "Negative regulation of crk by abl is essential for the antitumorigenic effects of ephrinb2,similar pathways may operate for crkl" SIGNOR-175135 PRKCB protein P05771 UNIPROT MFN1 protein Q8IWA4 UNIPROT "down-regulates activity" phosphorylation Ser86 AFFGRTSsGKSSVIN -1 30659190 t done miannu "Here we report that βIIPKC accumulates on the mitochondrial outer membrane and phosphorylates mitofusin 1 (Mfn1) at serine 86. Mfn1 phosphorylation results in partial loss of its GTPase activity and in a buildup of fragmented and dysfunctional mitochondria in heart failure." SIGNOR-273826 PRKCZ protein Q05513 UNIPROT NREP protein Q16612 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser59 LGSSELRsPRISYLH 9606 BTO:0004605 16229809 t done miannu "Site-directed mutagenesis of S59A retarded P311 degradation and induced glioma cell motility. In contrast, S59D mutation resulted in the rapid degradation of P311 and reduced glioma cell migration.Taken together, our results show that the serine phosphorylation of P311 is dependent on the function of both PKCε and PKCz." SIGNOR-273831 CHUK protein O15111 UNIPROT RELA protein Q04206 UNIPROT "up-regulates activity" phosphorylation Ser536 SGDEDFSsIADMDFS 9606 BTO:0000567 SIGNOR-C14 SIGNOR-C13 10521409 t lperfetto "Our data suggest that the stimulation of nfkb by akt is dependent on the phosphorylation of p65 at s534, mediated by ikk (ikb kinase) alfa and beta." SIGNOR-71270 PTPN6 protein P29350 UNIPROT EGFR protein P00533 UNIPROT down-regulates dephosphorylation Tyr1197 STAENAEyLRVAPQS 9606 9733788 t tpavlidou "The sh2-domain ptpase shp-1 binds to and dephosphorylates autophosphorylated egfr and may participate in modulation of egfr signaling in epithelial cells. Reduced shp-1 binding to the egfr y1173f mutant resulted in a reduced receptor dephosphorylation by coexpressed shp-1 and less interference with egf-dependent mitogen-activated protein kinase stimulation." SIGNOR-59965 "Exon junction complex" complex SIGNOR-C369 SIGNOR Upf-EJC complex SIGNOR-C367 SIGNOR "up-regulates activity" binding -1 18066079 t miannu "Nonsense-mediated mRNA decay (NMD) eliminates mRNAs containing a premature translation termination codon through the recruitment of the conserved NMD factors UPF1, UPF2 and UPF3. In humans, a dynamic assembly pathway allows UPF1 to join UPF2 and UPF3 recruited to the mRNA by the exon-junction complex (EJC). " SIGNOR-265244 "CCR4-NOT complex" complex SIGNOR-C439 SIGNOR NANOS2 protein P60321 UNIPROT "down-regulates quantity by repression" "post transcriptional regulation" 9606 31320642 t lperfetto "In addition to its role in bulk mRNA decay, CCR4-NOT can also catalyze the deadenylation or promote translational repression of specific mRNA targets to which it is recruited by RNA binding proteins, such as Nanos, Roquin and Puf/Pumilio proteins" SIGNOR-268349 "Caspase 8 complex" complex SIGNOR-C231 SIGNOR CASP6 protein P55212 UNIPROT up-regulates cleavage 9606 9727491 t gcesareni "Casp8 can activate downstream caspases like caspase-6, and caspase-7 by directly cleaving them." SIGNOR-256466 PRKD1 protein Q15139 UNIPROT REM1 protein O75628 UNIPROT "up-regulates activity" phosphorylation Ser18 TPLHRRAsTPLPLSP 9606 BTO:0000567 22076634 t done miannu "We found that activation of protein kinase D1, a protein kinase downstream of α(1)-adrenergic signaling, leads to direct phosphorylation of Rem1 at Ser18. This results in an increase of the channel activity and plasma membrane expression observed by using a combination of electrophysiology, live cell confocal microscopy, and immunohistochemistry in heterologous expression system and neonatal cardiomyocytes. " SIGNOR-273832 PRKDC protein P78527 UNIPROT H1-2 protein P16403 UNIPROT "down-regulates activity" phosphorylation Thr146 KKAAGGAtPKKSAKK 9606 BTO:0001938 22249259 t done miannu "Similarly, DNA-PK-mediated phosphorylation of H1.2 at T146 enhances p53 transcriptional activity by impeding H1.2 binding to p53 and thereby attenuating its suppressive effects on p53 transactivation. " SIGNOR-273834 PRKDC protein P78527 UNIPROT POLL protein Q9UGP5 UNIPROT "up-regulates activity" phosphorylation Thr204 EASDGEEtQVSAADL 9606 BTO:0000007 28109743 t done miannu " We show that Polλ is efficiently phosphorylated by DNA-PKcs in vitro and predominantly by ATM after DSB induction with ionizing radiation (IR) in vivo. We identify threonine 204 (T204) as a main target for ATM/DNA-PKcs phosphorylation on human Polλ, and establish that its phosphorylation may facilitate the repair of a subset of IR-induced DSBs and the efficient Polλ-mediated gap-filling during NHEJ. " SIGNOR-273835 AKT1 protein P31749 UNIPROT KDM5A protein P29375 UNIPROT "up-regulates activity" phosphorylation Thr285 QMRQRKGtLSVNFVD -1 27292631 t miannu "We immunoprecipitated ectopically expressed wild-type KDM5A or KDM5Amut5A and performed an in vitro kinase assay using recombinant AKT1 in the presence or absence of AKT inhibition.Wild-type KDM5A is phosphorylated by AKT1 and this modification is sensitive to AKT inhibition, whereas KDM5Amut5A is not phosphorylated in the presence of AKT1 (Figure 3C).These results suggest that AKT-mediated KDM5A phosphorylation enhances KDM5A promoter recruitment." SIGNOR-274061 RPS6KA1 protein Q15418 UNIPROT MAGI1 protein Q96QZ7 UNIPROT "up-regulates activity" phosphorylation Ser741 QPLERKDsQNSSQHS 9606 BTO:0001949 30944250 t done miannu " We report herein that p90RSK associates with MAGI1 in ECs and executes 2 independently regulated PTMs of MAGI1: S741 phosphorylation and K931 deSUMOylation. MAGI1-S741 phosphorylation is vital for Rap1 activation." SIGNOR-273837 RPS6KA1 protein Q15418 UNIPROT OSTF1 protein Q92882 UNIPROT "down-regulates activity" phosphorylation Ser202 TDAVRTLsNAEDYLD 9606 BTO:0000567 21501342 t done miannu "SH3P2 was phosphorylated on Ser(202) by ribosomal S6 kinase (RSK) in an ERK pathway-dependent manner, and such phosphorylation inhibited the ability of SH3P2 to suppress cell motility. " SIGNOR-273838 EIF2B4 protein Q9UI10 UNIPROT EIF2S2 protein P20042 UNIPROT "up-regulates activity" "guanine nucleotide exchange factor" 9606 15054402 t lperfetto "EIF2B converts the protein synthesis initiation factor 2 (eIF2) from an inactive GDP-bound form to an active eIF2-GTP complex owing to its guanine nucleotide exchange factor (GEF) activity." SIGNOR-269132 ATM protein Q13315 UNIPROT POLL protein Q9UGP5 UNIPROT "up-regulates activity" phosphorylation Thr204 EASDGEEtQVSAADL 9606 BTO:0000007 28109743 t done miannu " We show that Polλ is efficiently phosphorylated by DNA-PKcs in vitro and predominantly by ATM after DSB induction with ionizing radiation (IR) in vivo. We identify threonine 204 (T204) as a main target for ATM/DNA-PKcs phosphorylation on human Polλ, and establish that its phosphorylation may facilitate the repair of a subset of IR-induced DSBs and the efficient Polλ-mediated gap-filling during NHEJ. " SIGNOR-273836 MAPK1 protein P28482 UNIPROT RXRA protein P19793 UNIPROT "down-regulates activity" phosphorylation Ser260 NMGLNPSsPNDPVTN 9606 17604322 t lperfetto "In colon cancer cells, the Ras/mitogen‐activated protein kinase (MAPK) pathway phosphorylates RXRalpha, which impairs its function as a heterodimeric partner for PPARgamma|A point‐mutated RXRalpha T82A/S260A, which mimics the unphosphorylated form of RXRalpha, can form a heterodimer with PPARgamma and thereby activate target gene expression by binding to the PPRE" SIGNOR-88658 PTPRG protein P23470 UNIPROT CDK2 protein P24941 UNIPROT "down-regulates activity" dephosphorylation Tyr15 EKIGEGTyGVVYKAR -1 25624455 t miannu "PTPRG activation by the P1-WD peptide affected the tyrosine phosphorylation of several signaling molecules. Data analysis identified 31 molecules whose phosphorylation was modified in a statistically significant manner (Table I). inhibition of ABL1, BMX, BTK, DAB1, ITGB1, JAK2, KDR, KIT, LIMK1, MET, PDGFRB, SHC1, and VCL correlates with tyrosine dephosphorylation. In contrast, SRC inhibition correlates with hyperphosphorylation of the inhibitory Tyr530 residue and with dephosphorylation of the activatory Tyr419. Moreover, CDK2 and CTTN inhibition correlates with a hyperphosphorylation of the inhibitory Tyr15 and Tyr470, respectively. In contrast, a subgroup of 13 proteins, including BLNK, DOK2, ERBB2, GRIN2B, INSR, PDGFRA, PRKCD, PXN, STAT1, STAT2, STAT3, STAT5A, and ZAP70, appears to be activated by PTPRG activity." SIGNOR-254695 KLHL12 protein Q53G59 UNIPROT "Cullin 3-RBX1-Skp1" complex SIGNOR-C526 SIGNOR "up-regulates activity" binding 9606 BTO:0000007 32433973 t miannu "  Lunapark Is Ubiquitylated by the CRL3KLHL12 Ubiquitin Ligase Complex. Taken together, these results demonstrate that Lunapark is ubiquitylated by the CRL3KLHL12 ubiquitin ligase, and the CRL3KLHL12-dependent ubiquitylation of Lunapark does not lead to its proteasomal degradation. Inhibition of Lunapark Ubiquitylation Affects Lysosomal Recruitment of mTORC2" SIGNOR-272198 TWIST1 protein Q15672 UNIPROT ITGB1 protein P05556 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0002590 17487558 f miannu "Immunoblot analysis showed that HEY/si-TWIST cells exhibited decreased expression levels of CD29, CD44 and CD54 compared to those of HEY/si-scrambled cells" SIGNOR-255516 Ub:E2 complex SIGNOR-C497 SIGNOR RNFT1 protein Q5M7Z0 UNIPROT "up-regulates activity" ubiquitination 9606 34199813 t miannu "The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t" SIGNOR-271262 YWHAE protein P62258 UNIPROT TBP protein P20226 UNIPROT "up-regulates activity" binding 10449590 t lperfetto "The in vitro binding with general transcription factors TBP and TFIIB together with its nuclear location provide evidence supporting a role for 14-3-3 proteins as transcriptional activators or coactivators when part of a DNA binding complex." SIGNOR-262834 JNK proteinfamily SIGNOR-PF15 SIGNOR FOXO proteinfamily SIGNOR-PF27 SIGNOR up-regulates phosphorylation Ser230 PEGATPTsPVGHFAK 9606 BTO:0000848 BTO:0001253 20959475 t lperfetto "Braf(v600e) signaling through mitogen-activated protein kinase/extracellular signal-regulated kinase kinase resulted in increased reactive oxygen species levels and c-jun nh(2) terminal kinase-mediated activation of foxo4 via its phosphorylation on thr(223), ser(226), thr(447), and thr(451)." SIGNOR-252953 3-isobutyl-1-methylxanthine chemical CHEBI:48518 ChEBI CEBPA protein P49715 UNIPROT up-regulates 9606 11279134 f fspada "The differentiation of 3t3-l1 preadipocytes is regulated in part by a cascade of transcriptional events involving activation of the ccaat/enhancer-binding proteins (c/ebps) and peroxisome proliferator-activated receptor gamma (ppargamma) by dexamethasone (dex), 3-isobutyl-1-methylxanthine (mix), and insulin" SIGNOR-106478 ibuprofen chemical CHEBI:5855 ChEBI PTGS1 protein P23219 UNIPROT "down-regulates activity" "chemical inhibition" -1 9057869 t miannu "Naproxen had similar activity against both COX-1 and COX-2 enzymes (IC50s of 3.2 and 2.5 μM, respectively), whereas ibuprofen was approximately 100-fold more potent for COX-2 (IC50 = 0.1 μM) than for COX-1 (IC50 = 11 μM), and indomethacin was about 50-fold more potent for COX-1 (IC50 = 0.012 μM) than for COX-2 (IC50 = 0.56 μM)." SIGNOR-258605 CDKL1 protein Q00532 UNIPROT RB1 protein P06400 UNIPROT "up-regulates activity" phosphorylation 9606 28352193 t miannu "We also proved that as a downstream molecule of the P15 pathway, Rb is inhibited after CDKL1 knockdown. Rb is a well-known tumor suppressor in cell cycle regulation.28 Phosphorylation of Rb negatively regulates the cell cycle through E2F repression.29–31 However, Rb contains 13 conserved sites that are phosphorylated by the CDK–P15 complex in cycling cells and phosphorylation will cause site-specific and diverse conformational changes in the complex.32,33 Further studies need to be conducted to decipher the phosphorylated site of Rb related to CDKL1 knockdown." SIGNOR-273863 TNK1 protein Q13470 UNIPROT PLCG1 protein P19174 UNIPROT "up-regulates